BARCELONA – As many as 40%-60% of children have diabetic ketoacidosis (DKA) at the time of being diagnosed with type 1 diabetes, according to data from two U.S. analyses – and the figures have been rising for the past 10 years.

Between 2010 and 2017, the prevalence of DKA at diagnosis in children who were followed up at the Barbara Davies Cancer Center in Denver (n = 2,429) went from 41% to 59%, with a 7% annual rise, Arleta Rewers, MD, PhD, of Children’s Hospital Colorado, Denver, reported at the annual meeting of the European Association for the Study of Diabetes.

Meanwhile, in another analysis that included multiple U.S. centers and about 7,600 cases of youth-onset type 1 diabetes, the overall prevalence of DKA at diagnosis was 38.5% between 2010 and 2016. However, the prevalence had increased from 35% in 2010 to 40.6% in 2016, according to Elizabeth T. Jensen, MPH, PhD, of Wake Forest University, Winston-Salem, N.C. The annual increase in prevalence of DKA at diagnosis of type 1 disease was 2%, adjusted for sociodemographic factors.
 

Rising prevalence

“DKA occurs most commonly at the time of type 1 diabetes diagnosis,” observed Dr. Jensen, who noted that “in the United States, among children, it’s younger children, uninsured or underinsured children, and children from minority racial or ethnic groups, who are at greatest risk.”

Sara Freeman/MDedge News

Dr. Jensen and colleagues had previously shown that the prevalence of DKA at diagnosis was around 30% between 2002 and 2010, with no significant change in its prevalence. However, more recent reports from referral-based, single-center studies had suggested there was an increase, and that led her and her colleagues to take a closer look at the data.

To characterize the risk factors for DKA and the prevalence of DKA over time, Dr. Jensen and her team used the SEARCH for Diabetes in Youth database, which, she said, was “uniquely suited” for this purpose. SEARCH is a population-based, multicenter study conducted in centers in five U.S. states: South Carolina, Ohio, Colorado, California, and Washington.

A diagnosis of DKA was based on blood bicarbonate levels of less than 15 mmol/L, a venous pH of less than 7.25 or arterial or capillary pH of less than 7.3, or if there was any documentation of a DKA diagnosis.

As expected, the prevalence of DKA was highest in the youngest age group (0-4 years), Dr. Jensen said, but the increase in prevalence in that group was no different from the increases seen over time in the other age groups (5-9 years, 10-14 years, and 15 years or older).

There were no differences in the prevalence of DKA between the sexes, although there was a general increase over time. Similar trends were seen in DKA prevalence by race or ethnicity and by season, or time of year.

Of note, higher rates of DKA were seen in children who were covered by public health insurance, than in those covered by private insurance, although there was no difference in the rate of increase in DKA prevalence between the two groups. Dr. Jensen noted that only 64% of this study population had private insurance.

She said that future research in this area would need to look at the economic drivers and the “changing landscape of health insurance coverage in the United States.”
 

Expansion in health coverage

In presenting the findings of a study showing an increase in the prevalence of DKA at diagnosis of type 1 diabetes in children in Colorado from 2010 to 2017, Dr. Rewers said that the increase “paradoxically occurred” at a time of increasing health insurance coverage, a reference to the expansion of Medicaid during 2008-2012 and implementation in 2013 of the Affordable Care Act.

“Our group in Colorado has followed the frequency of DKA for almost 2 decades,” Dr. Rewers said. It’s important to study DKA as it is linked to worse glycemic control – with children with DKA having an HbA_{1c level of} around 1% higher than those without DKA – and the potential for future, long-term complications.

Dr. Rewers noted that the increase in DKA at diagnosis of type 1 diabetes was more rapid in the children who had private rather than public health insurance. Of 1,187 patients with DKA, 57% had private health insurance, and 37% had public insurance, compared with 66% and 28%, respectively, in those without DKA. In 2010, the prevalence of DKA at diagnosis was 35.3% in those who were privately insured and 52.2% of those with public health insurance, but by 2017, a similar percentage of DKA was seen in the privately and publicly insured children (59.6% and 58.5%, respectively).

She said one possible explanation for that might be that “increased enrollment in high-deductible insurance plans could discourage families with private insurance from seeking timely care.”

Another explanation is that there is a low awareness of type 1 diabetes in the general population, she added. “Educational campaigns and autoimmunity screening have been shown to reduce DKA at diabetes diagnosis, but unfortunately they are not used widely at this point.”
 

Identifying at-risk children

“Diabetic ketoacidosis is a serious complication of diabetes [and] is difficult to diagnose because of the variability of the symptoms, said Angela Ibald-Mulli, PhD, who presented the findings of a retrospective cohort study in which she and her colleagues used a “discovery algorithm” called Q-Finder to identify the predictive factors for DKA in youth with type 1 diabetes, based on data from the Diabetes Prospective Follow-up Registry (DPV).

Sara Freeman/MDedge News

“The better we know the risk factors, the better we can care for our patients,” she emphasized.

The investigators obtained data on 108,223 patients with a diagnosis of type 1 disease and with more than two visits related to diabetes. The prevalence of DKA – defined as a pH of less than 7.3 during hospitalization occurring at least 10 days after the onset of type 1 diabetes – was 5.2%, said Dr. Ibald-Mulli, head of Medical Evidence Generation Primary Care at Sanofi, Paris.

A total of 129 different features were considered for their association with DKA – including comorbidities, sociodemographic factors, laboratory values, and concomitant medications – and were then used to identify, test, and the validate likely risk profiles.

After comparing the characteristics of patients with and without DKA, eight significant factors, all of which have been reported previously in the DPV cohort, were seen: younger age, lower body weight, higher HbA_1c, younger age at onset of T1D; shorter disease duration; having a migration background; being less active; and having had more medical visits.

The investigators used the algorithm, and found 11 distinct profiles associated with DKA: an HbA_1c higher than 8.87%; being aged 6-10 years; being aged 11-15 years; a diagnosis of nephropathy; DKA being present at onset; a prevalence of hypoglycemia with coma; a diagnosis of thyroiditis; a standardized body mass index lower than 16.9; not using short-acting insulin; younger than age 15 years; and not using continuous glucose monitoring.

Almost two-thirds of patients (64.7%) belonged to at least one of these risk profiles, Dr. Ibald-Mulli observed, with 7.1% of them having DKA, compared with 1.6% who belonged to none of the profiles.

Dr. Ibald-Mulli said it was important to note that the DKA risk profiles could overlap. “The more profiles a patient belongs to, the higher is the risk of having DKA,” she emphasized, adding that most patients (88.8%) with DKA belonged to just one profile, and fewer than 5% belonged to three or more profiles.

“Overall, the results of the algorithm confirmed known risk-factor profiles that had been previously identified by conventional statistical methods,” she concluded. It also provided “additional insights that can be further explored.”

SEARCH is funded by the Centers for Disease and Prevention and the National Institute of Diabetes and Digestive and Kidney Diseases. The DPV Registry is funded by multiple sponsors, including the European Federation for the Study of Diabetes and other academic institutions with the support of several commercial partners. Sanofi sponsored the study presented by Dr. Ibald-Mulli. Dr. Rewers made no disclosures, and Dr. Jensen did not have any conflicts of interest to declare. Dr. Ibald-Mulli is an employee of Sanofi.

SOURCE: Rewers A et al. EASD 2019, Abstract 115; Jensen E et al. EASD 2019, Abstract 116; Ibald-Mulli A et al. EASD 2019, Abstract 117.

BARCELONA – As many as 40%-60% of children have diabetic ketoacidosis (DKA) at the time of being diagnosed with type 1 diabetes, according to data from two U.S. analyses – and the figures have been rising for the past 10 years.

Between 2010 and 2017, the prevalence of DKA at diagnosis in children who were followed up at the Barbara Davies Cancer Center in Denver (n = 2,429) went from 41% to 59%, with a 7% annual rise, Arleta Rewers, MD, PhD, of Children’s Hospital Colorado, Denver, reported at the annual meeting of the European Association for the Study of Diabetes.

Meanwhile, in another analysis that included multiple U.S. centers and about 7,600 cases of youth-onset type 1 diabetes, the overall prevalence of DKA at diagnosis was 38.5% between 2010 and 2016. However, the prevalence had increased from 35% in 2010 to 40.6% in 2016, according to Elizabeth T. Jensen, MPH, PhD, of Wake Forest University, Winston-Salem, N.C. The annual increase in prevalence of DKA at diagnosis of type 1 disease was 2%, adjusted for sociodemographic factors.
 

Rising prevalence

“DKA occurs most commonly at the time of type 1 diabetes diagnosis,” observed Dr. Jensen, who noted that “in the United States, among children, it’s younger children, uninsured or underinsured children, and children from minority racial or ethnic groups, who are at greatest risk.”

Sara Freeman/MDedge News

Dr. Jensen and colleagues had previously shown that the prevalence of DKA at diagnosis was around 30% between 2002 and 2010, with no significant change in its prevalence. However, more recent reports from referral-based, single-center studies had suggested there was an increase, and that led her and her colleagues to take a closer look at the data.

To characterize the risk factors for DKA and the prevalence of DKA over time, Dr. Jensen and her team used the SEARCH for Diabetes in Youth database, which, she said, was “uniquely suited” for this purpose. SEARCH is a population-based, multicenter study conducted in centers in five U.S. states: South Carolina, Ohio, Colorado, California, and Washington.

A diagnosis of DKA was based on blood bicarbonate levels of less than 15 mmol/L, a venous pH of less than 7.25 or arterial or capillary pH of less than 7.3, or if there was any documentation of a DKA diagnosis.

As expected, the prevalence of DKA was highest in the youngest age group (0-4 years), Dr. Jensen said, but the increase in prevalence in that group was no different from the increases seen over time in the other age groups (5-9 years, 10-14 years, and 15 years or older).

There were no differences in the prevalence of DKA between the sexes, although there was a general increase over time. Similar trends were seen in DKA prevalence by race or ethnicity and by season, or time of year.

Of note, higher rates of DKA were seen in children who were covered by public health insurance, than in those covered by private insurance, although there was no difference in the rate of increase in DKA prevalence between the two groups. Dr. Jensen noted that only 64% of this study population had private insurance.

She said that future research in this area would need to look at the economic drivers and the “changing landscape of health insurance coverage in the United States.”
 

Expansion in health coverage

In presenting the findings of a study showing an increase in the prevalence of DKA at diagnosis of type 1 diabetes in children in Colorado from 2010 to 2017, Dr. Rewers said that the increase “paradoxically occurred” at a time of increasing health insurance coverage, a reference to the expansion of Medicaid during 2008-2012 and implementation in 2013 of the Affordable Care Act.

“Our group in Colorado has followed the frequency of DKA for almost 2 decades,” Dr. Rewers said. It’s important to study DKA as it is linked to worse glycemic control – with children with DKA having an HbA_{1c level of} around 1% higher than those without DKA – and the potential for future, long-term complications.

Dr. Rewers noted that the increase in DKA at diagnosis of type 1 diabetes was more rapid in the children who had private rather than public health insurance. Of 1,187 patients with DKA, 57% had private health insurance, and 37% had public insurance, compared with 66% and 28%, respectively, in those without DKA. In 2010, the prevalence of DKA at diagnosis was 35.3% in those who were privately insured and 52.2% of those with public health insurance, but by 2017, a similar percentage of DKA was seen in the privately and publicly insured children (59.6% and 58.5%, respectively).

She said one possible explanation for that might be that “increased enrollment in high-deductible insurance plans could discourage families with private insurance from seeking timely care.”

Another explanation is that there is a low awareness of type 1 diabetes in the general population, she added. “Educational campaigns and autoimmunity screening have been shown to reduce DKA at diabetes diagnosis, but unfortunately they are not used widely at this point.”
 

Identifying at-risk children

“Diabetic ketoacidosis is a serious complication of diabetes [and] is difficult to diagnose because of the variability of the symptoms, said Angela Ibald-Mulli, PhD, who presented the findings of a retrospective cohort study in which she and her colleagues used a “discovery algorithm” called Q-Finder to identify the predictive factors for DKA in youth with type 1 diabetes, based on data from the Diabetes Prospective Follow-up Registry (DPV).

Sara Freeman/MDedge News

“The better we know the risk factors, the better we can care for our patients,” she emphasized.

The investigators obtained data on 108,223 patients with a diagnosis of type 1 disease and with more than two visits related to diabetes. The prevalence of DKA – defined as a pH of less than 7.3 during hospitalization occurring at least 10 days after the onset of type 1 diabetes – was 5.2%, said Dr. Ibald-Mulli, head of Medical Evidence Generation Primary Care at Sanofi, Paris.

A total of 129 different features were considered for their association with DKA – including comorbidities, sociodemographic factors, laboratory values, and concomitant medications – and were then used to identify, test, and the validate likely risk profiles.

After comparing the characteristics of patients with and without DKA, eight significant factors, all of which have been reported previously in the DPV cohort, were seen: younger age, lower body weight, higher HbA_1c, younger age at onset of T1D; shorter disease duration; having a migration background; being less active; and having had more medical visits.

The investigators used the algorithm, and found 11 distinct profiles associated with DKA: an HbA_1c higher than 8.87%; being aged 6-10 years; being aged 11-15 years; a diagnosis of nephropathy; DKA being present at onset; a prevalence of hypoglycemia with coma; a diagnosis of thyroiditis; a standardized body mass index lower than 16.9; not using short-acting insulin; younger than age 15 years; and not using continuous glucose monitoring.

Almost two-thirds of patients (64.7%) belonged to at least one of these risk profiles, Dr. Ibald-Mulli observed, with 7.1% of them having DKA, compared with 1.6% who belonged to none of the profiles.

Dr. Ibald-Mulli said it was important to note that the DKA risk profiles could overlap. “The more profiles a patient belongs to, the higher is the risk of having DKA,” she emphasized, adding that most patients (88.8%) with DKA belonged to just one profile, and fewer than 5% belonged to three or more profiles.

“Overall, the results of the algorithm confirmed known risk-factor profiles that had been previously identified by conventional statistical methods,” she concluded. It also provided “additional insights that can be further explored.”

SEARCH is funded by the Centers for Disease and Prevention and the National Institute of Diabetes and Digestive and Kidney Diseases. The DPV Registry is funded by multiple sponsors, including the European Federation for the Study of Diabetes and other academic institutions with the support of several commercial partners. Sanofi sponsored the study presented by Dr. Ibald-Mulli. Dr. Rewers made no disclosures, and Dr. Jensen did not have any conflicts of interest to declare. Dr. Ibald-Mulli is an employee of Sanofi.

SOURCE: Rewers A et al. EASD 2019, Abstract 115; Jensen E et al. EASD 2019, Abstract 116; Ibald-Mulli A et al. EASD 2019, Abstract 117.

BARCELONA – As many as 40%-60% of children have diabetic ketoacidosis (DKA) at the time of being diagnosed with type 1 diabetes, according to data from two U.S. analyses – and the figures have been rising for the past 10 years.

Between 2010 and 2017, the prevalence of DKA at diagnosis in children who were followed up at the Barbara Davies Cancer Center in Denver (n = 2,429) went from 41% to 59%, with a 7% annual rise, Arleta Rewers, MD, PhD, of Children’s Hospital Colorado, Denver, reported at the annual meeting of the European Association for the Study of Diabetes.

Meanwhile, in another analysis that included multiple U.S. centers and about 7,600 cases of youth-onset type 1 diabetes, the overall prevalence of DKA at diagnosis was 38.5% between 2010 and 2016. However, the prevalence had increased from 35% in 2010 to 40.6% in 2016, according to Elizabeth T. Jensen, MPH, PhD, of Wake Forest University, Winston-Salem, N.C. The annual increase in prevalence of DKA at diagnosis of type 1 disease was 2%, adjusted for sociodemographic factors.
 

Rising prevalence

“DKA occurs most commonly at the time of type 1 diabetes diagnosis,” observed Dr. Jensen, who noted that “in the United States, among children, it’s younger children, uninsured or underinsured children, and children from minority racial or ethnic groups, who are at greatest risk.”

Sara Freeman/MDedge News

Dr. Jensen and colleagues had previously shown that the prevalence of DKA at diagnosis was around 30% between 2002 and 2010, with no significant change in its prevalence. However, more recent reports from referral-based, single-center studies had suggested there was an increase, and that led her and her colleagues to take a closer look at the data.

To characterize the risk factors for DKA and the prevalence of DKA over time, Dr. Jensen and her team used the SEARCH for Diabetes in Youth database, which, she said, was “uniquely suited” for this purpose. SEARCH is a population-based, multicenter study conducted in centers in five U.S. states: South Carolina, Ohio, Colorado, California, and Washington.

A diagnosis of DKA was based on blood bicarbonate levels of less than 15 mmol/L, a venous pH of less than 7.25 or arterial or capillary pH of less than 7.3, or if there was any documentation of a DKA diagnosis.

As expected, the prevalence of DKA was highest in the youngest age group (0-4 years), Dr. Jensen said, but the increase in prevalence in that group was no different from the increases seen over time in the other age groups (5-9 years, 10-14 years, and 15 years or older).

There were no differences in the prevalence of DKA between the sexes, although there was a general increase over time. Similar trends were seen in DKA prevalence by race or ethnicity and by season, or time of year.

Of note, higher rates of DKA were seen in children who were covered by public health insurance, than in those covered by private insurance, although there was no difference in the rate of increase in DKA prevalence between the two groups. Dr. Jensen noted that only 64% of this study population had private insurance.

She said that future research in this area would need to look at the economic drivers and the “changing landscape of health insurance coverage in the United States.”
 

Expansion in health coverage

In presenting the findings of a study showing an increase in the prevalence of DKA at diagnosis of type 1 diabetes in children in Colorado from 2010 to 2017, Dr. Rewers said that the increase “paradoxically occurred” at a time of increasing health insurance coverage, a reference to the expansion of Medicaid during 2008-2012 and implementation in 2013 of the Affordable Care Act.

“Our group in Colorado has followed the frequency of DKA for almost 2 decades,” Dr. Rewers said. It’s important to study DKA as it is linked to worse glycemic control – with children with DKA having an HbA_{1c level of} around 1% higher than those without DKA – and the potential for future, long-term complications.

Dr. Rewers noted that the increase in DKA at diagnosis of type 1 diabetes was more rapid in the children who had private rather than public health insurance. Of 1,187 patients with DKA, 57% had private health insurance, and 37% had public insurance, compared with 66% and 28%, respectively, in those without DKA. In 2010, the prevalence of DKA at diagnosis was 35.3% in those who were privately insured and 52.2% of those with public health insurance, but by 2017, a similar percentage of DKA was seen in the privately and publicly insured children (59.6% and 58.5%, respectively).

She said one possible explanation for that might be that “increased enrollment in high-deductible insurance plans could discourage families with private insurance from seeking timely care.”

Another explanation is that there is a low awareness of type 1 diabetes in the general population, she added. “Educational campaigns and autoimmunity screening have been shown to reduce DKA at diabetes diagnosis, but unfortunately they are not used widely at this point.”
 

Identifying at-risk children

“Diabetic ketoacidosis is a serious complication of diabetes [and] is difficult to diagnose because of the variability of the symptoms, said Angela Ibald-Mulli, PhD, who presented the findings of a retrospective cohort study in which she and her colleagues used a “discovery algorithm” called Q-Finder to identify the predictive factors for DKA in youth with type 1 diabetes, based on data from the Diabetes Prospective Follow-up Registry (DPV).

Sara Freeman/MDedge News

“The better we know the risk factors, the better we can care for our patients,” she emphasized.

The investigators obtained data on 108,223 patients with a diagnosis of type 1 disease and with more than two visits related to diabetes. The prevalence of DKA – defined as a pH of less than 7.3 during hospitalization occurring at least 10 days after the onset of type 1 diabetes – was 5.2%, said Dr. Ibald-Mulli, head of Medical Evidence Generation Primary Care at Sanofi, Paris.

A total of 129 different features were considered for their association with DKA – including comorbidities, sociodemographic factors, laboratory values, and concomitant medications – and were then used to identify, test, and the validate likely risk profiles.

After comparing the characteristics of patients with and without DKA, eight significant factors, all of which have been reported previously in the DPV cohort, were seen: younger age, lower body weight, higher HbA_1c, younger age at onset of T1D; shorter disease duration; having a migration background; being less active; and having had more medical visits.

The investigators used the algorithm, and found 11 distinct profiles associated with DKA: an HbA_1c higher than 8.87%; being aged 6-10 years; being aged 11-15 years; a diagnosis of nephropathy; DKA being present at onset; a prevalence of hypoglycemia with coma; a diagnosis of thyroiditis; a standardized body mass index lower than 16.9; not using short-acting insulin; younger than age 15 years; and not using continuous glucose monitoring.

Almost two-thirds of patients (64.7%) belonged to at least one of these risk profiles, Dr. Ibald-Mulli observed, with 7.1% of them having DKA, compared with 1.6% who belonged to none of the profiles.

Dr. Ibald-Mulli said it was important to note that the DKA risk profiles could overlap. “The more profiles a patient belongs to, the higher is the risk of having DKA,” she emphasized, adding that most patients (88.8%) with DKA belonged to just one profile, and fewer than 5% belonged to three or more profiles.

“Overall, the results of the algorithm confirmed known risk-factor profiles that had been previously identified by conventional statistical methods,” she concluded. It also provided “additional insights that can be further explored.”

SEARCH is funded by the Centers for Disease and Prevention and the National Institute of Diabetes and Digestive and Kidney Diseases. The DPV Registry is funded by multiple sponsors, including the European Federation for the Study of Diabetes and other academic institutions with the support of several commercial partners. Sanofi sponsored the study presented by Dr. Ibald-Mulli. Dr. Rewers made no disclosures, and Dr. Jensen did not have any conflicts of interest to declare. Dr. Ibald-Mulli is an employee of Sanofi.

SOURCE: Rewers A et al. EASD 2019, Abstract 115; Jensen E et al. EASD 2019, Abstract 116; Ibald-Mulli A et al. EASD 2019, Abstract 117.

Cardiovascular disease (CVD) remains the leading cause of global mortality. In 2015, 41.5% of the US population had at least 1 form of CVD and CVD accounted for nearly 18 million deaths worldwide.1,2 The major disease categories represented include myocardial infarction (MI), sudden death, strokes, calcific aortic valve stenosis (CAVS), and peripheral vascular disease.^1,2 In terms of health care costs, quality of life, and caregiver burden, the overall impact of disease prevalence continues to rise.^1,3-6 There is an urgent need for more precise and earlier CVD risk assessment to guide lifestyle and therapeutic interventions for prevention of disease progression as well as potential reversal of preclinical disease. Even at a young age, visible coronary atherosclerosis has been found in up to 11% of “healthy” active individuals during autopsies for trauma fatalities.^7,8

The impact of CVD on the US and global populations is profound. In 2011, CVD prevalence was predicted to reach 40% by 2030.9 That estimate was exceeded in 2015, and it is now predicted that by 2035, 45% of the US population will suffer from some form of clinical or preclinical CVD. In 2015, the decadeslong decline in CVD mortality was reversed for the first time since 1969, showing a 1% increase in deaths from CVD.¹ Nearly 300,000 of those using US Department of Veterans Affairs (VA) services were hospitalized for CVD between 2010 and 2014.¹⁰ The annual direct and indirect costs related to CVD in the US are estimated at $329.7 billion, and these costs are predicted to top $1 trillion by 2035.¹ Heart attack, coronary atherosclerosis, and stroke accounted for 3 of the 10 most expensive conditions treated in US hospitals in 2013.¹¹ Globally, the estimate for CVD-related direct and indirect costs was $863 billion in 2010 and may exceed $1 trillion by 2030.¹²

The nature of military service adds additional risk factors, such as posttraumatic stress disorder, depression, sleep disorders and physical trauma which increase CVD morbidity/ mortality in service members, veterans, and their families.^13-16 In addition, living in lowerincome areas (countries or neighborhoods) can increase the risk of both CVD incidence and fatalities, particularly in younger individuals.^17-20 The Military Health System (MHS) and VA are responsible for the care of those individuals who have voluntarily taken on these additional risks through their time in service. This responsibility calls for rapid translation to practice tools and resources that can support interventions to minimize as many modifiable risk factors as possible and improve longterm health. This strategy aligns with the World Health Organization’s (WHO) focus on prevention of disease progression through interventions targeting modifiable risk.^3-6,21-23 The driving force behind the launch of the US Department of Health and Human Services (HHS) Million Hearts program was the goal of preventing 1 million heart attacks and strokes by 2017 with risk reduction through aspirin, blood pressure control, cholesterol management, smoking cessation, sodium reduction, and physical activity.^24,25 While some reductions in CVD events have been documented, the outcomes fell short of the goals set, highlighting both the need and value of continued and expanded efforts for CVD risk reduction.²⁶

More precise assessment of risk factors during preventative care, as well as after a diagnosis of CVD, may improve the timeliness and precision of earlier interventions (both lifestyle and therapeutic) that reduce CVD morbidity and mortality^.27 Personalized or precision medicine approaches take into account differences in socioeconomic, environmental, and lifestyle factors that are potentially reversible, as well as gender, race, and ethnicity.^28-31 Current methods of predicting CVD risk have considerable room for improvement.²⁷ About 40% of patients with newly diagnosed CVD have normal traditional cholesterol profiles, including those whose first cardiac event proves fatal.^29-33 Currently available risk scores (hundreds have been described in the literature) mischaracterize risk in minority populations and women, and have shown deficiencies in identifying preclinical atherosclerosis.^34,35 The failure to recognize preclinical CVD in military personnel during their active duty life cycle results in missed opportunities for improved health and readiness sustainment.

Most CVD risk prediction models incorporate some form of blood lipids. Total cholesterol (TC) is most commonly used in clinical practice, along with high-density lipoprotein (HDLC), low-density lipoprotein (LDLC), and triglycerides (TG).^23,27,36 High LDLC and/or TC are well established as lipid-related CVD risk factors and are incorporated into many CVD risk scoring systems/models described in the literature.²⁷ LDLC reduction is commonly recommended as CVD prevention, but even with optimal statin treatment, there is still considerable residual risk for new and recurrent CVD events.^{28,32,34,35,37-42}

Incorporating novel biomarkers and alternative lipid measurements may improve risk prediction and aid targeted treatment, ultimately reducing CVD events.²⁷ Apolipoprotein B (ApoB) is a major atherogenic component embedded in LDL and VLDL correlating to non-HDLC and may be useful in the setting of triglycerides ≥ 200 mg/d as levels > 130 mg/ dL appear to be risk-enhancing, but measurements may be unreliable.⁴³ According to the 2018 Cholesterol Guidelines, lipoprotein(a) [Lp(a)] elevation also is recognized as a risk-enhancing factor that is particularly implicated when there is a strong family history of premature atherosclerotic CVD or personal history of CVD not explained by major risk factors.⁴³

Lp(a) elevation is a largely underrecognized category of lipid disorder that impacts up to 20% to 30% of the population globally and within the US, although there is considerable variability by geographic location and ethnicity.⁴⁴ Globally, Lp(a) elevation places > 1 billion people at moderate to high risk for CVD.44 Lp(a) has a strong genetic component and is recognized as a distinct and independent risk factor for MI, sudden death, strokes and CAVS. Lp(a) has an extensive body of evidence to support its distinct role both as a causal factor in CVD and as an augmentation to traditional risk factors.^44-48

Lipoproteni(a) Elevation Use For Diagnosis

The importance of Lp(a) elevation as a clinical diagnosis rather than a laboratory abnormality alone was brought forward by the Lipoprotein(a) Foundation. Its founder, Sandra Tremulis, is a survivor of an acute coronary event that occurred when she was 39-years old, despite running marathons and having none of the traditional CVD lifestyle risk factors.⁴⁹ This experience inspired her to create the Lipoprotein(a) Foundation to give a voice to families living with or at risk for CVD due to Lp(a) elevation.

As often happens in the progress of medicine, patients and their families drive change based on their personal experiences with the gaps in standard clinical practice. It was this foundation—not a member of the medical establishment—that submitted the formal request for the addition of new ICD-10-CM diagnostic and family history codes for Lp(a) elevation during the Centers for Disease Control and Prevention (CDC) September 2017 ICD-10-CM Coordination and Maintenance Committee meeting.⁵⁰ In June 2018, the final ICD-10-CM code addenda for 2019 was released and included the new codes E78.⁴¹ (Elevated Lp[a]) and Z83.430 (Family history of elevated Lp[a]).⁵² After the new codes were approved, both the American Heart Association and the National Lipid Association added recommendations regarding Lp(a) testing to their clinical practice guidelines.^43,52

Practically, these codes standardize billing and payment for legitimate clinical work and laboratory testing. Prior to the addition of Lp(a) elevation as a clinical diagnosis, testing and treatment of Lp(a) elevation was considered experimental and not medically necessary until after a cardiovascular event had already occurred. Services for Lp(a) elevation were therefore not reimbursed by many healthcare organizations and insurance companies. The new ICD-10-CM codes encourage the assessment of Lp(a) both in individuals with early onset major CVD events and in presumably fit, healthy individuals, particularly when there is a family history of Lp(a) elevation. Given that Lp(a) levels do not change significantly over time, the current understanding is that only a single measurement is needed to define the individual risk over a lifetime.^41,42,44,45 As therapies targeting Lp(a) levels evolve, repeated measurements may be indicated to monitor response and direct changes in management. “Elevated Lipoprotein(a)” is the first laboratory testing abnormality that has achieved the status of a clinical diagnosis.

Lp(a) Measurements

There is considerable complexity to the measurement of lipoproteins in blood samples due to heterogeneity in both density and size of particles as illustrated in the Figure.⁵³

For traditional lipids measured in clinical practice, the size and density ranges from small high-density lipoprotein (HDL) through LDLC and intermediate- density lipoprotein (IDL) to the largest least dense particles in the very low-density lipoprotein (VLDL) and chylomicron remnant fractions. Standard lipid profiles consist of mass concentration measurements (mg/dL) of TC, TG, HDLC, and LDLC.⁵³ Non-HDLC (calculated as: TC−HDLC) consists of all cholesterol found in atherogenic lipoproteins, including remnant-C and Lp(a). Until recently, the cholesterol content of Lp(a), corresponding to about 30% of Lp(a) total mass, was included in the TC, non-HDLC and LDLC measurements with no separate reporting by the majority of clinical laboratories.

