Cardiology

Severe renal arteriosclerosis was associated with a ninefold increased risk of atherosclerotic cardiovascular disease in patients with lupus nephritis, based on data from an observational study of 189 individuals.

Mohammed Haneefa Nizamudeen/Getty Images

Atherosclerotic cardiovascular disease (ASCVD) has traditionally been thought to be a late complication of systemic lupus erythematosus (SLE), but this has been challenged in recent population-based studies of patients with SLE and lupus nephritis (LN) that indicated an early and increased risk of ASCVD at the time of diagnosis. However, it is unclear which early risk factors may predispose patients to ASCVD, Shivani Garg, MD, of the University of Wisconsin, Madison, and colleagues wrote in a study published in Arthritis Care & Research.

In patients with IgA nephropathy and renal transplantation, previous studies have shown that severe renal arteriosclerosis (r-ASCL) based on kidney biopsies at the time of diagnosis predicts ASCVD, but “a few studies including LN biopsies failed to report a similar association between the presence of severe r-ASCL and ASCVD occurrence,” possibly because of underreporting of r-ASCL. Dr. Garg and colleagues also noted the problem of underreporting of r-ASCL in their own previous study of its prevalence in LN patients at the time of diagnosis.

To get a more detailed view of how r-ASCL may be linked to early occurrence of ASCVD in LN patients, Dr. Garg and coauthors identified 189 consecutive patients with incident LN who underwent diagnostic biopsies between 1994 and 2017. The median age of the patients was 25 years, 78% were women, and 73% were white. The researchers developed a composite score for r-ASCL severity based on reported and overread biopsies.

Overall, 31% of the patients had any reported r-ASCL, and 7% had moderate-severe r-ASCL. After incorporating systematically reexamined r-ASCL grades, the prevalence of any and moderate-severe r-ASCL increased to 39% and 12%, respectively.

Based on their composite of reported and overread r-ASCL grade, severe r-ASCL in diagnostic LN biopsies was associated with a ninefold increased risk of ASCVD.

The researchers identified 22 incident ASCVD events over an 11-year follow-up for an overall 12% incidence of ASCVD in LN. ASCVD was defined as ischemic heart disease (including myocardial infarction, coronary artery revascularization, abnormal stress test, abnormal angiogram, and events documented by a cardiologist); stroke and transient ischemic attack (TIA); and peripheral vascular disease. Incident ASCVD was defined as the first ASCVD event between 1 and 10 years after LN diagnosis.

The most common ASCVD events were stroke or TIA (12 patients), events related to ischemic heart disease (7 patients), and events related to peripheral vascular disease (3 patients).

Lack of statin use

The researchers also hypothesized that the presence of gaps in statin use among eligible LN patients would be present in their study population. “Among the 20 patients with incident ASCVD events after LN diagnosis in our cohort, none was on statin therapy at the time of LN diagnosis,” the researchers said, noting that current guidelines from the American College of Rheumatology and the European League Against Rheumatism (now known as the European Alliance of Associations for Rheumatology) recommend initiating statin therapy at the time of LN diagnosis in all patients who have hyperlipidemia and chronic kidney disease (CKD) stage ≥3. “Further, 11 patients (55%) met high-risk criteria (hyperlipidemia and CKD stage ≥3) to implement statin therapy at the time of LN diagnosis, yet only one patient (9%) was initiated on statin therapy.” In addition, patients with stage 3 or higher CKD were more likely to develop ASCVD than patients without stage 3 or higher CKD, they said.

The study findings were limited by several factors including the majority white study population, the ability to overread only 25% of the biopsies, and the lack of data on the potential role of chronic lesions in ASCVD, the researchers noted. However, the results were strengthened by the use of a validated LN cohort, and the data provide “the basis to establish severe composite r-ASCL as a predictor of ASCVD events using a larger sample size in different cohorts,” they said.

The study received no outside funding. The researchers had no financial conflicts to disclose.

Severe renal arteriosclerosis was associated with a ninefold increased risk of atherosclerotic cardiovascular disease in patients with lupus nephritis, based on data from an observational study of 189 individuals.

Mohammed Haneefa Nizamudeen/Getty Images

Atherosclerotic cardiovascular disease (ASCVD) has traditionally been thought to be a late complication of systemic lupus erythematosus (SLE), but this has been challenged in recent population-based studies of patients with SLE and lupus nephritis (LN) that indicated an early and increased risk of ASCVD at the time of diagnosis. However, it is unclear which early risk factors may predispose patients to ASCVD, Shivani Garg, MD, of the University of Wisconsin, Madison, and colleagues wrote in a study published in Arthritis Care & Research.

In patients with IgA nephropathy and renal transplantation, previous studies have shown that severe renal arteriosclerosis (r-ASCL) based on kidney biopsies at the time of diagnosis predicts ASCVD, but “a few studies including LN biopsies failed to report a similar association between the presence of severe r-ASCL and ASCVD occurrence,” possibly because of underreporting of r-ASCL. Dr. Garg and colleagues also noted the problem of underreporting of r-ASCL in their own previous study of its prevalence in LN patients at the time of diagnosis.

To get a more detailed view of how r-ASCL may be linked to early occurrence of ASCVD in LN patients, Dr. Garg and coauthors identified 189 consecutive patients with incident LN who underwent diagnostic biopsies between 1994 and 2017. The median age of the patients was 25 years, 78% were women, and 73% were white. The researchers developed a composite score for r-ASCL severity based on reported and overread biopsies.

Overall, 31% of the patients had any reported r-ASCL, and 7% had moderate-severe r-ASCL. After incorporating systematically reexamined r-ASCL grades, the prevalence of any and moderate-severe r-ASCL increased to 39% and 12%, respectively.

Based on their composite of reported and overread r-ASCL grade, severe r-ASCL in diagnostic LN biopsies was associated with a ninefold increased risk of ASCVD.

The researchers identified 22 incident ASCVD events over an 11-year follow-up for an overall 12% incidence of ASCVD in LN. ASCVD was defined as ischemic heart disease (including myocardial infarction, coronary artery revascularization, abnormal stress test, abnormal angiogram, and events documented by a cardiologist); stroke and transient ischemic attack (TIA); and peripheral vascular disease. Incident ASCVD was defined as the first ASCVD event between 1 and 10 years after LN diagnosis.

The most common ASCVD events were stroke or TIA (12 patients), events related to ischemic heart disease (7 patients), and events related to peripheral vascular disease (3 patients).

Lack of statin use

The researchers also hypothesized that the presence of gaps in statin use among eligible LN patients would be present in their study population. “Among the 20 patients with incident ASCVD events after LN diagnosis in our cohort, none was on statin therapy at the time of LN diagnosis,” the researchers said, noting that current guidelines from the American College of Rheumatology and the European League Against Rheumatism (now known as the European Alliance of Associations for Rheumatology) recommend initiating statin therapy at the time of LN diagnosis in all patients who have hyperlipidemia and chronic kidney disease (CKD) stage ≥3. “Further, 11 patients (55%) met high-risk criteria (hyperlipidemia and CKD stage ≥3) to implement statin therapy at the time of LN diagnosis, yet only one patient (9%) was initiated on statin therapy.” In addition, patients with stage 3 or higher CKD were more likely to develop ASCVD than patients without stage 3 or higher CKD, they said.

The study findings were limited by several factors including the majority white study population, the ability to overread only 25% of the biopsies, and the lack of data on the potential role of chronic lesions in ASCVD, the researchers noted. However, the results were strengthened by the use of a validated LN cohort, and the data provide “the basis to establish severe composite r-ASCL as a predictor of ASCVD events using a larger sample size in different cohorts,” they said.

The study received no outside funding. The researchers had no financial conflicts to disclose.

Severe renal arteriosclerosis was associated with a ninefold increased risk of atherosclerotic cardiovascular disease in patients with lupus nephritis, based on data from an observational study of 189 individuals.

Mohammed Haneefa Nizamudeen/Getty Images

Atherosclerotic cardiovascular disease (ASCVD) has traditionally been thought to be a late complication of systemic lupus erythematosus (SLE), but this has been challenged in recent population-based studies of patients with SLE and lupus nephritis (LN) that indicated an early and increased risk of ASCVD at the time of diagnosis. However, it is unclear which early risk factors may predispose patients to ASCVD, Shivani Garg, MD, of the University of Wisconsin, Madison, and colleagues wrote in a study published in Arthritis Care & Research.

In patients with IgA nephropathy and renal transplantation, previous studies have shown that severe renal arteriosclerosis (r-ASCL) based on kidney biopsies at the time of diagnosis predicts ASCVD, but “a few studies including LN biopsies failed to report a similar association between the presence of severe r-ASCL and ASCVD occurrence,” possibly because of underreporting of r-ASCL. Dr. Garg and colleagues also noted the problem of underreporting of r-ASCL in their own previous study of its prevalence in LN patients at the time of diagnosis.

To get a more detailed view of how r-ASCL may be linked to early occurrence of ASCVD in LN patients, Dr. Garg and coauthors identified 189 consecutive patients with incident LN who underwent diagnostic biopsies between 1994 and 2017. The median age of the patients was 25 years, 78% were women, and 73% were white. The researchers developed a composite score for r-ASCL severity based on reported and overread biopsies.

Overall, 31% of the patients had any reported r-ASCL, and 7% had moderate-severe r-ASCL. After incorporating systematically reexamined r-ASCL grades, the prevalence of any and moderate-severe r-ASCL increased to 39% and 12%, respectively.

Based on their composite of reported and overread r-ASCL grade, severe r-ASCL in diagnostic LN biopsies was associated with a ninefold increased risk of ASCVD.

The researchers identified 22 incident ASCVD events over an 11-year follow-up for an overall 12% incidence of ASCVD in LN. ASCVD was defined as ischemic heart disease (including myocardial infarction, coronary artery revascularization, abnormal stress test, abnormal angiogram, and events documented by a cardiologist); stroke and transient ischemic attack (TIA); and peripheral vascular disease. Incident ASCVD was defined as the first ASCVD event between 1 and 10 years after LN diagnosis.

The most common ASCVD events were stroke or TIA (12 patients), events related to ischemic heart disease (7 patients), and events related to peripheral vascular disease (3 patients).

Lack of statin use

The researchers also hypothesized that the presence of gaps in statin use among eligible LN patients would be present in their study population. “Among the 20 patients with incident ASCVD events after LN diagnosis in our cohort, none was on statin therapy at the time of LN diagnosis,” the researchers said, noting that current guidelines from the American College of Rheumatology and the European League Against Rheumatism (now known as the European Alliance of Associations for Rheumatology) recommend initiating statin therapy at the time of LN diagnosis in all patients who have hyperlipidemia and chronic kidney disease (CKD) stage ≥3. “Further, 11 patients (55%) met high-risk criteria (hyperlipidemia and CKD stage ≥3) to implement statin therapy at the time of LN diagnosis, yet only one patient (9%) was initiated on statin therapy.” In addition, patients with stage 3 or higher CKD were more likely to develop ASCVD than patients without stage 3 or higher CKD, they said.

The study findings were limited by several factors including the majority white study population, the ability to overread only 25% of the biopsies, and the lack of data on the potential role of chronic lesions in ASCVD, the researchers noted. However, the results were strengthened by the use of a validated LN cohort, and the data provide “the basis to establish severe composite r-ASCL as a predictor of ASCVD events using a larger sample size in different cohorts,” they said.

The study received no outside funding. The researchers had no financial conflicts to disclose.

THE CASE

A 20-year-old man presented to our clinic with a 3-day history of nonradiating chest pain located at the center of his chest. Past medical history included idiopathic neonatal giant-cell hepatitis and subsequent liver transplant at 1 month of age; he had been followed by the transplant team without rejection or infection and was in otherwise good health prior to the chest pain.

On the day of symptom onset, he was walking inside his house and fell to his knees with a chest pain described as “a punch” to the center of the chest that lasted for a few seconds. He was able to continue his daily activities without limitation despite a constant, squeezing, centrally located chest pain. The pain worsened with cough and exertion.

A few hours later, he went to an urgent care center for evaluation. There, he reported, his chest radiograph and electrocardiogram (EKG) results were normal and he was given a diagnosis of musculoskeletal chest pain. Over the next 3 days, his chest pain persisted but did not worsen. He was taking 500 mg of naproxen every 8 hours with no improvement. No other acute or chronic medications were being taken. He had no significant family history. A review of systems was otherwise negative.

On physical exam, his vital statistics included a height of 6’4”; weight, 261 lb; body mass index, 31.8; temperature, 98.7 °F; blood pressure, 134/77 mm Hg; heart rate, 92 beats/min; respiratory rate, 18 breaths/min; and oxygen saturation, 96%. Throughout the exam, he demonstrated no acute distress, appeared well, and was talkative; however, he reported having a “constant, squeezing” chest pain that did not worsen with palpation of the chest. The rest of his physical exam was unremarkable.

Although he reported that his EKG and chest radiograph were normal 3 days prior, repeat chest radiograph and EKG were ordered due to his unexplained, active chest pain and the lack of immediate access to the prior results.

THE DIAGNOSIS

The chest radiograph (FIGURE 1A) showed a “mildly ectatic ascending thoracic aorta” that had increased since a chest radiograph from 6 years prior (FIGURE 1B) and “was concerning for an aneurysm.” Computed tomography (CT) angiography (FIGURE 2) then confirmed a 7-cm aneurysm of the ascending aorta, with findings suggestive of a retrograde ascending aortic dissection.

DISCUSSION

The average age of a patient with acute aortic dissection (AAD) is 63 years; only 7% occur in people younger than 40.¹ AAD is often accompanied by a predisposing risk factor such as a connective tissue disease, bicuspid aortic valve, longstanding hypertension, trauma, or larger aortic dimensions.^2,3 Younger patients are more likely to have predisposing risk factors of Marfan syndrome, prior aortic surgery, or a bicuspid aortic valve.³

Continue to: A literature review did not reveal...

A literature review did not reveal any known correlation between the patient’s history of giant-cell hepatitis or antirejection therapy with thoracic aortic dissection. Furthermore, liver transplant is not known to be a specific risk factor for AAD in pediatric patients or outside the immediate postoperative period. Therefore, there were no known predisposing risk factors for AAD in our patient.

The most common clinical feature of AAD is chest pain, which occurs in 75% of patients.¹ Other clinical symptoms include hypertension and diaphoresis.^2,4 However, classic clinical findings are not always displayed, making the diagnosis difficult.^2,4 The classical description of “tearing pain” is seen in only 51% of patients, and 5% to 15% of patients present without any pain.¹

Commonly missed or misdiagnosed. The diagnosis of AAD has been missed during the initial exam in 38% of patients.⁴ As seen in our case, symptoms may be initially diagnosed as musculoskeletal chest pain. Based on symptoms, AAD can be incorrectly diagnosed as an acute myocardial infarction or vascular embolization.^2,4

Every hour after symptom onset, the mortality rate of untreated AAD increases 1% to 2%,with no difference based on age.^3,4 Different reports have shown mortality rates between 7% and 30%.⁴

Effective imaging is crucial to the diagnosis and treatment of AAD, given the occurrence of atypical presentation, missed diagnosis, and high mortality rate.⁴ A chest radiograph will show a widened mediastinum, but the preferred diagnostic tests are a CT or transthoracic echocardiogram.^2,4 Once the diagnosis of AAD is confirmed, an aortic angiogram is the preferred test to determine the extent of the dissection prior to surgical treatment.²

Continue to: Classification dictates treatment

Classification dictates treatment. AAD is classified based on where the dissection of the aorta occurs. If the dissection involves the ascending aorta, it is classified as a type A AAD and should immediately be treated with emergent surgery in order to prevent complications including myocardial infarction, cardiac tamponade, and aortic rupture.^2,4,5 If the dissection is limited to the descending aorta, it is classified as a type B AAD and can be medically managed by controlling pain and lowering blood pressure; if symptoms persist, surgical management may be required.² After hospital discharge, AAD patients are followed closely with medical therapy, serial imaging, and reoperation if necessary.⁴

Our patient underwent emergent surgery for aortic root/ascending aortic replacement with a mechanical valve. He tolerated the procedure well. Surgical tissue pathology of the aortic segment showed a wall of elastic vessel with medial degeneration and dissection, and the tissue pathology of the aorta leaflets showed valvular tissue with myxoid degeneration.

THE TAKEAWAY

It is critical to keep AAD in the differential diagnosis of a patient presenting with acute onset of chest pain, as AAD often has an atypical presentation and can easily be misdiagnosed. Effective imaging is crucial to diagnosis, and immediate treatment is essential to patient survival.

CORRESPONDENCE
Rachel A. Reedy, PA, University of Florida, Department of General Pediatrics, 7046 SW Archer Road, Gainesville, FL 32608; rreedy@ufl.edu

THE CASE

A 20-year-old man presented to our clinic with a 3-day history of nonradiating chest pain located at the center of his chest. Past medical history included idiopathic neonatal giant-cell hepatitis and subsequent liver transplant at 1 month of age; he had been followed by the transplant team without rejection or infection and was in otherwise good health prior to the chest pain.

On the day of symptom onset, he was walking inside his house and fell to his knees with a chest pain described as “a punch” to the center of the chest that lasted for a few seconds. He was able to continue his daily activities without limitation despite a constant, squeezing, centrally located chest pain. The pain worsened with cough and exertion.

A few hours later, he went to an urgent care center for evaluation. There, he reported, his chest radiograph and electrocardiogram (EKG) results were normal and he was given a diagnosis of musculoskeletal chest pain. Over the next 3 days, his chest pain persisted but did not worsen. He was taking 500 mg of naproxen every 8 hours with no improvement. No other acute or chronic medications were being taken. He had no significant family history. A review of systems was otherwise negative.

On physical exam, his vital statistics included a height of 6’4”; weight, 261 lb; body mass index, 31.8; temperature, 98.7 °F; blood pressure, 134/77 mm Hg; heart rate, 92 beats/min; respiratory rate, 18 breaths/min; and oxygen saturation, 96%. Throughout the exam, he demonstrated no acute distress, appeared well, and was talkative; however, he reported having a “constant, squeezing” chest pain that did not worsen with palpation of the chest. The rest of his physical exam was unremarkable.

Although he reported that his EKG and chest radiograph were normal 3 days prior, repeat chest radiograph and EKG were ordered due to his unexplained, active chest pain and the lack of immediate access to the prior results.

THE DIAGNOSIS

The chest radiograph (FIGURE 1A) showed a “mildly ectatic ascending thoracic aorta” that had increased since a chest radiograph from 6 years prior (FIGURE 1B) and “was concerning for an aneurysm.” Computed tomography (CT) angiography (FIGURE 2) then confirmed a 7-cm aneurysm of the ascending aorta, with findings suggestive of a retrograde ascending aortic dissection.

DISCUSSION

The average age of a patient with acute aortic dissection (AAD) is 63 years; only 7% occur in people younger than 40.¹ AAD is often accompanied by a predisposing risk factor such as a connective tissue disease, bicuspid aortic valve, longstanding hypertension, trauma, or larger aortic dimensions.^2,3 Younger patients are more likely to have predisposing risk factors of Marfan syndrome, prior aortic surgery, or a bicuspid aortic valve.³

Continue to: A literature review did not reveal...

A literature review did not reveal any known correlation between the patient’s history of giant-cell hepatitis or antirejection therapy with thoracic aortic dissection. Furthermore, liver transplant is not known to be a specific risk factor for AAD in pediatric patients or outside the immediate postoperative period. Therefore, there were no known predisposing risk factors for AAD in our patient.

The most common clinical feature of AAD is chest pain, which occurs in 75% of patients.¹ Other clinical symptoms include hypertension and diaphoresis.^2,4 However, classic clinical findings are not always displayed, making the diagnosis difficult.^2,4 The classical description of “tearing pain” is seen in only 51% of patients, and 5% to 15% of patients present without any pain.¹

Commonly missed or misdiagnosed. The diagnosis of AAD has been missed during the initial exam in 38% of patients.⁴ As seen in our case, symptoms may be initially diagnosed as musculoskeletal chest pain. Based on symptoms, AAD can be incorrectly diagnosed as an acute myocardial infarction or vascular embolization.^2,4

Every hour after symptom onset, the mortality rate of untreated AAD increases 1% to 2%,with no difference based on age.^3,4 Different reports have shown mortality rates between 7% and 30%.⁴

Effective imaging is crucial to the diagnosis and treatment of AAD, given the occurrence of atypical presentation, missed diagnosis, and high mortality rate.⁴ A chest radiograph will show a widened mediastinum, but the preferred diagnostic tests are a CT or transthoracic echocardiogram.^2,4 Once the diagnosis of AAD is confirmed, an aortic angiogram is the preferred test to determine the extent of the dissection prior to surgical treatment.²

Continue to: Classification dictates treatment

Classification dictates treatment. AAD is classified based on where the dissection of the aorta occurs. If the dissection involves the ascending aorta, it is classified as a type A AAD and should immediately be treated with emergent surgery in order to prevent complications including myocardial infarction, cardiac tamponade, and aortic rupture.^2,4,5 If the dissection is limited to the descending aorta, it is classified as a type B AAD and can be medically managed by controlling pain and lowering blood pressure; if symptoms persist, surgical management may be required.² After hospital discharge, AAD patients are followed closely with medical therapy, serial imaging, and reoperation if necessary.⁴

Our patient underwent emergent surgery for aortic root/ascending aortic replacement with a mechanical valve. He tolerated the procedure well. Surgical tissue pathology of the aortic segment showed a wall of elastic vessel with medial degeneration and dissection, and the tissue pathology of the aorta leaflets showed valvular tissue with myxoid degeneration.

THE TAKEAWAY

It is critical to keep AAD in the differential diagnosis of a patient presenting with acute onset of chest pain, as AAD often has an atypical presentation and can easily be misdiagnosed. Effective imaging is crucial to diagnosis, and immediate treatment is essential to patient survival.

CORRESPONDENCE
Rachel A. Reedy, PA, University of Florida, Department of General Pediatrics, 7046 SW Archer Road, Gainesville, FL 32608; rreedy@ufl.edu

THE CASE

A 20-year-old man presented to our clinic with a 3-day history of nonradiating chest pain located at the center of his chest. Past medical history included idiopathic neonatal giant-cell hepatitis and subsequent liver transplant at 1 month of age; he had been followed by the transplant team without rejection or infection and was in otherwise good health prior to the chest pain.

On the day of symptom onset, he was walking inside his house and fell to his knees with a chest pain described as “a punch” to the center of the chest that lasted for a few seconds. He was able to continue his daily activities without limitation despite a constant, squeezing, centrally located chest pain. The pain worsened with cough and exertion.

A few hours later, he went to an urgent care center for evaluation. There, he reported, his chest radiograph and electrocardiogram (EKG) results were normal and he was given a diagnosis of musculoskeletal chest pain. Over the next 3 days, his chest pain persisted but did not worsen. He was taking 500 mg of naproxen every 8 hours with no improvement. No other acute or chronic medications were being taken. He had no significant family history. A review of systems was otherwise negative.

On physical exam, his vital statistics included a height of 6’4”; weight, 261 lb; body mass index, 31.8; temperature, 98.7 °F; blood pressure, 134/77 mm Hg; heart rate, 92 beats/min; respiratory rate, 18 breaths/min; and oxygen saturation, 96%. Throughout the exam, he demonstrated no acute distress, appeared well, and was talkative; however, he reported having a “constant, squeezing” chest pain that did not worsen with palpation of the chest. The rest of his physical exam was unremarkable.

Although he reported that his EKG and chest radiograph were normal 3 days prior, repeat chest radiograph and EKG were ordered due to his unexplained, active chest pain and the lack of immediate access to the prior results.

THE DIAGNOSIS

The chest radiograph (FIGURE 1A) showed a “mildly ectatic ascending thoracic aorta” that had increased since a chest radiograph from 6 years prior (FIGURE 1B) and “was concerning for an aneurysm.” Computed tomography (CT) angiography (FIGURE 2) then confirmed a 7-cm aneurysm of the ascending aorta, with findings suggestive of a retrograde ascending aortic dissection.

DISCUSSION

The average age of a patient with acute aortic dissection (AAD) is 63 years; only 7% occur in people younger than 40.¹ AAD is often accompanied by a predisposing risk factor such as a connective tissue disease, bicuspid aortic valve, longstanding hypertension, trauma, or larger aortic dimensions.^2,3 Younger patients are more likely to have predisposing risk factors of Marfan syndrome, prior aortic surgery, or a bicuspid aortic valve.³

Continue to: A literature review did not reveal...

A literature review did not reveal any known correlation between the patient’s history of giant-cell hepatitis or antirejection therapy with thoracic aortic dissection. Furthermore, liver transplant is not known to be a specific risk factor for AAD in pediatric patients or outside the immediate postoperative period. Therefore, there were no known predisposing risk factors for AAD in our patient.

The most common clinical feature of AAD is chest pain, which occurs in 75% of patients.¹ Other clinical symptoms include hypertension and diaphoresis.^2,4 However, classic clinical findings are not always displayed, making the diagnosis difficult.^2,4 The classical description of “tearing pain” is seen in only 51% of patients, and 5% to 15% of patients present without any pain.¹

Commonly missed or misdiagnosed. The diagnosis of AAD has been missed during the initial exam in 38% of patients.⁴ As seen in our case, symptoms may be initially diagnosed as musculoskeletal chest pain. Based on symptoms, AAD can be incorrectly diagnosed as an acute myocardial infarction or vascular embolization.^2,4

Every hour after symptom onset, the mortality rate of untreated AAD increases 1% to 2%,with no difference based on age.^3,4 Different reports have shown mortality rates between 7% and 30%.⁴

Effective imaging is crucial to the diagnosis and treatment of AAD, given the occurrence of atypical presentation, missed diagnosis, and high mortality rate.⁴ A chest radiograph will show a widened mediastinum, but the preferred diagnostic tests are a CT or transthoracic echocardiogram.^2,4 Once the diagnosis of AAD is confirmed, an aortic angiogram is the preferred test to determine the extent of the dissection prior to surgical treatment.²

Continue to: Classification dictates treatment

Classification dictates treatment. AAD is classified based on where the dissection of the aorta occurs. If the dissection involves the ascending aorta, it is classified as a type A AAD and should immediately be treated with emergent surgery in order to prevent complications including myocardial infarction, cardiac tamponade, and aortic rupture.^2,4,5 If the dissection is limited to the descending aorta, it is classified as a type B AAD and can be medically managed by controlling pain and lowering blood pressure; if symptoms persist, surgical management may be required.² After hospital discharge, AAD patients are followed closely with medical therapy, serial imaging, and reoperation if necessary.⁴

Our patient underwent emergent surgery for aortic root/ascending aortic replacement with a mechanical valve. He tolerated the procedure well. Surgical tissue pathology of the aortic segment showed a wall of elastic vessel with medial degeneration and dissection, and the tissue pathology of the aorta leaflets showed valvular tissue with myxoid degeneration.

THE TAKEAWAY

It is critical to keep AAD in the differential diagnosis of a patient presenting with acute onset of chest pain, as AAD often has an atypical presentation and can easily be misdiagnosed. Effective imaging is crucial to diagnosis, and immediate treatment is essential to patient survival.

CORRESPONDENCE
Rachel A. Reedy, PA, University of Florida, Department of General Pediatrics, 7046 SW Archer Road, Gainesville, FL 32608; rreedy@ufl.edu

Chronic kidney disease (CKD) is a significant comorbidity of diabetes mellitus. The Kidney Disease Outcomes Quality Initiative (KDOQI) of the National Kidney Foundation defines CKD as the presence of kidney damage or decreased kidney function for ≥ 3 months. CKD caused by diabetes is called diabetic kidney disease (DKD), which is 1 of 3 principal microvascular complications of diabetes. DKD can progress to end-stage renal disease (ESRD), requiring kidney replacement therapy, and is the leading cause of CKD and ESRD in the United States.^1-3 Studies have also shown that, particularly in patients with diabetes, CKD considerably increases the risk of cardiovascular events, which often occur prior to ESRD.^1,4

This article provides the latest recommendations for evaluating and managing DKD to help you prevent or slow its progression.

Defining and categorizing diabetic kidney disease

CKD is defined as persistently elevated excretion of urinary albumin (albuminuria) and decreased estimated glomerular filtration rate (eGFR), or as the presence of signs of progressive kidney damage.^5,6 DKD, also known as diabetic nephropathy, is CKD attributed to long-term diabetes. A patient’s eGFR is the established basis for assignment to a stage (1, 2, 3a, 3b, 4, or 5) of CKD (TABLE 1⁷) and, along with the category of albuminuria (A1, A2, or A3), can indicate prognosis.

Taking its toll in diabetes

As many as 40% of patients with diabetes develop DKD.^8-10 Most studies of DKD have been conducted in patients with type 1 diabetes (T1D), because the time of clinical onset is typically known.

Type 1 diabetes. DKD usually occurs 10 to 15 years, or later, after the onset of diabetes.⁶ As many as 30% of people with T1D have albuminuria approximately 15 years after onset of diabetes; almost one-half of those develop DKD.^5,11 After approximately 22.5 years without albuminuria, patients with T1D have approximately a 1% annual risk of DKD.¹²

Type 2 diabetes (T2D). DKD is often present at diagnosis, likely due to a delay in diagnosis and briefer clinical exposure, compared to T1D. Albuminuria has been reported in as many as 40% of patients with T2D approximately 10 years after onset of diabetes.^12,13

Multiple risk factors with no standout “predictor”

Genetic susceptibility, ethnicity, glycemic control, smoking, blood pressure (BP), and the eGFR have been identified as risk factors for renal involvement in diabetes; obesity, oral contraceptives, and age can also contribute. Although each risk factor increases the risk of DKD, no single factor is adequately predictive. Moderately increased albuminuria, the earliest sign of DKD, is associated with progressive nephropathy.¹²

Continue to: How great is the risk?

How great is the risk? From disease onset to proteinuria and from proteinuria to ESRD, the risk of DKD in T1D and T2D is similar. With appropriate treatment, albuminuria can regress, and the risk of ESRD can be < 20% at 10 years in T1D.¹² As in T1D, good glycemic control might result in regression of albuminuria in T2D.¹⁴

As many as 30% of people with T1D have albuminuria approximately 15 years after onset of diabetes; almost one-half of those develop DKD.

For unknown reasons, the degree of albuminuria can exist independent of the progression of DKD. Factors responsible for a progressive decline in eGFR in DKD without albuminuria are unknown.^12,15

Patient evaluation with an eye toward comorbidities

A comprehensive initial medical evaluation for DKD includes a review of microvascular complications; visits to specialists; lifestyle and behavior patterns (eg, diet, sleep, substance use, and social support); and medication adherence, adverse drug effects, and alternative medicines. Although DKD is often a clinical diagnosis, it can be ruled in by persistent albuminuria or decreased eGFR, or both, in established diabetes or diabetic retinopathy when other causes are unlikely (see “Recommended DKD screening protocol,” below).

Screening for mental health conditions and barriers to self-management is also key.⁶

Comorbidities, of course, can complicate disease management in patients with diabetes.^16-20 Providers and patients therefore need to be aware of potential diabetic comorbidities. For example, DKD and even moderately increased albuminuria significantly increase the risk of cardiovascular disease (CVD).¹² Other possible comorbidities include (but are not limited to) nonalcoholic steatohepatitis, fracture, hearing impairment, cancer (eg, liver, pancreas, endometrium, colon, rectum, breast, and bladder), pancreatitis, hypogonadism, obstructive sleep apnea, periodontal disease, anxiety, depression, and eating disorders.⁶

Continue to: Recommended DKD screening protocol

 

 

Recommended DKD screening protocol

In all cases of T2D, in cases of T1D of ≥ 5 years’ duration, and in patients with diabetes and comorbid hypertension, perform annual screening for albuminuria, an elevated creatinine level, and a decline in eGFR.

Screen for potential comorbidities of DKD: For example, the risk of cardiovascular disease is significantly elevated in even moderately increased albuminuria.

To confirm the diagnosis of DKD, at least 2 of 3 urine specimens must demonstrate an elevated urinary albumin:creatinine ratio (UACR) over a 3- to 6-month period.²¹ Apart from renal damage, exercise within 24 hours before specimen collection, infection, fever, congestive heart failure, hyperglycemia, menstruation, and hypertension can elevate the UACR.⁶

Levels of the UACR are established as follows²²:

• Normal UACR is defined as < 30 milligrams of albumin per gram of creatinine (expressed as “mg/g”).
• Increased urinary albumin excretion is defined as ≥ 30 mg/g.
• Moderately increased albuminuria, a predictor of potential nephropathy, is the excretion of 30 to 300 mg/g.
• Severely increased albuminuria is excretion > 300 mg/g; it is often followed by a gradual decline in eGFR that, without treatment, eventually leads to ESRD.

The rate of decline in eGFR once albuminuria is severely increased is equivalent in T1D and T2D.¹² Without intervention, the time from severely increased albuminuria to ESRD in T1D and T2D averages approximately 6 or 7 years.

Clinical features

DKD is typically a clinical diagnosis seen in patients with longstanding diabetes, albuminuria, retinopathy, or a reduced eGFR in the absence of another primary cause of kidney damage. In patients with T1D and DKD, signs of retinopathy and neuropathy are almost always present at diagnosis, unless a diagnosis is made early in the course of diabetes.¹² Therefore, the presence of retinopathy suggests that diabetes is the likely cause of CKD.

Continue to: The presence of microvascular disease...

The presence of microvascular disease in patients with T2D and DKD is less predictable.¹² In T2D patients who do not have retinopathy, consider causes of CKD other than DKD. Features suggesting that the cause of CKD is an underlying condition other than diabetes are rapidly increasing albuminuria or decreasing eGFR; urinary sediment comprising red blood cells or white blood cells; and nephrotic syndrome.⁶

As the prevalence of diabetes increases, it has become more common to diagnose DKD by eGFR without albuminuria—underscoring the importance of routine monitoring of eGFR in patients with diabetes.⁶

Sources of expert guidance. The Chronic Kidney Disease Epidemiology Collaboration equation²³ is preferred for calculating eGFR from serum creatinine: An eGFR < 60 mL/min/1.73 m² is considered abnormal.^3,12 At these rates, the prevalence of complications related to CKD rises and screening for complications becomes necessary.

A more comprehensive classification of the stages of CKD, incorporating albuminuria and progression of CKD, has been recommended by Kidney Disease: Improving Global Outcomes (KDIGO).⁷ Because eGFR and excretion of albumin vary, abnormal test results need to be verified over time to stage the degree of CKD.^3,12 Kidney damage often manifests as albuminuria, but also as hematuria, other types of abnormal urinary sediment, radiographic abnormalities, and other abnormal presentations.

Management

Nutritional factors

Excessive protein intake has been shown to increase albuminuria, worsen renal function, and increase CVD mortality in DKD.^24-26 Therefore, daily dietary protein intake of 0.8 g/kg body weight is recommended for patients who are not on dialysis.³ Patients on dialysis might require higher protein intake to preserve muscle mass caused by protein-energy wasting, which is common in dialysis patients.⁶

Continue to: Low sodium intake

Low sodium intake in CKD patients has been shown to decrease BP and thus slow the progression of renal disease and lower the risk of CVD. The recommended dietary sodium intake in CKD patients is 1500-3000 mg/d.³

Low potassium intake. Hyperkalemia is a serious complication of CKD. A low-potassium diet is recommended in ESRD patients who have a potassium level > 5.5 mEq/L.⁶

Blood pressure

Preventing and treating hypertension is critical to slowing the progression of CKD and reducing cardiovascular risk. BP should be measured at every clinic visit. Aside from lifestyle changes, medication might be needed to reach target BP.

The American Diabetes Association recommends a BP goal of ≤ 140/90 mm Hg for hypertensive patients with diabetes, although they do state that a lower BP target (≤ 130/80 mm Hg) might be more appropriate for patients with DKD.²⁷

The American College of Cardiology recommends that hypertensive patients with CKD have a BP target of ≤ 130/80 mm Hg.²⁸

Continue to: ACE inhibitors and ARBs

Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) have renoprotective benefits. These agents are recommended as first-line medications for patients with diabetes, hypertension, and an eGFR < 60 mL/min/1.73 m² and a UACR > 300 mg/g.^29-31 Evidence also supports their use when the UACR is 30 to 299 mg/g.

Studies have shown that, in patients with DKD, ACE inhibitors and ARBs can slow the progression of renal disease.^29,30,32 There is no difference between ACE inhibitors and ARBs in their effectiveness for preventing progression of DKD.⁶ There is no added benefit in combining an ACE inhibitor and an ARB³³; notably, combination ACE inhibitor and ARB therapy can increase the risk of adverse events, such as hyperkalemia and acute kidney injury, especially in patients with DKD.³³

There is no evidence for starting an ACE inhibitor or ARB to prevent CKD in patients with diabetes who are not hypertensive.⁵

ACE inhibitors and ARBs should be used with caution in women of childbearing age, who should use a reliable form of contraception if taking one of these drugs.

Diuretics. Thiazide-type and loop diuretics might potentiate the positive effects of ACE inhibitors and ARBs. KDOQI guidelines recommend that, in patients who require a second agent to control BP, a diuretic should be considered in combination with an ACE inhibitor or an ARB.²⁰ A loop diuretic is preferred if the eGFR is < 30 mL/min/1.73 m².

Continue to: Nondihydropyridine calcium-channel blockers

Nondihydropyridine calcium-channel blockers (CCBs), such as diltiazem and verapamil, have been shown to be more effective then dihydrophyridine CCBs, such as amlodipine and nifedipine, in slowing the progression of renal disease because of their antiproteinuric effects. However, the antiproteinuric effects of nondihydropyridine CCBs are not as strong as those of ACE inhibitors or ARBs, and these drugs do not appear to potentiate the effects of an ACE inhibitor or ARB when used in combination.²⁰

Confirmation of suspected DKD requires an elevated albumin:creatinine ratio in at least 2 of 3 urine specimens over a 3- to 6-month period.

Nondihydropyridine CCBs might be a reasonable alternative in patients who cannot tolerate an ACE inhibitor or an ARB.

Mineralocorticoid receptor antagonists in combination with an ACE inhibitor or ARB have been demonstrated to reduce albuminuria in short-term studies.^34,35

Glycemic levels

Studies conducted in patients with T1D, and others in patients with T2D, have shown that tight glycemic control can delay the onset and slow the progression of albuminuria and a decline in the eGFR.^10,36-39 The target glycated hemoglobin (A1C) should be < 7% to prevent or slow progression of DKD.⁴⁰ However, patients with DKD have an increased risk of hypoglycemic events and increased mortality with more intensive glycemic control.^40,41 Given those findings, some patients with DKD and significant comorbidities, ESRD, or limited life expectancy might need to have an A1C target set at 8%.^6,42

Adjustments to antidiabetes medications in DKD

In patients with stages 3 to 5 DKD, several common antidiabetic medications might need to be adjusted or discontinued because they decrease creatinine clearance.

Continue to: First-generation sulfonylureas

First-generation sulfonylureas should be avoided in DKD. Glipizide and gliclazide are preferred among second-generation sulfonylureas because they do not increase the risk of hypoglycemia in DKD patients, although patients taking these medications still require close monitoring of their blood glucose level.²⁰

Metformin. In 2016, recommendations changed for the use of metformin in patients with DKD: The eGFR, not the serum creatinine level, should guide treatment.⁴³ Metformin can be used safely in patients with (1) an eGFR of < 60 mL/min/1.73 m² and (2) an eGFR of 30 mL/min/1.73 m² with close monitoring. Metformin should not be initiated if the eGFR is < 45 mL/min/1.73 m².⁴³ 

Antidiabetes medications with direct effect on the kidney

Several antidiabetes medications have a direct effect on the kidney apart from their effect on the blood glucose level.