After > 50 years of research on the structure and biochemistry of Lp(a), the physiology and biological functions of these complex and polymorphic lipoprotein particles are not fully understood. Lp(a) is composed of a lipoprotein particle similar in composition to LDL (protein and lipid), containing 1 molecule of ApoB wrapped around a core of cholesteryl ester and triglyceride with phospholipids and unesterified cholesterol at its surface.⁴⁸ The presence of a unique hydrophilic, highly glycosylated protein referred to as apolopoprotienA (apo[a]), covalently attached to ApoB-100 by a single disulfide bridge, differentiates Lp(a) from LDL.⁴⁸ Cholesterol rich ApoB is an important component within many lipoproteins pathogenic for atherosclerosis and CVD.^45,47,53

The apo(a) contributes to the increased density of Lp(a) compared to LDLC with associated reduced binding affinity to the LDL receptor. This reduced receptor binding affinity is a presumed mechanism for the lack of Lp(a) plasma level response to statin therapies, which increase hepatic LDL receptor activity.⁴⁷ Apo(a) evolved from the plasminogen gene through duplication and remodeling and demonstrates extensive heterogeneity in protein size, with > 40 different apo(a) isoforms resulting in > 40 different Lp(a) particle sizes. Size of the apo(a) particle is determined by the number of pleated structures known as kringles. Most people (> 80%) carry 2 different-sized apo(a) isoforms. Plasma Lp(a) level is determined by the net production of apo(a) in each isoform, and the smaller apo(a) isoforms are associated with higher plasma levels of Lp(a).⁴⁵

Given the heterogeneity in Lp(a) molecular weight, which can vary even within individuals, recommendations have been made for reporting results as particle numbers or concentrations (nmol/L or mmol/L) rather than as mass concentration (mg/dL).⁵⁵ However, the majority of the large CVD morbidity and mortality outcomes studies used Lp(a) mass concentration levels in mg/ dL to characterize risk levels.^56,57 There is no standardized method to convert Lp(a) measurements from mg/dL to nmol/L.⁵⁵ Current assays using WHO standardized reagents and controls are reliable for categorizing risk levels.⁵⁸

The European Atherosclerosis Society consensus panel recommended that desirable Lp(a) levels should be below the 80th percentile (< 50 mg/dL or < 125 nmol/L) in patients with intermediate or high CVD risk.⁵⁹ Subsequent epidemiological and Mendelian randomization studies have been performed in general populations with no history of CVD and demonstrated that increased CVD risk can be detected with Lp(a) levels as low as 25 to 30 mg/dL.^56,60-63 In secondary prevention populations with prior CVD and optimal treatment (statins, antiplatelet drugs), recurrent event risk was also increased with elevated Lp(a).^63-66

Using immunoturbidometric assays, Varvel and colleagues reported the prevalence of elevated Lp(a) mass concentration levels (mg/dL) in > 500,000 US patients undergoing clinical evaluations based on data from a referral laboratory of patients.⁵⁸ The mean Lp(a) levels were 34.0 mg/dL with median (interquartile range [IQR]) levels at 17 (7-47) mg/dL and overall range of 0 to 907 mg/dL.⁵⁸ Females had higher Lp(a) levels compared to males but no ethnic or racial breakdown was provided. Lp(a) levels > 30 mg/dL and > 50 mg/dL were present in 35% and 24% of subjects, respectively. Table 1 displays the relationship between various Lp(a) level cut-offs to mean levels of LDLC, estimated LDLC corrected for Lp(a), TC, HDLC, and TG.⁵⁸ The data demonstrate that Lp(a) elevation cannot be inferred from LDLC levels nor from any of the other traditional lipoprotein measures. Patients with high risk Lp(a) levels may have normal LDLC. While Lp(a) thresholds have been identified for stratification of CVD risk, the target levels for risk reduction have not been specifically defined, particularly since therapies are not widely available for reduction of Lp(a). Table 2 provides an overview of clinical lipoprotein measurements that may be reasonable targets for therapeutic interventions and reduction of CVD risk.^44,53,55 In general, existing studies suggest that radical reduction (> 80%) is required to impact long-term outcomes, particularly in individuals with severe disease.^68,69

LDLC reduction alone leaves a residual CVD risk that is greater than the risk reduced.40 In addition, the autoimmune inflammation and lipid specific autoantibodies play an important role in increased CVD morbidity and mortality risk.^70,71 The presence of autoantibodies such as antiphospholipid antibodies (without a specific autoimmune disease diagnosis) increases the risk of subclinical atherosclerosis.^72,73 Certain autoimmune diseases such as systemic lupus erythematosus are recognized as independent risk factors for CVD.^74,75 Autoantibodies appear to mediate CVD events and mortality risk, independent of traditional therapies for risk reduction.⁷³ Further research is needed to clarify the role of autoantibodies as markers of increased or decreased CVD risk and their mechanism of action.

Autoantibodies directed at new antigens in lipoproteins within atherosclerotic lesions can modulate the impact of atherosclerosis via activation of the innate and adaptive immune system.⁷⁶ The lipid-associated neopeptides are recognized as damage-associated or danger- associated molecular patterns (DAMPs), also known as alarmins, which signal molecules that can trigger and perpetuate noninfectious inflammatory responses.^77-79 Plasma autoantibodies (immunoglobulin M and G [IgM, IgG]) modify proinflammatory oxidation-specific epitopes on oxidized phospholipids (oxPL) within lipoproteins and are linked with markers of inflammation and CVD events.^80-82 Modified LDLC and ApoB-100 immune complexes with specific autoantibodies in the IgG class are associated with increased CVD.⁷⁶ These and other risk-modulating autoantibodies may explain some of the variability in CVD outcomes by ethnicity and between individuals.

Some antibodies to oxidized LDL (ox-LDL) may have a protective role in the development of atherosclerosis.^83,84 In a cohort of > 500 women, the number of carotid atherosclerotic plaques and total carotid plaque area were inversely correlated with a specific IgM autoantibody (MDA-p210).⁸⁴ High concentrations of Lp(a)- containing circulating immune complexes and Lp(a)-specific IgM and IgG have been described in patients with coronary heart disease (CHD).⁸⁵ Like ox-LDL, oxidized Lp(a) [ox-Lp(a)] is more potent than native Lp(a) in increasing atherosclerosis risk and is increased in patients with CHD compared to healthy controls.^86-88 Ox-Lp(a) levels may represent an even stronger risk marker for CVD than ox-LDL.⁸⁵

Possible Mechanisms of Pathogenesis

While the precise quantification of Lp(a) in human plasma (or serum) has been challenging, current clinical laboratories use standardized international reference reagents and controls in their assays. Most current Lp(a) assays are based on immunological methods (eg, immunonephelometry, immunoturbidimetry, or enzyme linked immunosorbent assay [ELISA]) using antibodies against apo(a).⁸⁹ Apo(a) contains 10 subtypes of kringle IV and 1 copy of kringle V. Some assays use antibodies against kringle-IV type 2; however, it has been recommended that newer methods should use antibodies against the specific bridging kringle-IV Type 9 domain, which has a more stable bond and is present as a single copy.^48,89 Other approaches to Lp(a) measurement include ultraperformance liquid chromatography/mass spectrometry that can determine both the concentration and particle size of apo(a).^48,90 For routine clinical care, currently available assays reporting in mg/dL can be considered fairly accurate for separating low-risk from moderate-to-high-risk patients.⁴⁵

The physiologic role of Lp(a) in humans remains to be fully defined and individuals with extremely low plasma Lp(a) levels present no disease or deficiency syndromes.⁹¹ Lp(a) accumulates in endothelial injuries and binds to components of the vessel wall and subendothelial matrix, presumably due to the strong lysine binding site in apo(a).⁴⁶ Mediated by apo(a), the binding stimulates chemotactic activation of monocytes/macrophages and thereby modulating angiogenesis and inflammation.⁸⁹ Lp(a) may contribute to CVD and CAVS via its LDL-like component, with proinflammatory effects of oxidized phospholipids (OxPL) on both ApoB and apo(a) and antifibrinolytic/prothrombotic effects of apo(a).⁹² In Vitro studies have demonstrated that apo(a) modifies cellular function of cultured vascular endothelial cells (promoting stress fiber formation, endothelial contraction and vascular permeability), smooth muscles, and monocytes/ macrophages (promoting differentiation of proinflammatory M1-1 type macrophages) via complex mechanisms of cell signaling and cytokine production.89 Lp(a) is the only monogenetic risk factor for aortic valve calcification and stenosis⁹³ and is strongly linked specifically with the single nucleotide polymorphism (SNP) rs10455872 in the gene LPA encoding for apo(a).⁹⁴

CVD Risk Predictive Value

There are a large number of studies demonstrating that Lp(a) elevations are an independent predictor of adverse cardiovascular outcomes including MI, sudden death, strokes, calcific aortic valve stenosis and peripheral vascular disease (Table 3). The Copenhagen City Heart Study and Copenhagen General Population Study are well known prospective population- based cohort studies that track outcomes through national patient registries.⁹⁵ These studies demonstrate increased risk for MI, CHD, CAVS, and heart failure when subjects with very high Lp(a) levels (50-115 mg/dL) are compared with subjects with very low Lp(a) levels (< 5 mg/dL).^96-100 Subjects with less extreme Lp(a) elevations (> 30 mg/dL) also show increased risk of CVD when they have comorbid LDLC elevations.¹⁰¹ However, the Copenhagen studies are composed exclusively of white subjects and the effects of Lp(a) are known to vary with race or ethnicity.

The Multi-Ethnic Study of Atherosclerosis (MESA) recruited an ethnically diverse sample of > 6,000 Americans, aged 45 to 84 years, without CVD, into an ongoing prospective cohort study. Research using subjects from this study has found consistently increased risk of CHD, heart failure, subclinical aortic valve calcification, and more severe CAVS in white subjects with elevated Lp(a).^60,102,103 Black subjects with elevated Lp(a) had increased risk of CHD and more severe CAVS and Hispanic subjects with Lp(a) elevation were at higher risk for CHD.^60,102 So far, no studies of MESA subjects have identified a relationship between Lp(a) elevation and CVD events for Asian-Americans subjects (predominantly of Chinese descent). There is a need for ongoing research to more precisely define relevant cut-off levels by race, ethnicity and sex.

The Atherosclerosis Risk in Communities (ARIC) Study was a prospective multiethnic cohort study including > 15,000 US adults, aged 45 to 64 years.¹⁰³ Lp(a) elevations in this cohort were associated with greater risks for first CVD events, heart failure, and recurrent CVD events.^61,64,105 The risk of stroke for subjects with elevated Lp(a) was greater for black and white women, and for black men.^61,106 However, a meta-analysis of case-control studies showed increased ischemic stroke risk in both men and women with elevated Lp(a).⁵⁷

A recent European meta-analysis collected blood samples and outcome data from > 50,000 subjects in 7 prospective cohort studies. Using a central laboratory to standardize Lp(a) measurements, researchers found increased risk of major coronary events and new CVD in subjects with Lp(a) > 50 mg/dL compared to those below that threshold.¹⁰⁷

Although many of these studies show modest increases in risk of CVD events with Lp(a) elevation, it should be noted that other studies do not demonstrate such consistent associations. This is particularly true in studies of women and nonwhite ethnic groups.^103,108-112 The variability of study results may be due to other confounding factors such as autoantibodies that either upregulate or downregulate atherogenicity of LDLC and potentially other lipoproteins. This is particularly relevant to women who have an increased risk for autoimmune disease.

Lp(a) has significant genetic heritability—75% in Europeans and 85% in African Americans.¹¹³ In whites, the LPA gene on chromosome 6p26- 27 with the polymorphism genetic variants rs10455872 and rs3798220 is consistently associated with elevated Lp(a) levels.^63,100,113 However, the degree of Lp(a) elevation associated with these specific genetic variants varies by ethnicity.^78,113,115

Lifestyle and Cardiovascular Health

It is noteworthy that the Lp(a) genetic risks can also be modified by lifestyle risk reduction even in the absence of significant blood level reductions. For example, Khera and colleagues constructed a genetic risk profile for CVD that included genes related to Lp(a).¹¹⁶ Subjects with high genetic risk were more likely to experience CVD events compared with subjects with low genetic risk. However, risks for CVD were attenuated by 4 healthy lifestyle factors: current nonsmoker, body mass index < 30, at least weekly physical activity, and a healthy diet. Subjects with high genetic risk and an unhealthy lifestyle (0 or 1 of the 4 healthy lifestyle factors) were the most likely to develop CVD (Hazard ratio [HR], 3.5), but that risk was lower for subjects with healthy (3 or 4 of the 4 healthy lifestyle factors) and intermediate lifestyles (2 of the 4 healthy lifestyle factors) (HR, 1.9 and 2.2, respectively), despite despite high genetic risk for CVD.

While the independent CVD risk associated with elevated Lp(a) does not appear to be responsive to lifestyle risk reduction alone, certainly elevated LDLC and traditional risk factors can increase the overall CVD risk and are worthy of preventive interventions. In particular, inflammation from any source exacerbates CVD risk. Proatherogenic diet, insufficient sleep, lack of exercise, and maladaptive stress responses are other targets for personalized CVD risk reduction. ^28,117 Studies of dietary modifications and other lifestyle factors have shown reduced risk of CVD events, despite lack of reduction in Lp(a) levels.^119,120 It is noteworthy that statin therapy (with or without ezetimibe) fails to impact CAVS progression, likely because statins either raise or have no effect on Lp(a) levels.^92,119

Until recently, there has been no evidence supporting any therapeutic intervention causing clinically meaningful reductions in Lp(a). Table 4 lists major drug classes and their effects on Lp(a) and CVD outcomes; however, a detailed discussion of each of these therapies is beyond the scope of this review. Drugs that reduce Lp(a) by 20-30% have varying effects on CVD outcomes, from no effect^122,123 to a 10% to 20% decrease in CVD events when compared with a placebo.^124,125 Because these drugs also produce substantial reductions in LDLC, it is not possible to determine how much of the beneficial effects are due to reductions in Lp(a).

Lipoprotein apheresis produces profound reductions in Lp(a) of 60 to 80% in very highrisk populations.^69,126 Within-subjects comparisons show up to 80% reductions in CVD events, relative to event rates prior to treatment initiation.^69,127 Early trials of antisense oligonucleotide against apo(a) therapies show potential to produce similar outcomes.^128,129 These treatments may be particularly effective in patients with isolated Lp(a) elevations.

Summary

Lp(a) elevation is a major contributor to cardiovascular disease risk and has been recognized as an ICD-10-CM coded clinical diagnosis, the first laboratory abnormality to be defined a clinical disease in the asymptomatic healthy young individuals. This change addresses currently under- diagnosed CVD risk independent of LDLC reduction strategies. A brief overview of recent guidelines for the clinical use of Lp(a) testing from the American Heart Association^43,151 and the National Lipid Association52 can be found in Table 5. Although drug therapies for lowering Lp(a) levels remain limited, new treatment options are actively being developed.

Many Americans with high Lp(a) have not yet been identified. Expanded one-time screening can inform these patients of their cardiovascular risk and increase their access to early, aggressive lifestyle modification and optimal lipid-lowering therapy. Given the further increased CVD risk factors for military service members and veterans, a case can be made for broader screening and enhanced surveillance of elevated Lp(a) in these presumably healthy and fit individuals as well as management focused on modifiable risk factors.

Acknowledgements

This program initiative was conducted by the Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc. as part of the Integrative Cardiac Health Project at Walter Reed National Military Medical Center (WRNMMC), and is made possible by a cooperative agreement that was awarded and administered by the US Army Medical Research & Materiel Command (USAMRMC), at Fort Detrick under Contract Number: W81XWH-16-2-0007. It reflects literature review preparatory work for a research protocol but does not involve an actual research project. The work in this manuscript was supported by the staff of the Integrative Cardiac Health Project (ICHP) with special thanks to Claire Fuller, Elaine Walizer, Dr. Mariam Kashani and the entire health coaching team.

Cardiovascular disease (CVD) remains the leading cause of global mortality. In 2015, 41.5% of the US population had at least 1 form of CVD and CVD accounted for nearly 18 million deaths worldwide.1,2 The major disease categories represented include myocardial infarction (MI), sudden death, strokes, calcific aortic valve stenosis (CAVS), and peripheral vascular disease.^1,2 In terms of health care costs, quality of life, and caregiver burden, the overall impact of disease prevalence continues to rise.^1,3-6 There is an urgent need for more precise and earlier CVD risk assessment to guide lifestyle and therapeutic interventions for prevention of disease progression as well as potential reversal of preclinical disease. Even at a young age, visible coronary atherosclerosis has been found in up to 11% of “healthy” active individuals during autopsies for trauma fatalities.^7,8

The impact of CVD on the US and global populations is profound. In 2011, CVD prevalence was predicted to reach 40% by 2030.9 That estimate was exceeded in 2015, and it is now predicted that by 2035, 45% of the US population will suffer from some form of clinical or preclinical CVD. In 2015, the decadeslong decline in CVD mortality was reversed for the first time since 1969, showing a 1% increase in deaths from CVD.¹ Nearly 300,000 of those using US Department of Veterans Affairs (VA) services were hospitalized for CVD between 2010 and 2014.¹⁰ The annual direct and indirect costs related to CVD in the US are estimated at $329.7 billion, and these costs are predicted to top $1 trillion by 2035.¹ Heart attack, coronary atherosclerosis, and stroke accounted for 3 of the 10 most expensive conditions treated in US hospitals in 2013.¹¹ Globally, the estimate for CVD-related direct and indirect costs was $863 billion in 2010 and may exceed $1 trillion by 2030.¹²

The nature of military service adds additional risk factors, such as posttraumatic stress disorder, depression, sleep disorders and physical trauma which increase CVD morbidity/ mortality in service members, veterans, and their families.^13-16 In addition, living in lowerincome areas (countries or neighborhoods) can increase the risk of both CVD incidence and fatalities, particularly in younger individuals.^17-20 The Military Health System (MHS) and VA are responsible for the care of those individuals who have voluntarily taken on these additional risks through their time in service. This responsibility calls for rapid translation to practice tools and resources that can support interventions to minimize as many modifiable risk factors as possible and improve longterm health. This strategy aligns with the World Health Organization’s (WHO) focus on prevention of disease progression through interventions targeting modifiable risk.^3-6,21-23 The driving force behind the launch of the US Department of Health and Human Services (HHS) Million Hearts program was the goal of preventing 1 million heart attacks and strokes by 2017 with risk reduction through aspirin, blood pressure control, cholesterol management, smoking cessation, sodium reduction, and physical activity.^24,25 While some reductions in CVD events have been documented, the outcomes fell short of the goals set, highlighting both the need and value of continued and expanded efforts for CVD risk reduction.²⁶

More precise assessment of risk factors during preventative care, as well as after a diagnosis of CVD, may improve the timeliness and precision of earlier interventions (both lifestyle and therapeutic) that reduce CVD morbidity and mortality^.27 Personalized or precision medicine approaches take into account differences in socioeconomic, environmental, and lifestyle factors that are potentially reversible, as well as gender, race, and ethnicity.^28-31 Current methods of predicting CVD risk have considerable room for improvement.²⁷ About 40% of patients with newly diagnosed CVD have normal traditional cholesterol profiles, including those whose first cardiac event proves fatal.^29-33 Currently available risk scores (hundreds have been described in the literature) mischaracterize risk in minority populations and women, and have shown deficiencies in identifying preclinical atherosclerosis.^34,35 The failure to recognize preclinical CVD in military personnel during their active duty life cycle results in missed opportunities for improved health and readiness sustainment.

Most CVD risk prediction models incorporate some form of blood lipids. Total cholesterol (TC) is most commonly used in clinical practice, along with high-density lipoprotein (HDLC), low-density lipoprotein (LDLC), and triglycerides (TG).^23,27,36 High LDLC and/or TC are well established as lipid-related CVD risk factors and are incorporated into many CVD risk scoring systems/models described in the literature.²⁷ LDLC reduction is commonly recommended as CVD prevention, but even with optimal statin treatment, there is still considerable residual risk for new and recurrent CVD events.^{28,32,34,35,37-42}

Incorporating novel biomarkers and alternative lipid measurements may improve risk prediction and aid targeted treatment, ultimately reducing CVD events.²⁷ Apolipoprotein B (ApoB) is a major atherogenic component embedded in LDL and VLDL correlating to non-HDLC and may be useful in the setting of triglycerides ≥ 200 mg/d as levels > 130 mg/ dL appear to be risk-enhancing, but measurements may be unreliable.⁴³ According to the 2018 Cholesterol Guidelines, lipoprotein(a) [Lp(a)] elevation also is recognized as a risk-enhancing factor that is particularly implicated when there is a strong family history of premature atherosclerotic CVD or personal history of CVD not explained by major risk factors.⁴³

Lp(a) elevation is a largely underrecognized category of lipid disorder that impacts up to 20% to 30% of the population globally and within the US, although there is considerable variability by geographic location and ethnicity.⁴⁴ Globally, Lp(a) elevation places > 1 billion people at moderate to high risk for CVD.44 Lp(a) has a strong genetic component and is recognized as a distinct and independent risk factor for MI, sudden death, strokes and CAVS. Lp(a) has an extensive body of evidence to support its distinct role both as a causal factor in CVD and as an augmentation to traditional risk factors.^44-48

Lipoproteni(a) Elevation Use For Diagnosis

The importance of Lp(a) elevation as a clinical diagnosis rather than a laboratory abnormality alone was brought forward by the Lipoprotein(a) Foundation. Its founder, Sandra Tremulis, is a survivor of an acute coronary event that occurred when she was 39-years old, despite running marathons and having none of the traditional CVD lifestyle risk factors.⁴⁹ This experience inspired her to create the Lipoprotein(a) Foundation to give a voice to families living with or at risk for CVD due to Lp(a) elevation.

As often happens in the progress of medicine, patients and their families drive change based on their personal experiences with the gaps in standard clinical practice. It was this foundation—not a member of the medical establishment—that submitted the formal request for the addition of new ICD-10-CM diagnostic and family history codes for Lp(a) elevation during the Centers for Disease Control and Prevention (CDC) September 2017 ICD-10-CM Coordination and Maintenance Committee meeting.⁵⁰ In June 2018, the final ICD-10-CM code addenda for 2019 was released and included the new codes E78.⁴¹ (Elevated Lp[a]) and Z83.430 (Family history of elevated Lp[a]).⁵² After the new codes were approved, both the American Heart Association and the National Lipid Association added recommendations regarding Lp(a) testing to their clinical practice guidelines.^43,52

Practically, these codes standardize billing and payment for legitimate clinical work and laboratory testing. Prior to the addition of Lp(a) elevation as a clinical diagnosis, testing and treatment of Lp(a) elevation was considered experimental and not medically necessary until after a cardiovascular event had already occurred. Services for Lp(a) elevation were therefore not reimbursed by many healthcare organizations and insurance companies. The new ICD-10-CM codes encourage the assessment of Lp(a) both in individuals with early onset major CVD events and in presumably fit, healthy individuals, particularly when there is a family history of Lp(a) elevation. Given that Lp(a) levels do not change significantly over time, the current understanding is that only a single measurement is needed to define the individual risk over a lifetime.^41,42,44,45 As therapies targeting Lp(a) levels evolve, repeated measurements may be indicated to monitor response and direct changes in management. “Elevated Lipoprotein(a)” is the first laboratory testing abnormality that has achieved the status of a clinical diagnosis.

Lp(a) Measurements

There is considerable complexity to the measurement of lipoproteins in blood samples due to heterogeneity in both density and size of particles as illustrated in the Figure.⁵³

For traditional lipids measured in clinical practice, the size and density ranges from small high-density lipoprotein (HDL) through LDLC and intermediate- density lipoprotein (IDL) to the largest least dense particles in the very low-density lipoprotein (VLDL) and chylomicron remnant fractions. Standard lipid profiles consist of mass concentration measurements (mg/dL) of TC, TG, HDLC, and LDLC.⁵³ Non-HDLC (calculated as: TC−HDLC) consists of all cholesterol found in atherogenic lipoproteins, including remnant-C and Lp(a). Until recently, the cholesterol content of Lp(a), corresponding to about 30% of Lp(a) total mass, was included in the TC, non-HDLC and LDLC measurements with no separate reporting by the majority of clinical laboratories.

After > 50 years of research on the structure and biochemistry of Lp(a), the physiology and biological functions of these complex and polymorphic lipoprotein particles are not fully understood. Lp(a) is composed of a lipoprotein particle similar in composition to LDL (protein and lipid), containing 1 molecule of ApoB wrapped around a core of cholesteryl ester and triglyceride with phospholipids and unesterified cholesterol at its surface.⁴⁸ The presence of a unique hydrophilic, highly glycosylated protein referred to as apolopoprotienA (apo[a]), covalently attached to ApoB-100 by a single disulfide bridge, differentiates Lp(a) from LDL.⁴⁸ Cholesterol rich ApoB is an important component within many lipoproteins pathogenic for atherosclerosis and CVD.^45,47,53

The apo(a) contributes to the increased density of Lp(a) compared to LDLC with associated reduced binding affinity to the LDL receptor. This reduced receptor binding affinity is a presumed mechanism for the lack of Lp(a) plasma level response to statin therapies, which increase hepatic LDL receptor activity.⁴⁷ Apo(a) evolved from the plasminogen gene through duplication and remodeling and demonstrates extensive heterogeneity in protein size, with > 40 different apo(a) isoforms resulting in > 40 different Lp(a) particle sizes. Size of the apo(a) particle is determined by the number of pleated structures known as kringles. Most people (> 80%) carry 2 different-sized apo(a) isoforms. Plasma Lp(a) level is determined by the net production of apo(a) in each isoform, and the smaller apo(a) isoforms are associated with higher plasma levels of Lp(a).⁴⁵

Given the heterogeneity in Lp(a) molecular weight, which can vary even within individuals, recommendations have been made for reporting results as particle numbers or concentrations (nmol/L or mmol/L) rather than as mass concentration (mg/dL).⁵⁵ However, the majority of the large CVD morbidity and mortality outcomes studies used Lp(a) mass concentration levels in mg/ dL to characterize risk levels.^56,57 There is no standardized method to convert Lp(a) measurements from mg/dL to nmol/L.⁵⁵ Current assays using WHO standardized reagents and controls are reliable for categorizing risk levels.⁵⁸

The European Atherosclerosis Society consensus panel recommended that desirable Lp(a) levels should be below the 80th percentile (< 50 mg/dL or < 125 nmol/L) in patients with intermediate or high CVD risk.⁵⁹ Subsequent epidemiological and Mendelian randomization studies have been performed in general populations with no history of CVD and demonstrated that increased CVD risk can be detected with Lp(a) levels as low as 25 to 30 mg/dL.^56,60-63 In secondary prevention populations with prior CVD and optimal treatment (statins, antiplatelet drugs), recurrent event risk was also increased with elevated Lp(a).^63-66

Using immunoturbidometric assays, Varvel and colleagues reported the prevalence of elevated Lp(a) mass concentration levels (mg/dL) in > 500,000 US patients undergoing clinical evaluations based on data from a referral laboratory of patients.⁵⁸ The mean Lp(a) levels were 34.0 mg/dL with median (interquartile range [IQR]) levels at 17 (7-47) mg/dL and overall range of 0 to 907 mg/dL.⁵⁸ Females had higher Lp(a) levels compared to males but no ethnic or racial breakdown was provided. Lp(a) levels > 30 mg/dL and > 50 mg/dL were present in 35% and 24% of subjects, respectively. Table 1 displays the relationship between various Lp(a) level cut-offs to mean levels of LDLC, estimated LDLC corrected for Lp(a), TC, HDLC, and TG.⁵⁸ The data demonstrate that Lp(a) elevation cannot be inferred from LDLC levels nor from any of the other traditional lipoprotein measures. Patients with high risk Lp(a) levels may have normal LDLC. While Lp(a) thresholds have been identified for stratification of CVD risk, the target levels for risk reduction have not been specifically defined, particularly since therapies are not widely available for reduction of Lp(a). Table 2 provides an overview of clinical lipoprotein measurements that may be reasonable targets for therapeutic interventions and reduction of CVD risk.^44,53,55 In general, existing studies suggest that radical reduction (> 80%) is required to impact long-term outcomes, particularly in individuals with severe disease.^68,69

LDLC reduction alone leaves a residual CVD risk that is greater than the risk reduced.40 In addition, the autoimmune inflammation and lipid specific autoantibodies play an important role in increased CVD morbidity and mortality risk.^70,71 The presence of autoantibodies such as antiphospholipid antibodies (without a specific autoimmune disease diagnosis) increases the risk of subclinical atherosclerosis.^72,73 Certain autoimmune diseases such as systemic lupus erythematosus are recognized as independent risk factors for CVD.^74,75 Autoantibodies appear to mediate CVD events and mortality risk, independent of traditional therapies for risk reduction.⁷³ Further research is needed to clarify the role of autoantibodies as markers of increased or decreased CVD risk and their mechanism of action.

Autoantibodies directed at new antigens in lipoproteins within atherosclerotic lesions can modulate the impact of atherosclerosis via activation of the innate and adaptive immune system.⁷⁶ The lipid-associated neopeptides are recognized as damage-associated or danger- associated molecular patterns (DAMPs), also known as alarmins, which signal molecules that can trigger and perpetuate noninfectious inflammatory responses.^77-79 Plasma autoantibodies (immunoglobulin M and G [IgM, IgG]) modify proinflammatory oxidation-specific epitopes on oxidized phospholipids (oxPL) within lipoproteins and are linked with markers of inflammation and CVD events.^80-82 Modified LDLC and ApoB-100 immune complexes with specific autoantibodies in the IgG class are associated with increased CVD.⁷⁶ These and other risk-modulating autoantibodies may explain some of the variability in CVD outcomes by ethnicity and between individuals.