Sodium-glucose co-transporter 2 (SGLT2) inhibitors have been shown to reduce albuminuria and slow the decrease of eGFR independent of glycemic control. In addition, SGLT2 inhibitors have also been shown to have cardiovascular benefits in patients with DKD.^44,45 

Glucagon-like peptide 1 (GLP-1) receptor agonists have been shown to delay and decrease the progression of DKD.^46-48 Also, similar to what is seen with SGLT2 inhibitors, GLP-1 agonists have demonstrable cardiovascular benefit in patients with DKD.^46,48

Continue to: Dyslipidemia and DKD

 

 

Dyslipidemia and DKD

Because the risk of CVD is increased in patients with DKD, addressing other modifiable risk factors, including dyslipidemia, is recommended in these patients. Patients with diabetes and stages 1 to 4 DKD should be treated with a high-intensity statin or a combination of a statin and ezetimibe.^49,50

Tight glycemic control in T1D and T2D can delay the onset, and slow the progression, of albuminuria and a decline in the eGFR.

If a patient is taking a statin and starting dialysis, it’s important to discuss with him or her whether to continue the statin, based on perceived benefits and risks. It is not recommended that statins be initiated in patients on dialysis unless there is a specific cardiovascular indication for doing so. Risk reduction with a statin has been shown to be significantly less in dialysis patients than in patients who are not being treated with dialysis.⁴⁹

Complications of CKD

Anemia is a common complication of CKD. KDIGO recommends measuring the ­hemoglobin concentration annually in DKD stage 3 patients without anemia; at least every 6 months in stage 4 patients; and at least every 3 months in stage 5. DKD patients with anemia should have additional laboratory testing: the absolute reticulocyte count, serum ferritin, serum transferrin saturation, vitamin B12, and folate.⁵¹

Mineral and bone disorder should be screened for in patients with DKD. TABLE 2⁵² outlines when clinical laboratory tests should be ordered to assess for mineral bone disease.

When to refer to a nephrologist

Refer patients with stage 4 or 5 CKD (eGFR, ≤ 30 mL/min/1.73 m²) to a nephrologist for discussion of kidney replacement therapy.⁶ Patients with stage 3a CKD and severely increased albuminuria or with stage 3b CKD and moderately or severely increased albuminuria should also be referred to a nephrologist for intervention to delay disease progression.

Continue to: Identifying the need for early referral...

Nutritional control is important in DKD: A lowsodium diet can slow progression of DKD, and a low-potassium diet can prevent hyperkalemia in end-stage renal disease.

Identifying the need for early referral to a nephrologist has been shown to reduce the cost, and improve the quality, of care.⁵³ Other indications for earlier referral include uncertainty about the etiology of renal disease, persistent or severe albuminuria, persistent hematuria, a rapid decline in eGFR, and acute kidney injury. Additionally, referral at an earlier stage of DKD might be needed to assist with complications associated with DKD, such as anemia, secondary hyperparathyroidism, mineral and bone disorder, resistant hypertension, fluid overload, and electrolyte disturbances.⁶

ACKNOWLEDGEMENT
The authors thank Colleen Colbert, PhD, and Iqbal Ahmad, PhD, for their review and critique of the manuscript of this article. They also thank Christopher Babiuch, MD, for his guidance in the preparation of the manuscript.

CORRESPONDENCE
Faraz Ahmad, MD, MPH, Care Point East Family Medicine, 543 Taylor Avenue, 2nd floor, Columbus, OH 43203; faraz. ahmad@osumc.edu.

Chronic kidney disease (CKD) is a significant comorbidity of diabetes mellitus. The Kidney Disease Outcomes Quality Initiative (KDOQI) of the National Kidney Foundation defines CKD as the presence of kidney damage or decreased kidney function for ≥ 3 months. CKD caused by diabetes is called diabetic kidney disease (DKD), which is 1 of 3 principal microvascular complications of diabetes. DKD can progress to end-stage renal disease (ESRD), requiring kidney replacement therapy, and is the leading cause of CKD and ESRD in the United States.^1-3 Studies have also shown that, particularly in patients with diabetes, CKD considerably increases the risk of cardiovascular events, which often occur prior to ESRD.^1,4

This article provides the latest recommendations for evaluating and managing DKD to help you prevent or slow its progression.

Defining and categorizing diabetic kidney disease

CKD is defined as persistently elevated excretion of urinary albumin (albuminuria) and decreased estimated glomerular filtration rate (eGFR), or as the presence of signs of progressive kidney damage.^5,6 DKD, also known as diabetic nephropathy, is CKD attributed to long-term diabetes. A patient’s eGFR is the established basis for assignment to a stage (1, 2, 3a, 3b, 4, or 5) of CKD (TABLE 1⁷) and, along with the category of albuminuria (A1, A2, or A3), can indicate prognosis.

Taking its toll in diabetes

As many as 40% of patients with diabetes develop DKD.^8-10 Most studies of DKD have been conducted in patients with type 1 diabetes (T1D), because the time of clinical onset is typically known.

Type 1 diabetes. DKD usually occurs 10 to 15 years, or later, after the onset of diabetes.⁶ As many as 30% of people with T1D have albuminuria approximately 15 years after onset of diabetes; almost one-half of those develop DKD.^5,11 After approximately 22.5 years without albuminuria, patients with T1D have approximately a 1% annual risk of DKD.¹²

Type 2 diabetes (T2D). DKD is often present at diagnosis, likely due to a delay in diagnosis and briefer clinical exposure, compared to T1D. Albuminuria has been reported in as many as 40% of patients with T2D approximately 10 years after onset of diabetes.^12,13

Multiple risk factors with no standout “predictor”

Genetic susceptibility, ethnicity, glycemic control, smoking, blood pressure (BP), and the eGFR have been identified as risk factors for renal involvement in diabetes; obesity, oral contraceptives, and age can also contribute. Although each risk factor increases the risk of DKD, no single factor is adequately predictive. Moderately increased albuminuria, the earliest sign of DKD, is associated with progressive nephropathy.¹²

Continue to: How great is the risk?

How great is the risk? From disease onset to proteinuria and from proteinuria to ESRD, the risk of DKD in T1D and T2D is similar. With appropriate treatment, albuminuria can regress, and the risk of ESRD can be < 20% at 10 years in T1D.¹² As in T1D, good glycemic control might result in regression of albuminuria in T2D.¹⁴

As many as 30% of people with T1D have albuminuria approximately 15 years after onset of diabetes; almost one-half of those develop DKD.

For unknown reasons, the degree of albuminuria can exist independent of the progression of DKD. Factors responsible for a progressive decline in eGFR in DKD without albuminuria are unknown.^12,15

Patient evaluation with an eye toward comorbidities

A comprehensive initial medical evaluation for DKD includes a review of microvascular complications; visits to specialists; lifestyle and behavior patterns (eg, diet, sleep, substance use, and social support); and medication adherence, adverse drug effects, and alternative medicines. Although DKD is often a clinical diagnosis, it can be ruled in by persistent albuminuria or decreased eGFR, or both, in established diabetes or diabetic retinopathy when other causes are unlikely (see “Recommended DKD screening protocol,” below).

Screening for mental health conditions and barriers to self-management is also key.⁶

Comorbidities, of course, can complicate disease management in patients with diabetes.^16-20 Providers and patients therefore need to be aware of potential diabetic comorbidities. For example, DKD and even moderately increased albuminuria significantly increase the risk of cardiovascular disease (CVD).¹² Other possible comorbidities include (but are not limited to) nonalcoholic steatohepatitis, fracture, hearing impairment, cancer (eg, liver, pancreas, endometrium, colon, rectum, breast, and bladder), pancreatitis, hypogonadism, obstructive sleep apnea, periodontal disease, anxiety, depression, and eating disorders.⁶

Continue to: Recommended DKD screening protocol

 

 

Recommended DKD screening protocol

In all cases of T2D, in cases of T1D of ≥ 5 years’ duration, and in patients with diabetes and comorbid hypertension, perform annual screening for albuminuria, an elevated creatinine level, and a decline in eGFR.

Screen for potential comorbidities of DKD: For example, the risk of cardiovascular disease is significantly elevated in even moderately increased albuminuria.

To confirm the diagnosis of DKD, at least 2 of 3 urine specimens must demonstrate an elevated urinary albumin:creatinine ratio (UACR) over a 3- to 6-month period.²¹ Apart from renal damage, exercise within 24 hours before specimen collection, infection, fever, congestive heart failure, hyperglycemia, menstruation, and hypertension can elevate the UACR.⁶

Levels of the UACR are established as follows²²:

• Normal UACR is defined as < 30 milligrams of albumin per gram of creatinine (expressed as “mg/g”).
• Increased urinary albumin excretion is defined as ≥ 30 mg/g.
• Moderately increased albuminuria, a predictor of potential nephropathy, is the excretion of 30 to 300 mg/g.
• Severely increased albuminuria is excretion > 300 mg/g; it is often followed by a gradual decline in eGFR that, without treatment, eventually leads to ESRD.

The rate of decline in eGFR once albuminuria is severely increased is equivalent in T1D and T2D.¹² Without intervention, the time from severely increased albuminuria to ESRD in T1D and T2D averages approximately 6 or 7 years.

Clinical features

DKD is typically a clinical diagnosis seen in patients with longstanding diabetes, albuminuria, retinopathy, or a reduced eGFR in the absence of another primary cause of kidney damage. In patients with T1D and DKD, signs of retinopathy and neuropathy are almost always present at diagnosis, unless a diagnosis is made early in the course of diabetes.¹² Therefore, the presence of retinopathy suggests that diabetes is the likely cause of CKD.

Continue to: The presence of microvascular disease...

The presence of microvascular disease in patients with T2D and DKD is less predictable.¹² In T2D patients who do not have retinopathy, consider causes of CKD other than DKD. Features suggesting that the cause of CKD is an underlying condition other than diabetes are rapidly increasing albuminuria or decreasing eGFR; urinary sediment comprising red blood cells or white blood cells; and nephrotic syndrome.⁶

As the prevalence of diabetes increases, it has become more common to diagnose DKD by eGFR without albuminuria—underscoring the importance of routine monitoring of eGFR in patients with diabetes.⁶

Sources of expert guidance. The Chronic Kidney Disease Epidemiology Collaboration equation²³ is preferred for calculating eGFR from serum creatinine: An eGFR < 60 mL/min/1.73 m² is considered abnormal.^3,12 At these rates, the prevalence of complications related to CKD rises and screening for complications becomes necessary.

A more comprehensive classification of the stages of CKD, incorporating albuminuria and progression of CKD, has been recommended by Kidney Disease: Improving Global Outcomes (KDIGO).⁷ Because eGFR and excretion of albumin vary, abnormal test results need to be verified over time to stage the degree of CKD.^3,12 Kidney damage often manifests as albuminuria, but also as hematuria, other types of abnormal urinary sediment, radiographic abnormalities, and other abnormal presentations.

Management

Nutritional factors

Excessive protein intake has been shown to increase albuminuria, worsen renal function, and increase CVD mortality in DKD.^24-26 Therefore, daily dietary protein intake of 0.8 g/kg body weight is recommended for patients who are not on dialysis.³ Patients on dialysis might require higher protein intake to preserve muscle mass caused by protein-energy wasting, which is common in dialysis patients.⁶

Continue to: Low sodium intake

Low sodium intake in CKD patients has been shown to decrease BP and thus slow the progression of renal disease and lower the risk of CVD. The recommended dietary sodium intake in CKD patients is 1500-3000 mg/d.³

Low potassium intake. Hyperkalemia is a serious complication of CKD. A low-potassium diet is recommended in ESRD patients who have a potassium level > 5.5 mEq/L.⁶

Blood pressure

Preventing and treating hypertension is critical to slowing the progression of CKD and reducing cardiovascular risk. BP should be measured at every clinic visit. Aside from lifestyle changes, medication might be needed to reach target BP.

The American Diabetes Association recommends a BP goal of ≤ 140/90 mm Hg for hypertensive patients with diabetes, although they do state that a lower BP target (≤ 130/80 mm Hg) might be more appropriate for patients with DKD.²⁷

The American College of Cardiology recommends that hypertensive patients with CKD have a BP target of ≤ 130/80 mm Hg.²⁸

Continue to: ACE inhibitors and ARBs

Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) have renoprotective benefits. These agents are recommended as first-line medications for patients with diabetes, hypertension, and an eGFR < 60 mL/min/1.73 m² and a UACR > 300 mg/g.^29-31 Evidence also supports their use when the UACR is 30 to 299 mg/g.

Studies have shown that, in patients with DKD, ACE inhibitors and ARBs can slow the progression of renal disease.^29,30,32 There is no difference between ACE inhibitors and ARBs in their effectiveness for preventing progression of DKD.⁶ There is no added benefit in combining an ACE inhibitor and an ARB³³; notably, combination ACE inhibitor and ARB therapy can increase the risk of adverse events, such as hyperkalemia and acute kidney injury, especially in patients with DKD.³³

There is no evidence for starting an ACE inhibitor or ARB to prevent CKD in patients with diabetes who are not hypertensive.⁵

ACE inhibitors and ARBs should be used with caution in women of childbearing age, who should use a reliable form of contraception if taking one of these drugs.

Diuretics. Thiazide-type and loop diuretics might potentiate the positive effects of ACE inhibitors and ARBs. KDOQI guidelines recommend that, in patients who require a second agent to control BP, a diuretic should be considered in combination with an ACE inhibitor or an ARB.²⁰ A loop diuretic is preferred if the eGFR is < 30 mL/min/1.73 m².

Continue to: Nondihydropyridine calcium-channel blockers

Nondihydropyridine calcium-channel blockers (CCBs), such as diltiazem and verapamil, have been shown to be more effective then dihydrophyridine CCBs, such as amlodipine and nifedipine, in slowing the progression of renal disease because of their antiproteinuric effects. However, the antiproteinuric effects of nondihydropyridine CCBs are not as strong as those of ACE inhibitors or ARBs, and these drugs do not appear to potentiate the effects of an ACE inhibitor or ARB when used in combination.²⁰

Confirmation of suspected DKD requires an elevated albumin:creatinine ratio in at least 2 of 3 urine specimens over a 3- to 6-month period.

Nondihydropyridine CCBs might be a reasonable alternative in patients who cannot tolerate an ACE inhibitor or an ARB.

Mineralocorticoid receptor antagonists in combination with an ACE inhibitor or ARB have been demonstrated to reduce albuminuria in short-term studies.^34,35

Glycemic levels

Studies conducted in patients with T1D, and others in patients with T2D, have shown that tight glycemic control can delay the onset and slow the progression of albuminuria and a decline in the eGFR.^10,36-39 The target glycated hemoglobin (A1C) should be < 7% to prevent or slow progression of DKD.⁴⁰ However, patients with DKD have an increased risk of hypoglycemic events and increased mortality with more intensive glycemic control.^40,41 Given those findings, some patients with DKD and significant comorbidities, ESRD, or limited life expectancy might need to have an A1C target set at 8%.^6,42

Adjustments to antidiabetes medications in DKD

In patients with stages 3 to 5 DKD, several common antidiabetic medications might need to be adjusted or discontinued because they decrease creatinine clearance.

Continue to: First-generation sulfonylureas

First-generation sulfonylureas should be avoided in DKD. Glipizide and gliclazide are preferred among second-generation sulfonylureas because they do not increase the risk of hypoglycemia in DKD patients, although patients taking these medications still require close monitoring of their blood glucose level.²⁰

Metformin. In 2016, recommendations changed for the use of metformin in patients with DKD: The eGFR, not the serum creatinine level, should guide treatment.⁴³ Metformin can be used safely in patients with (1) an eGFR of < 60 mL/min/1.73 m² and (2) an eGFR of 30 mL/min/1.73 m² with close monitoring. Metformin should not be initiated if the eGFR is < 45 mL/min/1.73 m².⁴³ 

Antidiabetes medications with direct effect on the kidney

Several antidiabetes medications have a direct effect on the kidney apart from their effect on the blood glucose level.

Sodium-glucose co-transporter 2 (SGLT2) inhibitors have been shown to reduce albuminuria and slow the decrease of eGFR independent of glycemic control. In addition, SGLT2 inhibitors have also been shown to have cardiovascular benefits in patients with DKD.^44,45 

Glucagon-like peptide 1 (GLP-1) receptor agonists have been shown to delay and decrease the progression of DKD.^46-48 Also, similar to what is seen with SGLT2 inhibitors, GLP-1 agonists have demonstrable cardiovascular benefit in patients with DKD.^46,48

Continue to: Dyslipidemia and DKD

 

 

Dyslipidemia and DKD

Because the risk of CVD is increased in patients with DKD, addressing other modifiable risk factors, including dyslipidemia, is recommended in these patients. Patients with diabetes and stages 1 to 4 DKD should be treated with a high-intensity statin or a combination of a statin and ezetimibe.^49,50

Tight glycemic control in T1D and T2D can delay the onset, and slow the progression, of albuminuria and a decline in the eGFR.

If a patient is taking a statin and starting dialysis, it’s important to discuss with him or her whether to continue the statin, based on perceived benefits and risks. It is not recommended that statins be initiated in patients on dialysis unless there is a specific cardiovascular indication for doing so. Risk reduction with a statin has been shown to be significantly less in dialysis patients than in patients who are not being treated with dialysis.⁴⁹

Complications of CKD

Anemia is a common complication of CKD. KDIGO recommends measuring the ­hemoglobin concentration annually in DKD stage 3 patients without anemia; at least every 6 months in stage 4 patients; and at least every 3 months in stage 5. DKD patients with anemia should have additional laboratory testing: the absolute reticulocyte count, serum ferritin, serum transferrin saturation, vitamin B12, and folate.⁵¹

Mineral and bone disorder should be screened for in patients with DKD. TABLE 2⁵² outlines when clinical laboratory tests should be ordered to assess for mineral bone disease.

When to refer to a nephrologist

Refer patients with stage 4 or 5 CKD (eGFR, ≤ 30 mL/min/1.73 m²) to a nephrologist for discussion of kidney replacement therapy.⁶ Patients with stage 3a CKD and severely increased albuminuria or with stage 3b CKD and moderately or severely increased albuminuria should also be referred to a nephrologist for intervention to delay disease progression.

Continue to: Identifying the need for early referral...

Nutritional control is important in DKD: A lowsodium diet can slow progression of DKD, and a low-potassium diet can prevent hyperkalemia in end-stage renal disease.

Identifying the need for early referral to a nephrologist has been shown to reduce the cost, and improve the quality, of care.⁵³ Other indications for earlier referral include uncertainty about the etiology of renal disease, persistent or severe albuminuria, persistent hematuria, a rapid decline in eGFR, and acute kidney injury. Additionally, referral at an earlier stage of DKD might be needed to assist with complications associated with DKD, such as anemia, secondary hyperparathyroidism, mineral and bone disorder, resistant hypertension, fluid overload, and electrolyte disturbances.⁶

ACKNOWLEDGEMENT
The authors thank Colleen Colbert, PhD, and Iqbal Ahmad, PhD, for their review and critique of the manuscript of this article. They also thank Christopher Babiuch, MD, for his guidance in the preparation of the manuscript.

CORRESPONDENCE
Faraz Ahmad, MD, MPH, Care Point East Family Medicine, 543 Taylor Avenue, 2nd floor, Columbus, OH 43203; faraz. ahmad@osumc.edu.

Chronic kidney disease (CKD) is a significant comorbidity of diabetes mellitus. The Kidney Disease Outcomes Quality Initiative (KDOQI) of the National Kidney Foundation defines CKD as the presence of kidney damage or decreased kidney function for ≥ 3 months. CKD caused by diabetes is called diabetic kidney disease (DKD), which is 1 of 3 principal microvascular complications of diabetes. DKD can progress to end-stage renal disease (ESRD), requiring kidney replacement therapy, and is the leading cause of CKD and ESRD in the United States.^1-3 Studies have also shown that, particularly in patients with diabetes, CKD considerably increases the risk of cardiovascular events, which often occur prior to ESRD.^1,4

This article provides the latest recommendations for evaluating and managing DKD to help you prevent or slow its progression.

Defining and categorizing diabetic kidney disease

CKD is defined as persistently elevated excretion of urinary albumin (albuminuria) and decreased estimated glomerular filtration rate (eGFR), or as the presence of signs of progressive kidney damage.^5,6 DKD, also known as diabetic nephropathy, is CKD attributed to long-term diabetes. A patient’s eGFR is the established basis for assignment to a stage (1, 2, 3a, 3b, 4, or 5) of CKD (TABLE 1⁷) and, along with the category of albuminuria (A1, A2, or A3), can indicate prognosis.

Taking its toll in diabetes

As many as 40% of patients with diabetes develop DKD.^8-10 Most studies of DKD have been conducted in patients with type 1 diabetes (T1D), because the time of clinical onset is typically known.

Type 1 diabetes. DKD usually occurs 10 to 15 years, or later, after the onset of diabetes.⁶ As many as 30% of people with T1D have albuminuria approximately 15 years after onset of diabetes; almost one-half of those develop DKD.^5,11 After approximately 22.5 years without albuminuria, patients with T1D have approximately a 1% annual risk of DKD.¹²

Type 2 diabetes (T2D). DKD is often present at diagnosis, likely due to a delay in diagnosis and briefer clinical exposure, compared to T1D. Albuminuria has been reported in as many as 40% of patients with T2D approximately 10 years after onset of diabetes.^12,13

Multiple risk factors with no standout “predictor”

Genetic susceptibility, ethnicity, glycemic control, smoking, blood pressure (BP), and the eGFR have been identified as risk factors for renal involvement in diabetes; obesity, oral contraceptives, and age can also contribute. Although each risk factor increases the risk of DKD, no single factor is adequately predictive. Moderately increased albuminuria, the earliest sign of DKD, is associated with progressive nephropathy.¹²

Continue to: How great is the risk?

How great is the risk? From disease onset to proteinuria and from proteinuria to ESRD, the risk of DKD in T1D and T2D is similar. With appropriate treatment, albuminuria can regress, and the risk of ESRD can be < 20% at 10 years in T1D.¹² As in T1D, good glycemic control might result in regression of albuminuria in T2D.¹⁴

As many as 30% of people with T1D have albuminuria approximately 15 years after onset of diabetes; almost one-half of those develop DKD.

For unknown reasons, the degree of albuminuria can exist independent of the progression of DKD. Factors responsible for a progressive decline in eGFR in DKD without albuminuria are unknown.^12,15

Patient evaluation with an eye toward comorbidities

A comprehensive initial medical evaluation for DKD includes a review of microvascular complications; visits to specialists; lifestyle and behavior patterns (eg, diet, sleep, substance use, and social support); and medication adherence, adverse drug effects, and alternative medicines. Although DKD is often a clinical diagnosis, it can be ruled in by persistent albuminuria or decreased eGFR, or both, in established diabetes or diabetic retinopathy when other causes are unlikely (see “Recommended DKD screening protocol,” below).

Screening for mental health conditions and barriers to self-management is also key.⁶

Comorbidities, of course, can complicate disease management in patients with diabetes.^16-20 Providers and patients therefore need to be aware of potential diabetic comorbidities. For example, DKD and even moderately increased albuminuria significantly increase the risk of cardiovascular disease (CVD).¹² Other possible comorbidities include (but are not limited to) nonalcoholic steatohepatitis, fracture, hearing impairment, cancer (eg, liver, pancreas, endometrium, colon, rectum, breast, and bladder), pancreatitis, hypogonadism, obstructive sleep apnea, periodontal disease, anxiety, depression, and eating disorders.⁶

Continue to: Recommended DKD screening protocol

 

 

Recommended DKD screening protocol

In all cases of T2D, in cases of T1D of ≥ 5 years’ duration, and in patients with diabetes and comorbid hypertension, perform annual screening for albuminuria, an elevated creatinine level, and a decline in eGFR.

Screen for potential comorbidities of DKD: For example, the risk of cardiovascular disease is significantly elevated in even moderately increased albuminuria.

To confirm the diagnosis of DKD, at least 2 of 3 urine specimens must demonstrate an elevated urinary albumin:creatinine ratio (UACR) over a 3- to 6-month period.²¹ Apart from renal damage, exercise within 24 hours before specimen collection, infection, fever, congestive heart failure, hyperglycemia, menstruation, and hypertension can elevate the UACR.⁶

Levels of the UACR are established as follows²²:

• Normal UACR is defined as < 30 milligrams of albumin per gram of creatinine (expressed as “mg/g”).
• Increased urinary albumin excretion is defined as ≥ 30 mg/g.
• Moderately increased albuminuria, a predictor of potential nephropathy, is the excretion of 30 to 300 mg/g.
• Severely increased albuminuria is excretion > 300 mg/g; it is often followed by a gradual decline in eGFR that, without treatment, eventually leads to ESRD.

The rate of decline in eGFR once albuminuria is severely increased is equivalent in T1D and T2D.¹² Without intervention, the time from severely increased albuminuria to ESRD in T1D and T2D averages approximately 6 or 7 years.

Clinical features

DKD is typically a clinical diagnosis seen in patients with longstanding diabetes, albuminuria, retinopathy, or a reduced eGFR in the absence of another primary cause of kidney damage. In patients with T1D and DKD, signs of retinopathy and neuropathy are almost always present at diagnosis, unless a diagnosis is made early in the course of diabetes.¹² Therefore, the presence of retinopathy suggests that diabetes is the likely cause of CKD.

Continue to: The presence of microvascular disease...

The presence of microvascular disease in patients with T2D and DKD is less predictable.¹² In T2D patients who do not have retinopathy, consider causes of CKD other than DKD. Features suggesting that the cause of CKD is an underlying condition other than diabetes are rapidly increasing albuminuria or decreasing eGFR; urinary sediment comprising red blood cells or white blood cells; and nephrotic syndrome.⁶

As the prevalence of diabetes increases, it has become more common to diagnose DKD by eGFR without albuminuria—underscoring the importance of routine monitoring of eGFR in patients with diabetes.⁶

Sources of expert guidance. The Chronic Kidney Disease Epidemiology Collaboration equation²³ is preferred for calculating eGFR from serum creatinine: An eGFR < 60 mL/min/1.73 m² is considered abnormal.^3,12 At these rates, the prevalence of complications related to CKD rises and screening for complications becomes necessary.

A more comprehensive classification of the stages of CKD, incorporating albuminuria and progression of CKD, has been recommended by Kidney Disease: Improving Global Outcomes (KDIGO).⁷ Because eGFR and excretion of albumin vary, abnormal test results need to be verified over time to stage the degree of CKD.^3,12 Kidney damage often manifests as albuminuria, but also as hematuria, other types of abnormal urinary sediment, radiographic abnormalities, and other abnormal presentations.

Management

Nutritional factors

Excessive protein intake has been shown to increase albuminuria, worsen renal function, and increase CVD mortality in DKD.^24-26 Therefore, daily dietary protein intake of 0.8 g/kg body weight is recommended for patients who are not on dialysis.³ Patients on dialysis might require higher protein intake to preserve muscle mass caused by protein-energy wasting, which is common in dialysis patients.⁶

Continue to: Low sodium intake

Low sodium intake in CKD patients has been shown to decrease BP and thus slow the progression of renal disease and lower the risk of CVD. The recommended dietary sodium intake in CKD patients is 1500-3000 mg/d.³

Low potassium intake. Hyperkalemia is a serious complication of CKD. A low-potassium diet is recommended in ESRD patients who have a potassium level > 5.5 mEq/L.⁶

Blood pressure

Preventing and treating hypertension is critical to slowing the progression of CKD and reducing cardiovascular risk. BP should be measured at every clinic visit. Aside from lifestyle changes, medication might be needed to reach target BP.

The American Diabetes Association recommends a BP goal of ≤ 140/90 mm Hg for hypertensive patients with diabetes, although they do state that a lower BP target (≤ 130/80 mm Hg) might be more appropriate for patients with DKD.²⁷

The American College of Cardiology recommends that hypertensive patients with CKD have a BP target of ≤ 130/80 mm Hg.²⁸

Continue to: ACE inhibitors and ARBs

Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) have renoprotective benefits. These agents are recommended as first-line medications for patients with diabetes, hypertension, and an eGFR < 60 mL/min/1.73 m² and a UACR > 300 mg/g.^29-31 Evidence also supports their use when the UACR is 30 to 299 mg/g.

Studies have shown that, in patients with DKD, ACE inhibitors and ARBs can slow the progression of renal disease.^29,30,32 There is no difference between ACE inhibitors and ARBs in their effectiveness for preventing progression of DKD.⁶ There is no added benefit in combining an ACE inhibitor and an ARB³³; notably, combination ACE inhibitor and ARB therapy can increase the risk of adverse events, such as hyperkalemia and acute kidney injury, especially in patients with DKD.³³

There is no evidence for starting an ACE inhibitor or ARB to prevent CKD in patients with diabetes who are not hypertensive.⁵

ACE inhibitors and ARBs should be used with caution in women of childbearing age, who should use a reliable form of contraception if taking one of these drugs.

Diuretics. Thiazide-type and loop diuretics might potentiate the positive effects of ACE inhibitors and ARBs. KDOQI guidelines recommend that, in patients who require a second agent to control BP, a diuretic should be considered in combination with an ACE inhibitor or an ARB.²⁰ A loop diuretic is preferred if the eGFR is < 30 mL/min/1.73 m².

Continue to: Nondihydropyridine calcium-channel blockers

Nondihydropyridine calcium-channel blockers (CCBs), such as diltiazem and verapamil, have been shown to be more effective then dihydrophyridine CCBs, such as amlodipine and nifedipine, in slowing the progression of renal disease because of their antiproteinuric effects. However, the antiproteinuric effects of nondihydropyridine CCBs are not as strong as those of ACE inhibitors or ARBs, and these drugs do not appear to potentiate the effects of an ACE inhibitor or ARB when used in combination.²⁰

Confirmation of suspected DKD requires an elevated albumin:creatinine ratio in at least 2 of 3 urine specimens over a 3- to 6-month period.

Nondihydropyridine CCBs might be a reasonable alternative in patients who cannot tolerate an ACE inhibitor or an ARB.

Mineralocorticoid receptor antagonists in combination with an ACE inhibitor or ARB have been demonstrated to reduce albuminuria in short-term studies.^34,35

Glycemic levels

Studies conducted in patients with T1D, and others in patients with T2D, have shown that tight glycemic control can delay the onset and slow the progression of albuminuria and a decline in the eGFR.^10,36-39 The target glycated hemoglobin (A1C) should be < 7% to prevent or slow progression of DKD.⁴⁰ However, patients with DKD have an increased risk of hypoglycemic events and increased mortality with more intensive glycemic control.^40,41 Given those findings, some patients with DKD and significant comorbidities, ESRD, or limited life expectancy might need to have an A1C target set at 8%.^6,42

Adjustments to antidiabetes medications in DKD

In patients with stages 3 to 5 DKD, several common antidiabetic medications might need to be adjusted or discontinued because they decrease creatinine clearance.

Continue to: First-generation sulfonylureas

First-generation sulfonylureas should be avoided in DKD. Glipizide and gliclazide are preferred among second-generation sulfonylureas because they do not increase the risk of hypoglycemia in DKD patients, although patients taking these medications still require close monitoring of their blood glucose level.²⁰

Metformin. In 2016, recommendations changed for the use of metformin in patients with DKD: The eGFR, not the serum creatinine level, should guide treatment.⁴³ Metformin can be used safely in patients with (1) an eGFR of < 60 mL/min/1.73 m² and (2) an eGFR of 30 mL/min/1.73 m² with close monitoring. Metformin should not be initiated if the eGFR is < 45 mL/min/1.73 m².⁴³ 

Antidiabetes medications with direct effect on the kidney

Several antidiabetes medications have a direct effect on the kidney apart from their effect on the blood glucose level.

Sodium-glucose co-transporter 2 (SGLT2) inhibitors have been shown to reduce albuminuria and slow the decrease of eGFR independent of glycemic control. In addition, SGLT2 inhibitors have also been shown to have cardiovascular benefits in patients with DKD.^44,45 

Glucagon-like peptide 1 (GLP-1) receptor agonists have been shown to delay and decrease the progression of DKD.^46-48 Also, similar to what is seen with SGLT2 inhibitors, GLP-1 agonists have demonstrable cardiovascular benefit in patients with DKD.^46,48

Continue to: Dyslipidemia and DKD

 

 

Dyslipidemia and DKD

Because the risk of CVD is increased in patients with DKD, addressing other modifiable risk factors, including dyslipidemia, is recommended in these patients. Patients with diabetes and stages 1 to 4 DKD should be treated with a high-intensity statin or a combination of a statin and ezetimibe.^49,50

Tight glycemic control in T1D and T2D can delay the onset, and slow the progression, of albuminuria and a decline in the eGFR.

If a patient is taking a statin and starting dialysis, it’s important to discuss with him or her whether to continue the statin, based on perceived benefits and risks. It is not recommended that statins be initiated in patients on dialysis unless there is a specific cardiovascular indication for doing so. Risk reduction with a statin has been shown to be significantly less in dialysis patients than in patients who are not being treated with dialysis.⁴⁹

Complications of CKD

Anemia is a common complication of CKD. KDIGO recommends measuring the ­hemoglobin concentration annually in DKD stage 3 patients without anemia; at least every 6 months in stage 4 patients; and at least every 3 months in stage 5. DKD patients with anemia should have additional laboratory testing: the absolute reticulocyte count, serum ferritin, serum transferrin saturation, vitamin B12, and folate.⁵¹

Mineral and bone disorder should be screened for in patients with DKD. TABLE 2⁵² outlines when clinical laboratory tests should be ordered to assess for mineral bone disease.

When to refer to a nephrologist

Refer patients with stage 4 or 5 CKD (eGFR, ≤ 30 mL/min/1.73 m²) to a nephrologist for discussion of kidney replacement therapy.⁶ Patients with stage 3a CKD and severely increased albuminuria or with stage 3b CKD and moderately or severely increased albuminuria should also be referred to a nephrologist for intervention to delay disease progression.

Continue to: Identifying the need for early referral...

Nutritional control is important in DKD: A lowsodium diet can slow progression of DKD, and a low-potassium diet can prevent hyperkalemia in end-stage renal disease.

Identifying the need for early referral to a nephrologist has been shown to reduce the cost, and improve the quality, of care.⁵³ Other indications for earlier referral include uncertainty about the etiology of renal disease, persistent or severe albuminuria, persistent hematuria, a rapid decline in eGFR, and acute kidney injury. Additionally, referral at an earlier stage of DKD might be needed to assist with complications associated with DKD, such as anemia, secondary hyperparathyroidism, mineral and bone disorder, resistant hypertension, fluid overload, and electrolyte disturbances.⁶

ACKNOWLEDGEMENT
The authors thank Colleen Colbert, PhD, and Iqbal Ahmad, PhD, for their review and critique of the manuscript of this article. They also thank Christopher Babiuch, MD, for his guidance in the preparation of the manuscript.

CORRESPONDENCE
Faraz Ahmad, MD, MPH, Care Point East Family Medicine, 543 Taylor Avenue, 2nd floor, Columbus, OH 43203; faraz. ahmad@osumc.edu.

Primary care physicians (PCPs) generate only a small part of the $75 billion to $100 billion wasted every year on low-value care, according to a brief report published online Jan. 18 in Annals of Internal Medicine.

However, one expert said there are better ways to curb low-value care than focusing on which specialties are guilty of the practice.

Analyzing a 20% random sample of Medicare Part B claims, Aaron Baum, PhD, with the Icahn School of Medicine at Mount Sinai, New York, and colleagues found that the services primary care physicians performed or ordered made up on average 8.3% of the low-value care their patients received (interquartile range, 3.9%-15.1%; 95th percentile, 35.6%) and their referrals made up 15.4% (IQR, 6.3%-26.4%; 95th percentile, 44.6%).

By specialty, cardiology had the worst record with 27% of all spending on low-value services ($1.8 billion) attributed to that specialty. Yet, of the 25 highest-spending specialties in the report, 12 of them were associated with 1% or less than 1% each of all low-value spending, indicating the waste was widely distributed.

Dr. Baum said in an interview that though there are some PCPs guilty of high spending on low-value services, overall, most primary care physicians’ low-value services add up to only 0.3% of Part B spending. He noted that Part B spending is about one-third of all Medicare spending.

Primary care is often thought to be at the core of care management and spending and PCPs are often seen as the gatekeepers, but this analysis suggests that efforts to make big differences in curtailing low-value spending might be more effective elsewhere.

“There’s only so much spending you can reduce by changing primary care physicians’ services that they directly perform,” Dr. Baum said.
 

Low-value care is costly, can be harmful

Mark Fendrick, MD, director of the University of Michigan’s Center for Value-Based Insurance Design in Ann Arbor, said in an interview that the report adds confirmation to previous research that has consistently shown low-value care is “extremely common, very costly, and provided by primary care providers and specialists alike.” He noted that it can also be harmful.

“The math is simple,” he said. “If we want to improve coverage and lower patient costs for essential services like visits, diagnostic tests, and drugs, we have to reduce spending on those services that do not make Americans any healthier.”

The study ranked 31 clinical services judged to be low value by physician societies, Medicare and clinical guidelines, and their use among beneficiaries enrolled between 2007 and 2014. Here’s how the top six low-value services compare.

Dr. Fendrick said a weakness of the paper is the years of the data (2007-2014). Some of the criteria around low-value care have changed since then. The age that a prostate-specific antigen test becomes low-value is now 70 years, for instance, instead of 75. He added that some of the figures attributed to non-PCP providers appear out of date.

Dr. Fendrick said, “I understand that there are Medicare patients who end up at a gastroenterologist or surgeon’s office to get colorectal cancer screening, but it would be very hard for me to believe that half of stress tests and over half of colon cancer screening over [age] 85 [years] and half of PSA for people over 75 did not have some type of referring clinicians involved. I certainly don’t think that would be the case in 2020-2021.”

Dr. Baum said those years were the latest years available for the data points needed for this analysis, but he and his colleagues were working to update the data for future publication.

Dr. Fendrick said not much has changed in recent years in terms of waste on low-value care, even with campaigns such as Choosing Wisely dedicated to identifying low-value services or procedures in each specialty.

“I believe there’s not a particular group of clinicians one way or the other who are actually doing any better now than they were 7 years ago,” he said. He would rather focus less on which specialties are associated with the most low-value care and more on the underlying policies that encourage low-value care.

“If you’re going to get paid for doing a stress test and get paid nothing or significantly less if you don’t, the incentives are in the wrong direction,” he said.

Dr. Fendrick said the pandemic era provides an opportunity to eliminate low-value care because use of those services has dropped drastically as resources have been diverted to COVID-19 patients and many services have been delayed or canceled.

He said he has been pushing an approach that providers should be paid more after the pandemic “to do the things we want them to do.”

As an example, he said, instead of paying $886 million on colonoscopies for people over the age of 85, “why don’t we put a policy in place that would make it better for patients by lowering cost sharing and better for providers by paying them more to do the service on the people who need it as opposed to the people who don’t?”

The research was funded by the American Board of Family Medicine Foundation. Dr. Baum and a coauthor reported receiving personal fees from American Board of Family Medicine Foundation during the conduct of the study. Another coauthor reported receiving personal fees from Collective Health, HealthRight 360, PLOS Medicine, and the New England Journal of Medicine, outside the submitted work. Dr. Fendrick disclosed no relevant financial relationships.

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

Primary care physicians (PCPs) generate only a small part of the $75 billion to $100 billion wasted every year on low-value care, according to a brief report published online Jan. 18 in Annals of Internal Medicine.

However, one expert said there are better ways to curb low-value care than focusing on which specialties are guilty of the practice.

Analyzing a 20% random sample of Medicare Part B claims, Aaron Baum, PhD, with the Icahn School of Medicine at Mount Sinai, New York, and colleagues found that the services primary care physicians performed or ordered made up on average 8.3% of the low-value care their patients received (interquartile range, 3.9%-15.1%; 95th percentile, 35.6%) and their referrals made up 15.4% (IQR, 6.3%-26.4%; 95th percentile, 44.6%).

By specialty, cardiology had the worst record with 27% of all spending on low-value services ($1.8 billion) attributed to that specialty. Yet, of the 25 highest-spending specialties in the report, 12 of them were associated with 1% or less than 1% each of all low-value spending, indicating the waste was widely distributed.

Dr. Baum said in an interview that though there are some PCPs guilty of high spending on low-value services, overall, most primary care physicians’ low-value services add up to only 0.3% of Part B spending. He noted that Part B spending is about one-third of all Medicare spending.

Primary care is often thought to be at the core of care management and spending and PCPs are often seen as the gatekeepers, but this analysis suggests that efforts to make big differences in curtailing low-value spending might be more effective elsewhere.