Some antibodies to oxidized LDL (ox-LDL) may have a protective role in the development of atherosclerosis.^83,84 In a cohort of > 500 women, the number of carotid atherosclerotic plaques and total carotid plaque area were inversely correlated with a specific IgM autoantibody (MDA-p210).⁸⁴ High concentrations of Lp(a)- containing circulating immune complexes and Lp(a)-specific IgM and IgG have been described in patients with coronary heart disease (CHD).⁸⁵ Like ox-LDL, oxidized Lp(a) [ox-Lp(a)] is more potent than native Lp(a) in increasing atherosclerosis risk and is increased in patients with CHD compared to healthy controls.^86-88 Ox-Lp(a) levels may represent an even stronger risk marker for CVD than ox-LDL.⁸⁵

Possible Mechanisms of Pathogenesis

While the precise quantification of Lp(a) in human plasma (or serum) has been challenging, current clinical laboratories use standardized international reference reagents and controls in their assays. Most current Lp(a) assays are based on immunological methods (eg, immunonephelometry, immunoturbidimetry, or enzyme linked immunosorbent assay [ELISA]) using antibodies against apo(a).⁸⁹ Apo(a) contains 10 subtypes of kringle IV and 1 copy of kringle V. Some assays use antibodies against kringle-IV type 2; however, it has been recommended that newer methods should use antibodies against the specific bridging kringle-IV Type 9 domain, which has a more stable bond and is present as a single copy.^48,89 Other approaches to Lp(a) measurement include ultraperformance liquid chromatography/mass spectrometry that can determine both the concentration and particle size of apo(a).^48,90 For routine clinical care, currently available assays reporting in mg/dL can be considered fairly accurate for separating low-risk from moderate-to-high-risk patients.⁴⁵

The physiologic role of Lp(a) in humans remains to be fully defined and individuals with extremely low plasma Lp(a) levels present no disease or deficiency syndromes.⁹¹ Lp(a) accumulates in endothelial injuries and binds to components of the vessel wall and subendothelial matrix, presumably due to the strong lysine binding site in apo(a).⁴⁶ Mediated by apo(a), the binding stimulates chemotactic activation of monocytes/macrophages and thereby modulating angiogenesis and inflammation.⁸⁹ Lp(a) may contribute to CVD and CAVS via its LDL-like component, with proinflammatory effects of oxidized phospholipids (OxPL) on both ApoB and apo(a) and antifibrinolytic/prothrombotic effects of apo(a).⁹² In Vitro studies have demonstrated that apo(a) modifies cellular function of cultured vascular endothelial cells (promoting stress fiber formation, endothelial contraction and vascular permeability), smooth muscles, and monocytes/ macrophages (promoting differentiation of proinflammatory M1-1 type macrophages) via complex mechanisms of cell signaling and cytokine production.89 Lp(a) is the only monogenetic risk factor for aortic valve calcification and stenosis⁹³ and is strongly linked specifically with the single nucleotide polymorphism (SNP) rs10455872 in the gene LPA encoding for apo(a).⁹⁴

CVD Risk Predictive Value

There are a large number of studies demonstrating that Lp(a) elevations are an independent predictor of adverse cardiovascular outcomes including MI, sudden death, strokes, calcific aortic valve stenosis and peripheral vascular disease (Table 3). The Copenhagen City Heart Study and Copenhagen General Population Study are well known prospective population- based cohort studies that track outcomes through national patient registries.⁹⁵ These studies demonstrate increased risk for MI, CHD, CAVS, and heart failure when subjects with very high Lp(a) levels (50-115 mg/dL) are compared with subjects with very low Lp(a) levels (< 5 mg/dL).^96-100 Subjects with less extreme Lp(a) elevations (> 30 mg/dL) also show increased risk of CVD when they have comorbid LDLC elevations.¹⁰¹ However, the Copenhagen studies are composed exclusively of white subjects and the effects of Lp(a) are known to vary with race or ethnicity.

The Multi-Ethnic Study of Atherosclerosis (MESA) recruited an ethnically diverse sample of > 6,000 Americans, aged 45 to 84 years, without CVD, into an ongoing prospective cohort study. Research using subjects from this study has found consistently increased risk of CHD, heart failure, subclinical aortic valve calcification, and more severe CAVS in white subjects with elevated Lp(a).^60,102,103 Black subjects with elevated Lp(a) had increased risk of CHD and more severe CAVS and Hispanic subjects with Lp(a) elevation were at higher risk for CHD.^60,102 So far, no studies of MESA subjects have identified a relationship between Lp(a) elevation and CVD events for Asian-Americans subjects (predominantly of Chinese descent). There is a need for ongoing research to more precisely define relevant cut-off levels by race, ethnicity and sex.

The Atherosclerosis Risk in Communities (ARIC) Study was a prospective multiethnic cohort study including > 15,000 US adults, aged 45 to 64 years.¹⁰³ Lp(a) elevations in this cohort were associated with greater risks for first CVD events, heart failure, and recurrent CVD events.^61,64,105 The risk of stroke for subjects with elevated Lp(a) was greater for black and white women, and for black men.^61,106 However, a meta-analysis of case-control studies showed increased ischemic stroke risk in both men and women with elevated Lp(a).⁵⁷

A recent European meta-analysis collected blood samples and outcome data from > 50,000 subjects in 7 prospective cohort studies. Using a central laboratory to standardize Lp(a) measurements, researchers found increased risk of major coronary events and new CVD in subjects with Lp(a) > 50 mg/dL compared to those below that threshold.¹⁰⁷

Although many of these studies show modest increases in risk of CVD events with Lp(a) elevation, it should be noted that other studies do not demonstrate such consistent associations. This is particularly true in studies of women and nonwhite ethnic groups.^103,108-112 The variability of study results may be due to other confounding factors such as autoantibodies that either upregulate or downregulate atherogenicity of LDLC and potentially other lipoproteins. This is particularly relevant to women who have an increased risk for autoimmune disease.

Lp(a) has significant genetic heritability—75% in Europeans and 85% in African Americans.¹¹³ In whites, the LPA gene on chromosome 6p26- 27 with the polymorphism genetic variants rs10455872 and rs3798220 is consistently associated with elevated Lp(a) levels.^63,100,113 However, the degree of Lp(a) elevation associated with these specific genetic variants varies by ethnicity.^78,113,115

Lifestyle and Cardiovascular Health

It is noteworthy that the Lp(a) genetic risks can also be modified by lifestyle risk reduction even in the absence of significant blood level reductions. For example, Khera and colleagues constructed a genetic risk profile for CVD that included genes related to Lp(a).¹¹⁶ Subjects with high genetic risk were more likely to experience CVD events compared with subjects with low genetic risk. However, risks for CVD were attenuated by 4 healthy lifestyle factors: current nonsmoker, body mass index < 30, at least weekly physical activity, and a healthy diet. Subjects with high genetic risk and an unhealthy lifestyle (0 or 1 of the 4 healthy lifestyle factors) were the most likely to develop CVD (Hazard ratio [HR], 3.5), but that risk was lower for subjects with healthy (3 or 4 of the 4 healthy lifestyle factors) and intermediate lifestyles (2 of the 4 healthy lifestyle factors) (HR, 1.9 and 2.2, respectively), despite despite high genetic risk for CVD.

While the independent CVD risk associated with elevated Lp(a) does not appear to be responsive to lifestyle risk reduction alone, certainly elevated LDLC and traditional risk factors can increase the overall CVD risk and are worthy of preventive interventions. In particular, inflammation from any source exacerbates CVD risk. Proatherogenic diet, insufficient sleep, lack of exercise, and maladaptive stress responses are other targets for personalized CVD risk reduction. ^28,117 Studies of dietary modifications and other lifestyle factors have shown reduced risk of CVD events, despite lack of reduction in Lp(a) levels.^119,120 It is noteworthy that statin therapy (with or without ezetimibe) fails to impact CAVS progression, likely because statins either raise or have no effect on Lp(a) levels.^92,119

Until recently, there has been no evidence supporting any therapeutic intervention causing clinically meaningful reductions in Lp(a). Table 4 lists major drug classes and their effects on Lp(a) and CVD outcomes; however, a detailed discussion of each of these therapies is beyond the scope of this review. Drugs that reduce Lp(a) by 20-30% have varying effects on CVD outcomes, from no effect^122,123 to a 10% to 20% decrease in CVD events when compared with a placebo.^124,125 Because these drugs also produce substantial reductions in LDLC, it is not possible to determine how much of the beneficial effects are due to reductions in Lp(a).

Lipoprotein apheresis produces profound reductions in Lp(a) of 60 to 80% in very highrisk populations.^69,126 Within-subjects comparisons show up to 80% reductions in CVD events, relative to event rates prior to treatment initiation.^69,127 Early trials of antisense oligonucleotide against apo(a) therapies show potential to produce similar outcomes.^128,129 These treatments may be particularly effective in patients with isolated Lp(a) elevations.

Summary

Lp(a) elevation is a major contributor to cardiovascular disease risk and has been recognized as an ICD-10-CM coded clinical diagnosis, the first laboratory abnormality to be defined a clinical disease in the asymptomatic healthy young individuals. This change addresses currently under- diagnosed CVD risk independent of LDLC reduction strategies. A brief overview of recent guidelines for the clinical use of Lp(a) testing from the American Heart Association^43,151 and the National Lipid Association52 can be found in Table 5. Although drug therapies for lowering Lp(a) levels remain limited, new treatment options are actively being developed.

Many Americans with high Lp(a) have not yet been identified. Expanded one-time screening can inform these patients of their cardiovascular risk and increase their access to early, aggressive lifestyle modification and optimal lipid-lowering therapy. Given the further increased CVD risk factors for military service members and veterans, a case can be made for broader screening and enhanced surveillance of elevated Lp(a) in these presumably healthy and fit individuals as well as management focused on modifiable risk factors.

Acknowledgements

This program initiative was conducted by the Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc. as part of the Integrative Cardiac Health Project at Walter Reed National Military Medical Center (WRNMMC), and is made possible by a cooperative agreement that was awarded and administered by the US Army Medical Research & Materiel Command (USAMRMC), at Fort Detrick under Contract Number: W81XWH-16-2-0007. It reflects literature review preparatory work for a research protocol but does not involve an actual research project. The work in this manuscript was supported by the staff of the Integrative Cardiac Health Project (ICHP) with special thanks to Claire Fuller, Elaine Walizer, Dr. Mariam Kashani and the entire health coaching team.

Cardiovascular disease (CVD) remains the leading cause of global mortality. In 2015, 41.5% of the US population had at least 1 form of CVD and CVD accounted for nearly 18 million deaths worldwide.1,2 The major disease categories represented include myocardial infarction (MI), sudden death, strokes, calcific aortic valve stenosis (CAVS), and peripheral vascular disease.^1,2 In terms of health care costs, quality of life, and caregiver burden, the overall impact of disease prevalence continues to rise.^1,3-6 There is an urgent need for more precise and earlier CVD risk assessment to guide lifestyle and therapeutic interventions for prevention of disease progression as well as potential reversal of preclinical disease. Even at a young age, visible coronary atherosclerosis has been found in up to 11% of “healthy” active individuals during autopsies for trauma fatalities.^7,8

The impact of CVD on the US and global populations is profound. In 2011, CVD prevalence was predicted to reach 40% by 2030.9 That estimate was exceeded in 2015, and it is now predicted that by 2035, 45% of the US population will suffer from some form of clinical or preclinical CVD. In 2015, the decadeslong decline in CVD mortality was reversed for the first time since 1969, showing a 1% increase in deaths from CVD.¹ Nearly 300,000 of those using US Department of Veterans Affairs (VA) services were hospitalized for CVD between 2010 and 2014.¹⁰ The annual direct and indirect costs related to CVD in the US are estimated at $329.7 billion, and these costs are predicted to top $1 trillion by 2035.¹ Heart attack, coronary atherosclerosis, and stroke accounted for 3 of the 10 most expensive conditions treated in US hospitals in 2013.¹¹ Globally, the estimate for CVD-related direct and indirect costs was $863 billion in 2010 and may exceed $1 trillion by 2030.¹²

The nature of military service adds additional risk factors, such as posttraumatic stress disorder, depression, sleep disorders and physical trauma which increase CVD morbidity/ mortality in service members, veterans, and their families.^13-16 In addition, living in lowerincome areas (countries or neighborhoods) can increase the risk of both CVD incidence and fatalities, particularly in younger individuals.^17-20 The Military Health System (MHS) and VA are responsible for the care of those individuals who have voluntarily taken on these additional risks through their time in service. This responsibility calls for rapid translation to practice tools and resources that can support interventions to minimize as many modifiable risk factors as possible and improve longterm health. This strategy aligns with the World Health Organization’s (WHO) focus on prevention of disease progression through interventions targeting modifiable risk.^3-6,21-23 The driving force behind the launch of the US Department of Health and Human Services (HHS) Million Hearts program was the goal of preventing 1 million heart attacks and strokes by 2017 with risk reduction through aspirin, blood pressure control, cholesterol management, smoking cessation, sodium reduction, and physical activity.^24,25 While some reductions in CVD events have been documented, the outcomes fell short of the goals set, highlighting both the need and value of continued and expanded efforts for CVD risk reduction.²⁶

More precise assessment of risk factors during preventative care, as well as after a diagnosis of CVD, may improve the timeliness and precision of earlier interventions (both lifestyle and therapeutic) that reduce CVD morbidity and mortality^.27 Personalized or precision medicine approaches take into account differences in socioeconomic, environmental, and lifestyle factors that are potentially reversible, as well as gender, race, and ethnicity.^28-31 Current methods of predicting CVD risk have considerable room for improvement.²⁷ About 40% of patients with newly diagnosed CVD have normal traditional cholesterol profiles, including those whose first cardiac event proves fatal.^29-33 Currently available risk scores (hundreds have been described in the literature) mischaracterize risk in minority populations and women, and have shown deficiencies in identifying preclinical atherosclerosis.^34,35 The failure to recognize preclinical CVD in military personnel during their active duty life cycle results in missed opportunities for improved health and readiness sustainment.

Most CVD risk prediction models incorporate some form of blood lipids. Total cholesterol (TC) is most commonly used in clinical practice, along with high-density lipoprotein (HDLC), low-density lipoprotein (LDLC), and triglycerides (TG).^23,27,36 High LDLC and/or TC are well established as lipid-related CVD risk factors and are incorporated into many CVD risk scoring systems/models described in the literature.²⁷ LDLC reduction is commonly recommended as CVD prevention, but even with optimal statin treatment, there is still considerable residual risk for new and recurrent CVD events.^{28,32,34,35,37-42}

Incorporating novel biomarkers and alternative lipid measurements may improve risk prediction and aid targeted treatment, ultimately reducing CVD events.²⁷ Apolipoprotein B (ApoB) is a major atherogenic component embedded in LDL and VLDL correlating to non-HDLC and may be useful in the setting of triglycerides ≥ 200 mg/d as levels > 130 mg/ dL appear to be risk-enhancing, but measurements may be unreliable.⁴³ According to the 2018 Cholesterol Guidelines, lipoprotein(a) [Lp(a)] elevation also is recognized as a risk-enhancing factor that is particularly implicated when there is a strong family history of premature atherosclerotic CVD or personal history of CVD not explained by major risk factors.⁴³

Lp(a) elevation is a largely underrecognized category of lipid disorder that impacts up to 20% to 30% of the population globally and within the US, although there is considerable variability by geographic location and ethnicity.⁴⁴ Globally, Lp(a) elevation places > 1 billion people at moderate to high risk for CVD.44 Lp(a) has a strong genetic component and is recognized as a distinct and independent risk factor for MI, sudden death, strokes and CAVS. Lp(a) has an extensive body of evidence to support its distinct role both as a causal factor in CVD and as an augmentation to traditional risk factors.^44-48

Lipoproteni(a) Elevation Use For Diagnosis

The importance of Lp(a) elevation as a clinical diagnosis rather than a laboratory abnormality alone was brought forward by the Lipoprotein(a) Foundation. Its founder, Sandra Tremulis, is a survivor of an acute coronary event that occurred when she was 39-years old, despite running marathons and having none of the traditional CVD lifestyle risk factors.⁴⁹ This experience inspired her to create the Lipoprotein(a) Foundation to give a voice to families living with or at risk for CVD due to Lp(a) elevation.

As often happens in the progress of medicine, patients and their families drive change based on their personal experiences with the gaps in standard clinical practice. It was this foundation—not a member of the medical establishment—that submitted the formal request for the addition of new ICD-10-CM diagnostic and family history codes for Lp(a) elevation during the Centers for Disease Control and Prevention (CDC) September 2017 ICD-10-CM Coordination and Maintenance Committee meeting.⁵⁰ In June 2018, the final ICD-10-CM code addenda for 2019 was released and included the new codes E78.⁴¹ (Elevated Lp[a]) and Z83.430 (Family history of elevated Lp[a]).⁵² After the new codes were approved, both the American Heart Association and the National Lipid Association added recommendations regarding Lp(a) testing to their clinical practice guidelines.^43,52

Practically, these codes standardize billing and payment for legitimate clinical work and laboratory testing. Prior to the addition of Lp(a) elevation as a clinical diagnosis, testing and treatment of Lp(a) elevation was considered experimental and not medically necessary until after a cardiovascular event had already occurred. Services for Lp(a) elevation were therefore not reimbursed by many healthcare organizations and insurance companies. The new ICD-10-CM codes encourage the assessment of Lp(a) both in individuals with early onset major CVD events and in presumably fit, healthy individuals, particularly when there is a family history of Lp(a) elevation. Given that Lp(a) levels do not change significantly over time, the current understanding is that only a single measurement is needed to define the individual risk over a lifetime.^41,42,44,45 As therapies targeting Lp(a) levels evolve, repeated measurements may be indicated to monitor response and direct changes in management. “Elevated Lipoprotein(a)” is the first laboratory testing abnormality that has achieved the status of a clinical diagnosis.

Lp(a) Measurements

There is considerable complexity to the measurement of lipoproteins in blood samples due to heterogeneity in both density and size of particles as illustrated in the Figure.⁵³

For traditional lipids measured in clinical practice, the size and density ranges from small high-density lipoprotein (HDL) through LDLC and intermediate- density lipoprotein (IDL) to the largest least dense particles in the very low-density lipoprotein (VLDL) and chylomicron remnant fractions. Standard lipid profiles consist of mass concentration measurements (mg/dL) of TC, TG, HDLC, and LDLC.⁵³ Non-HDLC (calculated as: TC−HDLC) consists of all cholesterol found in atherogenic lipoproteins, including remnant-C and Lp(a). Until recently, the cholesterol content of Lp(a), corresponding to about 30% of Lp(a) total mass, was included in the TC, non-HDLC and LDLC measurements with no separate reporting by the majority of clinical laboratories.

After > 50 years of research on the structure and biochemistry of Lp(a), the physiology and biological functions of these complex and polymorphic lipoprotein particles are not fully understood. Lp(a) is composed of a lipoprotein particle similar in composition to LDL (protein and lipid), containing 1 molecule of ApoB wrapped around a core of cholesteryl ester and triglyceride with phospholipids and unesterified cholesterol at its surface.⁴⁸ The presence of a unique hydrophilic, highly glycosylated protein referred to as apolopoprotienA (apo[a]), covalently attached to ApoB-100 by a single disulfide bridge, differentiates Lp(a) from LDL.⁴⁸ Cholesterol rich ApoB is an important component within many lipoproteins pathogenic for atherosclerosis and CVD.^45,47,53

The apo(a) contributes to the increased density of Lp(a) compared to LDLC with associated reduced binding affinity to the LDL receptor. This reduced receptor binding affinity is a presumed mechanism for the lack of Lp(a) plasma level response to statin therapies, which increase hepatic LDL receptor activity.⁴⁷ Apo(a) evolved from the plasminogen gene through duplication and remodeling and demonstrates extensive heterogeneity in protein size, with > 40 different apo(a) isoforms resulting in > 40 different Lp(a) particle sizes. Size of the apo(a) particle is determined by the number of pleated structures known as kringles. Most people (> 80%) carry 2 different-sized apo(a) isoforms. Plasma Lp(a) level is determined by the net production of apo(a) in each isoform, and the smaller apo(a) isoforms are associated with higher plasma levels of Lp(a).⁴⁵

Given the heterogeneity in Lp(a) molecular weight, which can vary even within individuals, recommendations have been made for reporting results as particle numbers or concentrations (nmol/L or mmol/L) rather than as mass concentration (mg/dL).⁵⁵ However, the majority of the large CVD morbidity and mortality outcomes studies used Lp(a) mass concentration levels in mg/ dL to characterize risk levels.^56,57 There is no standardized method to convert Lp(a) measurements from mg/dL to nmol/L.⁵⁵ Current assays using WHO standardized reagents and controls are reliable for categorizing risk levels.⁵⁸

The European Atherosclerosis Society consensus panel recommended that desirable Lp(a) levels should be below the 80th percentile (< 50 mg/dL or < 125 nmol/L) in patients with intermediate or high CVD risk.⁵⁹ Subsequent epidemiological and Mendelian randomization studies have been performed in general populations with no history of CVD and demonstrated that increased CVD risk can be detected with Lp(a) levels as low as 25 to 30 mg/dL.^56,60-63 In secondary prevention populations with prior CVD and optimal treatment (statins, antiplatelet drugs), recurrent event risk was also increased with elevated Lp(a).^63-66

Using immunoturbidometric assays, Varvel and colleagues reported the prevalence of elevated Lp(a) mass concentration levels (mg/dL) in > 500,000 US patients undergoing clinical evaluations based on data from a referral laboratory of patients.⁵⁸ The mean Lp(a) levels were 34.0 mg/dL with median (interquartile range [IQR]) levels at 17 (7-47) mg/dL and overall range of 0 to 907 mg/dL.⁵⁸ Females had higher Lp(a) levels compared to males but no ethnic or racial breakdown was provided. Lp(a) levels > 30 mg/dL and > 50 mg/dL were present in 35% and 24% of subjects, respectively. Table 1 displays the relationship between various Lp(a) level cut-offs to mean levels of LDLC, estimated LDLC corrected for Lp(a), TC, HDLC, and TG.⁵⁸ The data demonstrate that Lp(a) elevation cannot be inferred from LDLC levels nor from any of the other traditional lipoprotein measures. Patients with high risk Lp(a) levels may have normal LDLC. While Lp(a) thresholds have been identified for stratification of CVD risk, the target levels for risk reduction have not been specifically defined, particularly since therapies are not widely available for reduction of Lp(a). Table 2 provides an overview of clinical lipoprotein measurements that may be reasonable targets for therapeutic interventions and reduction of CVD risk.^44,53,55 In general, existing studies suggest that radical reduction (> 80%) is required to impact long-term outcomes, particularly in individuals with severe disease.^68,69

LDLC reduction alone leaves a residual CVD risk that is greater than the risk reduced.40 In addition, the autoimmune inflammation and lipid specific autoantibodies play an important role in increased CVD morbidity and mortality risk.^70,71 The presence of autoantibodies such as antiphospholipid antibodies (without a specific autoimmune disease diagnosis) increases the risk of subclinical atherosclerosis.^72,73 Certain autoimmune diseases such as systemic lupus erythematosus are recognized as independent risk factors for CVD.^74,75 Autoantibodies appear to mediate CVD events and mortality risk, independent of traditional therapies for risk reduction.⁷³ Further research is needed to clarify the role of autoantibodies as markers of increased or decreased CVD risk and their mechanism of action.

Autoantibodies directed at new antigens in lipoproteins within atherosclerotic lesions can modulate the impact of atherosclerosis via activation of the innate and adaptive immune system.⁷⁶ The lipid-associated neopeptides are recognized as damage-associated or danger- associated molecular patterns (DAMPs), also known as alarmins, which signal molecules that can trigger and perpetuate noninfectious inflammatory responses.^77-79 Plasma autoantibodies (immunoglobulin M and G [IgM, IgG]) modify proinflammatory oxidation-specific epitopes on oxidized phospholipids (oxPL) within lipoproteins and are linked with markers of inflammation and CVD events.^80-82 Modified LDLC and ApoB-100 immune complexes with specific autoantibodies in the IgG class are associated with increased CVD.⁷⁶ These and other risk-modulating autoantibodies may explain some of the variability in CVD outcomes by ethnicity and between individuals.

Some antibodies to oxidized LDL (ox-LDL) may have a protective role in the development of atherosclerosis.^83,84 In a cohort of > 500 women, the number of carotid atherosclerotic plaques and total carotid plaque area were inversely correlated with a specific IgM autoantibody (MDA-p210).⁸⁴ High concentrations of Lp(a)- containing circulating immune complexes and Lp(a)-specific IgM and IgG have been described in patients with coronary heart disease (CHD).⁸⁵ Like ox-LDL, oxidized Lp(a) [ox-Lp(a)] is more potent than native Lp(a) in increasing atherosclerosis risk and is increased in patients with CHD compared to healthy controls.^86-88 Ox-Lp(a) levels may represent an even stronger risk marker for CVD than ox-LDL.⁸⁵

Possible Mechanisms of Pathogenesis

While the precise quantification of Lp(a) in human plasma (or serum) has been challenging, current clinical laboratories use standardized international reference reagents and controls in their assays. Most current Lp(a) assays are based on immunological methods (eg, immunonephelometry, immunoturbidimetry, or enzyme linked immunosorbent assay [ELISA]) using antibodies against apo(a).⁸⁹ Apo(a) contains 10 subtypes of kringle IV and 1 copy of kringle V. Some assays use antibodies against kringle-IV type 2; however, it has been recommended that newer methods should use antibodies against the specific bridging kringle-IV Type 9 domain, which has a more stable bond and is present as a single copy.^48,89 Other approaches to Lp(a) measurement include ultraperformance liquid chromatography/mass spectrometry that can determine both the concentration and particle size of apo(a).^48,90 For routine clinical care, currently available assays reporting in mg/dL can be considered fairly accurate for separating low-risk from moderate-to-high-risk patients.⁴⁵

The physiologic role of Lp(a) in humans remains to be fully defined and individuals with extremely low plasma Lp(a) levels present no disease or deficiency syndromes.⁹¹ Lp(a) accumulates in endothelial injuries and binds to components of the vessel wall and subendothelial matrix, presumably due to the strong lysine binding site in apo(a).⁴⁶ Mediated by apo(a), the binding stimulates chemotactic activation of monocytes/macrophages and thereby modulating angiogenesis and inflammation.⁸⁹ Lp(a) may contribute to CVD and CAVS via its LDL-like component, with proinflammatory effects of oxidized phospholipids (OxPL) on both ApoB and apo(a) and antifibrinolytic/prothrombotic effects of apo(a).⁹² In Vitro studies have demonstrated that apo(a) modifies cellular function of cultured vascular endothelial cells (promoting stress fiber formation, endothelial contraction and vascular permeability), smooth muscles, and monocytes/ macrophages (promoting differentiation of proinflammatory M1-1 type macrophages) via complex mechanisms of cell signaling and cytokine production.89 Lp(a) is the only monogenetic risk factor for aortic valve calcification and stenosis⁹³ and is strongly linked specifically with the single nucleotide polymorphism (SNP) rs10455872 in the gene LPA encoding for apo(a).⁹⁴

CVD Risk Predictive Value

There are a large number of studies demonstrating that Lp(a) elevations are an independent predictor of adverse cardiovascular outcomes including MI, sudden death, strokes, calcific aortic valve stenosis and peripheral vascular disease (Table 3). The Copenhagen City Heart Study and Copenhagen General Population Study are well known prospective population- based cohort studies that track outcomes through national patient registries.⁹⁵ These studies demonstrate increased risk for MI, CHD, CAVS, and heart failure when subjects with very high Lp(a) levels (50-115 mg/dL) are compared with subjects with very low Lp(a) levels (< 5 mg/dL).^96-100 Subjects with less extreme Lp(a) elevations (> 30 mg/dL) also show increased risk of CVD when they have comorbid LDLC elevations.¹⁰¹ However, the Copenhagen studies are composed exclusively of white subjects and the effects of Lp(a) are known to vary with race or ethnicity.

The Multi-Ethnic Study of Atherosclerosis (MESA) recruited an ethnically diverse sample of > 6,000 Americans, aged 45 to 84 years, without CVD, into an ongoing prospective cohort study. Research using subjects from this study has found consistently increased risk of CHD, heart failure, subclinical aortic valve calcification, and more severe CAVS in white subjects with elevated Lp(a).^60,102,103 Black subjects with elevated Lp(a) had increased risk of CHD and more severe CAVS and Hispanic subjects with Lp(a) elevation were at higher risk for CHD.^60,102 So far, no studies of MESA subjects have identified a relationship between Lp(a) elevation and CVD events for Asian-Americans subjects (predominantly of Chinese descent). There is a need for ongoing research to more precisely define relevant cut-off levels by race, ethnicity and sex.

The Atherosclerosis Risk in Communities (ARIC) Study was a prospective multiethnic cohort study including > 15,000 US adults, aged 45 to 64 years.¹⁰³ Lp(a) elevations in this cohort were associated with greater risks for first CVD events, heart failure, and recurrent CVD events.^61,64,105 The risk of stroke for subjects with elevated Lp(a) was greater for black and white women, and for black men.^61,106 However, a meta-analysis of case-control studies showed increased ischemic stroke risk in both men and women with elevated Lp(a).⁵⁷

A recent European meta-analysis collected blood samples and outcome data from > 50,000 subjects in 7 prospective cohort studies. Using a central laboratory to standardize Lp(a) measurements, researchers found increased risk of major coronary events and new CVD in subjects with Lp(a) > 50 mg/dL compared to those below that threshold.¹⁰⁷

Although many of these studies show modest increases in risk of CVD events with Lp(a) elevation, it should be noted that other studies do not demonstrate such consistent associations. This is particularly true in studies of women and nonwhite ethnic groups.^103,108-112 The variability of study results may be due to other confounding factors such as autoantibodies that either upregulate or downregulate atherogenicity of LDLC and potentially other lipoproteins. This is particularly relevant to women who have an increased risk for autoimmune disease.

Lp(a) has significant genetic heritability—75% in Europeans and 85% in African Americans.¹¹³ In whites, the LPA gene on chromosome 6p26- 27 with the polymorphism genetic variants rs10455872 and rs3798220 is consistently associated with elevated Lp(a) levels.^63,100,113 However, the degree of Lp(a) elevation associated with these specific genetic variants varies by ethnicity.^78,113,115

Lifestyle and Cardiovascular Health

It is noteworthy that the Lp(a) genetic risks can also be modified by lifestyle risk reduction even in the absence of significant blood level reductions. For example, Khera and colleagues constructed a genetic risk profile for CVD that included genes related to Lp(a).¹¹⁶ Subjects with high genetic risk were more likely to experience CVD events compared with subjects with low genetic risk. However, risks for CVD were attenuated by 4 healthy lifestyle factors: current nonsmoker, body mass index < 30, at least weekly physical activity, and a healthy diet. Subjects with high genetic risk and an unhealthy lifestyle (0 or 1 of the 4 healthy lifestyle factors) were the most likely to develop CVD (Hazard ratio [HR], 3.5), but that risk was lower for subjects with healthy (3 or 4 of the 4 healthy lifestyle factors) and intermediate lifestyles (2 of the 4 healthy lifestyle factors) (HR, 1.9 and 2.2, respectively), despite despite high genetic risk for CVD.

While the independent CVD risk associated with elevated Lp(a) does not appear to be responsive to lifestyle risk reduction alone, certainly elevated LDLC and traditional risk factors can increase the overall CVD risk and are worthy of preventive interventions. In particular, inflammation from any source exacerbates CVD risk. Proatherogenic diet, insufficient sleep, lack of exercise, and maladaptive stress responses are other targets for personalized CVD risk reduction. ^28,117 Studies of dietary modifications and other lifestyle factors have shown reduced risk of CVD events, despite lack of reduction in Lp(a) levels.^119,120 It is noteworthy that statin therapy (with or without ezetimibe) fails to impact CAVS progression, likely because statins either raise or have no effect on Lp(a) levels.^92,119

Until recently, there has been no evidence supporting any therapeutic intervention causing clinically meaningful reductions in Lp(a). Table 4 lists major drug classes and their effects on Lp(a) and CVD outcomes; however, a detailed discussion of each of these therapies is beyond the scope of this review. Drugs that reduce Lp(a) by 20-30% have varying effects on CVD outcomes, from no effect^122,123 to a 10% to 20% decrease in CVD events when compared with a placebo.^124,125 Because these drugs also produce substantial reductions in LDLC, it is not possible to determine how much of the beneficial effects are due to reductions in Lp(a).

Lipoprotein apheresis produces profound reductions in Lp(a) of 60 to 80% in very highrisk populations.^69,126 Within-subjects comparisons show up to 80% reductions in CVD events, relative to event rates prior to treatment initiation.^69,127 Early trials of antisense oligonucleotide against apo(a) therapies show potential to produce similar outcomes.^128,129 These treatments may be particularly effective in patients with isolated Lp(a) elevations.

Summary

Lp(a) elevation is a major contributor to cardiovascular disease risk and has been recognized as an ICD-10-CM coded clinical diagnosis, the first laboratory abnormality to be defined a clinical disease in the asymptomatic healthy young individuals. This change addresses currently under- diagnosed CVD risk independent of LDLC reduction strategies. A brief overview of recent guidelines for the clinical use of Lp(a) testing from the American Heart Association^43,151 and the National Lipid Association52 can be found in Table 5. Although drug therapies for lowering Lp(a) levels remain limited, new treatment options are actively being developed.

Many Americans with high Lp(a) have not yet been identified. Expanded one-time screening can inform these patients of their cardiovascular risk and increase their access to early, aggressive lifestyle modification and optimal lipid-lowering therapy. Given the further increased CVD risk factors for military service members and veterans, a case can be made for broader screening and enhanced surveillance of elevated Lp(a) in these presumably healthy and fit individuals as well as management focused on modifiable risk factors.

Acknowledgements

This program initiative was conducted by the Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc. as part of the Integrative Cardiac Health Project at Walter Reed National Military Medical Center (WRNMMC), and is made possible by a cooperative agreement that was awarded and administered by the US Army Medical Research & Materiel Command (USAMRMC), at Fort Detrick under Contract Number: W81XWH-16-2-0007. It reflects literature review preparatory work for a research protocol but does not involve an actual research project. The work in this manuscript was supported by the staff of the Integrative Cardiac Health Project (ICHP) with special thanks to Claire Fuller, Elaine Walizer, Dr. Mariam Kashani and the entire health coaching team.

Hepatitis C virus testing should be combined with HIV integrated care services among people who inject drugs (PWID), according to researchers reporting on a multisite randomized trial of nearly 12,000 HIV-infected individuals in India.

Courtesy NIH

HCV antibody prevalence at these sites ranged from 7.2%-76.6%. Across six integrated care centers (ICCs), 5,263 clients underwent HCV testing, of whom 2,278 were newly diagnosed. At evaluation, PWID in ICC clusters were nearly four times more likely to report being tested for HCV than those in usual care clusters (adjusted prevalence ratio [aPR]: 3.69), according to the report by Sunil Suhas Solomon, MD, of Johns Hopkins University School of Medicine, Baltimore, and colleagues.

PWID in ICC clusters were also seven times more likely to be aware of their HCV status (aPR: 7.11; 95% confidence interval: 1.14, 44.3) and significantly more likely to initiate treatment, (aPR: 9.86; 95% CI: 1.52, 63.8), than individuals in usual care, the authors stated in their report published online ahead of press in the Journal of Hepatology.

“These data provide among the first empirical support of the benefits of integrating HCV testing with HIV prevention and treatment services for PWID. Over a short duration, we observed significant impact on community-level HCV testing and awareness of HCV status among PWID. While additional strategies might be required to improve population awareness levels, integration of HCV testing with HIV programs for PWID particularly given the high burden of HIV/HCV coinfection represents a critical first step,” the researchers concluded.

The study was funded by the National Institutes of Health and the Elton John AIDS Foundation. The authors reported that they had no relevant disclosures.

[email protected]

SOURCE: Solomon, SS et al. J Hepatol. 2019. doi.org/10.1016/j.jhep.2019.09.022.

Hepatitis C virus testing should be combined with HIV integrated care services among people who inject drugs (PWID), according to researchers reporting on a multisite randomized trial of nearly 12,000 HIV-infected individuals in India.

Courtesy NIH

HCV antibody prevalence at these sites ranged from 7.2%-76.6%. Across six integrated care centers (ICCs), 5,263 clients underwent HCV testing, of whom 2,278 were newly diagnosed. At evaluation, PWID in ICC clusters were nearly four times more likely to report being tested for HCV than those in usual care clusters (adjusted prevalence ratio [aPR]: 3.69), according to the report by Sunil Suhas Solomon, MD, of Johns Hopkins University School of Medicine, Baltimore, and colleagues.

PWID in ICC clusters were also seven times more likely to be aware of their HCV status (aPR: 7.11; 95% confidence interval: 1.14, 44.3) and significantly more likely to initiate treatment, (aPR: 9.86; 95% CI: 1.52, 63.8), than individuals in usual care, the authors stated in their report published online ahead of press in the Journal of Hepatology.

“These data provide among the first empirical support of the benefits of integrating HCV testing with HIV prevention and treatment services for PWID. Over a short duration, we observed significant impact on community-level HCV testing and awareness of HCV status among PWID. While additional strategies might be required to improve population awareness levels, integration of HCV testing with HIV programs for PWID particularly given the high burden of HIV/HCV coinfection represents a critical first step,” the researchers concluded.

The study was funded by the National Institutes of Health and the Elton John AIDS Foundation. The authors reported that they had no relevant disclosures.

[email protected]

SOURCE: Solomon, SS et al. J Hepatol. 2019. doi.org/10.1016/j.jhep.2019.09.022.

Hepatitis C virus testing should be combined with HIV integrated care services among people who inject drugs (PWID), according to researchers reporting on a multisite randomized trial of nearly 12,000 HIV-infected individuals in India.

Courtesy NIH

HCV antibody prevalence at these sites ranged from 7.2%-76.6%. Across six integrated care centers (ICCs), 5,263 clients underwent HCV testing, of whom 2,278 were newly diagnosed. At evaluation, PWID in ICC clusters were nearly four times more likely to report being tested for HCV than those in usual care clusters (adjusted prevalence ratio [aPR]: 3.69), according to the report by Sunil Suhas Solomon, MD, of Johns Hopkins University School of Medicine, Baltimore, and colleagues.

PWID in ICC clusters were also seven times more likely to be aware of their HCV status (aPR: 7.11; 95% confidence interval: 1.14, 44.3) and significantly more likely to initiate treatment, (aPR: 9.86; 95% CI: 1.52, 63.8), than individuals in usual care, the authors stated in their report published online ahead of press in the Journal of Hepatology.

“These data provide among the first empirical support of the benefits of integrating HCV testing with HIV prevention and treatment services for PWID. Over a short duration, we observed significant impact on community-level HCV testing and awareness of HCV status among PWID. While additional strategies might be required to improve population awareness levels, integration of HCV testing with HIV programs for PWID particularly given the high burden of HIV/HCV coinfection represents a critical first step,” the researchers concluded.

The study was funded by the National Institutes of Health and the Elton John AIDS Foundation. The authors reported that they had no relevant disclosures.

[email protected]

SOURCE: Solomon, SS et al. J Hepatol. 2019. doi.org/10.1016/j.jhep.2019.09.022.

NATIONAL HARBOR, MD. – Drug shortages are health care crises that burden health care providers, payers, and patients, but without sufficient studies quantifying their impact, the magnitude of their detriment flies largely under the radar.

“Statistically speaking, there is no proof that patients are worse off from drug shortages,” Matt Grissinger, RPh, director of error-reporting programs at the Institute for Safe Medication Practices, told the audience at the annual conference of the Academy of Managed Care Pharmacy. The data and anecdotes he presented suggest the contrary.

As Mr. Grissinger pointed out, drug shortages can create a sequela of events that stress health care workers seeking to find the next-best available and most appropriate therapy for their patients. In the process, numerous medication-related errors can occur, resulting in patient harm, including adverse drug events and even death.

One potential problems is erroneous or inappropriate drug substitution stemming from mis- or uncalculated doses because of factors such as incorrect labeling and lack of knowledge regarding acceptable therapeutic interchanges. Other potential errors include non–therapeutically equivalent drug substitutions, resulting in supraoptimal therapy or overdoses, and unfamiliarity with drug labeling from outsourced facilities.

As a result, patients may experience worse outcomes as a consequence of the drug shortage: Worsening of the disease, disease prolongation, side effects stemming from alternative drug selections, untreated pain, psychological effects, severe electrolyte imbalances, severe acid/base imbalances, and death.

While a paper trail can help piece together clues regarding how a medication error occurred, documentation or lack thereof can also introduce errors when drug shortages occur.

Any changes to a drug order or prescription that deviate from the prescriber’s original request require prescriber approval but can still create opportunities for error. While documenting these changes and updating labeling is essential, appropriate documentation does not always occur and raises the question of who is responsible for making such changes.

Drug shortages also challenge a clinician’s professional judgment. Mr. Grissinger cited an example in which a nurse used half of a 0.5-mg single-use vial of promethazine for a patient requiring a 0.25 mg dose. The nurse wrote on the label that the remainder should be saved. While the vial was manufactured for one-time use, whether to discard the unused contents in a situation of drug shortages required the nurse to make a judgment call. In this case, the nurse chose to save the balance of the drug – a choice Mr. Grissinger stated he might have made had he been in a similar situation.

Additionally, drug shortages can create a climate in which more ethical questions arise – especially with regard to disease states such as cancer.

“If you only have 10 vials of vincristine, who gets it?” Mr. Grissinger asked the audience.

To help answer these difficult life-or-death questions, hospital settings need to engage the ethics committees and social workers.

While education plays a vital role in bringing attention to and addressing errors stemming from drug shortages, Mr. Grissinger cautioned the audience not to rely on education as the solution.

“Education is a poor strategy for addressing drug shortages,” he said. While education can draw awareness to drug shortages and subsequent medication-related errors, Mr. Grissinger recommends that organizations implement strategies to help ameliorate the havoc created by drug shortages.

Drug shortage assessment checklists can help organizations evaluate the impact of shortages by verifying inventory, and proactively searching for alternatives. From there, they can enact strategies such as assigning priority to patients who have the greatest need, altering packaging and concentrations, and finding suitable therapeutic substitutions.

NATIONAL HARBOR, MD. – Drug shortages are health care crises that burden health care providers, payers, and patients, but without sufficient studies quantifying their impact, the magnitude of their detriment flies largely under the radar.

“Statistically speaking, there is no proof that patients are worse off from drug shortages,” Matt Grissinger, RPh, director of error-reporting programs at the Institute for Safe Medication Practices, told the audience at the annual conference of the Academy of Managed Care Pharmacy. The data and anecdotes he presented suggest the contrary.

As Mr. Grissinger pointed out, drug shortages can create a sequela of events that stress health care workers seeking to find the next-best available and most appropriate therapy for their patients. In the process, numerous medication-related errors can occur, resulting in patient harm, including adverse drug events and even death.

One potential problems is erroneous or inappropriate drug substitution stemming from mis- or uncalculated doses because of factors such as incorrect labeling and lack of knowledge regarding acceptable therapeutic interchanges. Other potential errors include non–therapeutically equivalent drug substitutions, resulting in supraoptimal therapy or overdoses, and unfamiliarity with drug labeling from outsourced facilities.

As a result, patients may experience worse outcomes as a consequence of the drug shortage: Worsening of the disease, disease prolongation, side effects stemming from alternative drug selections, untreated pain, psychological effects, severe electrolyte imbalances, severe acid/base imbalances, and death.

While a paper trail can help piece together clues regarding how a medication error occurred, documentation or lack thereof can also introduce errors when drug shortages occur.

Any changes to a drug order or prescription that deviate from the prescriber’s original request require prescriber approval but can still create opportunities for error. While documenting these changes and updating labeling is essential, appropriate documentation does not always occur and raises the question of who is responsible for making such changes.

Drug shortages also challenge a clinician’s professional judgment. Mr. Grissinger cited an example in which a nurse used half of a 0.5-mg single-use vial of promethazine for a patient requiring a 0.25 mg dose. The nurse wrote on the label that the remainder should be saved. While the vial was manufactured for one-time use, whether to discard the unused contents in a situation of drug shortages required the nurse to make a judgment call. In this case, the nurse chose to save the balance of the drug – a choice Mr. Grissinger stated he might have made had he been in a similar situation.

Additionally, drug shortages can create a climate in which more ethical questions arise – especially with regard to disease states such as cancer.

“If you only have 10 vials of vincristine, who gets it?” Mr. Grissinger asked the audience.

To help answer these difficult life-or-death questions, hospital settings need to engage the ethics committees and social workers.

While education plays a vital role in bringing attention to and addressing errors stemming from drug shortages, Mr. Grissinger cautioned the audience not to rely on education as the solution.

“Education is a poor strategy for addressing drug shortages,” he said. While education can draw awareness to drug shortages and subsequent medication-related errors, Mr. Grissinger recommends that organizations implement strategies to help ameliorate the havoc created by drug shortages.

Drug shortage assessment checklists can help organizations evaluate the impact of shortages by verifying inventory, and proactively searching for alternatives. From there, they can enact strategies such as assigning priority to patients who have the greatest need, altering packaging and concentrations, and finding suitable therapeutic substitutions.

NATIONAL HARBOR, MD. – Drug shortages are health care crises that burden health care providers, payers, and patients, but without sufficient studies quantifying their impact, the magnitude of their detriment flies largely under the radar.

“Statistically speaking, there is no proof that patients are worse off from drug shortages,” Matt Grissinger, RPh, director of error-reporting programs at the Institute for Safe Medication Practices, told the audience at the annual conference of the Academy of Managed Care Pharmacy. The data and anecdotes he presented suggest the contrary.

As Mr. Grissinger pointed out, drug shortages can create a sequela of events that stress health care workers seeking to find the next-best available and most appropriate therapy for their patients. In the process, numerous medication-related errors can occur, resulting in patient harm, including adverse drug events and even death.

One potential problems is erroneous or inappropriate drug substitution stemming from mis- or uncalculated doses because of factors such as incorrect labeling and lack of knowledge regarding acceptable therapeutic interchanges. Other potential errors include non–therapeutically equivalent drug substitutions, resulting in supraoptimal therapy or overdoses, and unfamiliarity with drug labeling from outsourced facilities.

As a result, patients may experience worse outcomes as a consequence of the drug shortage: Worsening of the disease, disease prolongation, side effects stemming from alternative drug selections, untreated pain, psychological effects, severe electrolyte imbalances, severe acid/base imbalances, and death.

While a paper trail can help piece together clues regarding how a medication error occurred, documentation or lack thereof can also introduce errors when drug shortages occur.

Any changes to a drug order or prescription that deviate from the prescriber’s original request require prescriber approval but can still create opportunities for error. While documenting these changes and updating labeling is essential, appropriate documentation does not always occur and raises the question of who is responsible for making such changes.

Drug shortages also challenge a clinician’s professional judgment. Mr. Grissinger cited an example in which a nurse used half of a 0.5-mg single-use vial of promethazine for a patient requiring a 0.25 mg dose. The nurse wrote on the label that the remainder should be saved. While the vial was manufactured for one-time use, whether to discard the unused contents in a situation of drug shortages required the nurse to make a judgment call. In this case, the nurse chose to save the balance of the drug – a choice Mr. Grissinger stated he might have made had he been in a similar situation.

Additionally, drug shortages can create a climate in which more ethical questions arise – especially with regard to disease states such as cancer.

“If you only have 10 vials of vincristine, who gets it?” Mr. Grissinger asked the audience.

To help answer these difficult life-or-death questions, hospital settings need to engage the ethics committees and social workers.

While education plays a vital role in bringing attention to and addressing errors stemming from drug shortages, Mr. Grissinger cautioned the audience not to rely on education as the solution.

“Education is a poor strategy for addressing drug shortages,” he said. While education can draw awareness to drug shortages and subsequent medication-related errors, Mr. Grissinger recommends that organizations implement strategies to help ameliorate the havoc created by drug shortages.

Drug shortage assessment checklists can help organizations evaluate the impact of shortages by verifying inventory, and proactively searching for alternatives. From there, they can enact strategies such as assigning priority to patients who have the greatest need, altering packaging and concentrations, and finding suitable therapeutic substitutions.

Attendees at a public meeting on Nov. 4 gave the US Food and Drug Administration conflicting views on whether the agency should continue to allow a relatively loose regulatory environment for fecal microbiota transplants (FMT) – debating the limits of “enforcement discretion” the FDA now has in place.

The question is especially relevant as use of the procedure is growing, while safety data are not being rigorously collected in all cases. The death of an immunocompromised FMT patient earlier in 2018 from an invasive bacterial infection caused by drug-resistant Escherichia coli, as reported by Medscape Medical News, is seen by some as an example of the consequences of a loose policy.

Still, the American Gastroenterological Association (AGA) presented new, unpublished follow-up data at the meeting that showed that the majority of FMT patients in a national registry had no adverse events.

Some companies developing FMT-based products argued at the meeting that the agency should impose stricter requirements, while stool banks and clinicians offering the therapy outside of clinical trials said that the current policy – in place since 2013 – in which the FDA has exercised “enforcement discretion,” should be allowed to continue.

“Enforcement discretion has been successful in enabling and overcoming key barriers to access to treatment,” said Majdi Osman, MD, clinical program director at OpenBiome, a nonprofit stool bank based in Cambridge, Mass. Dr. Osman said that 98% of the U.S. population now lives within a 2-hour drive of an FMT provider.

Amanda Kabage, a researcher and donor program coordinator for the Microbiota Therapeutics program at the University of Minnesota in Minneapolis, and herself a former recipient of FMT, said she was in favor of continuing the FDA policy.

“If enforcement discretion were to go away, patients far sicker than I was will not have access. They’ll get sicker and they will die,” Ms. Kabage said.

But, she added, the FDA had missed an opportunity by not insisting on collecting outcomes and safety data. Minnesota has established a patient registry to do just that, and physicians cannot administer FMT unless they agree to participate, she said. In response, FDA panelists noted that the agency cannot mandate data collection under an enforcement policy.

Lee Jones, founder and chief executive officer of Rebiotix/Ferring, a biotech company focused on the development of microbiome-based therapeutics, argued for tighter restrictions, however, claiming that increased access – and the FDA policy – had led to a fourfold decrease in enrollment since the company began study of its lead FMT product, RBX2660, in 2013.

“We’re dealing with an orphan indication and the patients were hard to come by to begin with,” she said at the meeting. “Enforcement discretion has slowed our clinical development and delayed patient access to FDA-approved therapies by over 2 years.”

An investigator at the University of Texas Health Science Center at Houston, Herbert DuPont, MD, who has administered FMT and is conducting a trial for Rebiotix, said his center wanted the FDA policy to continue “allowing multiple groups to perform FMT for recurrent [Clostridium difficile], because of the incredible public health need.”

But, he added, “We’re very concerned about industry and ability to do clinical trials.”

Those trials are important, Dr. DuPont said. “I think we have to address very actively how industry can move these products through,” he said, “because all of us want to remove the F from FMT,” by isolating the necessary elements of the process while not having the risk sometimes associated with human stool.
 

Policy slow to evolve

“I’m frustrated that it’s taken over 6 years and three draft guidances to get us this far,” Christian John Lillis, executive director of the Peggy Lillis Foundation – a group dedicated to creating awareness about the dangers of C. difficile – said at the meeting.

Mr. Lillis said that probably several thousand deaths had been prevented through increased FMT access, but that it was time to create a concrete policy that advanced the therapy.

The FDA guidance issued in 2013 allowed physicians to provide FMT for recurrent or refractory C. difficile infection without filing an investigational new drug (IND) application.

Clinicians must obtain informed consent that includes a discussion of the risks, and a statement that FMT is investigational. In March 2016, the agency issued revised draft guidance that it was aiming to require stool banks to apply for INDs, as reported by Medscape Medical News.

OpenBiome has flourished under the current policy. It has provided more than 50,000 treatments to 1,200 hospitals and clinics, and has provided FMT for 49 clinical trials and for 16 single patients who received INDs, Dr. Osman said.

But requiring INDs for all centers is a bad idea, he said. “IND requirements are insurmountable for most health centers,” Dr. Osman said, noting that most of the FMT material OpenBiome produces is sent to community-based physicians.

“These requirements would likely mean restrictions in access for stool bank–provided FMT and potentially pushing patients to physician-directed FMT or discouraging physicians from using FMT at all,” he said.

Stacy Kahn, MD, FMT director at Boston Children’s Hospital in Massachusetts, said that having ready access from a stool bank was crucial.

“Universal donor FMT is much easier, much faster and much more cost effective than what we can do as clinicians,” she said.
 

New safety and efficacy data

One unpublished study showed that 75% of patients treated since 2011 had a sustained cure, noted Colleen Kelly, MD, a Brown University professor of medicine and principal investigator for the National Institutes of Health–funded national FMT registry (although the data in this study were not from the FMT registry).

The study, which was a collaboration between the Alpert Medical School of Brown University, Brigham and Women’s Hospital, and Indiana University School of Medicine, attempted follow-up on 533 patients; 208 were successfully contacted, and an additional 55 had died, none due to FMT.

Dr. Kelly also presented data from the FMT National Registry showing that at 1 month posttransplant, two (1%) of 253 patients had an infection possibly related to FMT; one with Bacteroides fragilis and one with enteropathogenic E. coli. Seven hospitalizations were deemed related or possibly related to FMT, including two recurrences of C. difficile.

At 6 months posttransplant, 8 (5%) of 152 patients had a serious infection, and 23 patients reported a diagnosis of a new condition, primarily diarrhea-predominant irritable bowel syndrome, which is common post FMT, said Dr. Kelly, who presented the data on behalf of AGA, which administers the registry.

The AGA supports a continuation of the enforcement discretion as a means to maintain patient access where the evidence supports the use of FMT, but the group does not back use of FMT outside medical supervision, Dr. Kelly said.
 

This article originally appeared on Medscape. For more news, follow Medscape on Facebook, Twitter, Instagram, and YouTube.

Attendees at a public meeting on Nov. 4 gave the US Food and Drug Administration conflicting views on whether the agency should continue to allow a relatively loose regulatory environment for fecal microbiota transplants (FMT) – debating the limits of “enforcement discretion” the FDA now has in place.

The question is especially relevant as use of the procedure is growing, while safety data are not being rigorously collected in all cases. The death of an immunocompromised FMT patient earlier in 2018 from an invasive bacterial infection caused by drug-resistant Escherichia coli, as reported by Medscape Medical News, is seen by some as an example of the consequences of a loose policy.

Still, the American Gastroenterological Association (AGA) presented new, unpublished follow-up data at the meeting that showed that the majority of FMT patients in a national registry had no adverse events.

Some companies developing FMT-based products argued at the meeting that the agency should impose stricter requirements, while stool banks and clinicians offering the therapy outside of clinical trials said that the current policy – in place since 2013 – in which the FDA has exercised “enforcement discretion,” should be allowed to continue.

“Enforcement discretion has been successful in enabling and overcoming key barriers to access to treatment,” said Majdi Osman, MD, clinical program director at OpenBiome, a nonprofit stool bank based in Cambridge, Mass. Dr. Osman said that 98% of the U.S. population now lives within a 2-hour drive of an FMT provider.

Amanda Kabage, a researcher and donor program coordinator for the Microbiota Therapeutics program at the University of Minnesota in Minneapolis, and herself a former recipient of FMT, said she was in favor of continuing the FDA policy.

“If enforcement discretion were to go away, patients far sicker than I was will not have access. They’ll get sicker and they will die,” Ms. Kabage said.

But, she added, the FDA had missed an opportunity by not insisting on collecting outcomes and safety data. Minnesota has established a patient registry to do just that, and physicians cannot administer FMT unless they agree to participate, she said. In response, FDA panelists noted that the agency cannot mandate data collection under an enforcement policy.

Lee Jones, founder and chief executive officer of Rebiotix/Ferring, a biotech company focused on the development of microbiome-based therapeutics, argued for tighter restrictions, however, claiming that increased access – and the FDA policy – had led to a fourfold decrease in enrollment since the company began study of its lead FMT product, RBX2660, in 2013.

“We’re dealing with an orphan indication and the patients were hard to come by to begin with,” she said at the meeting. “Enforcement discretion has slowed our clinical development and delayed patient access to FDA-approved therapies by over 2 years.”

An investigator at the University of Texas Health Science Center at Houston, Herbert DuPont, MD, who has administered FMT and is conducting a trial for Rebiotix, said his center wanted the FDA policy to continue “allowing multiple groups to perform FMT for recurrent [Clostridium difficile], because of the incredible public health need.”

But, he added, “We’re very concerned about industry and ability to do clinical trials.”

Those trials are important, Dr. DuPont said. “I think we have to address very actively how industry can move these products through,” he said, “because all of us want to remove the F from FMT,” by isolating the necessary elements of the process while not having the risk sometimes associated with human stool.
 

Policy slow to evolve

“I’m frustrated that it’s taken over 6 years and three draft guidances to get us this far,” Christian John Lillis, executive director of the Peggy Lillis Foundation – a group dedicated to creating awareness about the dangers of C. difficile – said at the meeting.

Mr. Lillis said that probably several thousand deaths had been prevented through increased FMT access, but that it was time to create a concrete policy that advanced the therapy.

The FDA guidance issued in 2013 allowed physicians to provide FMT for recurrent or refractory C. difficile infection without filing an investigational new drug (IND) application.

Clinicians must obtain informed consent that includes a discussion of the risks, and a statement that FMT is investigational. In March 2016, the agency issued revised draft guidance that it was aiming to require stool banks to apply for INDs, as reported by Medscape Medical News.

OpenBiome has flourished under the current policy. It has provided more than 50,000 treatments to 1,200 hospitals and clinics, and has provided FMT for 49 clinical trials and for 16 single patients who received INDs, Dr. Osman said.

But requiring INDs for all centers is a bad idea, he said. “IND requirements are insurmountable for most health centers,” Dr. Osman said, noting that most of the FMT material OpenBiome produces is sent to community-based physicians.

“These requirements would likely mean restrictions in access for stool bank–provided FMT and potentially pushing patients to physician-directed FMT or discouraging physicians from using FMT at all,” he said.

Stacy Kahn, MD, FMT director at Boston Children’s Hospital in Massachusetts, said that having ready access from a stool bank was crucial.

“Universal donor FMT is much easier, much faster and much more cost effective than what we can do as clinicians,” she said.
 

New safety and efficacy data

One unpublished study showed that 75% of patients treated since 2011 had a sustained cure, noted Colleen Kelly, MD, a Brown University professor of medicine and principal investigator for the National Institutes of Health–funded national FMT registry (although the data in this study were not from the FMT registry).

The study, which was a collaboration between the Alpert Medical School of Brown University, Brigham and Women’s Hospital, and Indiana University School of Medicine, attempted follow-up on 533 patients; 208 were successfully contacted, and an additional 55 had died, none due to FMT.

Dr. Kelly also presented data from the FMT National Registry showing that at 1 month posttransplant, two (1%) of 253 patients had an infection possibly related to FMT; one with Bacteroides fragilis and one with enteropathogenic E. coli. Seven hospitalizations were deemed related or possibly related to FMT, including two recurrences of C. difficile.

At 6 months posttransplant, 8 (5%) of 152 patients had a serious infection, and 23 patients reported a diagnosis of a new condition, primarily diarrhea-predominant irritable bowel syndrome, which is common post FMT, said Dr. Kelly, who presented the data on behalf of AGA, which administers the registry.

The AGA supports a continuation of the enforcement discretion as a means to maintain patient access where the evidence supports the use of FMT, but the group does not back use of FMT outside medical supervision, Dr. Kelly said.
 

This article originally appeared on Medscape. For more news, follow Medscape on Facebook, Twitter, Instagram, and YouTube.

Attendees at a public meeting on Nov. 4 gave the US Food and Drug Administration conflicting views on whether the agency should continue to allow a relatively loose regulatory environment for fecal microbiota transplants (FMT) – debating the limits of “enforcement discretion” the FDA now has in place.

The question is especially relevant as use of the procedure is growing, while safety data are not being rigorously collected in all cases. The death of an immunocompromised FMT patient earlier in 2018 from an invasive bacterial infection caused by drug-resistant Escherichia coli, as reported by Medscape Medical News, is seen by some as an example of the consequences of a loose policy.

Still, the American Gastroenterological Association (AGA) presented new, unpublished follow-up data at the meeting that showed that the majority of FMT patients in a national registry had no adverse events.

Some companies developing FMT-based products argued at the meeting that the agency should impose stricter requirements, while stool banks and clinicians offering the therapy outside of clinical trials said that the current policy – in place since 2013 – in which the FDA has exercised “enforcement discretion,” should be allowed to continue.