“There’s only so much spending you can reduce by changing primary care physicians’ services that they directly perform,” Dr. Baum said.
 

Low-value care is costly, can be harmful

Mark Fendrick, MD, director of the University of Michigan’s Center for Value-Based Insurance Design in Ann Arbor, said in an interview that the report adds confirmation to previous research that has consistently shown low-value care is “extremely common, very costly, and provided by primary care providers and specialists alike.” He noted that it can also be harmful.

“The math is simple,” he said. “If we want to improve coverage and lower patient costs for essential services like visits, diagnostic tests, and drugs, we have to reduce spending on those services that do not make Americans any healthier.”

The study ranked 31 clinical services judged to be low value by physician societies, Medicare and clinical guidelines, and their use among beneficiaries enrolled between 2007 and 2014. Here’s how the top six low-value services compare.

Dr. Fendrick said a weakness of the paper is the years of the data (2007-2014). Some of the criteria around low-value care have changed since then. The age that a prostate-specific antigen test becomes low-value is now 70 years, for instance, instead of 75. He added that some of the figures attributed to non-PCP providers appear out of date.

Dr. Fendrick said, “I understand that there are Medicare patients who end up at a gastroenterologist or surgeon’s office to get colorectal cancer screening, but it would be very hard for me to believe that half of stress tests and over half of colon cancer screening over [age] 85 [years] and half of PSA for people over 75 did not have some type of referring clinicians involved. I certainly don’t think that would be the case in 2020-2021.”

Dr. Baum said those years were the latest years available for the data points needed for this analysis, but he and his colleagues were working to update the data for future publication.

Dr. Fendrick said not much has changed in recent years in terms of waste on low-value care, even with campaigns such as Choosing Wisely dedicated to identifying low-value services or procedures in each specialty.

“I believe there’s not a particular group of clinicians one way or the other who are actually doing any better now than they were 7 years ago,” he said. He would rather focus less on which specialties are associated with the most low-value care and more on the underlying policies that encourage low-value care.

“If you’re going to get paid for doing a stress test and get paid nothing or significantly less if you don’t, the incentives are in the wrong direction,” he said.

Dr. Fendrick said the pandemic era provides an opportunity to eliminate low-value care because use of those services has dropped drastically as resources have been diverted to COVID-19 patients and many services have been delayed or canceled.

He said he has been pushing an approach that providers should be paid more after the pandemic “to do the things we want them to do.”

As an example, he said, instead of paying $886 million on colonoscopies for people over the age of 85, “why don’t we put a policy in place that would make it better for patients by lowering cost sharing and better for providers by paying them more to do the service on the people who need it as opposed to the people who don’t?”

The research was funded by the American Board of Family Medicine Foundation. Dr. Baum and a coauthor reported receiving personal fees from American Board of Family Medicine Foundation during the conduct of the study. Another coauthor reported receiving personal fees from Collective Health, HealthRight 360, PLOS Medicine, and the New England Journal of Medicine, outside the submitted work. Dr. Fendrick disclosed no relevant financial relationships.

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

Primary care physicians (PCPs) generate only a small part of the $75 billion to $100 billion wasted every year on low-value care, according to a brief report published online Jan. 18 in Annals of Internal Medicine.

However, one expert said there are better ways to curb low-value care than focusing on which specialties are guilty of the practice.

Analyzing a 20% random sample of Medicare Part B claims, Aaron Baum, PhD, with the Icahn School of Medicine at Mount Sinai, New York, and colleagues found that the services primary care physicians performed or ordered made up on average 8.3% of the low-value care their patients received (interquartile range, 3.9%-15.1%; 95th percentile, 35.6%) and their referrals made up 15.4% (IQR, 6.3%-26.4%; 95th percentile, 44.6%).

By specialty, cardiology had the worst record with 27% of all spending on low-value services ($1.8 billion) attributed to that specialty. Yet, of the 25 highest-spending specialties in the report, 12 of them were associated with 1% or less than 1% each of all low-value spending, indicating the waste was widely distributed.

Dr. Baum said in an interview that though there are some PCPs guilty of high spending on low-value services, overall, most primary care physicians’ low-value services add up to only 0.3% of Part B spending. He noted that Part B spending is about one-third of all Medicare spending.

Primary care is often thought to be at the core of care management and spending and PCPs are often seen as the gatekeepers, but this analysis suggests that efforts to make big differences in curtailing low-value spending might be more effective elsewhere.

“There’s only so much spending you can reduce by changing primary care physicians’ services that they directly perform,” Dr. Baum said.
 

Low-value care is costly, can be harmful

Mark Fendrick, MD, director of the University of Michigan’s Center for Value-Based Insurance Design in Ann Arbor, said in an interview that the report adds confirmation to previous research that has consistently shown low-value care is “extremely common, very costly, and provided by primary care providers and specialists alike.” He noted that it can also be harmful.

“The math is simple,” he said. “If we want to improve coverage and lower patient costs for essential services like visits, diagnostic tests, and drugs, we have to reduce spending on those services that do not make Americans any healthier.”

The study ranked 31 clinical services judged to be low value by physician societies, Medicare and clinical guidelines, and their use among beneficiaries enrolled between 2007 and 2014. Here’s how the top six low-value services compare.

Dr. Fendrick said a weakness of the paper is the years of the data (2007-2014). Some of the criteria around low-value care have changed since then. The age that a prostate-specific antigen test becomes low-value is now 70 years, for instance, instead of 75. He added that some of the figures attributed to non-PCP providers appear out of date.

Dr. Fendrick said, “I understand that there are Medicare patients who end up at a gastroenterologist or surgeon’s office to get colorectal cancer screening, but it would be very hard for me to believe that half of stress tests and over half of colon cancer screening over [age] 85 [years] and half of PSA for people over 75 did not have some type of referring clinicians involved. I certainly don’t think that would be the case in 2020-2021.”

Dr. Baum said those years were the latest years available for the data points needed for this analysis, but he and his colleagues were working to update the data for future publication.

Dr. Fendrick said not much has changed in recent years in terms of waste on low-value care, even with campaigns such as Choosing Wisely dedicated to identifying low-value services or procedures in each specialty.

“I believe there’s not a particular group of clinicians one way or the other who are actually doing any better now than they were 7 years ago,” he said. He would rather focus less on which specialties are associated with the most low-value care and more on the underlying policies that encourage low-value care.

“If you’re going to get paid for doing a stress test and get paid nothing or significantly less if you don’t, the incentives are in the wrong direction,” he said.

Dr. Fendrick said the pandemic era provides an opportunity to eliminate low-value care because use of those services has dropped drastically as resources have been diverted to COVID-19 patients and many services have been delayed or canceled.

He said he has been pushing an approach that providers should be paid more after the pandemic “to do the things we want them to do.”

As an example, he said, instead of paying $886 million on colonoscopies for people over the age of 85, “why don’t we put a policy in place that would make it better for patients by lowering cost sharing and better for providers by paying them more to do the service on the people who need it as opposed to the people who don’t?”

The research was funded by the American Board of Family Medicine Foundation. Dr. Baum and a coauthor reported receiving personal fees from American Board of Family Medicine Foundation during the conduct of the study. Another coauthor reported receiving personal fees from Collective Health, HealthRight 360, PLOS Medicine, and the New England Journal of Medicine, outside the submitted work. Dr. Fendrick disclosed no relevant financial relationships.

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

Background: It is common practice for providers to intensify antihypertensive regimen during admission for noncardiac conditions even if a patient has a history of well-controlled blood pressure as an outpatient. Many providers have assumed that these changes will benefit patients; however, this outcome had never been studied.

Patients discharged with regimen intensification were more likely to be readmitted (hazard ratio, 1.23; 95% confidence interval, 1.07-1.42; number needed to harm = 27), experience a medication-related serious adverse event (HR, 1.42; 95% CI, 1.06-1.88; NNH = 63), and have a cardiovascular event (HR, 1.65; 95% CI, 1.13-2.4) within 30 days of discharge. At 1 year, no significant difference in mortality, cardiovascular events, or systolic BP were noted between the two groups.

A subgroup analysis of patients with poorly controlled blood pressure as outpatients (defined as systolic blood pressure greater than 140 mm Hg) who had their anti-hypertensive medications intensified did not show significant difference in 30-day readmission, severe adverse events, or cardiovascular events.

Limitations of the study include observational design and majority male sex (97.5%) of the study population.

Bottom line: Intensification of antihypertensive regimen among older adults hospitalized for noncardiac conditions with well-controlled blood pressure as an outpatient can potentially cause harm.

Citation: Anderson TS et al. Clinical outcomes after intensifying antihypertensive medication regimens among older adults at hospital discharge. JAMA Intern Med. 2019 Aug 19. doi: 10.1001/jamainternmed.2019.3007.

Dr. Zarookian is a hospitalist at Maine Medical Center in Portland and Stephens Memorial Hospital in Norway, Maine.

Background: It is common practice for providers to intensify antihypertensive regimen during admission for noncardiac conditions even if a patient has a history of well-controlled blood pressure as an outpatient. Many providers have assumed that these changes will benefit patients; however, this outcome had never been studied.

Patients discharged with regimen intensification were more likely to be readmitted (hazard ratio, 1.23; 95% confidence interval, 1.07-1.42; number needed to harm = 27), experience a medication-related serious adverse event (HR, 1.42; 95% CI, 1.06-1.88; NNH = 63), and have a cardiovascular event (HR, 1.65; 95% CI, 1.13-2.4) within 30 days of discharge. At 1 year, no significant difference in mortality, cardiovascular events, or systolic BP were noted between the two groups.

A subgroup analysis of patients with poorly controlled blood pressure as outpatients (defined as systolic blood pressure greater than 140 mm Hg) who had their anti-hypertensive medications intensified did not show significant difference in 30-day readmission, severe adverse events, or cardiovascular events.

Limitations of the study include observational design and majority male sex (97.5%) of the study population.

Bottom line: Intensification of antihypertensive regimen among older adults hospitalized for noncardiac conditions with well-controlled blood pressure as an outpatient can potentially cause harm.

Citation: Anderson TS et al. Clinical outcomes after intensifying antihypertensive medication regimens among older adults at hospital discharge. JAMA Intern Med. 2019 Aug 19. doi: 10.1001/jamainternmed.2019.3007.

Dr. Zarookian is a hospitalist at Maine Medical Center in Portland and Stephens Memorial Hospital in Norway, Maine.

Background: It is common practice for providers to intensify antihypertensive regimen during admission for noncardiac conditions even if a patient has a history of well-controlled blood pressure as an outpatient. Many providers have assumed that these changes will benefit patients; however, this outcome had never been studied.

Patients discharged with regimen intensification were more likely to be readmitted (hazard ratio, 1.23; 95% confidence interval, 1.07-1.42; number needed to harm = 27), experience a medication-related serious adverse event (HR, 1.42; 95% CI, 1.06-1.88; NNH = 63), and have a cardiovascular event (HR, 1.65; 95% CI, 1.13-2.4) within 30 days of discharge. At 1 year, no significant difference in mortality, cardiovascular events, or systolic BP were noted between the two groups.

A subgroup analysis of patients with poorly controlled blood pressure as outpatients (defined as systolic blood pressure greater than 140 mm Hg) who had their anti-hypertensive medications intensified did not show significant difference in 30-day readmission, severe adverse events, or cardiovascular events.

Limitations of the study include observational design and majority male sex (97.5%) of the study population.

Bottom line: Intensification of antihypertensive regimen among older adults hospitalized for noncardiac conditions with well-controlled blood pressure as an outpatient can potentially cause harm.

Citation: Anderson TS et al. Clinical outcomes after intensifying antihypertensive medication regimens among older adults at hospital discharge. JAMA Intern Med. 2019 Aug 19. doi: 10.1001/jamainternmed.2019.3007.

Dr. Zarookian is a hospitalist at Maine Medical Center in Portland and Stephens Memorial Hospital in Norway, Maine.

“Increases in age at menarche are significantly associated with increases in cardiovascular health among women,” reported Yi Zheng, MPH, and colleagues at the University of Florida, Gainesville.

Mr. Zheng and colleagues conducted a cross-sectional analysis of 20,447 women aged 18 or older using data from a nationally representative sample of the 1999-2016 National Health and Nutrition Examinations Survey (NHANES). In all, 2,292 (11.2%) were determined to have ideal cardiovascular health (CVH).

Early menarche was confirmed to be related to increases in body mass index and greater incidence of type 2 diabetes, consistent with earlier studies, the authors confirmed. Those with nonideal CVH were more likely to have reported early menarche; those with ideal CVH were not only younger, but they also had college or graduate level education or above and higher poverty income ratio. Those with ideal CVH were also less likely to be to be of non-Hispanic Black heritage or to have been previously married.
 

BMI may be the missing link between early menarche and CVH

Unlike previous studies, the researchers found no significant link between early menarche and blood pressure, total cholesterol, smoking, physical activity, or diet using fully adjusted model data, leading them to conclude that “the associations between early menarche and CVH might be mainly driven by its associations with BMI.”

Mr. Zheng and colleagues suggested that future studies should evaluate the causal relationships between age at menarche and BMI and whether genetic factors and childhood lifestyle predispose women to early menarche and obesity.

“Our findings further highlighted that age at menarche may be used to identify high-risk population[s] and to guide targeted preventions to maintain and improve CVH,” the authors noted. Although they cited several strengths and limitations of the study, they emphasized that the wide use of Life’s Simple 7 factors (blood pressure, total cholesterol, glucose levels, smoking, BMI, physical activity, and diet) to measure CVH should “only be regarded as a surrogate construct, and future efforts are needed to better characterize CVH,” they cautioned.
 

The findings offer an opportunity to more closely track CVH in racial and ethnic groups

In a separate editorial, Ewa M. Gross-Sawicka, MD, PhD, and Eiran Z. Gorodeski, MD, MPH, both of the Harrington Heart and Vascular Institute, Cleveland, observed: “That the authors found African American women had the lowest overall CVH scores, even after adjusting for differences, highlights the importance of beginning cardiovascular health education earlier, especially for those in certain racial and ethnic groups.”

Dr. Gross-Sawicka and Dr. Gorodeski also raised several key questions that warrant further research: “1) Why do women who experience late menarche have improved cardiovascular health while those who experience early menarche have reduced cardiovascular health? 2) Why do the ‘beneficial’ effects of late menarche on CVH last 10 years longer than the ‘detrimental’ effects of early menarche? 3) Since both early and late menarche are associated with increased risk of cardiovascular disease, are women who experience menarche at an older age more cognizant of the cardiovascular risks compared with younger women and adjust their CVH accordingly?”

A key point also worth further consideration: “It is unclear whether age at menarche is directly associated with CVH, or if this relationship is mediated by the association of age at menarche and BMI and/or hyperglycemia,” said Dr. Gross-Sawicka and Dr. Gorodeski.

In an interview, Jan Shifren, MD, director, Midlife Women’s Health Center, Massachusetts General Hospital, Boston, noted, “The principal finding is that early menarche is associated with worse cardiovascular health, which may reflect the adverse impact of obesity and glucose intolerance on CVH, as obesity also is a risk factor for early menarche. The association between early menarche and worse CVH was significant only in women aged 25-34 years, but not in older women, possibly as other risk factors become more important as women age. One of the most concerning findings in this study ... is that only 11% had ideal CVH based on a combination of behavioral and health factors. As cardiovascular disease is the leading cause of death for women, we must do a better job of optimizing [their] cardiovascular health. Clinicians need to focus on optimizing cardiovascular health for all of their midlife patients, whether or not they experienced early menarche!”

Mr. Zheng and colleagues, as well as Dr. Shifren and Dr. Grodeski, had no conflicts of interest to report. Dr. Gross-Sawicka has received funding from Abbott and Novartis.

“Increases in age at menarche are significantly associated with increases in cardiovascular health among women,” reported Yi Zheng, MPH, and colleagues at the University of Florida, Gainesville.

Mr. Zheng and colleagues conducted a cross-sectional analysis of 20,447 women aged 18 or older using data from a nationally representative sample of the 1999-2016 National Health and Nutrition Examinations Survey (NHANES). In all, 2,292 (11.2%) were determined to have ideal cardiovascular health (CVH).

Early menarche was confirmed to be related to increases in body mass index and greater incidence of type 2 diabetes, consistent with earlier studies, the authors confirmed. Those with nonideal CVH were more likely to have reported early menarche; those with ideal CVH were not only younger, but they also had college or graduate level education or above and higher poverty income ratio. Those with ideal CVH were also less likely to be to be of non-Hispanic Black heritage or to have been previously married.
 

BMI may be the missing link between early menarche and CVH

Unlike previous studies, the researchers found no significant link between early menarche and blood pressure, total cholesterol, smoking, physical activity, or diet using fully adjusted model data, leading them to conclude that “the associations between early menarche and CVH might be mainly driven by its associations with BMI.”

Mr. Zheng and colleagues suggested that future studies should evaluate the causal relationships between age at menarche and BMI and whether genetic factors and childhood lifestyle predispose women to early menarche and obesity.

“Our findings further highlighted that age at menarche may be used to identify high-risk population[s] and to guide targeted preventions to maintain and improve CVH,” the authors noted. Although they cited several strengths and limitations of the study, they emphasized that the wide use of Life’s Simple 7 factors (blood pressure, total cholesterol, glucose levels, smoking, BMI, physical activity, and diet) to measure CVH should “only be regarded as a surrogate construct, and future efforts are needed to better characterize CVH,” they cautioned.
 

The findings offer an opportunity to more closely track CVH in racial and ethnic groups

In a separate editorial, Ewa M. Gross-Sawicka, MD, PhD, and Eiran Z. Gorodeski, MD, MPH, both of the Harrington Heart and Vascular Institute, Cleveland, observed: “That the authors found African American women had the lowest overall CVH scores, even after adjusting for differences, highlights the importance of beginning cardiovascular health education earlier, especially for those in certain racial and ethnic groups.”

Dr. Gross-Sawicka and Dr. Gorodeski also raised several key questions that warrant further research: “1) Why do women who experience late menarche have improved cardiovascular health while those who experience early menarche have reduced cardiovascular health? 2) Why do the ‘beneficial’ effects of late menarche on CVH last 10 years longer than the ‘detrimental’ effects of early menarche? 3) Since both early and late menarche are associated with increased risk of cardiovascular disease, are women who experience menarche at an older age more cognizant of the cardiovascular risks compared with younger women and adjust their CVH accordingly?”

A key point also worth further consideration: “It is unclear whether age at menarche is directly associated with CVH, or if this relationship is mediated by the association of age at menarche and BMI and/or hyperglycemia,” said Dr. Gross-Sawicka and Dr. Gorodeski.

In an interview, Jan Shifren, MD, director, Midlife Women’s Health Center, Massachusetts General Hospital, Boston, noted, “The principal finding is that early menarche is associated with worse cardiovascular health, which may reflect the adverse impact of obesity and glucose intolerance on CVH, as obesity also is a risk factor for early menarche. The association between early menarche and worse CVH was significant only in women aged 25-34 years, but not in older women, possibly as other risk factors become more important as women age. One of the most concerning findings in this study ... is that only 11% had ideal CVH based on a combination of behavioral and health factors. As cardiovascular disease is the leading cause of death for women, we must do a better job of optimizing [their] cardiovascular health. Clinicians need to focus on optimizing cardiovascular health for all of their midlife patients, whether or not they experienced early menarche!”

Mr. Zheng and colleagues, as well as Dr. Shifren and Dr. Grodeski, had no conflicts of interest to report. Dr. Gross-Sawicka has received funding from Abbott and Novartis.

“Increases in age at menarche are significantly associated with increases in cardiovascular health among women,” reported Yi Zheng, MPH, and colleagues at the University of Florida, Gainesville.

Mr. Zheng and colleagues conducted a cross-sectional analysis of 20,447 women aged 18 or older using data from a nationally representative sample of the 1999-2016 National Health and Nutrition Examinations Survey (NHANES). In all, 2,292 (11.2%) were determined to have ideal cardiovascular health (CVH).

Early menarche was confirmed to be related to increases in body mass index and greater incidence of type 2 diabetes, consistent with earlier studies, the authors confirmed. Those with nonideal CVH were more likely to have reported early menarche; those with ideal CVH were not only younger, but they also had college or graduate level education or above and higher poverty income ratio. Those with ideal CVH were also less likely to be to be of non-Hispanic Black heritage or to have been previously married.
 