“Enforcement discretion has been successful in enabling and overcoming key barriers to access to treatment,” said Majdi Osman, MD, clinical program director at OpenBiome, a nonprofit stool bank based in Cambridge, Mass. Dr. Osman said that 98% of the U.S. population now lives within a 2-hour drive of an FMT provider.

Amanda Kabage, a researcher and donor program coordinator for the Microbiota Therapeutics program at the University of Minnesota in Minneapolis, and herself a former recipient of FMT, said she was in favor of continuing the FDA policy.

“If enforcement discretion were to go away, patients far sicker than I was will not have access. They’ll get sicker and they will die,” Ms. Kabage said.

But, she added, the FDA had missed an opportunity by not insisting on collecting outcomes and safety data. Minnesota has established a patient registry to do just that, and physicians cannot administer FMT unless they agree to participate, she said. In response, FDA panelists noted that the agency cannot mandate data collection under an enforcement policy.

Lee Jones, founder and chief executive officer of Rebiotix/Ferring, a biotech company focused on the development of microbiome-based therapeutics, argued for tighter restrictions, however, claiming that increased access – and the FDA policy – had led to a fourfold decrease in enrollment since the company began study of its lead FMT product, RBX2660, in 2013.

“We’re dealing with an orphan indication and the patients were hard to come by to begin with,” she said at the meeting. “Enforcement discretion has slowed our clinical development and delayed patient access to FDA-approved therapies by over 2 years.”

An investigator at the University of Texas Health Science Center at Houston, Herbert DuPont, MD, who has administered FMT and is conducting a trial for Rebiotix, said his center wanted the FDA policy to continue “allowing multiple groups to perform FMT for recurrent [Clostridium difficile], because of the incredible public health need.”

But, he added, “We’re very concerned about industry and ability to do clinical trials.”

Those trials are important, Dr. DuPont said. “I think we have to address very actively how industry can move these products through,” he said, “because all of us want to remove the F from FMT,” by isolating the necessary elements of the process while not having the risk sometimes associated with human stool.
 

Policy slow to evolve

“I’m frustrated that it’s taken over 6 years and three draft guidances to get us this far,” Christian John Lillis, executive director of the Peggy Lillis Foundation – a group dedicated to creating awareness about the dangers of C. difficile – said at the meeting.

Mr. Lillis said that probably several thousand deaths had been prevented through increased FMT access, but that it was time to create a concrete policy that advanced the therapy.

The FDA guidance issued in 2013 allowed physicians to provide FMT for recurrent or refractory C. difficile infection without filing an investigational new drug (IND) application.

Clinicians must obtain informed consent that includes a discussion of the risks, and a statement that FMT is investigational. In March 2016, the agency issued revised draft guidance that it was aiming to require stool banks to apply for INDs, as reported by Medscape Medical News.

OpenBiome has flourished under the current policy. It has provided more than 50,000 treatments to 1,200 hospitals and clinics, and has provided FMT for 49 clinical trials and for 16 single patients who received INDs, Dr. Osman said.

But requiring INDs for all centers is a bad idea, he said. “IND requirements are insurmountable for most health centers,” Dr. Osman said, noting that most of the FMT material OpenBiome produces is sent to community-based physicians.

“These requirements would likely mean restrictions in access for stool bank–provided FMT and potentially pushing patients to physician-directed FMT or discouraging physicians from using FMT at all,” he said.

Stacy Kahn, MD, FMT director at Boston Children’s Hospital in Massachusetts, said that having ready access from a stool bank was crucial.

“Universal donor FMT is much easier, much faster and much more cost effective than what we can do as clinicians,” she said.
 

New safety and efficacy data

One unpublished study showed that 75% of patients treated since 2011 had a sustained cure, noted Colleen Kelly, MD, a Brown University professor of medicine and principal investigator for the National Institutes of Health–funded national FMT registry (although the data in this study were not from the FMT registry).

The study, which was a collaboration between the Alpert Medical School of Brown University, Brigham and Women’s Hospital, and Indiana University School of Medicine, attempted follow-up on 533 patients; 208 were successfully contacted, and an additional 55 had died, none due to FMT.

Dr. Kelly also presented data from the FMT National Registry showing that at 1 month posttransplant, two (1%) of 253 patients had an infection possibly related to FMT; one with Bacteroides fragilis and one with enteropathogenic E. coli. Seven hospitalizations were deemed related or possibly related to FMT, including two recurrences of C. difficile.

At 6 months posttransplant, 8 (5%) of 152 patients had a serious infection, and 23 patients reported a diagnosis of a new condition, primarily diarrhea-predominant irritable bowel syndrome, which is common post FMT, said Dr. Kelly, who presented the data on behalf of AGA, which administers the registry.

The AGA supports a continuation of the enforcement discretion as a means to maintain patient access where the evidence supports the use of FMT, but the group does not back use of FMT outside medical supervision, Dr. Kelly said.
 

This article originally appeared on Medscape. For more news, follow Medscape on Facebook, Twitter, Instagram, and YouTube.

Providing access to clinical trials for patients with diabetes mellitus can be a challenge, but a significant number of trials are now recruiting patients. The clinical trials listed below are all open as of October 31, 2019; and are focused on diabetes mellitus-related treatments for American Indians. For additional information and full inclusion/exclusion criteria, please consult clinicaltrials.gov.

Cross-Sectional and Longitudinal Studies of “Pre-Diabetes” in the Pima Indians

The Pima Indians of Arizona have the highest prevalence and incidence of type 2 diabetes of any population in the world. Prospective analyses in this population have identified insulin resistance and a defect in early insulin secretion as risk factors for the development of the disease. To identify the genetic and environmental determinants of diabetes we plan to study Pima Indian families to determine: (1) if there are genes that segregate with metabolic risk factors for diabetes which might therefore be genetic markers for type 2 diabetes; and (2) the mechanisms mediating genetic and environmental determinants of insulin resistance and impaired insulin secretion.

ID: NCT00340132
Sponsor: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Contact: Clifton Bogardus, MD, [email protected]
Location: NIDDK, Phoenix, AZ

Empaglifozin in Early Diabetic Kidney Disease

Diabetes is common among American Indian people and diabetic kidney disease is a common complication. Kidney disease caused by diabetes can lead to the need for kidney replacement, by dialysis or kidney transplant, and is also associated with higher risk of early death. A new diabetes medicine called empagliflozin may slow kidney disease from type 2 diabetes. Researchers want to learn if it protects the kidneys when used in very early stages of diabetic kidney disease.

ID: NCT03173963
Sponsor: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Contact: Helen C Looker, [email protected]
Location: NIDDK, Phoenix, AZ

Family Investigation of Nephropathy and Diabetes

The Family Investigation of Nephropathy and Diabetes (FIND) is a multicenter study designed to identify genetic determinants of diabetic kidney disease. FIND will be conducted in 11 centers and in many ethnic groups throughout the United States. Two different strategies will be used to localize genes predisposing to kidney disease: a family-based genetic linkage study and a case-control study that utilizes admixture linkage disequilibrium. The center will conduct family-based linkage studies among American Indian populations in the southwestern United States.

ID: NCT00342927
Sponsor: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Contact: William C Knowler, MD, [email protected]
Location: NIDDK, Phoenix, AZ

Look AHEAD: Action for Health in Diabetes

The Look AHEAD study is a multi-center, randomized clinical trial to examine the long-term effects of a lifestyle intervention designed to achieve and maintain weight loss. The study will investigate the effects of the intervention on heart attacks, stroke and cardiovascular-related death in individuals with type 2 diabetes who are also overweight or obese.

ID: NCT00017953
Sponsor: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Location: Southwestern American Indian Center, Phoenix, AZ

Vitamin D and Type 2 Diabetes Study

The goal of the Vitamin D and type 2 diabetes (D2d) study is to determine if vitamin D supplementation works to delay the onset of type 2 diabetes in people at risk for the disease and to gain a better understand how vitamin D affects glucose (sugar) metabolism.

ID: NCT01942694
Sponsor: Tufts Medical Center
Locations: Southwest American Indian Center; Phoenix, AZ; Orlando VA Medical Center, FL; Atlanta VA Medical Center, Decatur, GA; Omaha VA Medical Center, NE

Reducing Diabetes Risk Factors in American Indian Children: Tribal Turning Point (TTP)

This study will evaluate a behavioral intervention designed to reduce risk factors for type 2 diabetes in American Indian youth aged 7-10 years.

ID: NCT03573856
Sponsor: University of Colorado, Denver
Contact: Katherine Sauder, PhD, [email protected]; Dana Dabelea, MD, PhD, [email protected]
Location: Childrens Hospital Colorado, Aurora

Strong Men, Strong Communities Diabetes Risk Reduction in American Indian Men (SMSC)

SMSC will inform the design and implementation of culturally informed, community-based lifestyle interventions for diabetes prevention in AI men in our partner communities and elsewhere, as well as in men of other minority groups who experience a heavy burden of diabetes.

ID: NCT02953977
Sponsor: Washington State University
Contact: Kaimi Sinclair, PhD, MPH, [email protected] Location: IREACH, Seattle, WA

Growing Resilience in Wind River Indian Reservation (GR)

The Growing Resilience research leverages reservation-based assets of land, family, culture, and front-line tribal health organizations to develop and evaluate home food gardens as a family-based health promotion intervention to reduce disparities suffered by Native Americans in nearly every measure of health. Home gardening interventions show great promise for enabling families to improve their health, and this study aims to fulfill that promise with university and Wind River Indian Reservation partners. The investigators will develop an empowering, scalable, and sustainable family-based health promotion intervention with, by, and for Native American families and conduct the first randomized controlled trial to assess the health impacts of home gardens.

ID: NCT02672748
Sponsor: University of Wyoming
Location: University of Wyoming, Laramie

A Comparative Effectiveness Study of Major Glycemia-lowering Medications for Treatment of Type 2 Diabetes (GRADE)

The GRADE Study is a pragmatic, unmasked clinical trial that will compare commonly used diabetes medications, when combined with metformin, on glycemia-lowering effectiveness and patient-centered outcomes.

ID: NCT01794143
Sponsor: GRADE Study Group
Location: Southwestern American Indian Center, Phoenix, AZ

Home-Based Kidney Care in Native Americans of New Mexico (HBKC)

New Mexico American Indians are experiencing an epidemic of chronic kidney disease due primarily to the high rates of obesity and diabetes. The present study entitled Home-Based Kidney Care is designed to delay / reduce rates of end stage renal disease by early interventions in chronic kidney disease (CKD). Investigators propose to assess the safety and efficacy of conducting a full-scale study to determine if home based care delivered by a collaborative team composed of community health workers, the Albuquerque Area Indian Health Board and University of New Mexico faculty will decrease the risk for the development and the progression of CKD.

ID: NCT03179085
Sponsor: University of New Mexico
Contact: Vallabh Shah, PhD, [email protected]; Kevin English, PhD, [email protected]
Location: University of New Mexico, Albuquerque

Home-based Prediabetes Care in Acoma Pueblo - Study 1

Our major goal of implementing educational interventions to slow the current rate of increase in diabetes in Native communities is aligned with the National Institute of Health (NIGMS) and New Mexico INBRE’s vision in reducing health disparity using innovative interventions. The investigators propose following aims: (1) Recruit and Screen 300 community members in Acoma Pueblo, New Mexico to identify incident cases of pre-diabetes for the proposed study of Home Based Diabetes Care (HBDC); (2) Enroll 150 Acoma Natives aged 21-70 years, at risk for type 2 diabetes mellitus and conduct HBDC for a 16-week lifestyle intervention in a longitudinal cohort study.

ID: NCT04029298
Sponsor: University of New Mexico
Contact: Matthew Bouchonville, MD, [email protected]; Vallabh Shah, PhD, [email protected]

Providing access to clinical trials for patients with diabetes mellitus can be a challenge, but a significant number of trials are now recruiting patients. The clinical trials listed below are all open as of October 31, 2019; and are focused on diabetes mellitus-related treatments for American Indians. For additional information and full inclusion/exclusion criteria, please consult clinicaltrials.gov.

Cross-Sectional and Longitudinal Studies of “Pre-Diabetes” in the Pima Indians

The Pima Indians of Arizona have the highest prevalence and incidence of type 2 diabetes of any population in the world. Prospective analyses in this population have identified insulin resistance and a defect in early insulin secretion as risk factors for the development of the disease. To identify the genetic and environmental determinants of diabetes we plan to study Pima Indian families to determine: (1) if there are genes that segregate with metabolic risk factors for diabetes which might therefore be genetic markers for type 2 diabetes; and (2) the mechanisms mediating genetic and environmental determinants of insulin resistance and impaired insulin secretion.

ID: NCT00340132
Sponsor: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Contact: Clifton Bogardus, MD, [email protected]
Location: NIDDK, Phoenix, AZ

Empaglifozin in Early Diabetic Kidney Disease

Diabetes is common among American Indian people and diabetic kidney disease is a common complication. Kidney disease caused by diabetes can lead to the need for kidney replacement, by dialysis or kidney transplant, and is also associated with higher risk of early death. A new diabetes medicine called empagliflozin may slow kidney disease from type 2 diabetes. Researchers want to learn if it protects the kidneys when used in very early stages of diabetic kidney disease.

ID: NCT03173963
Sponsor: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Contact: Helen C Looker, [email protected]
Location: NIDDK, Phoenix, AZ

Family Investigation of Nephropathy and Diabetes

The Family Investigation of Nephropathy and Diabetes (FIND) is a multicenter study designed to identify genetic determinants of diabetic kidney disease. FIND will be conducted in 11 centers and in many ethnic groups throughout the United States. Two different strategies will be used to localize genes predisposing to kidney disease: a family-based genetic linkage study and a case-control study that utilizes admixture linkage disequilibrium. The center will conduct family-based linkage studies among American Indian populations in the southwestern United States.

ID: NCT00342927
Sponsor: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Contact: William C Knowler, MD, [email protected]
Location: NIDDK, Phoenix, AZ

Look AHEAD: Action for Health in Diabetes

The Look AHEAD study is a multi-center, randomized clinical trial to examine the long-term effects of a lifestyle intervention designed to achieve and maintain weight loss. The study will investigate the effects of the intervention on heart attacks, stroke and cardiovascular-related death in individuals with type 2 diabetes who are also overweight or obese.

ID: NCT00017953
Sponsor: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Location: Southwestern American Indian Center, Phoenix, AZ

Vitamin D and Type 2 Diabetes Study

The goal of the Vitamin D and type 2 diabetes (D2d) study is to determine if vitamin D supplementation works to delay the onset of type 2 diabetes in people at risk for the disease and to gain a better understand how vitamin D affects glucose (sugar) metabolism.

ID: NCT01942694
Sponsor: Tufts Medical Center
Locations: Southwest American Indian Center; Phoenix, AZ; Orlando VA Medical Center, FL; Atlanta VA Medical Center, Decatur, GA; Omaha VA Medical Center, NE

Reducing Diabetes Risk Factors in American Indian Children: Tribal Turning Point (TTP)

This study will evaluate a behavioral intervention designed to reduce risk factors for type 2 diabetes in American Indian youth aged 7-10 years.

ID: NCT03573856
Sponsor: University of Colorado, Denver
Contact: Katherine Sauder, PhD, [email protected]; Dana Dabelea, MD, PhD, [email protected]
Location: Childrens Hospital Colorado, Aurora

Strong Men, Strong Communities Diabetes Risk Reduction in American Indian Men (SMSC)

SMSC will inform the design and implementation of culturally informed, community-based lifestyle interventions for diabetes prevention in AI men in our partner communities and elsewhere, as well as in men of other minority groups who experience a heavy burden of diabetes.

ID: NCT02953977
Sponsor: Washington State University
Contact: Kaimi Sinclair, PhD, MPH, [email protected] Location: IREACH, Seattle, WA

Growing Resilience in Wind River Indian Reservation (GR)

The Growing Resilience research leverages reservation-based assets of land, family, culture, and front-line tribal health organizations to develop and evaluate home food gardens as a family-based health promotion intervention to reduce disparities suffered by Native Americans in nearly every measure of health. Home gardening interventions show great promise for enabling families to improve their health, and this study aims to fulfill that promise with university and Wind River Indian Reservation partners. The investigators will develop an empowering, scalable, and sustainable family-based health promotion intervention with, by, and for Native American families and conduct the first randomized controlled trial to assess the health impacts of home gardens.

ID: NCT02672748
Sponsor: University of Wyoming
Location: University of Wyoming, Laramie

A Comparative Effectiveness Study of Major Glycemia-lowering Medications for Treatment of Type 2 Diabetes (GRADE)

The GRADE Study is a pragmatic, unmasked clinical trial that will compare commonly used diabetes medications, when combined with metformin, on glycemia-lowering effectiveness and patient-centered outcomes.

ID: NCT01794143
Sponsor: GRADE Study Group
Location: Southwestern American Indian Center, Phoenix, AZ

Home-Based Kidney Care in Native Americans of New Mexico (HBKC)

New Mexico American Indians are experiencing an epidemic of chronic kidney disease due primarily to the high rates of obesity and diabetes. The present study entitled Home-Based Kidney Care is designed to delay / reduce rates of end stage renal disease by early interventions in chronic kidney disease (CKD). Investigators propose to assess the safety and efficacy of conducting a full-scale study to determine if home based care delivered by a collaborative team composed of community health workers, the Albuquerque Area Indian Health Board and University of New Mexico faculty will decrease the risk for the development and the progression of CKD.

ID: NCT03179085
Sponsor: University of New Mexico
Contact: Vallabh Shah, PhD, [email protected]; Kevin English, PhD, [email protected]
Location: University of New Mexico, Albuquerque

Home-based Prediabetes Care in Acoma Pueblo - Study 1

Our major goal of implementing educational interventions to slow the current rate of increase in diabetes in Native communities is aligned with the National Institute of Health (NIGMS) and New Mexico INBRE’s vision in reducing health disparity using innovative interventions. The investigators propose following aims: (1) Recruit and Screen 300 community members in Acoma Pueblo, New Mexico to identify incident cases of pre-diabetes for the proposed study of Home Based Diabetes Care (HBDC); (2) Enroll 150 Acoma Natives aged 21-70 years, at risk for type 2 diabetes mellitus and conduct HBDC for a 16-week lifestyle intervention in a longitudinal cohort study.

ID: NCT04029298
Sponsor: University of New Mexico
Contact: Matthew Bouchonville, MD, [email protected]; Vallabh Shah, PhD, [email protected]

Providing access to clinical trials for patients with diabetes mellitus can be a challenge, but a significant number of trials are now recruiting patients. The clinical trials listed below are all open as of October 31, 2019; and are focused on diabetes mellitus-related treatments for American Indians. For additional information and full inclusion/exclusion criteria, please consult clinicaltrials.gov.

Cross-Sectional and Longitudinal Studies of “Pre-Diabetes” in the Pima Indians

The Pima Indians of Arizona have the highest prevalence and incidence of type 2 diabetes of any population in the world. Prospective analyses in this population have identified insulin resistance and a defect in early insulin secretion as risk factors for the development of the disease. To identify the genetic and environmental determinants of diabetes we plan to study Pima Indian families to determine: (1) if there are genes that segregate with metabolic risk factors for diabetes which might therefore be genetic markers for type 2 diabetes; and (2) the mechanisms mediating genetic and environmental determinants of insulin resistance and impaired insulin secretion.

ID: NCT00340132
Sponsor: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Contact: Clifton Bogardus, MD, [email protected]
Location: NIDDK, Phoenix, AZ

Empaglifozin in Early Diabetic Kidney Disease

Diabetes is common among American Indian people and diabetic kidney disease is a common complication. Kidney disease caused by diabetes can lead to the need for kidney replacement, by dialysis or kidney transplant, and is also associated with higher risk of early death. A new diabetes medicine called empagliflozin may slow kidney disease from type 2 diabetes. Researchers want to learn if it protects the kidneys when used in very early stages of diabetic kidney disease.

ID: NCT03173963
Sponsor: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Contact: Helen C Looker, [email protected]
Location: NIDDK, Phoenix, AZ

Family Investigation of Nephropathy and Diabetes

The Family Investigation of Nephropathy and Diabetes (FIND) is a multicenter study designed to identify genetic determinants of diabetic kidney disease. FIND will be conducted in 11 centers and in many ethnic groups throughout the United States. Two different strategies will be used to localize genes predisposing to kidney disease: a family-based genetic linkage study and a case-control study that utilizes admixture linkage disequilibrium. The center will conduct family-based linkage studies among American Indian populations in the southwestern United States.

ID: NCT00342927
Sponsor: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Contact: William C Knowler, MD, [email protected]
Location: NIDDK, Phoenix, AZ

Look AHEAD: Action for Health in Diabetes

The Look AHEAD study is a multi-center, randomized clinical trial to examine the long-term effects of a lifestyle intervention designed to achieve and maintain weight loss. The study will investigate the effects of the intervention on heart attacks, stroke and cardiovascular-related death in individuals with type 2 diabetes who are also overweight or obese.

ID: NCT00017953
Sponsor: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Location: Southwestern American Indian Center, Phoenix, AZ

Vitamin D and Type 2 Diabetes Study

The goal of the Vitamin D and type 2 diabetes (D2d) study is to determine if vitamin D supplementation works to delay the onset of type 2 diabetes in people at risk for the disease and to gain a better understand how vitamin D affects glucose (sugar) metabolism.

ID: NCT01942694
Sponsor: Tufts Medical Center
Locations: Southwest American Indian Center; Phoenix, AZ; Orlando VA Medical Center, FL; Atlanta VA Medical Center, Decatur, GA; Omaha VA Medical Center, NE

Reducing Diabetes Risk Factors in American Indian Children: Tribal Turning Point (TTP)

This study will evaluate a behavioral intervention designed to reduce risk factors for type 2 diabetes in American Indian youth aged 7-10 years.

ID: NCT03573856
Sponsor: University of Colorado, Denver
Contact: Katherine Sauder, PhD, [email protected]; Dana Dabelea, MD, PhD, [email protected]
Location: Childrens Hospital Colorado, Aurora

Strong Men, Strong Communities Diabetes Risk Reduction in American Indian Men (SMSC)

SMSC will inform the design and implementation of culturally informed, community-based lifestyle interventions for diabetes prevention in AI men in our partner communities and elsewhere, as well as in men of other minority groups who experience a heavy burden of diabetes.

ID: NCT02953977
Sponsor: Washington State University
Contact: Kaimi Sinclair, PhD, MPH, [email protected] Location: IREACH, Seattle, WA

Growing Resilience in Wind River Indian Reservation (GR)

The Growing Resilience research leverages reservation-based assets of land, family, culture, and front-line tribal health organizations to develop and evaluate home food gardens as a family-based health promotion intervention to reduce disparities suffered by Native Americans in nearly every measure of health. Home gardening interventions show great promise for enabling families to improve their health, and this study aims to fulfill that promise with university and Wind River Indian Reservation partners. The investigators will develop an empowering, scalable, and sustainable family-based health promotion intervention with, by, and for Native American families and conduct the first randomized controlled trial to assess the health impacts of home gardens.

ID: NCT02672748
Sponsor: University of Wyoming
Location: University of Wyoming, Laramie

A Comparative Effectiveness Study of Major Glycemia-lowering Medications for Treatment of Type 2 Diabetes (GRADE)

The GRADE Study is a pragmatic, unmasked clinical trial that will compare commonly used diabetes medications, when combined with metformin, on glycemia-lowering effectiveness and patient-centered outcomes.

ID: NCT01794143
Sponsor: GRADE Study Group
Location: Southwestern American Indian Center, Phoenix, AZ

Home-Based Kidney Care in Native Americans of New Mexico (HBKC)

New Mexico American Indians are experiencing an epidemic of chronic kidney disease due primarily to the high rates of obesity and diabetes. The present study entitled Home-Based Kidney Care is designed to delay / reduce rates of end stage renal disease by early interventions in chronic kidney disease (CKD). Investigators propose to assess the safety and efficacy of conducting a full-scale study to determine if home based care delivered by a collaborative team composed of community health workers, the Albuquerque Area Indian Health Board and University of New Mexico faculty will decrease the risk for the development and the progression of CKD.

ID: NCT03179085
Sponsor: University of New Mexico
Contact: Vallabh Shah, PhD, [email protected]; Kevin English, PhD, [email protected]
Location: University of New Mexico, Albuquerque

Home-based Prediabetes Care in Acoma Pueblo - Study 1

Our major goal of implementing educational interventions to slow the current rate of increase in diabetes in Native communities is aligned with the National Institute of Health (NIGMS) and New Mexico INBRE’s vision in reducing health disparity using innovative interventions. The investigators propose following aims: (1) Recruit and Screen 300 community members in Acoma Pueblo, New Mexico to identify incident cases of pre-diabetes for the proposed study of Home Based Diabetes Care (HBDC); (2) Enroll 150 Acoma Natives aged 21-70 years, at risk for type 2 diabetes mellitus and conduct HBDC for a 16-week lifestyle intervention in a longitudinal cohort study.

ID: NCT04029298
Sponsor: University of New Mexico
Contact: Matthew Bouchonville, MD, [email protected]; Vallabh Shah, PhD, [email protected]

Individuals with diabetes mellitus (DM), peripheral vascular disease, or end-stage renal disease are at risk for a nontraumatic lower limb amputation.¹ Veterans have a high number of risk factors and are especially vulnerable. More than 70% of veterans enrolled in US Department of Veterans Affairs (VA) healthcare are at increased risk for developing DM due to excess weight, poor eating habits, and physical inactivity.² One in 4 veterans has DM, compared with 1 in 6 in the general population.²

DM can lead to long-term complications including limb amputations. Annually in the US about 73,000 nontraumatic lower limb amputations are performed and > 60% occur among persons with DM.³ Complications from diabetic wounds are the cause of 90% of lower limb amputations, and foot ulcers are the most prevalent complication.⁴ Diabetic ulcers are slow to heal due to vascular impairments and nerve damage.⁵ Peripheral vascular disease, a common comorbid condition, contributes to restricted blood flow and can lead to tissue death or gangrene requiring amputation.⁶

Between 2010 and 2014, VA Portland Healthcare System (VAPORHCS) had one of the highest national amputation rates in VA.⁷ A clinical chart review found that annual foot examinations and amputation risk assessments (ARAs) were not completed with all at-risk veterans. In 2013, a VA Office of Inspector General (OIG) national report found that more than one-third of veterans enrolled in VA with DM had no documentation of required annual foot exams.⁸ In 2017, VA released Directive 1410, which outlined the scope of care required to prevent and treat lower limb complications and amputations for veterans at risk for primary or secondary limb loss.¹ This national initiative is a comprehensive approach that engages multiprofessional teams to perform routine foot examinations and amputation risk assessments; identify and promptly treat foot ulcers; track, monitor and educate at-risk veterans; and participate in clinical education to enhance staff skills.

To decrease the amputation rate, VAPORHCS redesigned its foot-care program to comply with the national initiative. As is typical in VA, VAPORHCS uses a team-based approach in primary care. The basic 4-member team patient-aligned care team (PACT) consists of a physician or nurse practitioner (NP) primary care provider (PCP), a registered nurse (RN) care manager, a licensed practical nurse (LPN), and a medical staff assistant (MSA) for administrative support. Each PACT cares for about 1,800 veterans. Formerly, LPNs completed the annual diabetic foot exams, and PCPs verified the exams and completed the ARA based on the LPNs’ findings. If patients were moderate risk or high risk, they were referred to podiatry. The VAPORHCS audit found that not all at-risk veterans had both the foot exam and ARA completed, or were referred to podiatry when indicated. There was a need for a process improvement project to develop a seamless program consisting of all recommended foot care components crucial for timely care.

This quality improvement project sought to evaluate the effectiveness of the process changes by examining PCPs’ adoption of, and consistency in completing annual diabetic foot exams and ARAs with veterans. The goals of the project were to evaluate changes in the: (1) Number of accurate diabetic foot exams and amputation risk assessments completed with veterans with DM; (2) Number and timeliness of appropriate referrals to podiatry for an in-depth assessment and treatment of veterans found to be at moderate-to-high risk for lower limb amputations; and (3) Number of administrative text orders entered by PCPs for nurse care managers to offer foot care education and the completion of the education with veterans found to be at normal-to-low risk for lower limb amputations. The institutional review boards of VAPORHCS and Gonzaga University approved the study.

Methods

Established by the American Diabetes Association and endorsed by the American Association of Clinical Endocrinologists, the comprehensive foot exam includes a visual exam, pedal pulse checks, and a sensory exam.^9,10 The templated Computerized Patient Record System (CPRS) electronic health record note specifies normal and abnormal parameters of each section. On the same template, the provider assigns an ARA score based on the results of the completed foot exam. Risk scores range from 0 to 3 (0, normal or no risk; 1, low risk, 2; moderate risk; 3, high risk) If the veteran has normal or low risk, the PCP can encourage the veteran to remain at low risk by entering an administrative CPRS text order for the nurse care manager to offer education about daily foot care at the same visit or at a scheduled follow-up visit. This process facilitates nurse care managers to include routine foot care as integral to their usual duties coaching veterans to engage in self-care to manage chronic conditions. If the risk is assessed as moderate or high risk, PCPs are prompted to send a referral to podiatry to repeat the foot exam, verify the ARA score, and provide appropriate foot care treatment and follow-up.

On October 31, 2017, following training on the updated foot exam and ARA template with staff at the 13 VAPORHCS outpatient clinic sites, 2 sites piloted all components of the Comprehensive Foot Care program. An in-person training was completed with PCPs to review the changes of the foot care template in CPRS and to answer their questions about it. PCPs were required to complete both the 3-part foot exam and ARA at least once annually with veterans with DM.

An electronic clinical reminder was built to alert PCPs and PACTs that a veteran was either due or overdue for an exam and risk assessment. VA podiatrists agreed to complete the reminder with veterans under their care. One of the 2 sites was randomly selected for this study. Data were collected from August 1, 2017 to July 31, 2018. Patients were identified from the Diabetes Registry, a database established at VAPORHCS in 2008 to track veterans with DM to ensure quality care.¹¹ Veterans’ personal health identifiers from the registry were used to access their health records to complete chart reviews and assess the completion, accuracy and timeliness of all foot care components.