BMI may be the missing link between early menarche and CVH

Unlike previous studies, the researchers found no significant link between early menarche and blood pressure, total cholesterol, smoking, physical activity, or diet using fully adjusted model data, leading them to conclude that “the associations between early menarche and CVH might be mainly driven by its associations with BMI.”

Mr. Zheng and colleagues suggested that future studies should evaluate the causal relationships between age at menarche and BMI and whether genetic factors and childhood lifestyle predispose women to early menarche and obesity.

“Our findings further highlighted that age at menarche may be used to identify high-risk population[s] and to guide targeted preventions to maintain and improve CVH,” the authors noted. Although they cited several strengths and limitations of the study, they emphasized that the wide use of Life’s Simple 7 factors (blood pressure, total cholesterol, glucose levels, smoking, BMI, physical activity, and diet) to measure CVH should “only be regarded as a surrogate construct, and future efforts are needed to better characterize CVH,” they cautioned.
 

The findings offer an opportunity to more closely track CVH in racial and ethnic groups

In a separate editorial, Ewa M. Gross-Sawicka, MD, PhD, and Eiran Z. Gorodeski, MD, MPH, both of the Harrington Heart and Vascular Institute, Cleveland, observed: “That the authors found African American women had the lowest overall CVH scores, even after adjusting for differences, highlights the importance of beginning cardiovascular health education earlier, especially for those in certain racial and ethnic groups.”

Dr. Gross-Sawicka and Dr. Gorodeski also raised several key questions that warrant further research: “1) Why do women who experience late menarche have improved cardiovascular health while those who experience early menarche have reduced cardiovascular health? 2) Why do the ‘beneficial’ effects of late menarche on CVH last 10 years longer than the ‘detrimental’ effects of early menarche? 3) Since both early and late menarche are associated with increased risk of cardiovascular disease, are women who experience menarche at an older age more cognizant of the cardiovascular risks compared with younger women and adjust their CVH accordingly?”

A key point also worth further consideration: “It is unclear whether age at menarche is directly associated with CVH, or if this relationship is mediated by the association of age at menarche and BMI and/or hyperglycemia,” said Dr. Gross-Sawicka and Dr. Gorodeski.

In an interview, Jan Shifren, MD, director, Midlife Women’s Health Center, Massachusetts General Hospital, Boston, noted, “The principal finding is that early menarche is associated with worse cardiovascular health, which may reflect the adverse impact of obesity and glucose intolerance on CVH, as obesity also is a risk factor for early menarche. The association between early menarche and worse CVH was significant only in women aged 25-34 years, but not in older women, possibly as other risk factors become more important as women age. One of the most concerning findings in this study ... is that only 11% had ideal CVH based on a combination of behavioral and health factors. As cardiovascular disease is the leading cause of death for women, we must do a better job of optimizing [their] cardiovascular health. Clinicians need to focus on optimizing cardiovascular health for all of their midlife patients, whether or not they experienced early menarche!”

Mr. Zheng and colleagues, as well as Dr. Shifren and Dr. Grodeski, had no conflicts of interest to report. Dr. Gross-Sawicka has received funding from Abbott and Novartis.

Childhood treatment with recombinant human growth hormone was associated with a significantly increased risk of cardiovascular events, based on data from more than 3,000 individuals.

“Both excess levels of growth hormone and [growth hormone deficiency] have been associated with increased cardiovascular morbidity and mortality,” but data on long-term cardiovascular morbidity in individuals treated with growth hormone in childhood are lacking, wrote Anders Tinblad, MD, of Karolinska Institutet, Stockholm, and colleagues.

In a population-based cohort study published in JAMA Pediatrics, the researchers identified 3,408 Swedish patients treated as children with recombinant human growth hormone (rhGH) between Jan. 1, 1985, and Dec. 31, 2010, and compared each with 15 matched controls (a total of 50,036 controls). The patients were treated for one of three conditions: isolated growth hormone deficiency (GHD), small for gestational age (SGA), and idiopathic short stature (ISS).

Data on cardiovascular outcomes were collected from health care and population-based registers and analyzed between Jan. 1, 1985, and Dec. 31, 2014. The average age of the participants at the study’s end was 25.1 years.

In all, 1,809 cardiovascular disease events were recorded over a median follow-up period of 14.9 years, for an incidence rate of 25.6 events per 10,000 person-years in patients and 22.6 events per 10,000 person-years in controls.

When separated by sex, the incidence was higher in female patients compared with controls (31.2 vs. 23.4 events per 10,000 person-years, respectively, but similar in male patients vs. controls (23.3 vs. 22.3 events per 10,000 person-years). “Differences in estrogen levels or responsiveness to rhGH treatment have previously been hypothesized as possible explanations, but the underlying mechanism for this sex difference still remains unclear and merits further investigation,” the researchers wrote.

Overall, the highest adjusted hazard ratios occurred in subgroups of patients with the longest treatment duration (HR 2.08) and highest cumulative dose of growth hormone (HR 2.05), but no association was noted between highest daily hormone dose and cardiovascular event risk. Hazard ratios were higher across all three treatment subgroups of SGA, GHD, and ISS compared with controls (HR 1.97, 1.66, and 1.55, respectively).

“The association between childhood rhGH treatment and CVD events was also seen when assessing only severe CVD outcomes, but with even lower absolute risks,” the researchers noted.

The study findings were limited by several factors including the potential for confounding by treatment indication and the lack of long-term follow-up data given the relatively young age of the study population, the researchers said. The results were strengthened by the large sample size and showed that the absolute risk for overall and severe cardiovascular disease in children treated with growth hormones was low, “which could be reassuring to individual patients,” they added. However, “At the group level, and perhaps especially for female patients and those treated for SGA indication, further close monitoring and future studies of CVD safety are warranted,” they concluded.
 

Safety and ethical concerns persist

Although the study authors cite limited conclusions on causality and low absolute risk, several issues persist that prompt ongoing analysis of pediatric growth hormone use, namely “worrisome indirect evidence, challenges and limitations in the direct evidence, and the changing world of growth hormone treatment,” Adda Grimberg, MD, of the University of Pennsylvania, Philadelphia, wrote in an accompanying editorial.

“Although evidence asserts that neither growth hormone nor insulinlike growth factor I is carcinogenic, the basic science and oncology literatures are rife with reports showing that they can make aberrant cells more aggressive,” and such indirect evidence supports the need for more direct evidence of possible harm from growth hormone treatment, Dr. Grimberg wrote. Most current safety data on growth hormone come from postmarketing surveillance studies, but these studies do not include controls or data on outcomes after discontinuation of treatment, she noted.

The current study, while able to follow patients across the lifespan, cannot indicate “whether the small but increased risk of cardiovascular disease found in this study was caused by the pediatric growth hormone treatment that identified the participants, by the conditions being treated, by other potential confounder(s) not captured by the study’s methods, or by a combination of the above,” said Dr. Grimberg.

In addition, “the move from replacement of GHD to pharmacologic height augmentation in children who already make sufficient growth hormone had the potential to change the safety profile of treatment,” she said.

“Parents of patients in pediatric primary care practices and of patients seeking growth-related care in a subspecialty endocrine clinic rated treatment characteristics (i.e., proven efficacy and safety) as the factor most having a big or extreme effect on their growth-related medical decision-making,” Dr. Grimberg said. “The centrality of treatment safety to patient-family decision-making underscores the importance of continued scrutiny of growth hormone safety as the treatment and its recipients continue to evolve,” she concluded.

The study was supported by the Swedish Research Council, the Stockholm City Council, the Karolinska Institute, the Society for Child Care, Sahlgrenska University Hospital, and the Stockholm County Council’s combined clinical residency and PhD training program. Lead author Dr. Tidblad disclosed funding from the Society for Child Care and Stockholm County Council during the conduct of the study and personal fees from Pfizer. Dr. Grimberg disclosed serving as a member of the steering committee for the Pfizer International Growth Study Database, and as a consultant for the Pediatric Endocrine Society GH Deficiency Knowledge Center, sponsored by Sandoz AG.

Childhood treatment with recombinant human growth hormone was associated with a significantly increased risk of cardiovascular events, based on data from more than 3,000 individuals.

“Both excess levels of growth hormone and [growth hormone deficiency] have been associated with increased cardiovascular morbidity and mortality,” but data on long-term cardiovascular morbidity in individuals treated with growth hormone in childhood are lacking, wrote Anders Tinblad, MD, of Karolinska Institutet, Stockholm, and colleagues.

In a population-based cohort study published in JAMA Pediatrics, the researchers identified 3,408 Swedish patients treated as children with recombinant human growth hormone (rhGH) between Jan. 1, 1985, and Dec. 31, 2010, and compared each with 15 matched controls (a total of 50,036 controls). The patients were treated for one of three conditions: isolated growth hormone deficiency (GHD), small for gestational age (SGA), and idiopathic short stature (ISS).

Data on cardiovascular outcomes were collected from health care and population-based registers and analyzed between Jan. 1, 1985, and Dec. 31, 2014. The average age of the participants at the study’s end was 25.1 years.

In all, 1,809 cardiovascular disease events were recorded over a median follow-up period of 14.9 years, for an incidence rate of 25.6 events per 10,000 person-years in patients and 22.6 events per 10,000 person-years in controls.

When separated by sex, the incidence was higher in female patients compared with controls (31.2 vs. 23.4 events per 10,000 person-years, respectively, but similar in male patients vs. controls (23.3 vs. 22.3 events per 10,000 person-years). “Differences in estrogen levels or responsiveness to rhGH treatment have previously been hypothesized as possible explanations, but the underlying mechanism for this sex difference still remains unclear and merits further investigation,” the researchers wrote.

Overall, the highest adjusted hazard ratios occurred in subgroups of patients with the longest treatment duration (HR 2.08) and highest cumulative dose of growth hormone (HR 2.05), but no association was noted between highest daily hormone dose and cardiovascular event risk. Hazard ratios were higher across all three treatment subgroups of SGA, GHD, and ISS compared with controls (HR 1.97, 1.66, and 1.55, respectively).

“The association between childhood rhGH treatment and CVD events was also seen when assessing only severe CVD outcomes, but with even lower absolute risks,” the researchers noted.

The study findings were limited by several factors including the potential for confounding by treatment indication and the lack of long-term follow-up data given the relatively young age of the study population, the researchers said. The results were strengthened by the large sample size and showed that the absolute risk for overall and severe cardiovascular disease in children treated with growth hormones was low, “which could be reassuring to individual patients,” they added. However, “At the group level, and perhaps especially for female patients and those treated for SGA indication, further close monitoring and future studies of CVD safety are warranted,” they concluded.
 

Safety and ethical concerns persist

Although the study authors cite limited conclusions on causality and low absolute risk, several issues persist that prompt ongoing analysis of pediatric growth hormone use, namely “worrisome indirect evidence, challenges and limitations in the direct evidence, and the changing world of growth hormone treatment,” Adda Grimberg, MD, of the University of Pennsylvania, Philadelphia, wrote in an accompanying editorial.

“Although evidence asserts that neither growth hormone nor insulinlike growth factor I is carcinogenic, the basic science and oncology literatures are rife with reports showing that they can make aberrant cells more aggressive,” and such indirect evidence supports the need for more direct evidence of possible harm from growth hormone treatment, Dr. Grimberg wrote. Most current safety data on growth hormone come from postmarketing surveillance studies, but these studies do not include controls or data on outcomes after discontinuation of treatment, she noted.

The current study, while able to follow patients across the lifespan, cannot indicate “whether the small but increased risk of cardiovascular disease found in this study was caused by the pediatric growth hormone treatment that identified the participants, by the conditions being treated, by other potential confounder(s) not captured by the study’s methods, or by a combination of the above,” said Dr. Grimberg.

In addition, “the move from replacement of GHD to pharmacologic height augmentation in children who already make sufficient growth hormone had the potential to change the safety profile of treatment,” she said.

“Parents of patients in pediatric primary care practices and of patients seeking growth-related care in a subspecialty endocrine clinic rated treatment characteristics (i.e., proven efficacy and safety) as the factor most having a big or extreme effect on their growth-related medical decision-making,” Dr. Grimberg said. “The centrality of treatment safety to patient-family decision-making underscores the importance of continued scrutiny of growth hormone safety as the treatment and its recipients continue to evolve,” she concluded.

The study was supported by the Swedish Research Council, the Stockholm City Council, the Karolinska Institute, the Society for Child Care, Sahlgrenska University Hospital, and the Stockholm County Council’s combined clinical residency and PhD training program. Lead author Dr. Tidblad disclosed funding from the Society for Child Care and Stockholm County Council during the conduct of the study and personal fees from Pfizer. Dr. Grimberg disclosed serving as a member of the steering committee for the Pfizer International Growth Study Database, and as a consultant for the Pediatric Endocrine Society GH Deficiency Knowledge Center, sponsored by Sandoz AG.

Childhood treatment with recombinant human growth hormone was associated with a significantly increased risk of cardiovascular events, based on data from more than 3,000 individuals.

“Both excess levels of growth hormone and [growth hormone deficiency] have been associated with increased cardiovascular morbidity and mortality,” but data on long-term cardiovascular morbidity in individuals treated with growth hormone in childhood are lacking, wrote Anders Tinblad, MD, of Karolinska Institutet, Stockholm, and colleagues.

In a population-based cohort study published in JAMA Pediatrics, the researchers identified 3,408 Swedish patients treated as children with recombinant human growth hormone (rhGH) between Jan. 1, 1985, and Dec. 31, 2010, and compared each with 15 matched controls (a total of 50,036 controls). The patients were treated for one of three conditions: isolated growth hormone deficiency (GHD), small for gestational age (SGA), and idiopathic short stature (ISS).

Data on cardiovascular outcomes were collected from health care and population-based registers and analyzed between Jan. 1, 1985, and Dec. 31, 2014. The average age of the participants at the study’s end was 25.1 years.

In all, 1,809 cardiovascular disease events were recorded over a median follow-up period of 14.9 years, for an incidence rate of 25.6 events per 10,000 person-years in patients and 22.6 events per 10,000 person-years in controls.

When separated by sex, the incidence was higher in female patients compared with controls (31.2 vs. 23.4 events per 10,000 person-years, respectively, but similar in male patients vs. controls (23.3 vs. 22.3 events per 10,000 person-years). “Differences in estrogen levels or responsiveness to rhGH treatment have previously been hypothesized as possible explanations, but the underlying mechanism for this sex difference still remains unclear and merits further investigation,” the researchers wrote.

Overall, the highest adjusted hazard ratios occurred in subgroups of patients with the longest treatment duration (HR 2.08) and highest cumulative dose of growth hormone (HR 2.05), but no association was noted between highest daily hormone dose and cardiovascular event risk. Hazard ratios were higher across all three treatment subgroups of SGA, GHD, and ISS compared with controls (HR 1.97, 1.66, and 1.55, respectively).

“The association between childhood rhGH treatment and CVD events was also seen when assessing only severe CVD outcomes, but with even lower absolute risks,” the researchers noted.

The study findings were limited by several factors including the potential for confounding by treatment indication and the lack of long-term follow-up data given the relatively young age of the study population, the researchers said. The results were strengthened by the large sample size and showed that the absolute risk for overall and severe cardiovascular disease in children treated with growth hormones was low, “which could be reassuring to individual patients,” they added. However, “At the group level, and perhaps especially for female patients and those treated for SGA indication, further close monitoring and future studies of CVD safety are warranted,” they concluded.
 

Safety and ethical concerns persist

Although the study authors cite limited conclusions on causality and low absolute risk, several issues persist that prompt ongoing analysis of pediatric growth hormone use, namely “worrisome indirect evidence, challenges and limitations in the direct evidence, and the changing world of growth hormone treatment,” Adda Grimberg, MD, of the University of Pennsylvania, Philadelphia, wrote in an accompanying editorial.

“Although evidence asserts that neither growth hormone nor insulinlike growth factor I is carcinogenic, the basic science and oncology literatures are rife with reports showing that they can make aberrant cells more aggressive,” and such indirect evidence supports the need for more direct evidence of possible harm from growth hormone treatment, Dr. Grimberg wrote. Most current safety data on growth hormone come from postmarketing surveillance studies, but these studies do not include controls or data on outcomes after discontinuation of treatment, she noted.

The current study, while able to follow patients across the lifespan, cannot indicate “whether the small but increased risk of cardiovascular disease found in this study was caused by the pediatric growth hormone treatment that identified the participants, by the conditions being treated, by other potential confounder(s) not captured by the study’s methods, or by a combination of the above,” said Dr. Grimberg.

In addition, “the move from replacement of GHD to pharmacologic height augmentation in children who already make sufficient growth hormone had the potential to change the safety profile of treatment,” she said.

“Parents of patients in pediatric primary care practices and of patients seeking growth-related care in a subspecialty endocrine clinic rated treatment characteristics (i.e., proven efficacy and safety) as the factor most having a big or extreme effect on their growth-related medical decision-making,” Dr. Grimberg said. “The centrality of treatment safety to patient-family decision-making underscores the importance of continued scrutiny of growth hormone safety as the treatment and its recipients continue to evolve,” she concluded.

The study was supported by the Swedish Research Council, the Stockholm City Council, the Karolinska Institute, the Society for Child Care, Sahlgrenska University Hospital, and the Stockholm County Council’s combined clinical residency and PhD training program. Lead author Dr. Tidblad disclosed funding from the Society for Child Care and Stockholm County Council during the conduct of the study and personal fees from Pfizer. Dr. Grimberg disclosed serving as a member of the steering committee for the Pfizer International Growth Study Database, and as a consultant for the Pediatric Endocrine Society GH Deficiency Knowledge Center, sponsored by Sandoz AG.

A scoring system that predicts risk for new heart failure over 5 years that is based solely on a few familiar, readily available biomarkers could potentially help steer patients with diabetes or even prediabetes toward HF-preventive therapies, researchers proposed based on a new study.

They foresee the risk-stratification tool, based on data pooled from three major community-based cohort studies but not independently validated, as a way to select patients with diabetes and prediabetes for treatment with SGLT2 inhibitors.

Several members of that drug class, conceived as antidiabetic agents, have been shown to help in prevention or treatment of HF in patients with diabetes and those without diabetes but at increased cardiovascular (CV) risk. Yet their uptake in practice has been lagging, the group noted.

Most HF benefits in the SGLT2 inhibitor trials “were seen in patients who have established cardiovascular disease – basically a history of heart attack or stroke,” Ambarish Pandey, MD, MSCS, University of Texas Southwestern Medical Center, Dallas, said in an interview.

“So we wanted to see how we can identify high-risk patients without a history of cardiovascular disease using these biomarkers, as an approach to targeting SGLT2 inhibitors, which are fairly expensive therapies,” he said. Without such risk stratification, “you end up treating so many more patients to get very modest returns.”

The group developed a scoring system based on four biomarkers that are “easily measured with inexpensive tests,” Dr. Pandey said: high-sensitivity-assay cardiac troponin T (hs-cTnT) and C-reactive protein (hs-CRP) levels, N-terminal of the prohormone brain natriuretic peptide (NT-proBNP) levels, and electrocardiography for evidence of left-ventricular hypertrophy (ECG-LVH).

The derivation cohort consisted of participants in the Atherosclerosis Risk in Communities RIC, Dallas Heart Study, and Multi-Ethnic Study of Atherosclerosis Multi-Ethnic Study of Atherosclerosis epidemiologic studies who were free of coronary heart disease, stroke, or HF for whom there were sufficient data on CV risk factors and the four biomarkers. None were taking SGLT2 inhibitors at enrollment in their respective studies, the researchers noted.

Members of the pooled cohorts who had diabetes or prediabetes were assigned 1 point for each abnormal biomarker. The 5-year risk for incident HF went up continuously along with the score in people with diabetes and in those with prediabetes, the latter defined as a fasting plasma glucose level from 100 mg/dL to less than 126 mg/dL.

For those with a score of 1, compared with 0, for example, the risk for HF went up 82% with diabetes and 40% with prediabetes. But for those with a score of 3 or 4, the risk went up more than four and a half times with diabetes and more than three and a half times for those with prediabetes. Risk increases were independent of other likely HF risk factors and consistently significant.