The Diabetes Registry lists a veterans’ upcoming appointments and tracks their most recent clinic visits; laboratory tests; physical exams; and screening exams for foot, eye, and renal care. Newly diagnosed veterans are uploaded automatically into this registry by tracking all DM-related International Classification of Diseases (ICD-10) codes, hemoglobin A_1c (HbA_1c) levels ≥ 6.5%, or outpatient prescriptions for insulin or oral hypoglycemic agents.¹¹

Study Design

This quality improvement project evaluated PCPs’ actions in a program process change intended to improve foot care provided with veterans at-risk for nontraumatic lower limb amputations. Audits of CPRS records and the Diabetes Registry determined the results of the practice change. Data on the total number of foot exams, amputation risk scores, appropriate podiatry referrals, administrative orders for nurse coaching, and completed foot care education were collected during the study period. Data collected for the 3-month period preceding the process change established preimplementation comparison vs the postimplementation data. Data were collected at 3, 6, and 9 months after implementation. The foot exams and ARAs were reviewed to determine whether exams and assessments were completed accurately during the pre- and post-implementation timeframes. Incomplete or clearly incorrectly completed documentation were considered inaccurate. For example, it was considered inaccurate if only the foot exam portion was completed in the assessment and the ARA was not.

Data Analysis

Data on the total number of accurately completed foot examinations and ARAs, total number of podiatry referrals, and total number of administrative text orders placed by PCPs, and education completed by nurse care managers were assessed. Statistical significance was evaluated using χ² and Fisher exact test as appropriate. A Pearson correlation coefficient was used to determine whether there was a statistically significant increase in accurate foot examinations and ARAs as well as total number of podiatry referrals during the study period. Statistical analyses were performed using Stata 14.1 statistical software (College Station, TX).

Results

A total of 1,242 completed diabetic foot examinations were identified from August 1, 2017 to July 31, 2018 using the Diabetes Registry (Table). For the 3 months prior to the change, there were 191 appropriately completed foot examinations and ARAs. This number increased progressively over three 3-month periods (Figure 1). Within the 1-year study period, there was a statistically significant increase in the number of appropriate foot examinations (r = 0.495). PCPs placed 34 podiatry referrals during the prechange period. After the change, the number of appropriate referrals increased statistically significantly in the 3 following 3-month-periods (r = 0.222) (Figure 2).

To determine the accuracy of documentation and ratio of appropriate referrals, the 3-month prechange data was compared with the 9-month postchange period. There was a statistically significant increase from pre- to postchange accuracy of documentation for examinations and ARAs (53.1% vs. 97.7%). The percentage of appropriate podiatry referrals increased significantly from 41.5% to 76.8%. Overall, there was poor adherence to protocol for the text order and education that was implemented during the change. Only 4.6% of patients had an administrative text order entered into CPRS and 3.9% were provided with foot care coaching. There was no statistical difference in the use of text orders between the first 3-month period and the last 3-month period (5.2% vs. 2.1%). Similarly, there was no statistical difference in the rate of patient education between the first 3-month period and the final 3-month period (2.6% vs. 2.1%).

Notably, at the end of the first year of this evaluation, 119 veterans at the clinic did not show a recorded comprehensive foot examination since receiving a DM diagnosis and 299 veterans were due for an annual examination—a 25.2% gap of veterans without the recommended progression of foot care services. Of those that previously had a recorded foot examination, 51 (17.0%) veterans were found to be ≥ 2 years overdue.

Discussion

DM management requires a comprehensive team-based approach to help monitor for associated complications. At the VA, PACTs are veterans’ initial and primary point of contact for chronic condition management. PACTs have regular opportunities to engage veterans in initial and follow-up care and appropriate self-care. PCPs are critical in placing referrals for specialized care promptly to prevent and minimize complications such as foot ulcers, and ultimately, lower limb amputations.^9,10,12

When PCPs assume responsibility for the entire foot examination, they are able to identify problems early.¹ Left untreated, foot wounds and ulcers have the potential to grow into serious infections.⁹ Early risk identification and management can lead to increased patient satisfaction, improved life expectancy, quality of life, and ultimately, lower healthcare costs.¹²

Multiple studies have shown the clinical importance of foot examinations in preventative care. In one study, researchers found that completing foot examinations, among other early interventions, increased life expectancy and reduced foot complications.¹³ Diabetic foot management programs involving screening and categorizing patients into low- and high-risk groups had a 47.4% decrease in the incidence of amputations and 37.8% decrease in hospital admissions.¹⁴ Amputations were found to be inversely correlated with multidisciplinary foot care programs with reduction of lower limb amputations at 2 years.¹⁵ The Centers for Disease Control and Prevention found that comprehensive foot care programs that include a foot examination, ARA, appropriate referrals to specialists, and foot-care education and preventative services can reduce lower limb amputation rates by 45% to 85%.¹⁶

With one of the highest amputation rates in VA, VAPORHCS needed an integrated approach to ensure that appropriate foot care occurred regularly with veterans with DM. Prior to the process change, LPNs completed foot examinations and PCPs completed the ARA. Separating these clinical services resulted in few veterans receiving an amputation risk score. Of those with scores, the lack of a standardized program protocol resulted in discrepancies between ARAs from patient to patient as health care providers did not have clear or enough information to select the correct score and make the appropriate referrals. Thus, veterans previously identified as at moderate or high risk also lacked podiatric follow-up care.

The new quality-driven process change corrected the documentation process to nationally accepted standards. The goal was to create a consistent template in the electronic health record for all health care providers. The new template simplifies the documentation process and clarifies the amputation risk score assignment, which allows for proper foot care management. The PCP completes the process from assessment through referral, removing gaps in care and improving efficiency. Although this change was initially met with resistance from PCPs, it led to a significant increase in the number of patients with accurately documented examinations. Similarly, the number of appropriate referrals significantly rose during the study period. The standardized documentation process resulted in improved accurate examinations and ARAs over the past year. The new program also resulted in an increased number of appropriate podiatry referrals for those identified to be at moderate or high risk. This elevation of care is crucial for veterans to receive frequent follow-up visits for preventative care and/or treatment, including surgical modalities to promote limb salvage.

Barriers

This project identified several barriers to the Comprehensive Foot Care program. One major barrier was health care provider resistance to using the new process. For example, VAPORHCS podiatrists are not using the new template with established patients, which requires PCPs to complete the clinical reminder template for quality performance, an additional burden unrelated to clinical care. PCPs that do complete the foot examination/ARA templated note use the podiatrist’s visit note without personally assessing the patient.

PCPs also have been resistant to entering administrative text orders for preventative foot care in normal- or low-risk veterans (4.6% overall), which has resulted in decreased patient education (3.9% overall). Education for normal-risk and low-risk patients is designed to engage veterans in self-care and prevent risk progression, critical to prevention.

It was found that PCPs often did not ask nurses to coach normal- or low-risk veterans on preventative foot care, as suggested by the low rates at which patients were offered education. This is an area we will target with future quality improvement efforts. All patients with DM should have general education about risk factors and appropriate management of them to decrease their risk for complications.⁹ Preventative foot care education is a critical resource to share with patients during health coaching opportunities to clarify misunderstandings and support change talk when patients are ambivalent or resistant to change. Individual or group-based nurse visits can facilitate better coaching for patients.

At the VA, coaching begins with a conversation about what matters most to the veteran, facilitating the development of a personalized plan based on patients’ values, needs, preferences and goals.^9,10,12,17 Coaching allows nurses to assess veterans’ knowledge and willingness to engage in healthy habits; and identify additional resources to help them achieve their goals.

Limitations

There are many limitations to this short quality improvement analysis. For example, only 1 of 2 clinics that piloted the program change was evaluated. In addition, there are 11 other clinics that need additional in-depth education on the program change. Although this analysis was overwhelmingly positive, it may not be as successful at other clinic sites and may be subject to the Hawthorne effect—since the 2 piloted locations knew they were being observed for the quality improvement program and may have made an extra effort to be compliant.¹⁸ Additionally, we were unable to track the records of veterans receiving care through the VA Choice Program for this analysis resulting in a lack of documentation of completed diabetic foot examinations and a lack of internal referrals to VA podiatry.

Another major limitation of this project involved calculating the number of referrals placed to podiatry. On January 1, 2018, about halfway through the program evaluation, a national VA decision enabled veterans to self-refer to podiatry, which may have limited the number of podiatry referrals placed by PCPs. Finally, patients could refuse podiatry referrals. In the 9-month postimplementation period, 57 (64.8%) veterans declined podiatry referrals, according to their CPRS records.

Although, there was an improvement in the accuracy of diabetic foot examinations, ARAs, and appropriate podiatry referrals, the ultimate goal of reducing diabetic foot ulcers and lower limb amputations was not tracked due to the limited timeframe of this analysis. Tracking these endpoints with continuous plan-do-study-act cycles are needed for this ongoing quality improvement project.

Conclusion

The goal of the VAPORHCS Comprehensive Foot Care program is to provide veterans with a program that is predictable, easy and consistent to prevent and treat foot ulcers to reduce the rate of lower limb amputations. It requires multidisciplinary team collaboration for success. Implementation of this new comprehensive program has increased the number of accurate annual foot exams, ARAs and podiatry referrals. Despite these improvements, areas of future improvement include emphasizing patient education and ongoing provider compliance with annual assessments.

Author contributions
MHG proposed the program evaluation project idea. TVQ collected and analyzed the data and wrote the manuscript. MHG oversaw the project and edited the manuscript. TVQ is the guarantor of this project and takes responsibility for the contents of this journal article.

Acknowledgments
The authors thank Tyra Haebe, VAPORHCS Prevention of Amputation in Veterans Everywhere (PAVE) Manager, and the entire VAPORHCS PAVE committee for their support in this program evaluation project.

Individuals with diabetes mellitus (DM), peripheral vascular disease, or end-stage renal disease are at risk for a nontraumatic lower limb amputation.¹ Veterans have a high number of risk factors and are especially vulnerable. More than 70% of veterans enrolled in US Department of Veterans Affairs (VA) healthcare are at increased risk for developing DM due to excess weight, poor eating habits, and physical inactivity.² One in 4 veterans has DM, compared with 1 in 6 in the general population.²

DM can lead to long-term complications including limb amputations. Annually in the US about 73,000 nontraumatic lower limb amputations are performed and > 60% occur among persons with DM.³ Complications from diabetic wounds are the cause of 90% of lower limb amputations, and foot ulcers are the most prevalent complication.⁴ Diabetic ulcers are slow to heal due to vascular impairments and nerve damage.⁵ Peripheral vascular disease, a common comorbid condition, contributes to restricted blood flow and can lead to tissue death or gangrene requiring amputation.⁶

Between 2010 and 2014, VA Portland Healthcare System (VAPORHCS) had one of the highest national amputation rates in VA.⁷ A clinical chart review found that annual foot examinations and amputation risk assessments (ARAs) were not completed with all at-risk veterans. In 2013, a VA Office of Inspector General (OIG) national report found that more than one-third of veterans enrolled in VA with DM had no documentation of required annual foot exams.⁸ In 2017, VA released Directive 1410, which outlined the scope of care required to prevent and treat lower limb complications and amputations for veterans at risk for primary or secondary limb loss.¹ This national initiative is a comprehensive approach that engages multiprofessional teams to perform routine foot examinations and amputation risk assessments; identify and promptly treat foot ulcers; track, monitor and educate at-risk veterans; and participate in clinical education to enhance staff skills.

To decrease the amputation rate, VAPORHCS redesigned its foot-care program to comply with the national initiative. As is typical in VA, VAPORHCS uses a team-based approach in primary care. The basic 4-member team patient-aligned care team (PACT) consists of a physician or nurse practitioner (NP) primary care provider (PCP), a registered nurse (RN) care manager, a licensed practical nurse (LPN), and a medical staff assistant (MSA) for administrative support. Each PACT cares for about 1,800 veterans. Formerly, LPNs completed the annual diabetic foot exams, and PCPs verified the exams and completed the ARA based on the LPNs’ findings. If patients were moderate risk or high risk, they were referred to podiatry. The VAPORHCS audit found that not all at-risk veterans had both the foot exam and ARA completed, or were referred to podiatry when indicated. There was a need for a process improvement project to develop a seamless program consisting of all recommended foot care components crucial for timely care.

This quality improvement project sought to evaluate the effectiveness of the process changes by examining PCPs’ adoption of, and consistency in completing annual diabetic foot exams and ARAs with veterans. The goals of the project were to evaluate changes in the: (1) Number of accurate diabetic foot exams and amputation risk assessments completed with veterans with DM; (2) Number and timeliness of appropriate referrals to podiatry for an in-depth assessment and treatment of veterans found to be at moderate-to-high risk for lower limb amputations; and (3) Number of administrative text orders entered by PCPs for nurse care managers to offer foot care education and the completion of the education with veterans found to be at normal-to-low risk for lower limb amputations. The institutional review boards of VAPORHCS and Gonzaga University approved the study.

Methods

Established by the American Diabetes Association and endorsed by the American Association of Clinical Endocrinologists, the comprehensive foot exam includes a visual exam, pedal pulse checks, and a sensory exam.^9,10 The templated Computerized Patient Record System (CPRS) electronic health record note specifies normal and abnormal parameters of each section. On the same template, the provider assigns an ARA score based on the results of the completed foot exam. Risk scores range from 0 to 3 (0, normal or no risk; 1, low risk, 2; moderate risk; 3, high risk) If the veteran has normal or low risk, the PCP can encourage the veteran to remain at low risk by entering an administrative CPRS text order for the nurse care manager to offer education about daily foot care at the same visit or at a scheduled follow-up visit. This process facilitates nurse care managers to include routine foot care as integral to their usual duties coaching veterans to engage in self-care to manage chronic conditions. If the risk is assessed as moderate or high risk, PCPs are prompted to send a referral to podiatry to repeat the foot exam, verify the ARA score, and provide appropriate foot care treatment and follow-up.

On October 31, 2017, following training on the updated foot exam and ARA template with staff at the 13 VAPORHCS outpatient clinic sites, 2 sites piloted all components of the Comprehensive Foot Care program. An in-person training was completed with PCPs to review the changes of the foot care template in CPRS and to answer their questions about it. PCPs were required to complete both the 3-part foot exam and ARA at least once annually with veterans with DM.

An electronic clinical reminder was built to alert PCPs and PACTs that a veteran was either due or overdue for an exam and risk assessment. VA podiatrists agreed to complete the reminder with veterans under their care. One of the 2 sites was randomly selected for this study. Data were collected from August 1, 2017 to July 31, 2018. Patients were identified from the Diabetes Registry, a database established at VAPORHCS in 2008 to track veterans with DM to ensure quality care.¹¹ Veterans’ personal health identifiers from the registry were used to access their health records to complete chart reviews and assess the completion, accuracy and timeliness of all foot care components.

The Diabetes Registry lists a veterans’ upcoming appointments and tracks their most recent clinic visits; laboratory tests; physical exams; and screening exams for foot, eye, and renal care. Newly diagnosed veterans are uploaded automatically into this registry by tracking all DM-related International Classification of Diseases (ICD-10) codes, hemoglobin A_1c (HbA_1c) levels ≥ 6.5%, or outpatient prescriptions for insulin or oral hypoglycemic agents.¹¹

Study Design

This quality improvement project evaluated PCPs’ actions in a program process change intended to improve foot care provided with veterans at-risk for nontraumatic lower limb amputations. Audits of CPRS records and the Diabetes Registry determined the results of the practice change. Data on the total number of foot exams, amputation risk scores, appropriate podiatry referrals, administrative orders for nurse coaching, and completed foot care education were collected during the study period. Data collected for the 3-month period preceding the process change established preimplementation comparison vs the postimplementation data. Data were collected at 3, 6, and 9 months after implementation. The foot exams and ARAs were reviewed to determine whether exams and assessments were completed accurately during the pre- and post-implementation timeframes. Incomplete or clearly incorrectly completed documentation were considered inaccurate. For example, it was considered inaccurate if only the foot exam portion was completed in the assessment and the ARA was not.

Data Analysis

Data on the total number of accurately completed foot examinations and ARAs, total number of podiatry referrals, and total number of administrative text orders placed by PCPs, and education completed by nurse care managers were assessed. Statistical significance was evaluated using χ² and Fisher exact test as appropriate. A Pearson correlation coefficient was used to determine whether there was a statistically significant increase in accurate foot examinations and ARAs as well as total number of podiatry referrals during the study period. Statistical analyses were performed using Stata 14.1 statistical software (College Station, TX).

Results

A total of 1,242 completed diabetic foot examinations were identified from August 1, 2017 to July 31, 2018 using the Diabetes Registry (Table). For the 3 months prior to the change, there were 191 appropriately completed foot examinations and ARAs. This number increased progressively over three 3-month periods (Figure 1). Within the 1-year study period, there was a statistically significant increase in the number of appropriate foot examinations (r = 0.495). PCPs placed 34 podiatry referrals during the prechange period. After the change, the number of appropriate referrals increased statistically significantly in the 3 following 3-month-periods (r = 0.222) (Figure 2).

To determine the accuracy of documentation and ratio of appropriate referrals, the 3-month prechange data was compared with the 9-month postchange period. There was a statistically significant increase from pre- to postchange accuracy of documentation for examinations and ARAs (53.1% vs. 97.7%). The percentage of appropriate podiatry referrals increased significantly from 41.5% to 76.8%. Overall, there was poor adherence to protocol for the text order and education that was implemented during the change. Only 4.6% of patients had an administrative text order entered into CPRS and 3.9% were provided with foot care coaching. There was no statistical difference in the use of text orders between the first 3-month period and the last 3-month period (5.2% vs. 2.1%). Similarly, there was no statistical difference in the rate of patient education between the first 3-month period and the final 3-month period (2.6% vs. 2.1%).

Notably, at the end of the first year of this evaluation, 119 veterans at the clinic did not show a recorded comprehensive foot examination since receiving a DM diagnosis and 299 veterans were due for an annual examination—a 25.2% gap of veterans without the recommended progression of foot care services. Of those that previously had a recorded foot examination, 51 (17.0%) veterans were found to be ≥ 2 years overdue.

Discussion

DM management requires a comprehensive team-based approach to help monitor for associated complications. At the VA, PACTs are veterans’ initial and primary point of contact for chronic condition management. PACTs have regular opportunities to engage veterans in initial and follow-up care and appropriate self-care. PCPs are critical in placing referrals for specialized care promptly to prevent and minimize complications such as foot ulcers, and ultimately, lower limb amputations.^9,10,12

When PCPs assume responsibility for the entire foot examination, they are able to identify problems early.¹ Left untreated, foot wounds and ulcers have the potential to grow into serious infections.⁹ Early risk identification and management can lead to increased patient satisfaction, improved life expectancy, quality of life, and ultimately, lower healthcare costs.¹²

Multiple studies have shown the clinical importance of foot examinations in preventative care. In one study, researchers found that completing foot examinations, among other early interventions, increased life expectancy and reduced foot complications.¹³ Diabetic foot management programs involving screening and categorizing patients into low- and high-risk groups had a 47.4% decrease in the incidence of amputations and 37.8% decrease in hospital admissions.¹⁴ Amputations were found to be inversely correlated with multidisciplinary foot care programs with reduction of lower limb amputations at 2 years.¹⁵ The Centers for Disease Control and Prevention found that comprehensive foot care programs that include a foot examination, ARA, appropriate referrals to specialists, and foot-care education and preventative services can reduce lower limb amputation rates by 45% to 85%.¹⁶

With one of the highest amputation rates in VA, VAPORHCS needed an integrated approach to ensure that appropriate foot care occurred regularly with veterans with DM. Prior to the process change, LPNs completed foot examinations and PCPs completed the ARA. Separating these clinical services resulted in few veterans receiving an amputation risk score. Of those with scores, the lack of a standardized program protocol resulted in discrepancies between ARAs from patient to patient as health care providers did not have clear or enough information to select the correct score and make the appropriate referrals. Thus, veterans previously identified as at moderate or high risk also lacked podiatric follow-up care.

The new quality-driven process change corrected the documentation process to nationally accepted standards. The goal was to create a consistent template in the electronic health record for all health care providers. The new template simplifies the documentation process and clarifies the amputation risk score assignment, which allows for proper foot care management. The PCP completes the process from assessment through referral, removing gaps in care and improving efficiency. Although this change was initially met with resistance from PCPs, it led to a significant increase in the number of patients with accurately documented examinations. Similarly, the number of appropriate referrals significantly rose during the study period. The standardized documentation process resulted in improved accurate examinations and ARAs over the past year. The new program also resulted in an increased number of appropriate podiatry referrals for those identified to be at moderate or high risk. This elevation of care is crucial for veterans to receive frequent follow-up visits for preventative care and/or treatment, including surgical modalities to promote limb salvage.

Barriers

This project identified several barriers to the Comprehensive Foot Care program. One major barrier was health care provider resistance to using the new process. For example, VAPORHCS podiatrists are not using the new template with established patients, which requires PCPs to complete the clinical reminder template for quality performance, an additional burden unrelated to clinical care. PCPs that do complete the foot examination/ARA templated note use the podiatrist’s visit note without personally assessing the patient.

PCPs also have been resistant to entering administrative text orders for preventative foot care in normal- or low-risk veterans (4.6% overall), which has resulted in decreased patient education (3.9% overall). Education for normal-risk and low-risk patients is designed to engage veterans in self-care and prevent risk progression, critical to prevention.

It was found that PCPs often did not ask nurses to coach normal- or low-risk veterans on preventative foot care, as suggested by the low rates at which patients were offered education. This is an area we will target with future quality improvement efforts. All patients with DM should have general education about risk factors and appropriate management of them to decrease their risk for complications.⁹ Preventative foot care education is a critical resource to share with patients during health coaching opportunities to clarify misunderstandings and support change talk when patients are ambivalent or resistant to change. Individual or group-based nurse visits can facilitate better coaching for patients.

At the VA, coaching begins with a conversation about what matters most to the veteran, facilitating the development of a personalized plan based on patients’ values, needs, preferences and goals.^9,10,12,17 Coaching allows nurses to assess veterans’ knowledge and willingness to engage in healthy habits; and identify additional resources to help them achieve their goals.

Limitations

There are many limitations to this short quality improvement analysis. For example, only 1 of 2 clinics that piloted the program change was evaluated. In addition, there are 11 other clinics that need additional in-depth education on the program change. Although this analysis was overwhelmingly positive, it may not be as successful at other clinic sites and may be subject to the Hawthorne effect—since the 2 piloted locations knew they were being observed for the quality improvement program and may have made an extra effort to be compliant.¹⁸ Additionally, we were unable to track the records of veterans receiving care through the VA Choice Program for this analysis resulting in a lack of documentation of completed diabetic foot examinations and a lack of internal referrals to VA podiatry.

Another major limitation of this project involved calculating the number of referrals placed to podiatry. On January 1, 2018, about halfway through the program evaluation, a national VA decision enabled veterans to self-refer to podiatry, which may have limited the number of podiatry referrals placed by PCPs. Finally, patients could refuse podiatry referrals. In the 9-month postimplementation period, 57 (64.8%) veterans declined podiatry referrals, according to their CPRS records.

Although, there was an improvement in the accuracy of diabetic foot examinations, ARAs, and appropriate podiatry referrals, the ultimate goal of reducing diabetic foot ulcers and lower limb amputations was not tracked due to the limited timeframe of this analysis. Tracking these endpoints with continuous plan-do-study-act cycles are needed for this ongoing quality improvement project.

Conclusion

The goal of the VAPORHCS Comprehensive Foot Care program is to provide veterans with a program that is predictable, easy and consistent to prevent and treat foot ulcers to reduce the rate of lower limb amputations. It requires multidisciplinary team collaboration for success. Implementation of this new comprehensive program has increased the number of accurate annual foot exams, ARAs and podiatry referrals. Despite these improvements, areas of future improvement include emphasizing patient education and ongoing provider compliance with annual assessments.

Author contributions
MHG proposed the program evaluation project idea. TVQ collected and analyzed the data and wrote the manuscript. MHG oversaw the project and edited the manuscript. TVQ is the guarantor of this project and takes responsibility for the contents of this journal article.

Acknowledgments
The authors thank Tyra Haebe, VAPORHCS Prevention of Amputation in Veterans Everywhere (PAVE) Manager, and the entire VAPORHCS PAVE committee for their support in this program evaluation project.

Individuals with diabetes mellitus (DM), peripheral vascular disease, or end-stage renal disease are at risk for a nontraumatic lower limb amputation.¹ Veterans have a high number of risk factors and are especially vulnerable. More than 70% of veterans enrolled in US Department of Veterans Affairs (VA) healthcare are at increased risk for developing DM due to excess weight, poor eating habits, and physical inactivity.² One in 4 veterans has DM, compared with 1 in 6 in the general population.²

DM can lead to long-term complications including limb amputations. Annually in the US about 73,000 nontraumatic lower limb amputations are performed and > 60% occur among persons with DM.³ Complications from diabetic wounds are the cause of 90% of lower limb amputations, and foot ulcers are the most prevalent complication.⁴ Diabetic ulcers are slow to heal due to vascular impairments and nerve damage.⁵ Peripheral vascular disease, a common comorbid condition, contributes to restricted blood flow and can lead to tissue death or gangrene requiring amputation.⁶

Between 2010 and 2014, VA Portland Healthcare System (VAPORHCS) had one of the highest national amputation rates in VA.⁷ A clinical chart review found that annual foot examinations and amputation risk assessments (ARAs) were not completed with all at-risk veterans. In 2013, a VA Office of Inspector General (OIG) national report found that more than one-third of veterans enrolled in VA with DM had no documentation of required annual foot exams.⁸ In 2017, VA released Directive 1410, which outlined the scope of care required to prevent and treat lower limb complications and amputations for veterans at risk for primary or secondary limb loss.¹ This national initiative is a comprehensive approach that engages multiprofessional teams to perform routine foot examinations and amputation risk assessments; identify and promptly treat foot ulcers; track, monitor and educate at-risk veterans; and participate in clinical education to enhance staff skills.

To decrease the amputation rate, VAPORHCS redesigned its foot-care program to comply with the national initiative. As is typical in VA, VAPORHCS uses a team-based approach in primary care. The basic 4-member team patient-aligned care team (PACT) consists of a physician or nurse practitioner (NP) primary care provider (PCP), a registered nurse (RN) care manager, a licensed practical nurse (LPN), and a medical staff assistant (MSA) for administrative support. Each PACT cares for about 1,800 veterans. Formerly, LPNs completed the annual diabetic foot exams, and PCPs verified the exams and completed the ARA based on the LPNs’ findings. If patients were moderate risk or high risk, they were referred to podiatry. The VAPORHCS audit found that not all at-risk veterans had both the foot exam and ARA completed, or were referred to podiatry when indicated. There was a need for a process improvement project to develop a seamless program consisting of all recommended foot care components crucial for timely care.

This quality improvement project sought to evaluate the effectiveness of the process changes by examining PCPs’ adoption of, and consistency in completing annual diabetic foot exams and ARAs with veterans. The goals of the project were to evaluate changes in the: (1) Number of accurate diabetic foot exams and amputation risk assessments completed with veterans with DM; (2) Number and timeliness of appropriate referrals to podiatry for an in-depth assessment and treatment of veterans found to be at moderate-to-high risk for lower limb amputations; and (3) Number of administrative text orders entered by PCPs for nurse care managers to offer foot care education and the completion of the education with veterans found to be at normal-to-low risk for lower limb amputations. The institutional review boards of VAPORHCS and Gonzaga University approved the study.

Methods

Established by the American Diabetes Association and endorsed by the American Association of Clinical Endocrinologists, the comprehensive foot exam includes a visual exam, pedal pulse checks, and a sensory exam.^9,10 The templated Computerized Patient Record System (CPRS) electronic health record note specifies normal and abnormal parameters of each section. On the same template, the provider assigns an ARA score based on the results of the completed foot exam. Risk scores range from 0 to 3 (0, normal or no risk; 1, low risk, 2; moderate risk; 3, high risk) If the veteran has normal or low risk, the PCP can encourage the veteran to remain at low risk by entering an administrative CPRS text order for the nurse care manager to offer education about daily foot care at the same visit or at a scheduled follow-up visit. This process facilitates nurse care managers to include routine foot care as integral to their usual duties coaching veterans to engage in self-care to manage chronic conditions. If the risk is assessed as moderate or high risk, PCPs are prompted to send a referral to podiatry to repeat the foot exam, verify the ARA score, and provide appropriate foot care treatment and follow-up.

On October 31, 2017, following training on the updated foot exam and ARA template with staff at the 13 VAPORHCS outpatient clinic sites, 2 sites piloted all components of the Comprehensive Foot Care program. An in-person training was completed with PCPs to review the changes of the foot care template in CPRS and to answer their questions about it. PCPs were required to complete both the 3-part foot exam and ARA at least once annually with veterans with DM.

An electronic clinical reminder was built to alert PCPs and PACTs that a veteran was either due or overdue for an exam and risk assessment. VA podiatrists agreed to complete the reminder with veterans under their care. One of the 2 sites was randomly selected for this study. Data were collected from August 1, 2017 to July 31, 2018. Patients were identified from the Diabetes Registry, a database established at VAPORHCS in 2008 to track veterans with DM to ensure quality care.¹¹ Veterans’ personal health identifiers from the registry were used to access their health records to complete chart reviews and assess the completion, accuracy and timeliness of all foot care components.

The Diabetes Registry lists a veterans’ upcoming appointments and tracks their most recent clinic visits; laboratory tests; physical exams; and screening exams for foot, eye, and renal care. Newly diagnosed veterans are uploaded automatically into this registry by tracking all DM-related International Classification of Diseases (ICD-10) codes, hemoglobin A_1c (HbA_1c) levels ≥ 6.5%, or outpatient prescriptions for insulin or oral hypoglycemic agents.¹¹

Study Design

This quality improvement project evaluated PCPs’ actions in a program process change intended to improve foot care provided with veterans at-risk for nontraumatic lower limb amputations. Audits of CPRS records and the Diabetes Registry determined the results of the practice change. Data on the total number of foot exams, amputation risk scores, appropriate podiatry referrals, administrative orders for nurse coaching, and completed foot care education were collected during the study period. Data collected for the 3-month period preceding the process change established preimplementation comparison vs the postimplementation data. Data were collected at 3, 6, and 9 months after implementation. The foot exams and ARAs were reviewed to determine whether exams and assessments were completed accurately during the pre- and post-implementation timeframes. Incomplete or clearly incorrectly completed documentation were considered inaccurate. For example, it was considered inaccurate if only the foot exam portion was completed in the assessment and the ARA was not.

Data Analysis

Data on the total number of accurately completed foot examinations and ARAs, total number of podiatry referrals, and total number of administrative text orders placed by PCPs, and education completed by nurse care managers were assessed. Statistical significance was evaluated using χ² and Fisher exact test as appropriate. A Pearson correlation coefficient was used to determine whether there was a statistically significant increase in accurate foot examinations and ARAs as well as total number of podiatry referrals during the study period. Statistical analyses were performed using Stata 14.1 statistical software (College Station, TX).

Results

A total of 1,242 completed diabetic foot examinations were identified from August 1, 2017 to July 31, 2018 using the Diabetes Registry (Table). For the 3 months prior to the change, there were 191 appropriately completed foot examinations and ARAs. This number increased progressively over three 3-month periods (Figure 1). Within the 1-year study period, there was a statistically significant increase in the number of appropriate foot examinations (r = 0.495). PCPs placed 34 podiatry referrals during the prechange period. After the change, the number of appropriate referrals increased statistically significantly in the 3 following 3-month-periods (r = 0.222) (Figure 2).

To determine the accuracy of documentation and ratio of appropriate referrals, the 3-month prechange data was compared with the 9-month postchange period. There was a statistically significant increase from pre- to postchange accuracy of documentation for examinations and ARAs (53.1% vs. 97.7%). The percentage of appropriate podiatry referrals increased significantly from 41.5% to 76.8%. Overall, there was poor adherence to protocol for the text order and education that was implemented during the change. Only 4.6% of patients had an administrative text order entered into CPRS and 3.9% were provided with foot care coaching. There was no statistical difference in the use of text orders between the first 3-month period and the last 3-month period (5.2% vs. 2.1%). Similarly, there was no statistical difference in the rate of patient education between the first 3-month period and the final 3-month period (2.6% vs. 2.1%).

Notably, at the end of the first year of this evaluation, 119 veterans at the clinic did not show a recorded comprehensive foot examination since receiving a DM diagnosis and 299 veterans were due for an annual examination—a 25.2% gap of veterans without the recommended progression of foot care services. Of those that previously had a recorded foot examination, 51 (17.0%) veterans were found to be ≥ 2 years overdue.

Discussion

DM management requires a comprehensive team-based approach to help monitor for associated complications. At the VA, PACTs are veterans’ initial and primary point of contact for chronic condition management. PACTs have regular opportunities to engage veterans in initial and follow-up care and appropriate self-care. PCPs are critical in placing referrals for specialized care promptly to prevent and minimize complications such as foot ulcers, and ultimately, lower limb amputations.^9,10,12

When PCPs assume responsibility for the entire foot examination, they are able to identify problems early.¹ Left untreated, foot wounds and ulcers have the potential to grow into serious infections.⁹ Early risk identification and management can lead to increased patient satisfaction, improved life expectancy, quality of life, and ultimately, lower healthcare costs.¹²

Multiple studies have shown the clinical importance of foot examinations in preventative care. In one study, researchers found that completing foot examinations, among other early interventions, increased life expectancy and reduced foot complications.¹³ Diabetic foot management programs involving screening and categorizing patients into low- and high-risk groups had a 47.4% decrease in the incidence of amputations and 37.8% decrease in hospital admissions.¹⁴ Amputations were found to be inversely correlated with multidisciplinary foot care programs with reduction of lower limb amputations at 2 years.¹⁵ The Centers for Disease Control and Prevention found that comprehensive foot care programs that include a foot examination, ARA, appropriate referrals to specialists, and foot-care education and preventative services can reduce lower limb amputation rates by 45% to 85%.¹⁶

With one of the highest amputation rates in VA, VAPORHCS needed an integrated approach to ensure that appropriate foot care occurred regularly with veterans with DM. Prior to the process change, LPNs completed foot examinations and PCPs completed the ARA. Separating these clinical services resulted in few veterans receiving an amputation risk score. Of those with scores, the lack of a standardized program protocol resulted in discrepancies between ARAs from patient to patient as health care providers did not have clear or enough information to select the correct score and make the appropriate referrals. Thus, veterans previously identified as at moderate or high risk also lacked podiatric follow-up care.

The new quality-driven process change corrected the documentation process to nationally accepted standards. The goal was to create a consistent template in the electronic health record for all health care providers. The new template simplifies the documentation process and clarifies the amputation risk score assignment, which allows for proper foot care management. The PCP completes the process from assessment through referral, removing gaps in care and improving efficiency. Although this change was initially met with resistance from PCPs, it led to a significant increase in the number of patients with accurately documented examinations. Similarly, the number of appropriate referrals significantly rose during the study period. The standardized documentation process resulted in improved accurate examinations and ARAs over the past year. The new program also resulted in an increased number of appropriate podiatry referrals for those identified to be at moderate or high risk. This elevation of care is crucial for veterans to receive frequent follow-up visits for preventative care and/or treatment, including surgical modalities to promote limb salvage.

Barriers

This project identified several barriers to the Comprehensive Foot Care program. One major barrier was health care provider resistance to using the new process. For example, VAPORHCS podiatrists are not using the new template with established patients, which requires PCPs to complete the clinical reminder template for quality performance, an additional burden unrelated to clinical care. PCPs that do complete the foot examination/ARA templated note use the podiatrist’s visit note without personally assessing the patient.

PCPs also have been resistant to entering administrative text orders for preventative foot care in normal- or low-risk veterans (4.6% overall), which has resulted in decreased patient education (3.9% overall). Education for normal-risk and low-risk patients is designed to engage veterans in self-care and prevent risk progression, critical to prevention.

It was found that PCPs often did not ask nurses to coach normal- or low-risk veterans on preventative foot care, as suggested by the low rates at which patients were offered education. This is an area we will target with future quality improvement efforts. All patients with DM should have general education about risk factors and appropriate management of them to decrease their risk for complications.⁹ Preventative foot care education is a critical resource to share with patients during health coaching opportunities to clarify misunderstandings and support change talk when patients are ambivalent or resistant to change. Individual or group-based nurse visits can facilitate better coaching for patients.

At the VA, coaching begins with a conversation about what matters most to the veteran, facilitating the development of a personalized plan based on patients’ values, needs, preferences and goals.^9,10,12,17 Coaching allows nurses to assess veterans’ knowledge and willingness to engage in healthy habits; and identify additional resources to help them achieve their goals.

Limitations

There are many limitations to this short quality improvement analysis. For example, only 1 of 2 clinics that piloted the program change was evaluated. In addition, there are 11 other clinics that need additional in-depth education on the program change. Although this analysis was overwhelmingly positive, it may not be as successful at other clinic sites and may be subject to the Hawthorne effect—since the 2 piloted locations knew they were being observed for the quality improvement program and may have made an extra effort to be compliant.¹⁸ Additionally, we were unable to track the records of veterans receiving care through the VA Choice Program for this analysis resulting in a lack of documentation of completed diabetic foot examinations and a lack of internal referrals to VA podiatry.

Another major limitation of this project involved calculating the number of referrals placed to podiatry. On January 1, 2018, about halfway through the program evaluation, a national VA decision enabled veterans to self-refer to podiatry, which may have limited the number of podiatry referrals placed by PCPs. Finally, patients could refuse podiatry referrals. In the 9-month postimplementation period, 57 (64.8%) veterans declined podiatry referrals, according to their CPRS records.

Although, there was an improvement in the accuracy of diabetic foot examinations, ARAs, and appropriate podiatry referrals, the ultimate goal of reducing diabetic foot ulcers and lower limb amputations was not tracked due to the limited timeframe of this analysis. Tracking these endpoints with continuous plan-do-study-act cycles are needed for this ongoing quality improvement project.

Conclusion

The goal of the VAPORHCS Comprehensive Foot Care program is to provide veterans with a program that is predictable, easy and consistent to prevent and treat foot ulcers to reduce the rate of lower limb amputations. It requires multidisciplinary team collaboration for success. Implementation of this new comprehensive program has increased the number of accurate annual foot exams, ARAs and podiatry referrals. Despite these improvements, areas of future improvement include emphasizing patient education and ongoing provider compliance with annual assessments.

Author contributions
MHG proposed the program evaluation project idea. TVQ collected and analyzed the data and wrote the manuscript. MHG oversaw the project and edited the manuscript. TVQ is the guarantor of this project and takes responsibility for the contents of this journal article.

Acknowledgments
The authors thank Tyra Haebe, VAPORHCS Prevention of Amputation in Veterans Everywhere (PAVE) Manager, and the entire VAPORHCS PAVE committee for their support in this program evaluation project.

The US Department of Veterans Affairs (VA) remains the largest integrated health care system in the US serving 9 million veterans. Two recent studies that compared 30-day mortality and readmission rates between VA and non-VA hospitals among older men with acute myocardial infarction (AMI), and heart failure (HF). The studies found that hospitalization at VA hospitals was associated with lower risk-standardized 30-day all-cause mortality rates for MI and HF when compared with hospitalization at non-VA hospitals.^1,2

However, it is unknown whether the delivery of cardiovascular care is optimized in the VA system. For example, in comparisons between generalist-led hospitalized care for MI and HF, several studies have demonstrated that cardiology-led care has been associated with lower rates of mortality.^3-5 Although data on the types of cardiac technology and use of cardiac procedures were described previously, we have not found detailed information on the types of inpatient cardiology services provided at VA medical centers nationwide.^1,6,7 To develop further improvements in delivery of cardiovascular care within the VA, a better understanding of the types of resources that are currently available within the VA system must be made available. In this article, we present results of a national survey of cardiology services at VA facilities.

Methods

From February to March of 2017, we conducted a comprehensive nation-wide survey of all VA facilities to quantify the availability of cardiology services, excluding cardiothoracic surgical services. The survey questions are listed in the Appendix. The chief of medicine and the chief of cardiology were each e-mailed 3 times at every facility. If no response was received from a facility, we e-mailed the chief of staff 3 times. If there still was no response, the remaining facilities were contacted by phone and study authors (PE and WB) spoke to individuals directly regarding the structure of cardiology services at a facility. Responses were categorized by facility level of complexity. Complexity designation was determined by the VA Central Office (VACO)—level 1 facilities represent the most complex and level 3 facilities are the least complex. VACO also divides facility complexity into sublevels, for example level 1A facilities generally are associated with academic medical centers and provide the highest levels (tertiary or quaternary) of care.⁸

Results were coded according to a predetermined rubric for how cardiology services are structured (admitting service, consult service, inpatient, outpatient, other) and for how they were staffed (attending only, house staff, or advanced practice providers (APPs). After the first wave of surveys, 2 additional questions were added to the survey tool; these asked about employed vs contracted cardiologist and use of APPs. The results were tabulated and simple percentages calculated to express the prevalence of each structure and staffing model.

The study was reviewed and approved by the University of Utah/Salt Lake City VA Medical Center joint institutional review board and all authors completed human subjects research training.

Results

Study authors initially identified all 168 VA medical center facilities operating in 2017. Initial polling revealed that multiple facilities either were substations or had agreements for cardiology services from larger facilities, with 1 facility having 2 campuses with different levels of service at each. After adjusting for these nuances, the total number of potential respondents was 139. We obtained a response from 122 of the 139 facilities for an overall survey completion rate of 88%. Response rates varied by complexity level (Table 1). The survey received responses from all Level 1A and 1B facilities, 96% from Level 1C facilities; 83% (20/24) from level 2 facilities, and 62% (18/30) from level 3 facilities. (Please note that in the reference document providing detailed descriptions of the VA level of complexity has different numbers for each facility type given that there has been reassignments of the levels since our survey was completed.)⁸

We were specifically interested in inpatient cardiology services and whether facilities provided only consult services or inpatient services led by a cardiology attending. Having inpatient services does not exclude the availability of consult-liaison services (Table 2).

Higher complexity facilities (1A and 1B) were more likely to have dedicated, cardiology-led inpatient services, while lower complexity facilities relied on a cardiology consult service. Two-thirds of Level 3 facilities did not have inpatient cardiology services available.

Dedicated cardiovascular care unit (CCU) teams were the most common inpatient service provided, present in more than half of all Level 1 facilities and 83% of Level 1A facilities (Table 3). Cardiology-led floor teams were available in 45% and 33% of level 1A and 1B facilities, respectively, but were much less common in Level 1C and Levels 2 and 3 facilities (4%, 10%, 0%, respectively). Only 31% of Level 1 facilities had both a CCU team and a cardiology-led inpatient floor team. Inpatient consulting cardiologists were commonly available at Levels 1 and 2 facilities; however, only 33% of Level 3 facilities had inpatient consulting cardiologists.

Housestaff-managed inpatient services, teams consisting of, but not limited to, medical residents in training, led by a cardiology attending were present in 73% of Level 1 facilities. Interestingly, Level 1B facilities were more likely to have housestaff-led services than were Level 1A facilities (90% and 80% respectively). Inpatient advanced heart failure services were less common and available only in Level 1 facilities. We did not survey the specific details of the other (eg, led by a noncardiology attending physician) models of inpatient cardiology care provided.

Cardiac catheterization (including interventional cardiology and electrophysiology [EP]) services, varied considerably. Ninety percent of Level 1A facilities offered interventional services, compared with only 52% of Level 1C facilities offered interventions. EP services were divided into simple (device only) and complex (ablations). As noted, complex EP services were more common in more complex facilities; for example, 10% of Level 2 facilities offered device placement but none had advanced EP services.

Outpatient services were widely available. Most facilities offered outpatient consultative cardiology services, ranging from 95% (Level 1) to 89% (Level 3) and outpatient cardiology continuity clinics 99% (Level 1) to 72% (Level 3).

Regardless of level of complexity, > 80% of facilities employed cardiologists. Many also used contract cardiologists. No facility utilized only contracted cardiologists. Use of nurse practitioners (NPs) and physician assistants (PAs) to assist with managing inpatient services was relatively common, with 61% of Level 1 facilities using such services.

Discussion

Studies of patient outcomes for various conditions, including cardiac conditions, in the 1990s found that when compared with non-VA health-care systems, patient outcomes in the VA were less favorable.⁹ During the late 1990s, the VA embraced quality and safety initiatives that have continued to the present time.^9,10 Recent studies have found that, in most (but not all) cases, VA patient outcomes are as good as, and in many cases better, than are non-VA patient outcomes.^1,10,11 The exact changes that have improved care are not clear, though studies of other health care systems have considered variation in services and costs in relationship to morbidity and mortality outcomes.^12-14 In the context of better patient outcomes in VA hospitals, the present study provides insight into the cardiology services available at VA facilities throughout the nation.

Limitations

While this study provides background information that may be useful in comparing cardiology services between VA and non-VA systems, drawing causal relationships may not be warranted. For example, while the literature generally supports the concept of inpatient cardiology services led by an attending cardiologist, a substantial numbers of VA inpatient facilities have not yet adopted this model.^4-6 Even among more complex, level 1 facilities, we found that only 31% offered both an inpatient CCU and floor team service led by an attending cardiologist physician. Thus, 69% of Level 1 facilities reported caring for patients with a primary cardiology problem through a noncardiology admitting services (with access to a cardiology consultation service). Additional studies should be conducted that would evaluate patient outcomes in relationship to the types of services available at a given VA medical center. Patient outcomes in relationship to service provision between the VA and non-VA health care systems also are warranted.

This study is limited by its reliance on self-reporting. Although we believe that we reached respondents who were qualified to complete the survey, the accuracy of reporting was not independently validated. Further, we asked questions about the most frequent models of cardiology care but may not have captured more novel methods. In trying to keep the survey time to < 2 minutes, we did not explore other details of cardiology services, such as the availability of a dedicated pharmacist, nor more advanced procedures such as transcatheter aortic valve replacement. Additionally, the present study is a snapshot of cardiology services for a given period, and, as noted above, did not look at patient outcomes. Further research is needed to determine which service provided is most beneficial or feasible in improving patient outcomes, which includes examining the various models of inpatient cardiology-led services for optimal care delivery.

Conclusion

Cardiology services were widely available throughout the VA system. However, the types of services available varied considerably. Predictably, facilities that were more complex generally had more advanced services available. Providing a general overview of how cardiovascular care is being delivered currently across VA systems helps to identify areas for optimization within VA facilities of various complexities with initiatives such as implementation of cardiology-led inpatient services, which may be beneficial in improving patient care outcomes as demonstrated previously in other large healthcare systems.

Acknowledgments
This material is the result of work supported with resources and use of the facilities at the George E. Wahlen Salt Lake City VA Medical Center. We are grateful to all of those who responded to our survey, and the support of the facility leadership. We are thankful for Tasia M. Nash and Tammy Jackson who helped to organize the data, and to Leigh Eleazer for her help in the manuscript preparation and formatting. 

The US Department of Veterans Affairs (VA) remains the largest integrated health care system in the US serving 9 million veterans. Two recent studies that compared 30-day mortality and readmission rates between VA and non-VA hospitals among older men with acute myocardial infarction (AMI), and heart failure (HF). The studies found that hospitalization at VA hospitals was associated with lower risk-standardized 30-day all-cause mortality rates for MI and HF when compared with hospitalization at non-VA hospitals.^1,2

However, it is unknown whether the delivery of cardiovascular care is optimized in the VA system. For example, in comparisons between generalist-led hospitalized care for MI and HF, several studies have demonstrated that cardiology-led care has been associated with lower rates of mortality.^3-5 Although data on the types of cardiac technology and use of cardiac procedures were described previously, we have not found detailed information on the types of inpatient cardiology services provided at VA medical centers nationwide.^1,6,7 To develop further improvements in delivery of cardiovascular care within the VA, a better understanding of the types of resources that are currently available within the VA system must be made available. In this article, we present results of a national survey of cardiology services at VA facilities.

Methods

From February to March of 2017, we conducted a comprehensive nation-wide survey of all VA facilities to quantify the availability of cardiology services, excluding cardiothoracic surgical services. The survey questions are listed in the Appendix. The chief of medicine and the chief of cardiology were each e-mailed 3 times at every facility. If no response was received from a facility, we e-mailed the chief of staff 3 times. If there still was no response, the remaining facilities were contacted by phone and study authors (PE and WB) spoke to individuals directly regarding the structure of cardiology services at a facility. Responses were categorized by facility level of complexity. Complexity designation was determined by the VA Central Office (VACO)—level 1 facilities represent the most complex and level 3 facilities are the least complex. VACO also divides facility complexity into sublevels, for example level 1A facilities generally are associated with academic medical centers and provide the highest levels (tertiary or quaternary) of care.⁸

Results were coded according to a predetermined rubric for how cardiology services are structured (admitting service, consult service, inpatient, outpatient, other) and for how they were staffed (attending only, house staff, or advanced practice providers (APPs). After the first wave of surveys, 2 additional questions were added to the survey tool; these asked about employed vs contracted cardiologist and use of APPs. The results were tabulated and simple percentages calculated to express the prevalence of each structure and staffing model.

The study was reviewed and approved by the University of Utah/Salt Lake City VA Medical Center joint institutional review board and all authors completed human subjects research training.

Results

Study authors initially identified all 168 VA medical center facilities operating in 2017. Initial polling revealed that multiple facilities either were substations or had agreements for cardiology services from larger facilities, with 1 facility having 2 campuses with different levels of service at each. After adjusting for these nuances, the total number of potential respondents was 139. We obtained a response from 122 of the 139 facilities for an overall survey completion rate of 88%. Response rates varied by complexity level (Table 1). The survey received responses from all Level 1A and 1B facilities, 96% from Level 1C facilities; 83% (20/24) from level 2 facilities, and 62% (18/30) from level 3 facilities. (Please note that in the reference document providing detailed descriptions of the VA level of complexity has different numbers for each facility type given that there has been reassignments of the levels since our survey was completed.)⁸

We were specifically interested in inpatient cardiology services and whether facilities provided only consult services or inpatient services led by a cardiology attending. Having inpatient services does not exclude the availability of consult-liaison services (Table 2).

Higher complexity facilities (1A and 1B) were more likely to have dedicated, cardiology-led inpatient services, while lower complexity facilities relied on a cardiology consult service. Two-thirds of Level 3 facilities did not have inpatient cardiology services available.

Dedicated cardiovascular care unit (CCU) teams were the most common inpatient service provided, present in more than half of all Level 1 facilities and 83% of Level 1A facilities (Table 3). Cardiology-led floor teams were available in 45% and 33% of level 1A and 1B facilities, respectively, but were much less common in Level 1C and Levels 2 and 3 facilities (4%, 10%, 0%, respectively). Only 31% of Level 1 facilities had both a CCU team and a cardiology-led inpatient floor team. Inpatient consulting cardiologists were commonly available at Levels 1 and 2 facilities; however, only 33% of Level 3 facilities had inpatient consulting cardiologists.

Housestaff-managed inpatient services, teams consisting of, but not limited to, medical residents in training, led by a cardiology attending were present in 73% of Level 1 facilities. Interestingly, Level 1B facilities were more likely to have housestaff-led services than were Level 1A facilities (90% and 80% respectively). Inpatient advanced heart failure services were less common and available only in Level 1 facilities. We did not survey the specific details of the other (eg, led by a noncardiology attending physician) models of inpatient cardiology care provided.

Cardiac catheterization (including interventional cardiology and electrophysiology [EP]) services, varied considerably. Ninety percent of Level 1A facilities offered interventional services, compared with only 52% of Level 1C facilities offered interventions. EP services were divided into simple (device only) and complex (ablations). As noted, complex EP services were more common in more complex facilities; for example, 10% of Level 2 facilities offered device placement but none had advanced EP services.

Outpatient services were widely available. Most facilities offered outpatient consultative cardiology services, ranging from 95% (Level 1) to 89% (Level 3) and outpatient cardiology continuity clinics 99% (Level 1) to 72% (Level 3).

Regardless of level of complexity, > 80% of facilities employed cardiologists. Many also used contract cardiologists. No facility utilized only contracted cardiologists. Use of nurse practitioners (NPs) and physician assistants (PAs) to assist with managing inpatient services was relatively common, with 61% of Level 1 facilities using such services.

Discussion

Studies of patient outcomes for various conditions, including cardiac conditions, in the 1990s found that when compared with non-VA health-care systems, patient outcomes in the VA were less favorable.⁹ During the late 1990s, the VA embraced quality and safety initiatives that have continued to the present time.^9,10 Recent studies have found that, in most (but not all) cases, VA patient outcomes are as good as, and in many cases better, than are non-VA patient outcomes.^1,10,11 The exact changes that have improved care are not clear, though studies of other health care systems have considered variation in services and costs in relationship to morbidity and mortality outcomes.^12-14 In the context of better patient outcomes in VA hospitals, the present study provides insight into the cardiology services available at VA facilities throughout the nation.

Limitations

While this study provides background information that may be useful in comparing cardiology services between VA and non-VA systems, drawing causal relationships may not be warranted. For example, while the literature generally supports the concept of inpatient cardiology services led by an attending cardiologist, a substantial numbers of VA inpatient facilities have not yet adopted this model.^4-6 Even among more complex, level 1 facilities, we found that only 31% offered both an inpatient CCU and floor team service led by an attending cardiologist physician. Thus, 69% of Level 1 facilities reported caring for patients with a primary cardiology problem through a noncardiology admitting services (with access to a cardiology consultation service). Additional studies should be conducted that would evaluate patient outcomes in relationship to the types of services available at a given VA medical center. Patient outcomes in relationship to service provision between the VA and non-VA health care systems also are warranted.

This study is limited by its reliance on self-reporting. Although we believe that we reached respondents who were qualified to complete the survey, the accuracy of reporting was not independently validated. Further, we asked questions about the most frequent models of cardiology care but may not have captured more novel methods. In trying to keep the survey time to < 2 minutes, we did not explore other details of cardiology services, such as the availability of a dedicated pharmacist, nor more advanced procedures such as transcatheter aortic valve replacement. Additionally, the present study is a snapshot of cardiology services for a given period, and, as noted above, did not look at patient outcomes. Further research is needed to determine which service provided is most beneficial or feasible in improving patient outcomes, which includes examining the various models of inpatient cardiology-led services for optimal care delivery.

Conclusion

Cardiology services were widely available throughout the VA system. However, the types of services available varied considerably. Predictably, facilities that were more complex generally had more advanced services available. Providing a general overview of how cardiovascular care is being delivered currently across VA systems helps to identify areas for optimization within VA facilities of various complexities with initiatives such as implementation of cardiology-led inpatient services, which may be beneficial in improving patient care outcomes as demonstrated previously in other large healthcare systems.

Acknowledgments
This material is the result of work supported with resources and use of the facilities at the George E. Wahlen Salt Lake City VA Medical Center. We are grateful to all of those who responded to our survey, and the support of the facility leadership. We are thankful for Tasia M. Nash and Tammy Jackson who helped to organize the data, and to Leigh Eleazer for her help in the manuscript preparation and formatting. 

The US Department of Veterans Affairs (VA) remains the largest integrated health care system in the US serving 9 million veterans. Two recent studies that compared 30-day mortality and readmission rates between VA and non-VA hospitals among older men with acute myocardial infarction (AMI), and heart failure (HF). The studies found that hospitalization at VA hospitals was associated with lower risk-standardized 30-day all-cause mortality rates for MI and HF when compared with hospitalization at non-VA hospitals.^1,2

However, it is unknown whether the delivery of cardiovascular care is optimized in the VA system. For example, in comparisons between generalist-led hospitalized care for MI and HF, several studies have demonstrated that cardiology-led care has been associated with lower rates of mortality.^3-5 Although data on the types of cardiac technology and use of cardiac procedures were described previously, we have not found detailed information on the types of inpatient cardiology services provided at VA medical centers nationwide.^1,6,7 To develop further improvements in delivery of cardiovascular care within the VA, a better understanding of the types of resources that are currently available within the VA system must be made available. In this article, we present results of a national survey of cardiology services at VA facilities.

Methods

From February to March of 2017, we conducted a comprehensive nation-wide survey of all VA facilities to quantify the availability of cardiology services, excluding cardiothoracic surgical services. The survey questions are listed in the Appendix. The chief of medicine and the chief of cardiology were each e-mailed 3 times at every facility. If no response was received from a facility, we e-mailed the chief of staff 3 times. If there still was no response, the remaining facilities were contacted by phone and study authors (PE and WB) spoke to individuals directly regarding the structure of cardiology services at a facility. Responses were categorized by facility level of complexity. Complexity designation was determined by the VA Central Office (VACO)—level 1 facilities represent the most complex and level 3 facilities are the least complex. VACO also divides facility complexity into sublevels, for example level 1A facilities generally are associated with academic medical centers and provide the highest levels (tertiary or quaternary) of care.⁸

Results were coded according to a predetermined rubric for how cardiology services are structured (admitting service, consult service, inpatient, outpatient, other) and for how they were staffed (attending only, house staff, or advanced practice providers (APPs). After the first wave of surveys, 2 additional questions were added to the survey tool; these asked about employed vs contracted cardiologist and use of APPs. The results were tabulated and simple percentages calculated to express the prevalence of each structure and staffing model.

The study was reviewed and approved by the University of Utah/Salt Lake City VA Medical Center joint institutional review board and all authors completed human subjects research training.

Results

Study authors initially identified all 168 VA medical center facilities operating in 2017. Initial polling revealed that multiple facilities either were substations or had agreements for cardiology services from larger facilities, with 1 facility having 2 campuses with different levels of service at each. After adjusting for these nuances, the total number of potential respondents was 139. We obtained a response from 122 of the 139 facilities for an overall survey completion rate of 88%. Response rates varied by complexity level (Table 1). The survey received responses from all Level 1A and 1B facilities, 96% from Level 1C facilities; 83% (20/24) from level 2 facilities, and 62% (18/30) from level 3 facilities. (Please note that in the reference document providing detailed descriptions of the VA level of complexity has different numbers for each facility type given that there has been reassignments of the levels since our survey was completed.)⁸

We were specifically interested in inpatient cardiology services and whether facilities provided only consult services or inpatient services led by a cardiology attending. Having inpatient services does not exclude the availability of consult-liaison services (Table 2).

Higher complexity facilities (1A and 1B) were more likely to have dedicated, cardiology-led inpatient services, while lower complexity facilities relied on a cardiology consult service. Two-thirds of Level 3 facilities did not have inpatient cardiology services available.

Dedicated cardiovascular care unit (CCU) teams were the most common inpatient service provided, present in more than half of all Level 1 facilities and 83% of Level 1A facilities (Table 3). Cardiology-led floor teams were available in 45% and 33% of level 1A and 1B facilities, respectively, but were much less common in Level 1C and Levels 2 and 3 facilities (4%, 10%, 0%, respectively). Only 31% of Level 1 facilities had both a CCU team and a cardiology-led inpatient floor team. Inpatient consulting cardiologists were commonly available at Levels 1 and 2 facilities; however, only 33% of Level 3 facilities had inpatient consulting cardiologists.

Housestaff-managed inpatient services, teams consisting of, but not limited to, medical residents in training, led by a cardiology attending were present in 73% of Level 1 facilities. Interestingly, Level 1B facilities were more likely to have housestaff-led services than were Level 1A facilities (90% and 80% respectively). Inpatient advanced heart failure services were less common and available only in Level 1 facilities. We did not survey the specific details of the other (eg, led by a noncardiology attending physician) models of inpatient cardiology care provided.

Cardiac catheterization (including interventional cardiology and electrophysiology [EP]) services, varied considerably. Ninety percent of Level 1A facilities offered interventional services, compared with only 52% of Level 1C facilities offered interventions. EP services were divided into simple (device only) and complex (ablations). As noted, complex EP services were more common in more complex facilities; for example, 10% of Level 2 facilities offered device placement but none had advanced EP services.

Outpatient services were widely available. Most facilities offered outpatient consultative cardiology services, ranging from 95% (Level 1) to 89% (Level 3) and outpatient cardiology continuity clinics 99% (Level 1) to 72% (Level 3).

Regardless of level of complexity, > 80% of facilities employed cardiologists. Many also used contract cardiologists. No facility utilized only contracted cardiologists. Use of nurse practitioners (NPs) and physician assistants (PAs) to assist with managing inpatient services was relatively common, with 61% of Level 1 facilities using such services.