The analysis was published Jan. 6 in JACC: Heart Failure.

The biomarker score should be especially useful in patients considered at low to intermediate risk, based on clinical characteristics, as a means to identify residual HF risk and, potentially, select candidates for SGLT2-inhibitor therapy, Dr. Pandey said.

“The other purpose of the study was to broaden the scope of heart failure prevention in dysglycemia by looking also at prediabetes, not just diabetes,” he said. There isn’t much high-quality evidence supporting SGLT2-inhibitor therapy in prediabetes, but it follows that the drugs may be helpful in prediabetes because they are protective in patients with and without diabetes.

“Our work suggests that prediabetes patients who have elevated biomarkers are at a higher risk of heart failure,” Dr. Pandey said, suggesting that the HF risk score could potentially help select their drug therapy as well.

The current study seems “to provide a proof of concept that one can use circulating biomarkers to more precisely identify patients in whom therapies might be expected to exert greatest benefit,” which is especially important for potentially expensive agents like the SGLT2 inhibitors, James L. Januzzi, MD, Massachusetts General Hospital, Boston, said in an interview.

Importantly in the analysis, a greater number of biomarker abnormalities not only corresponded to rising levels of risk, the risk increases were “dramatic,” and therefore so was the supposed potential benefit of SGLT2-inhibitor therapy, said Dr. Januzzi, who isn’t a coauthor but was an editor for its publication in JACC: Heart Failure.

The uptake of SGLT2 inhibitors for heart failure in practice has been less rapid than hoped, he observed, so if “this hypothetical construct holds up” for the drug class, “it might actually help kick-start focusing on who might optimally receive the drugs.”

Elevated levels of hs-cTnT, hs-CRP, and NT-proBNP, as well as presence of ECG-LVH, were each independently associated with a significantly increased 5-year risk for HF in unadjusted and adjusted analyses of the 6,799 people in the pooled cohort, 33.2% of whom had diabetes and 66.8% of whom had prediabetes, the group writes.

The scoring system would require validation in other cohorts before it could be used, Dr. Pandey observed; once there is “robust validation,” it might be applied first to patients with dysglycemia at intermediate CV risk by standard clinical measures.

Certainly the HF risk-stratification scoring system requires validation in other studies, Dr. Januzzi agreed. But it is intuitively appealing, and the study’s results are consistent with “data that we’re submitting for publication imminently” based on the CANVAS CV-outcomes trial of the SGLT2 inhibitor canagliflozin (Invokana) in patients with diabetes.

Dr. Pandey disclosed receiving support from the Gilead Sciences Research Scholar Program and serving on an advisory board of Roche Diagnostics. Dr. Januzzi disclosed receiving grant support from Novartis, Applied Therapeutics, and Innolife; consulting for Abbott Diagnostics, Janssen, Novartis, Quidel, and Roche Diagnostics; and serving on end-point committees or data safety monitoring boards for trials supported by Abbott, AbbVie, Amgen, CVRx, Janssen, MyoKardia, and Takeda.

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

A scoring system that predicts risk for new heart failure over 5 years that is based solely on a few familiar, readily available biomarkers could potentially help steer patients with diabetes or even prediabetes toward HF-preventive therapies, researchers proposed based on a new study.

They foresee the risk-stratification tool, based on data pooled from three major community-based cohort studies but not independently validated, as a way to select patients with diabetes and prediabetes for treatment with SGLT2 inhibitors.

Several members of that drug class, conceived as antidiabetic agents, have been shown to help in prevention or treatment of HF in patients with diabetes and those without diabetes but at increased cardiovascular (CV) risk. Yet their uptake in practice has been lagging, the group noted.

Most HF benefits in the SGLT2 inhibitor trials “were seen in patients who have established cardiovascular disease – basically a history of heart attack or stroke,” Ambarish Pandey, MD, MSCS, University of Texas Southwestern Medical Center, Dallas, said in an interview.

“So we wanted to see how we can identify high-risk patients without a history of cardiovascular disease using these biomarkers, as an approach to targeting SGLT2 inhibitors, which are fairly expensive therapies,” he said. Without such risk stratification, “you end up treating so many more patients to get very modest returns.”

The group developed a scoring system based on four biomarkers that are “easily measured with inexpensive tests,” Dr. Pandey said: high-sensitivity-assay cardiac troponin T (hs-cTnT) and C-reactive protein (hs-CRP) levels, N-terminal of the prohormone brain natriuretic peptide (NT-proBNP) levels, and electrocardiography for evidence of left-ventricular hypertrophy (ECG-LVH).

The derivation cohort consisted of participants in the Atherosclerosis Risk in Communities RIC, Dallas Heart Study, and Multi-Ethnic Study of Atherosclerosis Multi-Ethnic Study of Atherosclerosis epidemiologic studies who were free of coronary heart disease, stroke, or HF for whom there were sufficient data on CV risk factors and the four biomarkers. None were taking SGLT2 inhibitors at enrollment in their respective studies, the researchers noted.

Members of the pooled cohorts who had diabetes or prediabetes were assigned 1 point for each abnormal biomarker. The 5-year risk for incident HF went up continuously along with the score in people with diabetes and in those with prediabetes, the latter defined as a fasting plasma glucose level from 100 mg/dL to less than 126 mg/dL.

For those with a score of 1, compared with 0, for example, the risk for HF went up 82% with diabetes and 40% with prediabetes. But for those with a score of 3 or 4, the risk went up more than four and a half times with diabetes and more than three and a half times for those with prediabetes. Risk increases were independent of other likely HF risk factors and consistently significant.

The analysis was published Jan. 6 in JACC: Heart Failure.

The biomarker score should be especially useful in patients considered at low to intermediate risk, based on clinical characteristics, as a means to identify residual HF risk and, potentially, select candidates for SGLT2-inhibitor therapy, Dr. Pandey said.

“The other purpose of the study was to broaden the scope of heart failure prevention in dysglycemia by looking also at prediabetes, not just diabetes,” he said. There isn’t much high-quality evidence supporting SGLT2-inhibitor therapy in prediabetes, but it follows that the drugs may be helpful in prediabetes because they are protective in patients with and without diabetes.

“Our work suggests that prediabetes patients who have elevated biomarkers are at a higher risk of heart failure,” Dr. Pandey said, suggesting that the HF risk score could potentially help select their drug therapy as well.

The current study seems “to provide a proof of concept that one can use circulating biomarkers to more precisely identify patients in whom therapies might be expected to exert greatest benefit,” which is especially important for potentially expensive agents like the SGLT2 inhibitors, James L. Januzzi, MD, Massachusetts General Hospital, Boston, said in an interview.

Importantly in the analysis, a greater number of biomarker abnormalities not only corresponded to rising levels of risk, the risk increases were “dramatic,” and therefore so was the supposed potential benefit of SGLT2-inhibitor therapy, said Dr. Januzzi, who isn’t a coauthor but was an editor for its publication in JACC: Heart Failure.

The uptake of SGLT2 inhibitors for heart failure in practice has been less rapid than hoped, he observed, so if “this hypothetical construct holds up” for the drug class, “it might actually help kick-start focusing on who might optimally receive the drugs.”

Elevated levels of hs-cTnT, hs-CRP, and NT-proBNP, as well as presence of ECG-LVH, were each independently associated with a significantly increased 5-year risk for HF in unadjusted and adjusted analyses of the 6,799 people in the pooled cohort, 33.2% of whom had diabetes and 66.8% of whom had prediabetes, the group writes.

The scoring system would require validation in other cohorts before it could be used, Dr. Pandey observed; once there is “robust validation,” it might be applied first to patients with dysglycemia at intermediate CV risk by standard clinical measures.

Certainly the HF risk-stratification scoring system requires validation in other studies, Dr. Januzzi agreed. But it is intuitively appealing, and the study’s results are consistent with “data that we’re submitting for publication imminently” based on the CANVAS CV-outcomes trial of the SGLT2 inhibitor canagliflozin (Invokana) in patients with diabetes.

Dr. Pandey disclosed receiving support from the Gilead Sciences Research Scholar Program and serving on an advisory board of Roche Diagnostics. Dr. Januzzi disclosed receiving grant support from Novartis, Applied Therapeutics, and Innolife; consulting for Abbott Diagnostics, Janssen, Novartis, Quidel, and Roche Diagnostics; and serving on end-point committees or data safety monitoring boards for trials supported by Abbott, AbbVie, Amgen, CVRx, Janssen, MyoKardia, and Takeda.

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

A scoring system that predicts risk for new heart failure over 5 years that is based solely on a few familiar, readily available biomarkers could potentially help steer patients with diabetes or even prediabetes toward HF-preventive therapies, researchers proposed based on a new study.

They foresee the risk-stratification tool, based on data pooled from three major community-based cohort studies but not independently validated, as a way to select patients with diabetes and prediabetes for treatment with SGLT2 inhibitors.

Several members of that drug class, conceived as antidiabetic agents, have been shown to help in prevention or treatment of HF in patients with diabetes and those without diabetes but at increased cardiovascular (CV) risk. Yet their uptake in practice has been lagging, the group noted.

Most HF benefits in the SGLT2 inhibitor trials “were seen in patients who have established cardiovascular disease – basically a history of heart attack or stroke,” Ambarish Pandey, MD, MSCS, University of Texas Southwestern Medical Center, Dallas, said in an interview.

“So we wanted to see how we can identify high-risk patients without a history of cardiovascular disease using these biomarkers, as an approach to targeting SGLT2 inhibitors, which are fairly expensive therapies,” he said. Without such risk stratification, “you end up treating so many more patients to get very modest returns.”

The group developed a scoring system based on four biomarkers that are “easily measured with inexpensive tests,” Dr. Pandey said: high-sensitivity-assay cardiac troponin T (hs-cTnT) and C-reactive protein (hs-CRP) levels, N-terminal of the prohormone brain natriuretic peptide (NT-proBNP) levels, and electrocardiography for evidence of left-ventricular hypertrophy (ECG-LVH).

The derivation cohort consisted of participants in the Atherosclerosis Risk in Communities RIC, Dallas Heart Study, and Multi-Ethnic Study of Atherosclerosis Multi-Ethnic Study of Atherosclerosis epidemiologic studies who were free of coronary heart disease, stroke, or HF for whom there were sufficient data on CV risk factors and the four biomarkers. None were taking SGLT2 inhibitors at enrollment in their respective studies, the researchers noted.

Members of the pooled cohorts who had diabetes or prediabetes were assigned 1 point for each abnormal biomarker. The 5-year risk for incident HF went up continuously along with the score in people with diabetes and in those with prediabetes, the latter defined as a fasting plasma glucose level from 100 mg/dL to less than 126 mg/dL.

For those with a score of 1, compared with 0, for example, the risk for HF went up 82% with diabetes and 40% with prediabetes. But for those with a score of 3 or 4, the risk went up more than four and a half times with diabetes and more than three and a half times for those with prediabetes. Risk increases were independent of other likely HF risk factors and consistently significant.

The analysis was published Jan. 6 in JACC: Heart Failure.

The biomarker score should be especially useful in patients considered at low to intermediate risk, based on clinical characteristics, as a means to identify residual HF risk and, potentially, select candidates for SGLT2-inhibitor therapy, Dr. Pandey said.

“The other purpose of the study was to broaden the scope of heart failure prevention in dysglycemia by looking also at prediabetes, not just diabetes,” he said. There isn’t much high-quality evidence supporting SGLT2-inhibitor therapy in prediabetes, but it follows that the drugs may be helpful in prediabetes because they are protective in patients with and without diabetes.

“Our work suggests that prediabetes patients who have elevated biomarkers are at a higher risk of heart failure,” Dr. Pandey said, suggesting that the HF risk score could potentially help select their drug therapy as well.

The current study seems “to provide a proof of concept that one can use circulating biomarkers to more precisely identify patients in whom therapies might be expected to exert greatest benefit,” which is especially important for potentially expensive agents like the SGLT2 inhibitors, James L. Januzzi, MD, Massachusetts General Hospital, Boston, said in an interview.

Importantly in the analysis, a greater number of biomarker abnormalities not only corresponded to rising levels of risk, the risk increases were “dramatic,” and therefore so was the supposed potential benefit of SGLT2-inhibitor therapy, said Dr. Januzzi, who isn’t a coauthor but was an editor for its publication in JACC: Heart Failure.

The uptake of SGLT2 inhibitors for heart failure in practice has been less rapid than hoped, he observed, so if “this hypothetical construct holds up” for the drug class, “it might actually help kick-start focusing on who might optimally receive the drugs.”

Elevated levels of hs-cTnT, hs-CRP, and NT-proBNP, as well as presence of ECG-LVH, were each independently associated with a significantly increased 5-year risk for HF in unadjusted and adjusted analyses of the 6,799 people in the pooled cohort, 33.2% of whom had diabetes and 66.8% of whom had prediabetes, the group writes.

The scoring system would require validation in other cohorts before it could be used, Dr. Pandey observed; once there is “robust validation,” it might be applied first to patients with dysglycemia at intermediate CV risk by standard clinical measures.

Certainly the HF risk-stratification scoring system requires validation in other studies, Dr. Januzzi agreed. But it is intuitively appealing, and the study’s results are consistent with “data that we’re submitting for publication imminently” based on the CANVAS CV-outcomes trial of the SGLT2 inhibitor canagliflozin (Invokana) in patients with diabetes.

Dr. Pandey disclosed receiving support from the Gilead Sciences Research Scholar Program and serving on an advisory board of Roche Diagnostics. Dr. Januzzi disclosed receiving grant support from Novartis, Applied Therapeutics, and Innolife; consulting for Abbott Diagnostics, Janssen, Novartis, Quidel, and Roche Diagnostics; and serving on end-point committees or data safety monitoring boards for trials supported by Abbott, AbbVie, Amgen, CVRx, Janssen, MyoKardia, and Takeda.

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

The Food and Drug Administration has determined that data collected on the dual SGLT1/2 inhibitor sotagliflozin (Zynquista) for treating patients with type 2 diabetes in the SOLOIST and SCORED pivotal trials can help support a New Drug Application (NDA) submission, according to a statement released on Jan. 14 by Lexicon Pharmaceuticals, the company developing this drug. Lexicon concurrently said that it hopes to potentially file this NDA later in 2021.

The statement said the FDA’s decision related to an NDA for “an indication to reduce the risk of cardiovascular death, hospitalization for heart failure, and urgent visits for heart failure in adult patients with type 2 diabetes with either worsening heart failure or additional risk factors for heart failure.”

Results from SOLOIST and SCORED, first reported in November 2020 at the American Heart Association scientific sessions, showed statistically significant benefits for their respective primary endpoints.

The findings also demonstrated several novel benefits from the first advanced clinical trials of an SGLT inhibitor that blocks both the SGLT2 protein in kidneys as well as the SGLT1 protein, which resides primarily in the gastrointestinal system and is the main route for glucose out of the gut.

In both SOLOIST and SCORED, patient outcomes on sotagliflozin tracked the benefits and adverse effects previously seen with several SGLT2 inhibitors (canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin), but in addition showed several unprecedented benefits: An ability to lower hemoglobin A1c in patients with severely depressed renal function, safe initiation in patients recently hospitalized for heart failure, the first prospective data to show improvements in patients with heart failure with preserved ejection fraction, and a higher level of protection against MIs and strokes than the SGLT2 inhibitors.

The FDA’s willingness to consider data from both trials in an NDA was not a given, as the primary endpoints for both trials underwent tweaking while they were underway to compensate for an unexpectedly early end to patient enrollment and follow-up caused by changes in drug company sponsorship and challenges introduced by the COVID-19 pandemic.

In 2019, the FDA denied the NDA for sotagliflozin as a treatment for patients with type 1 diabetes, but this indication received approval in Europe.

SOLOIST and SCORED were sponsored initially by Sanofi, and more recently by Lexicon.

mzoler@mdedge.com

The Food and Drug Administration has determined that data collected on the dual SGLT1/2 inhibitor sotagliflozin (Zynquista) for treating patients with type 2 diabetes in the SOLOIST and SCORED pivotal trials can help support a New Drug Application (NDA) submission, according to a statement released on Jan. 14 by Lexicon Pharmaceuticals, the company developing this drug. Lexicon concurrently said that it hopes to potentially file this NDA later in 2021.

The statement said the FDA’s decision related to an NDA for “an indication to reduce the risk of cardiovascular death, hospitalization for heart failure, and urgent visits for heart failure in adult patients with type 2 diabetes with either worsening heart failure or additional risk factors for heart failure.”

Results from SOLOIST and SCORED, first reported in November 2020 at the American Heart Association scientific sessions, showed statistically significant benefits for their respective primary endpoints.

The findings also demonstrated several novel benefits from the first advanced clinical trials of an SGLT inhibitor that blocks both the SGLT2 protein in kidneys as well as the SGLT1 protein, which resides primarily in the gastrointestinal system and is the main route for glucose out of the gut.

In both SOLOIST and SCORED, patient outcomes on sotagliflozin tracked the benefits and adverse effects previously seen with several SGLT2 inhibitors (canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin), but in addition showed several unprecedented benefits: An ability to lower hemoglobin A1c in patients with severely depressed renal function, safe initiation in patients recently hospitalized for heart failure, the first prospective data to show improvements in patients with heart failure with preserved ejection fraction, and a higher level of protection against MIs and strokes than the SGLT2 inhibitors.

The FDA’s willingness to consider data from both trials in an NDA was not a given, as the primary endpoints for both trials underwent tweaking while they were underway to compensate for an unexpectedly early end to patient enrollment and follow-up caused by changes in drug company sponsorship and challenges introduced by the COVID-19 pandemic.

In 2019, the FDA denied the NDA for sotagliflozin as a treatment for patients with type 1 diabetes, but this indication received approval in Europe.

SOLOIST and SCORED were sponsored initially by Sanofi, and more recently by Lexicon.

mzoler@mdedge.com

The Food and Drug Administration has determined that data collected on the dual SGLT1/2 inhibitor sotagliflozin (Zynquista) for treating patients with type 2 diabetes in the SOLOIST and SCORED pivotal trials can help support a New Drug Application (NDA) submission, according to a statement released on Jan. 14 by Lexicon Pharmaceuticals, the company developing this drug. Lexicon concurrently said that it hopes to potentially file this NDA later in 2021.

The statement said the FDA’s decision related to an NDA for “an indication to reduce the risk of cardiovascular death, hospitalization for heart failure, and urgent visits for heart failure in adult patients with type 2 diabetes with either worsening heart failure or additional risk factors for heart failure.”

Results from SOLOIST and SCORED, first reported in November 2020 at the American Heart Association scientific sessions, showed statistically significant benefits for their respective primary endpoints.

The findings also demonstrated several novel benefits from the first advanced clinical trials of an SGLT inhibitor that blocks both the SGLT2 protein in kidneys as well as the SGLT1 protein, which resides primarily in the gastrointestinal system and is the main route for glucose out of the gut.

In both SOLOIST and SCORED, patient outcomes on sotagliflozin tracked the benefits and adverse effects previously seen with several SGLT2 inhibitors (canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin), but in addition showed several unprecedented benefits: An ability to lower hemoglobin A1c in patients with severely depressed renal function, safe initiation in patients recently hospitalized for heart failure, the first prospective data to show improvements in patients with heart failure with preserved ejection fraction, and a higher level of protection against MIs and strokes than the SGLT2 inhibitors.

The FDA’s willingness to consider data from both trials in an NDA was not a given, as the primary endpoints for both trials underwent tweaking while they were underway to compensate for an unexpectedly early end to patient enrollment and follow-up caused by changes in drug company sponsorship and challenges introduced by the COVID-19 pandemic.

In 2019, the FDA denied the NDA for sotagliflozin as a treatment for patients with type 1 diabetes, but this indication received approval in Europe.

SOLOIST and SCORED were sponsored initially by Sanofi, and more recently by Lexicon.

mzoler@mdedge.com

While the direct toll of the COVID-19 pandemic is being tallied and shared on the nightly news, the indirect effects will undoubtedly take years to fully measure.

Floaria Bicher/iStock/Getty Images Plus

In two papers published online Jan. 11 in the Journal of the American College of Cardiology, researchers have started the process of quantifying the impact of the pandemic on the care of patients with cardiovascular disease (CVD).

In the first study, Rishi Wadhera, MD, MPP, MPhil, and colleagues from the Beth Israel Deaconess Medical Center and Harvard Medical School in Boston examined population-level data to determine how deaths from cardiovascular causes changed in the United States in the early months of the pandemic relative to the same periods in 2019.

In a second paper, Andrew J. Einstein, MD, PhD, from Columbia University Irving Medical Center/New York–Presbyterian Hospital and colleagues looked at the pandemic’s international impact on the diagnosis of heart disease.

Using data from the National Center for Health Statistics, Dr. Wadhera and colleagues compared death rates from cardiovascular causes in the United States from March 18, 2020, to June 2, 2020, (the first wave of the pandemic) and from Jan. 1, 2020, to March 17, 2020, (the period just before the pandemic started) and compared them to the same periods in 2019. ICD codes were used to identify underlying causes of death.

Relative to 2019, they found a significant increase in deaths from ischemic heart disease nationally (1.11; 95% confidence interval, 1.04-1.18), as well as an increase in deaths caused by hypertensive disease (1.17; 95% CI, 1.09-1.26). There was no apparent increase in deaths from heart failure, cerebrovascular disease, or other diseases of the circulatory system.

When they looked just at New York City, the area hit hardest during the early part of the pandemic, the relative increases in deaths from ischemic heart disease were more pronounced.

Deaths from ischemic heart disease or hypertensive diseases jumped 139% and 164%, respectively, between March 18, 2020, and June 2, 2020.

More modest increases in deaths were seen in the remainder of New York state, New Jersey, Michigan and Illinois, while Massachusetts and Louisiana did not see a change in cardiovascular deaths.

Several studies from different parts of the world have indicated a 40%-50% drop in hospitalization for myocardial infarction in the initial months of the pandemic, said Dr. Wadhera in an interview.

“We wanted to understand where did all the heart attacks go? And we worried that patients with urgent heart conditions were not seeking the medical care they needed. I think our data suggest that this may have been the case,” reported Dr. Wadhera.  

“This very much reflects the reality of what we’re seeing on the ground,” he told this news organization. “After the initial surge ended, when hospital volumes began to return to normal, we saw patients come into the hospital who clearly had a heart attack during the surge months – and were now experiencing complications of that event – because they had initially not come into the hospital due to concerns about exposure to the virus.”

A limitation of their data, he stressed, is whether some deaths coded as CVD deaths were really deaths from undiagnosed COVID-19. “It’s possible that some portion of the increased deaths we observed really reflect the cardiovascular complications of undiagnosed COVID-19, because we know that testing was quite limited during the early first surge of cases.”

“I think that basically three factors – patients avoiding the health care system because of fear of getting COVID, health care systems being strained and overwhelmed leading to the deferral of cardiovascular care and semi-elective procedures, and the cardiovascular complications of COVID-19 itself – all probably collectively contributed to the rise in cardiovascular deaths that we observed,” said Dr. Wadhera.

In an accompanying editorial, Michael N. Young, MD, Geisel School of Medicine at Dartmouth, Lebanon, N.H., and colleagues write that these data, taken together with an earlier study showing an increase in out-of-hospital cardiac arrests at the pandemic peak in New York City, “support the notion of excess fatalities due to unattended comorbid illnesses.” That said, attribution of death in the COVID era “remains problematic.”

In the second article, Andrew Einstein, MD, PhD, and the INCAPS COVID Investigators Group took a broader approach and looked at the impact of COVID-19 on cardiac diagnostic procedures in over 100 countries.

The INCAPS (International Atomic Energy Agency Noninvasive Cardiology Protocols Study) group has for the past decade conducted numerous studies addressing the use of best practices and worldwide practice variation in CVD diagnosis.

For this effort, they sent a survey link to INCAPS participants worldwide, ultimately including 909 survey responses from 108 countries in the final analysis.

Compared with March 2019, overall procedure volume decreased 42% in March 2020 and 64% in April 2020.

The greatest decreases were seen in stress testing (78%) and transesophageal echocardiography (76%), both procedures, noted Dr. Einstein, associated with a greater risk of aerosolization.

“Whether as we reset after COVID we return to the same place in terms of the use of cardiovascular diagnostic testing remains to be seen, but it certainly poses an opportunity to improve our utilization of various modes of testing,” said Dr. Einstein.

Using regression analysis, Dr. Einstein and colleagues were able to see that sites located in low-income and lower-middle-income countries saw an additional 22% reduction in cardiac procedures and less availability of personal protective equipment (PPE) and telehealth.

Fifty-two percent of survey respondents reported significant shortages of N95 masks early in the pandemic, with fewer issues in supplies of gloves, gowns, and face shields. Lower-income countries were more likely to face significant PPE shortages and less likely to be able to implement telehealth strategies to make up for reduced in-person care. PPE shortage itself, however, was not related to lower procedural volume on multivariable regression.

“It all really begs the question of whether there is more that the world can do to help out the developing world in terms of managing the pandemic in all its facets,” said Dr. Einstein in an interview, adding he was “shocked” to learn how difficult it was for some lower-income countries to get sufficient PPE.
 

Did shutdowns go too far?

Calling this a “remarkable study,” an editorial written by Darryl P. Leong, MBBS, PhD, John W. Eikelboom, MBBS, and Salim Yusuf, MBBS, DPhil, all from McMaster University, Hamilton, Ont., suggests that perhaps health systems in some places went too far in closing down during the first wave of the pandemic, naming specifically Canada, Eastern Europe, and Saudi Arabia as examples.

“Although these measures were taken to prepare for the worst, overwhelming numbers of patients with COVID-19 did not materialize during the first wave of the pandemic in these countries. It is possible that delaying so-called nonessential services may have been unnecessary and potentially harmful, because it likely led to delays in providing care for the treatment of serious non–COVID-19 illnesses.”

Since then, more experience and more data have largely allowed hospital systems to “tackle the ebb and flow” of COVID-19 cases in ways that limit shutdowns of important health services, they said.

Given the more pronounced effect in low- and middle-income countries, they stressed the need to focus resources on ways to promote prevention and treatment that do not rely on diagnostic procedures.

“This calls for more emphasis on developing efficient systems of telehealth, especially in poorer countries or in remote settings in all countries,” Dr. Leong and colleagues conclude.

Dr. Wadhera has reported research support from the National Heart, Lung, and Blood Institute, along with fellow senior author Robert W. Yeh, MD, MBA, who has also received personal fees and grants from several companies not related to the submitted work. Dr. Einstein, Dr. Leong, Dr. Eikelboom, and Dr. Yusuf have reported no relevant financial relationships.

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

While the direct toll of the COVID-19 pandemic is being tallied and shared on the nightly news, the indirect effects will undoubtedly take years to fully measure.

Floaria Bicher/iStock/Getty Images Plus

In two papers published online Jan. 11 in the Journal of the American College of Cardiology, researchers have started the process of quantifying the impact of the pandemic on the care of patients with cardiovascular disease (CVD).

In the first study, Rishi Wadhera, MD, MPP, MPhil, and colleagues from the Beth Israel Deaconess Medical Center and Harvard Medical School in Boston examined population-level data to determine how deaths from cardiovascular causes changed in the United States in the early months of the pandemic relative to the same periods in 2019.

In a second paper, Andrew J. Einstein, MD, PhD, from Columbia University Irving Medical Center/New York–Presbyterian Hospital and colleagues looked at the pandemic’s international impact on the diagnosis of heart disease.

Using data from the National Center for Health Statistics, Dr. Wadhera and colleagues compared death rates from cardiovascular causes in the United States from March 18, 2020, to June 2, 2020, (the first wave of the pandemic) and from Jan. 1, 2020, to March 17, 2020, (the period just before the pandemic started) and compared them to the same periods in 2019. ICD codes were used to identify underlying causes of death.

Relative to 2019, they found a significant increase in deaths from ischemic heart disease nationally (1.11; 95% confidence interval, 1.04-1.18), as well as an increase in deaths caused by hypertensive disease (1.17; 95% CI, 1.09-1.26). There was no apparent increase in deaths from heart failure, cerebrovascular disease, or other diseases of the circulatory system.

When they looked just at New York City, the area hit hardest during the early part of the pandemic, the relative increases in deaths from ischemic heart disease were more pronounced.

Deaths from ischemic heart disease or hypertensive diseases jumped 139% and 164%, respectively, between March 18, 2020, and June 2, 2020.

More modest increases in deaths were seen in the remainder of New York state, New Jersey, Michigan and Illinois, while Massachusetts and Louisiana did not see a change in cardiovascular deaths.

Several studies from different parts of the world have indicated a 40%-50% drop in hospitalization for myocardial infarction in the initial months of the pandemic, said Dr. Wadhera in an interview.

“We wanted to understand where did all the heart attacks go? And we worried that patients with urgent heart conditions were not seeking the medical care they needed. I think our data suggest that this may have been the case,” reported Dr. Wadhera.  

“This very much reflects the reality of what we’re seeing on the ground,” he told this news organization. “After the initial surge ended, when hospital volumes began to return to normal, we saw patients come into the hospital who clearly had a heart attack during the surge months – and were now experiencing complications of that event – because they had initially not come into the hospital due to concerns about exposure to the virus.”

A limitation of their data, he stressed, is whether some deaths coded as CVD deaths were really deaths from undiagnosed COVID-19. “It’s possible that some portion of the increased deaths we observed really reflect the cardiovascular complications of undiagnosed COVID-19, because we know that testing was quite limited during the early first surge of cases.”

“I think that basically three factors – patients avoiding the health care system because of fear of getting COVID, health care systems being strained and overwhelmed leading to the deferral of cardiovascular care and semi-elective procedures, and the cardiovascular complications of COVID-19 itself – all probably collectively contributed to the rise in cardiovascular deaths that we observed,” said Dr. Wadhera.

In an accompanying editorial, Michael N. Young, MD, Geisel School of Medicine at Dartmouth, Lebanon, N.H., and colleagues write that these data, taken together with an earlier study showing an increase in out-of-hospital cardiac arrests at the pandemic peak in New York City, “support the notion of excess fatalities due to unattended comorbid illnesses.” That said, attribution of death in the COVID era “remains problematic.”

In the second article, Andrew Einstein, MD, PhD, and the INCAPS COVID Investigators Group took a broader approach and looked at the impact of COVID-19 on cardiac diagnostic procedures in over 100 countries.

The INCAPS (International Atomic Energy Agency Noninvasive Cardiology Protocols Study) group has for the past decade conducted numerous studies addressing the use of best practices and worldwide practice variation in CVD diagnosis.

For this effort, they sent a survey link to INCAPS participants worldwide, ultimately including 909 survey responses from 108 countries in the final analysis.

Compared with March 2019, overall procedure volume decreased 42% in March 2020 and 64% in April 2020.

The greatest decreases were seen in stress testing (78%) and transesophageal echocardiography (76%), both procedures, noted Dr. Einstein, associated with a greater risk of aerosolization.

“Whether as we reset after COVID we return to the same place in terms of the use of cardiovascular diagnostic testing remains to be seen, but it certainly poses an opportunity to improve our utilization of various modes of testing,” said Dr. Einstein.

Using regression analysis, Dr. Einstein and colleagues were able to see that sites located in low-income and lower-middle-income countries saw an additional 22% reduction in cardiac procedures and less availability of personal protective equipment (PPE) and telehealth.

Fifty-two percent of survey respondents reported significant shortages of N95 masks early in the pandemic, with fewer issues in supplies of gloves, gowns, and face shields. Lower-income countries were more likely to face significant PPE shortages and less likely to be able to implement telehealth strategies to make up for reduced in-person care. PPE shortage itself, however, was not related to lower procedural volume on multivariable regression.

“It all really begs the question of whether there is more that the world can do to help out the developing world in terms of managing the pandemic in all its facets,” said Dr. Einstein in an interview, adding he was “shocked” to learn how difficult it was for some lower-income countries to get sufficient PPE.
 

Did shutdowns go too far?

Calling this a “remarkable study,” an editorial written by Darryl P. Leong, MBBS, PhD, John W. Eikelboom, MBBS, and Salim Yusuf, MBBS, DPhil, all from McMaster University, Hamilton, Ont., suggests that perhaps health systems in some places went too far in closing down during the first wave of the pandemic, naming specifically Canada, Eastern Europe, and Saudi Arabia as examples.

“Although these measures were taken to prepare for the worst, overwhelming numbers of patients with COVID-19 did not materialize during the first wave of the pandemic in these countries. It is possible that delaying so-called nonessential services may have been unnecessary and potentially harmful, because it likely led to delays in providing care for the treatment of serious non–COVID-19 illnesses.”

Since then, more experience and more data have largely allowed hospital systems to “tackle the ebb and flow” of COVID-19 cases in ways that limit shutdowns of important health services, they said.

Given the more pronounced effect in low- and middle-income countries, they stressed the need to focus resources on ways to promote prevention and treatment that do not rely on diagnostic procedures.

“This calls for more emphasis on developing efficient systems of telehealth, especially in poorer countries or in remote settings in all countries,” Dr. Leong and colleagues conclude.

Dr. Wadhera has reported research support from the National Heart, Lung, and Blood Institute, along with fellow senior author Robert W. Yeh, MD, MBA, who has also received personal fees and grants from several companies not related to the submitted work. Dr. Einstein, Dr. Leong, Dr. Eikelboom, and Dr. Yusuf have reported no relevant financial relationships.

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

While the direct toll of the COVID-19 pandemic is being tallied and shared on the nightly news, the indirect effects will undoubtedly take years to fully measure.

Floaria Bicher/iStock/Getty Images Plus

In two papers published online Jan. 11 in the Journal of the American College of Cardiology, researchers have started the process of quantifying the impact of the pandemic on the care of patients with cardiovascular disease (CVD).

In the first study, Rishi Wadhera, MD, MPP, MPhil, and colleagues from the Beth Israel Deaconess Medical Center and Harvard Medical School in Boston examined population-level data to determine how deaths from cardiovascular causes changed in the United States in the early months of the pandemic relative to the same periods in 2019.

In a second paper, Andrew J. Einstein, MD, PhD, from Columbia University Irving Medical Center/New York–Presbyterian Hospital and colleagues looked at the pandemic’s international impact on the diagnosis of heart disease.

Using data from the National Center for Health Statistics, Dr. Wadhera and colleagues compared death rates from cardiovascular causes in the United States from March 18, 2020, to June 2, 2020, (the first wave of the pandemic) and from Jan. 1, 2020, to March 17, 2020, (the period just before the pandemic started) and compared them to the same periods in 2019. ICD codes were used to identify underlying causes of death.

Relative to 2019, they found a significant increase in deaths from ischemic heart disease nationally (1.11; 95% confidence interval, 1.04-1.18), as well as an increase in deaths caused by hypertensive disease (1.17; 95% CI, 1.09-1.26). There was no apparent increase in deaths from heart failure, cerebrovascular disease, or other diseases of the circulatory system.

When they looked just at New York City, the area hit hardest during the early part of the pandemic, the relative increases in deaths from ischemic heart disease were more pronounced.

Deaths from ischemic heart disease or hypertensive diseases jumped 139% and 164%, respectively, between March 18, 2020, and June 2, 2020.

More modest increases in deaths were seen in the remainder of New York state, New Jersey, Michigan and Illinois, while Massachusetts and Louisiana did not see a change in cardiovascular deaths.

Several studies from different parts of the world have indicated a 40%-50% drop in hospitalization for myocardial infarction in the initial months of the pandemic, said Dr. Wadhera in an interview.

“We wanted to understand where did all the heart attacks go? And we worried that patients with urgent heart conditions were not seeking the medical care they needed. I think our data suggest that this may have been the case,” reported Dr. Wadhera.  

“This very much reflects the reality of what we’re seeing on the ground,” he told this news organization. “After the initial surge ended, when hospital volumes began to return to normal, we saw patients come into the hospital who clearly had a heart attack during the surge months – and were now experiencing complications of that event – because they had initially not come into the hospital due to concerns about exposure to the virus.”

A limitation of their data, he stressed, is whether some deaths coded as CVD deaths were really deaths from undiagnosed COVID-19. “It’s possible that some portion of the increased deaths we observed really reflect the cardiovascular complications of undiagnosed COVID-19, because we know that testing was quite limited during the early first surge of cases.”

“I think that basically three factors – patients avoiding the health care system because of fear of getting COVID, health care systems being strained and overwhelmed leading to the deferral of cardiovascular care and semi-elective procedures, and the cardiovascular complications of COVID-19 itself – all probably collectively contributed to the rise in cardiovascular deaths that we observed,” said Dr. Wadhera.

In an accompanying editorial, Michael N. Young, MD, Geisel School of Medicine at Dartmouth, Lebanon, N.H., and colleagues write that these data, taken together with an earlier study showing an increase in out-of-hospital cardiac arrests at the pandemic peak in New York City, “support the notion of excess fatalities due to unattended comorbid illnesses.” That said, attribution of death in the COVID era “remains problematic.”

In the second article, Andrew Einstein, MD, PhD, and the INCAPS COVID Investigators Group took a broader approach and looked at the impact of COVID-19 on cardiac diagnostic procedures in over 100 countries.

The INCAPS (International Atomic Energy Agency Noninvasive Cardiology Protocols Study) group has for the past decade conducted numerous studies addressing the use of best practices and worldwide practice variation in CVD diagnosis.

For this effort, they sent a survey link to INCAPS participants worldwide, ultimately including 909 survey responses from 108 countries in the final analysis.

Compared with March 2019, overall procedure volume decreased 42% in March 2020 and 64% in April 2020.

The greatest decreases were seen in stress testing (78%) and transesophageal echocardiography (76%), both procedures, noted Dr. Einstein, associated with a greater risk of aerosolization.

“Whether as we reset after COVID we return to the same place in terms of the use of cardiovascular diagnostic testing remains to be seen, but it certainly poses an opportunity to improve our utilization of various modes of testing,” said Dr. Einstein.

Using regression analysis, Dr. Einstein and colleagues were able to see that sites located in low-income and lower-middle-income countries saw an additional 22% reduction in cardiac procedures and less availability of personal protective equipment (PPE) and telehealth.

Fifty-two percent of survey respondents reported significant shortages of N95 masks early in the pandemic, with fewer issues in supplies of gloves, gowns, and face shields. Lower-income countries were more likely to face significant PPE shortages and less likely to be able to implement telehealth strategies to make up for reduced in-person care. PPE shortage itself, however, was not related to lower procedural volume on multivariable regression.

“It all really begs the question of whether there is more that the world can do to help out the developing world in terms of managing the pandemic in all its facets,” said Dr. Einstein in an interview, adding he was “shocked” to learn how difficult it was for some lower-income countries to get sufficient PPE.
 

Did shutdowns go too far?

Calling this a “remarkable study,” an editorial written by Darryl P. Leong, MBBS, PhD, John W. Eikelboom, MBBS, and Salim Yusuf, MBBS, DPhil, all from McMaster University, Hamilton, Ont., suggests that perhaps health systems in some places went too far in closing down during the first wave of the pandemic, naming specifically Canada, Eastern Europe, and Saudi Arabia as examples.

“Although these measures were taken to prepare for the worst, overwhelming numbers of patients with COVID-19 did not materialize during the first wave of the pandemic in these countries. It is possible that delaying so-called nonessential services may have been unnecessary and potentially harmful, because it likely led to delays in providing care for the treatment of serious non–COVID-19 illnesses.”

Since then, more experience and more data have largely allowed hospital systems to “tackle the ebb and flow” of COVID-19 cases in ways that limit shutdowns of important health services, they said.

Given the more pronounced effect in low- and middle-income countries, they stressed the need to focus resources on ways to promote prevention and treatment that do not rely on diagnostic procedures.

“This calls for more emphasis on developing efficient systems of telehealth, especially in poorer countries or in remote settings in all countries,” Dr. Leong and colleagues conclude.

Dr. Wadhera has reported research support from the National Heart, Lung, and Blood Institute, along with fellow senior author Robert W. Yeh, MD, MBA, who has also received personal fees and grants from several companies not related to the submitted work. Dr. Einstein, Dr. Leong, Dr. Eikelboom, and Dr. Yusuf have reported no relevant financial relationships.

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