Discussion

Studies of patient outcomes for various conditions, including cardiac conditions, in the 1990s found that when compared with non-VA health-care systems, patient outcomes in the VA were less favorable.⁹ During the late 1990s, the VA embraced quality and safety initiatives that have continued to the present time.^9,10 Recent studies have found that, in most (but not all) cases, VA patient outcomes are as good as, and in many cases better, than are non-VA patient outcomes.^1,10,11 The exact changes that have improved care are not clear, though studies of other health care systems have considered variation in services and costs in relationship to morbidity and mortality outcomes.^12-14 In the context of better patient outcomes in VA hospitals, the present study provides insight into the cardiology services available at VA facilities throughout the nation.

Limitations

While this study provides background information that may be useful in comparing cardiology services between VA and non-VA systems, drawing causal relationships may not be warranted. For example, while the literature generally supports the concept of inpatient cardiology services led by an attending cardiologist, a substantial numbers of VA inpatient facilities have not yet adopted this model.^4-6 Even among more complex, level 1 facilities, we found that only 31% offered both an inpatient CCU and floor team service led by an attending cardiologist physician. Thus, 69% of Level 1 facilities reported caring for patients with a primary cardiology problem through a noncardiology admitting services (with access to a cardiology consultation service). Additional studies should be conducted that would evaluate patient outcomes in relationship to the types of services available at a given VA medical center. Patient outcomes in relationship to service provision between the VA and non-VA health care systems also are warranted.

This study is limited by its reliance on self-reporting. Although we believe that we reached respondents who were qualified to complete the survey, the accuracy of reporting was not independently validated. Further, we asked questions about the most frequent models of cardiology care but may not have captured more novel methods. In trying to keep the survey time to < 2 minutes, we did not explore other details of cardiology services, such as the availability of a dedicated pharmacist, nor more advanced procedures such as transcatheter aortic valve replacement. Additionally, the present study is a snapshot of cardiology services for a given period, and, as noted above, did not look at patient outcomes. Further research is needed to determine which service provided is most beneficial or feasible in improving patient outcomes, which includes examining the various models of inpatient cardiology-led services for optimal care delivery.

Conclusion

Cardiology services were widely available throughout the VA system. However, the types of services available varied considerably. Predictably, facilities that were more complex generally had more advanced services available. Providing a general overview of how cardiovascular care is being delivered currently across VA systems helps to identify areas for optimization within VA facilities of various complexities with initiatives such as implementation of cardiology-led inpatient services, which may be beneficial in improving patient care outcomes as demonstrated previously in other large healthcare systems.

Acknowledgments
This material is the result of work supported with resources and use of the facilities at the George E. Wahlen Salt Lake City VA Medical Center. We are grateful to all of those who responded to our survey, and the support of the facility leadership. We are thankful for Tasia M. Nash and Tammy Jackson who helped to organize the data, and to Leigh Eleazer for her help in the manuscript preparation and formatting. 

Obesity is associated with a significant increase in mortality. It increases the risk of type 2 diabetes mellitus (T2DM), hypertension, hyperlipidemia, and coronary artery disease.¹ T2DM is strongly associated with obesity in all ethnic groups.

Medical nutrition therapy and weight loss are very important for DM management.² This includes providing education about diet modification, increased physical activity, daily calorie intake evaluation, and consistent carbohydrate intake. For patients with T2DM, health care providers (HCPs) should emphasize lowering caloric intake and inducing weight loss for those who are overweight (body mass index [BMI] between 25 and 29.9) and obese (BMI ≥ 30). This can improve glycemic control by decreasing insulin resistance. Initial recommendations for weight loss and physical activity are to lose between 5% and 10% of initial body weight and to accumulate at least 30 minutes of moderate physical activity over the course of most days of the week.^3,4

Several formulas are available to estimate baseline caloric intake for weight maintenance. For weight loss of 1 to 2 pounds per week, lowering 500 to 1,000 calories from daily weight maintenance calories serves the goal. The American Diabetes Association (ADA) also suggests that HCPs recommend diet, physical activity, and behavioral therapy designed to achieve > 5% weight loss to overweight and obese patients with T2DM.⁵

Recognizing the clinical benefits of achieving weight loss in overweight or obese patients with T2DM, we aimed to increase the number of visits in the Endocrine Clinic at Central Arkansas Veterans Healthcare System (CAVHS) in Little Rock that addressed obesity, documented calorie goal for patients who are overweight or obese, and performed an intervention with further education for the patient.

Methods

The study population included veterans with either type 1 DM (T1DM) or T2DM with BMI > 25 on any DM control regimen. We performed a health record review of the eligible patients seen in the CAVHS Endocrine Clinic from June 1, 2016 to July 31, 2016 to determine the baseline percentage of visits that addressed obesity and provided weight loss advice to patients. We obtained a list of patients seen in the clinic during the study period from Strategic Management Service Services at CAVHS. We also obtained information that age, gender, medications, BMI, and last Endocrine clinic HCP assessment from the electronic health record. We reviewed the HCPs notes, including fellows and faculty who were involved in the patients’ treatment, to determine whether their notes documented a BMI > 25 and whether they discussed an intervention for overweight or obesity with the patient. The CAVHS Institutional Review Board reviewed and approved the initiative as a quality improvement study.

Intervention

Our clinic has a defined group of HCPs that we targeted for the intervention. After getting baseline information, during August 2017 we educated these HCPs on the tools available to calculate calorie goal for the patients. We advised the HCPs to use the Mifflin St Jyor equation for estimating energy expenditure and set a goal of initial weight loss between 5% and 7% of body weight. We gave specific instructions and advice to the providers (Table 1). HCPs also received educational material to distribute to patients that provided information on the healthy plate method, discussed how to count calories, and advised them on ADA goals with carbohydrate limitation. We encouraged HCPs to recommend that patients cut between 500 and 1,000 calories daily from their current diet. HCPs also received advice to seek help from clinical dieticians and the VA MOVE! Weight Management Program when appropriate.

Study of Effect of the Intervention

To study the effect of this intervention, we reviewed documentation by HCPs and assessed patient satisfaction. We obtained a list of patients and reviewed HCP notes on patients with BMI > 25 to assess whether providers addressed obesity in November and December 2017. We also evaluated whether HCPs offered a specific intervention to address the problem, such as providing education material to the patient or an estimate of daily calorie goal, or referring them to clinical dietician and/or the MOVE program. Patients received a 5-question survey that assessed their understanding and satisfaction at the end of the visit (Table 2).

Results

Of the 100 charts reviewed prior to intervention, HCPs discussed obesity management with only 6% of patients. After the intervention, we collected data again through chart review of the patients who were overweight or obese and seen for DM in the same clinic during a 2-month period. Of the 100 charts reviewed, we noticed that recognition and management of obesity improved to 60%.

To evaluate the impact of this intervention, patients received a questionnaire at the end of the visit. Nearly all (97%) patients mentioned that the provider discussed weight management during that visit. Most (83%) patients mentioned that weight management was discussed with them during prior visits, while 70% of patients felt their knowledge on working on weight loss had improved. Almost half (46%) were interested in further referral to a dietician or the MOVE program if they did not achieve desired results, but 78% were confident that they could implement the discussed weight management measures.

Discussion

Increased body weight is associated with worsening of DM and can result in poor glycemic control. Achieving weight loss in overweight or obese patients with DM can lead to clinical benefits; however, this is a challenge. In one study, a DM prevention program with lifestyle intervention leading to weight loss significantly reduced the rate of progression from impaired glucose tolerance to DM over a 3-year period and improved cardiovascular risk factors like elevated blood pressure and dyslipidemia.⁶ A randomized trial of an intensive lifestyle intervention to increase physical activity and decrease caloric intake vs standard DM education in people with T2DM showed a modest weight loss of 8.6% of initial weight at 1 year.⁷ This weight loss was associated with significant improvement in blood pressure, glycemic control, fasting blood glucose, high-density lipoprotein (HDL) cholesterol, and triglyceride levels and significant reductions in the use of DM, hypertension, and lipid-lowering medications.⁷ Obesity attributes to dyslipidemia with increased levels of cholesterol, low-density lipoprotein, very low-density lipoprotein, triglycerides, and decreased levels of HDL by about 5%.⁸ Obesity also is associated with hypertension, coronary heart disease, heart failure, and cardiovascular and all-cause mortality.⁹

Limitations

Limitations of this study include the small sample size and that multiple HCPs were involved. The nature of intervention might have differed with different HCPs or in a different setting than a VA clinic. In addition, we did not evaluate the effect on weight loss in specific patients as we only reviewed charts to check whether HCPs addressed weight loss. Nevertheless, our intervention was effective because it improved patient and provider awareness. It also gave us the opportunity to create framework for further collaborations and community building. The Endocrinology department at CAVHS is currently collaborating with the MOVE program, which is a part of the nutrition and food services. We hope to have an endocrinologist involved to provide guidance on medication management for obesity.

Conclusion

At CAVHS a simple intervention was instituted to evaluate whether HCPs were discussing weight loss in patients with DM, providing them with information to assess patients’ daily calorie goal, and prompting them for intervention to achieve weight loss. The intervention led to better management of patients with DM and obesity and greater engagement in weight loss from patients.

This project was a team effort. The clinic nurse documented patient’s BMI on the check in slip. HCPs discussed the problem and specific intervention. The clinical dieticians provided focused education for patients. The clerks collected the patient responses to questionnaire. This project also improved communication within the Endocrine Clinic team. Documentation of HCPs pertaining to addressing obesity improved by 54%. Improved patient satisfaction and insight was evident on patient responses to the questionnaire.

We believe that HCP apathy is a major contributor to the problem of obesity. Small steps like these go a long way for further management of obesity. Most VA hospitals have MOVE programs that provide dietary advice and encourage behavioral changes. However, getting patients to commit to these programs is a challenge. Primary care and endocrine clinics are important services that may help with patient awareness.

This project helped us better recognize patients with obesity and provide them with initial counseling and dietary advice. We received help from clinical dieticians and gave patients the option to join MOVE in situations where initial advice did not yield results and for more consistent follow up.

We tried to improve the care for patients with DM who were overweight or obese at CAVHS by prompting HCPs to focus on obesity as a problem and perform interventions to address this problem. The activities carried out and the data collected were used for internal quality improvement and for encouraging further interventions in the care of these patients.

Obesity is associated with a significant increase in mortality. It increases the risk of type 2 diabetes mellitus (T2DM), hypertension, hyperlipidemia, and coronary artery disease.¹ T2DM is strongly associated with obesity in all ethnic groups.

Medical nutrition therapy and weight loss are very important for DM management.² This includes providing education about diet modification, increased physical activity, daily calorie intake evaluation, and consistent carbohydrate intake. For patients with T2DM, health care providers (HCPs) should emphasize lowering caloric intake and inducing weight loss for those who are overweight (body mass index [BMI] between 25 and 29.9) and obese (BMI ≥ 30). This can improve glycemic control by decreasing insulin resistance. Initial recommendations for weight loss and physical activity are to lose between 5% and 10% of initial body weight and to accumulate at least 30 minutes of moderate physical activity over the course of most days of the week.^3,4

Several formulas are available to estimate baseline caloric intake for weight maintenance. For weight loss of 1 to 2 pounds per week, lowering 500 to 1,000 calories from daily weight maintenance calories serves the goal. The American Diabetes Association (ADA) also suggests that HCPs recommend diet, physical activity, and behavioral therapy designed to achieve > 5% weight loss to overweight and obese patients with T2DM.⁵

Recognizing the clinical benefits of achieving weight loss in overweight or obese patients with T2DM, we aimed to increase the number of visits in the Endocrine Clinic at Central Arkansas Veterans Healthcare System (CAVHS) in Little Rock that addressed obesity, documented calorie goal for patients who are overweight or obese, and performed an intervention with further education for the patient.

Methods

The study population included veterans with either type 1 DM (T1DM) or T2DM with BMI > 25 on any DM control regimen. We performed a health record review of the eligible patients seen in the CAVHS Endocrine Clinic from June 1, 2016 to July 31, 2016 to determine the baseline percentage of visits that addressed obesity and provided weight loss advice to patients. We obtained a list of patients seen in the clinic during the study period from Strategic Management Service Services at CAVHS. We also obtained information that age, gender, medications, BMI, and last Endocrine clinic HCP assessment from the electronic health record. We reviewed the HCPs notes, including fellows and faculty who were involved in the patients’ treatment, to determine whether their notes documented a BMI > 25 and whether they discussed an intervention for overweight or obesity with the patient. The CAVHS Institutional Review Board reviewed and approved the initiative as a quality improvement study.

Intervention

Our clinic has a defined group of HCPs that we targeted for the intervention. After getting baseline information, during August 2017 we educated these HCPs on the tools available to calculate calorie goal for the patients. We advised the HCPs to use the Mifflin St Jyor equation for estimating energy expenditure and set a goal of initial weight loss between 5% and 7% of body weight. We gave specific instructions and advice to the providers (Table 1). HCPs also received educational material to distribute to patients that provided information on the healthy plate method, discussed how to count calories, and advised them on ADA goals with carbohydrate limitation. We encouraged HCPs to recommend that patients cut between 500 and 1,000 calories daily from their current diet. HCPs also received advice to seek help from clinical dieticians and the VA MOVE! Weight Management Program when appropriate.

Study of Effect of the Intervention

To study the effect of this intervention, we reviewed documentation by HCPs and assessed patient satisfaction. We obtained a list of patients and reviewed HCP notes on patients with BMI > 25 to assess whether providers addressed obesity in November and December 2017. We also evaluated whether HCPs offered a specific intervention to address the problem, such as providing education material to the patient or an estimate of daily calorie goal, or referring them to clinical dietician and/or the MOVE program. Patients received a 5-question survey that assessed their understanding and satisfaction at the end of the visit (Table 2).

Results

Of the 100 charts reviewed prior to intervention, HCPs discussed obesity management with only 6% of patients. After the intervention, we collected data again through chart review of the patients who were overweight or obese and seen for DM in the same clinic during a 2-month period. Of the 100 charts reviewed, we noticed that recognition and management of obesity improved to 60%.

To evaluate the impact of this intervention, patients received a questionnaire at the end of the visit. Nearly all (97%) patients mentioned that the provider discussed weight management during that visit. Most (83%) patients mentioned that weight management was discussed with them during prior visits, while 70% of patients felt their knowledge on working on weight loss had improved. Almost half (46%) were interested in further referral to a dietician or the MOVE program if they did not achieve desired results, but 78% were confident that they could implement the discussed weight management measures.

Discussion

Increased body weight is associated with worsening of DM and can result in poor glycemic control. Achieving weight loss in overweight or obese patients with DM can lead to clinical benefits; however, this is a challenge. In one study, a DM prevention program with lifestyle intervention leading to weight loss significantly reduced the rate of progression from impaired glucose tolerance to DM over a 3-year period and improved cardiovascular risk factors like elevated blood pressure and dyslipidemia.⁶ A randomized trial of an intensive lifestyle intervention to increase physical activity and decrease caloric intake vs standard DM education in people with T2DM showed a modest weight loss of 8.6% of initial weight at 1 year.⁷ This weight loss was associated with significant improvement in blood pressure, glycemic control, fasting blood glucose, high-density lipoprotein (HDL) cholesterol, and triglyceride levels and significant reductions in the use of DM, hypertension, and lipid-lowering medications.⁷ Obesity attributes to dyslipidemia with increased levels of cholesterol, low-density lipoprotein, very low-density lipoprotein, triglycerides, and decreased levels of HDL by about 5%.⁸ Obesity also is associated with hypertension, coronary heart disease, heart failure, and cardiovascular and all-cause mortality.⁹

Limitations

Limitations of this study include the small sample size and that multiple HCPs were involved. The nature of intervention might have differed with different HCPs or in a different setting than a VA clinic. In addition, we did not evaluate the effect on weight loss in specific patients as we only reviewed charts to check whether HCPs addressed weight loss. Nevertheless, our intervention was effective because it improved patient and provider awareness. It also gave us the opportunity to create framework for further collaborations and community building. The Endocrinology department at CAVHS is currently collaborating with the MOVE program, which is a part of the nutrition and food services. We hope to have an endocrinologist involved to provide guidance on medication management for obesity.

Conclusion

At CAVHS a simple intervention was instituted to evaluate whether HCPs were discussing weight loss in patients with DM, providing them with information to assess patients’ daily calorie goal, and prompting them for intervention to achieve weight loss. The intervention led to better management of patients with DM and obesity and greater engagement in weight loss from patients.

This project was a team effort. The clinic nurse documented patient’s BMI on the check in slip. HCPs discussed the problem and specific intervention. The clinical dieticians provided focused education for patients. The clerks collected the patient responses to questionnaire. This project also improved communication within the Endocrine Clinic team. Documentation of HCPs pertaining to addressing obesity improved by 54%. Improved patient satisfaction and insight was evident on patient responses to the questionnaire.

We believe that HCP apathy is a major contributor to the problem of obesity. Small steps like these go a long way for further management of obesity. Most VA hospitals have MOVE programs that provide dietary advice and encourage behavioral changes. However, getting patients to commit to these programs is a challenge. Primary care and endocrine clinics are important services that may help with patient awareness.

This project helped us better recognize patients with obesity and provide them with initial counseling and dietary advice. We received help from clinical dieticians and gave patients the option to join MOVE in situations where initial advice did not yield results and for more consistent follow up.

We tried to improve the care for patients with DM who were overweight or obese at CAVHS by prompting HCPs to focus on obesity as a problem and perform interventions to address this problem. The activities carried out and the data collected were used for internal quality improvement and for encouraging further interventions in the care of these patients.

Obesity is associated with a significant increase in mortality. It increases the risk of type 2 diabetes mellitus (T2DM), hypertension, hyperlipidemia, and coronary artery disease.¹ T2DM is strongly associated with obesity in all ethnic groups.

Medical nutrition therapy and weight loss are very important for DM management.² This includes providing education about diet modification, increased physical activity, daily calorie intake evaluation, and consistent carbohydrate intake. For patients with T2DM, health care providers (HCPs) should emphasize lowering caloric intake and inducing weight loss for those who are overweight (body mass index [BMI] between 25 and 29.9) and obese (BMI ≥ 30). This can improve glycemic control by decreasing insulin resistance. Initial recommendations for weight loss and physical activity are to lose between 5% and 10% of initial body weight and to accumulate at least 30 minutes of moderate physical activity over the course of most days of the week.^3,4

Several formulas are available to estimate baseline caloric intake for weight maintenance. For weight loss of 1 to 2 pounds per week, lowering 500 to 1,000 calories from daily weight maintenance calories serves the goal. The American Diabetes Association (ADA) also suggests that HCPs recommend diet, physical activity, and behavioral therapy designed to achieve > 5% weight loss to overweight and obese patients with T2DM.⁵

Recognizing the clinical benefits of achieving weight loss in overweight or obese patients with T2DM, we aimed to increase the number of visits in the Endocrine Clinic at Central Arkansas Veterans Healthcare System (CAVHS) in Little Rock that addressed obesity, documented calorie goal for patients who are overweight or obese, and performed an intervention with further education for the patient.

Methods

The study population included veterans with either type 1 DM (T1DM) or T2DM with BMI > 25 on any DM control regimen. We performed a health record review of the eligible patients seen in the CAVHS Endocrine Clinic from June 1, 2016 to July 31, 2016 to determine the baseline percentage of visits that addressed obesity and provided weight loss advice to patients. We obtained a list of patients seen in the clinic during the study period from Strategic Management Service Services at CAVHS. We also obtained information that age, gender, medications, BMI, and last Endocrine clinic HCP assessment from the electronic health record. We reviewed the HCPs notes, including fellows and faculty who were involved in the patients’ treatment, to determine whether their notes documented a BMI > 25 and whether they discussed an intervention for overweight or obesity with the patient. The CAVHS Institutional Review Board reviewed and approved the initiative as a quality improvement study.

Intervention

Our clinic has a defined group of HCPs that we targeted for the intervention. After getting baseline information, during August 2017 we educated these HCPs on the tools available to calculate calorie goal for the patients. We advised the HCPs to use the Mifflin St Jyor equation for estimating energy expenditure and set a goal of initial weight loss between 5% and 7% of body weight. We gave specific instructions and advice to the providers (Table 1). HCPs also received educational material to distribute to patients that provided information on the healthy plate method, discussed how to count calories, and advised them on ADA goals with carbohydrate limitation. We encouraged HCPs to recommend that patients cut between 500 and 1,000 calories daily from their current diet. HCPs also received advice to seek help from clinical dieticians and the VA MOVE! Weight Management Program when appropriate.

Study of Effect of the Intervention

To study the effect of this intervention, we reviewed documentation by HCPs and assessed patient satisfaction. We obtained a list of patients and reviewed HCP notes on patients with BMI > 25 to assess whether providers addressed obesity in November and December 2017. We also evaluated whether HCPs offered a specific intervention to address the problem, such as providing education material to the patient or an estimate of daily calorie goal, or referring them to clinical dietician and/or the MOVE program. Patients received a 5-question survey that assessed their understanding and satisfaction at the end of the visit (Table 2).

Results

Of the 100 charts reviewed prior to intervention, HCPs discussed obesity management with only 6% of patients. After the intervention, we collected data again through chart review of the patients who were overweight or obese and seen for DM in the same clinic during a 2-month period. Of the 100 charts reviewed, we noticed that recognition and management of obesity improved to 60%.

To evaluate the impact of this intervention, patients received a questionnaire at the end of the visit. Nearly all (97%) patients mentioned that the provider discussed weight management during that visit. Most (83%) patients mentioned that weight management was discussed with them during prior visits, while 70% of patients felt their knowledge on working on weight loss had improved. Almost half (46%) were interested in further referral to a dietician or the MOVE program if they did not achieve desired results, but 78% were confident that they could implement the discussed weight management measures.

Discussion

Increased body weight is associated with worsening of DM and can result in poor glycemic control. Achieving weight loss in overweight or obese patients with DM can lead to clinical benefits; however, this is a challenge. In one study, a DM prevention program with lifestyle intervention leading to weight loss significantly reduced the rate of progression from impaired glucose tolerance to DM over a 3-year period and improved cardiovascular risk factors like elevated blood pressure and dyslipidemia.⁶ A randomized trial of an intensive lifestyle intervention to increase physical activity and decrease caloric intake vs standard DM education in people with T2DM showed a modest weight loss of 8.6% of initial weight at 1 year.⁷ This weight loss was associated with significant improvement in blood pressure, glycemic control, fasting blood glucose, high-density lipoprotein (HDL) cholesterol, and triglyceride levels and significant reductions in the use of DM, hypertension, and lipid-lowering medications.⁷ Obesity attributes to dyslipidemia with increased levels of cholesterol, low-density lipoprotein, very low-density lipoprotein, triglycerides, and decreased levels of HDL by about 5%.⁸ Obesity also is associated with hypertension, coronary heart disease, heart failure, and cardiovascular and all-cause mortality.⁹

Limitations

Limitations of this study include the small sample size and that multiple HCPs were involved. The nature of intervention might have differed with different HCPs or in a different setting than a VA clinic. In addition, we did not evaluate the effect on weight loss in specific patients as we only reviewed charts to check whether HCPs addressed weight loss. Nevertheless, our intervention was effective because it improved patient and provider awareness. It also gave us the opportunity to create framework for further collaborations and community building. The Endocrinology department at CAVHS is currently collaborating with the MOVE program, which is a part of the nutrition and food services. We hope to have an endocrinologist involved to provide guidance on medication management for obesity.

Conclusion

At CAVHS a simple intervention was instituted to evaluate whether HCPs were discussing weight loss in patients with DM, providing them with information to assess patients’ daily calorie goal, and prompting them for intervention to achieve weight loss. The intervention led to better management of patients with DM and obesity and greater engagement in weight loss from patients.

This project was a team effort. The clinic nurse documented patient’s BMI on the check in slip. HCPs discussed the problem and specific intervention. The clinical dieticians provided focused education for patients. The clerks collected the patient responses to questionnaire. This project also improved communication within the Endocrine Clinic team. Documentation of HCPs pertaining to addressing obesity improved by 54%. Improved patient satisfaction and insight was evident on patient responses to the questionnaire.

We believe that HCP apathy is a major contributor to the problem of obesity. Small steps like these go a long way for further management of obesity. Most VA hospitals have MOVE programs that provide dietary advice and encourage behavioral changes. However, getting patients to commit to these programs is a challenge. Primary care and endocrine clinics are important services that may help with patient awareness.

This project helped us better recognize patients with obesity and provide them with initial counseling and dietary advice. We received help from clinical dieticians and gave patients the option to join MOVE in situations where initial advice did not yield results and for more consistent follow up.

We tried to improve the care for patients with DM who were overweight or obese at CAVHS by prompting HCPs to focus on obesity as a problem and perform interventions to address this problem. The activities carried out and the data collected were used for internal quality improvement and for encouraging further interventions in the care of these patients.

Differences in self-reported and EEG-measured responses to emotional scenes between patients with bipolar I disorder with and without a history of psychosis, and healthy controls are negligible, results of a cross-sectional study suggest.

“While prior research supports abnormalities in the emotional face response, this study suggests these neural and behavior differences do not fully generalize to scenes, indicating that nonsocial emotional responding may be intact in these patients,” reported Rebekah L. Trotti and colleagues.

The investigators conducted a multisite study among 130 participants with bipolar and a history of psychosis, 75 with bipolar and no history of psychosis, and 181 healthy controls. Although the investigators had hypothesized that, in keeping with findings from face-processing studies, emotional responses would be reduced in patients with bipolar I disorder, they found no differences on EEG in early posterior negativity and only small differences for late positive potential between the groups. The groups were presented with the same 60 scenes that were unpleasant, neutral, or pleasant. The study was published in the Journal of Psychiatric Research.

Participants rated each scene according to the Self-Assessment Manikin after the respective EEG readings were taken. No significant statistical differences were seen on these ratings between groups, reported Ms. Trotti, a graduate student in the behavioral and brain sciences program at the University of Georgia, Athens, and colleagues.

The investigators also assessed whether participants had psychosis and looked at medications they were taking. However, those analyses also showed no statistically significant differences between participants with bipolar I and a history of psychosis, those with bipolar and no history of psychosis, and healthy controls in the processing of emotional scenes. Ms. Trotti and colleagues noted that other ways of differentiating subtypes in this heterogeneous disorder, such as those based on biomarkers and brain structure rather than those laid out by the DSM, might yield the differences in neural activity they had expected.

“Future research on this topic should focus on neurocognitive subtypes of mood and psychotic disorders, as well as other domains of emotional responding and behavior,” Ms. Trotti and colleagues wrote.

[email protected]

SOURCE: Trotti RL et al. J Psychiatr Res. 2019. doi: 10.1016/j.jpsychires.2019.10.005.

Differences in self-reported and EEG-measured responses to emotional scenes between patients with bipolar I disorder with and without a history of psychosis, and healthy controls are negligible, results of a cross-sectional study suggest.

“While prior research supports abnormalities in the emotional face response, this study suggests these neural and behavior differences do not fully generalize to scenes, indicating that nonsocial emotional responding may be intact in these patients,” reported Rebekah L. Trotti and colleagues.

The investigators conducted a multisite study among 130 participants with bipolar and a history of psychosis, 75 with bipolar and no history of psychosis, and 181 healthy controls. Although the investigators had hypothesized that, in keeping with findings from face-processing studies, emotional responses would be reduced in patients with bipolar I disorder, they found no differences on EEG in early posterior negativity and only small differences for late positive potential between the groups. The groups were presented with the same 60 scenes that were unpleasant, neutral, or pleasant. The study was published in the Journal of Psychiatric Research.

Participants rated each scene according to the Self-Assessment Manikin after the respective EEG readings were taken. No significant statistical differences were seen on these ratings between groups, reported Ms. Trotti, a graduate student in the behavioral and brain sciences program at the University of Georgia, Athens, and colleagues.

The investigators also assessed whether participants had psychosis and looked at medications they were taking. However, those analyses also showed no statistically significant differences between participants with bipolar I and a history of psychosis, those with bipolar and no history of psychosis, and healthy controls in the processing of emotional scenes. Ms. Trotti and colleagues noted that other ways of differentiating subtypes in this heterogeneous disorder, such as those based on biomarkers and brain structure rather than those laid out by the DSM, might yield the differences in neural activity they had expected.

“Future research on this topic should focus on neurocognitive subtypes of mood and psychotic disorders, as well as other domains of emotional responding and behavior,” Ms. Trotti and colleagues wrote.

[email protected]

SOURCE: Trotti RL et al. J Psychiatr Res. 2019. doi: 10.1016/j.jpsychires.2019.10.005.

Differences in self-reported and EEG-measured responses to emotional scenes between patients with bipolar I disorder with and without a history of psychosis, and healthy controls are negligible, results of a cross-sectional study suggest.

“While prior research supports abnormalities in the emotional face response, this study suggests these neural and behavior differences do not fully generalize to scenes, indicating that nonsocial emotional responding may be intact in these patients,” reported Rebekah L. Trotti and colleagues.

The investigators conducted a multisite study among 130 participants with bipolar and a history of psychosis, 75 with bipolar and no history of psychosis, and 181 healthy controls. Although the investigators had hypothesized that, in keeping with findings from face-processing studies, emotional responses would be reduced in patients with bipolar I disorder, they found no differences on EEG in early posterior negativity and only small differences for late positive potential between the groups. The groups were presented with the same 60 scenes that were unpleasant, neutral, or pleasant. The study was published in the Journal of Psychiatric Research.

Participants rated each scene according to the Self-Assessment Manikin after the respective EEG readings were taken. No significant statistical differences were seen on these ratings between groups, reported Ms. Trotti, a graduate student in the behavioral and brain sciences program at the University of Georgia, Athens, and colleagues.

The investigators also assessed whether participants had psychosis and looked at medications they were taking. However, those analyses also showed no statistically significant differences between participants with bipolar I and a history of psychosis, those with bipolar and no history of psychosis, and healthy controls in the processing of emotional scenes. Ms. Trotti and colleagues noted that other ways of differentiating subtypes in this heterogeneous disorder, such as those based on biomarkers and brain structure rather than those laid out by the DSM, might yield the differences in neural activity they had expected.

“Future research on this topic should focus on neurocognitive subtypes of mood and psychotic disorders, as well as other domains of emotional responding and behavior,” Ms. Trotti and colleagues wrote.

[email protected]

SOURCE: Trotti RL et al. J Psychiatr Res. 2019. doi: 10.1016/j.jpsychires.2019.10.005.