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Emphysematous Aortitis due to Klebsiella Pneumoniae in a Patient With Poorly Controlled Diabetes Mellitus
Patients with poorly controlled diabetes mellitus and an infectious source can be predisposed to infectious aortitis.
Aortitis is the all-encompassing term ascribed to the inflammatory process in the aortic wall that can be either infective or noninfective in origin, commonly autoimmune or inflammatory large-vessel vasculitis.1 Infectious aortitis, also known as bacterial, microbial, or cryptogenic aortitis, as well as mycotic or infected aneurysm, is a rare entity in the current antibiotic era but potentially a life-threatening disorder.2 The potential complications of infectious aortitis include emphysematous aortitis (EA), pseudoaneurysm, aortic rupture, septic emboli, and fistula formation (eg, aorto-enteric fistula).2,3
EA is a rare but serious inflammatory condition of the aorta with a nonspecific clinical presentation associated with high morbidity and mortality.2-6 The condition is characterized by a localized collection of gas and purulent exudate at the aortic wall.1,3 A few cases of EA have previously been reported; however, no known cases have been reported in the literature due to Klebsiella pneumoniae (K pneumoniae).
The pathophysiology of EA is the presence of underlying damage to the arterial wall caused by a hematogenously inoculated gas-producing organism.2,3 Most reported cases of EA are due to endovascular graft complications. Under normal circumstances, the aortic intima is highly resistant to infectious pathogens; however, certain risk factors, such as diabetes mellitus (DM), atherosclerotic disease, preexisting aneurysm, cystic medial necrosis, vascular malformation, presence of medical devices, surgery, or impaired immunity can alter the integrity of the aortic intimal layer and predispose the aortic intima to infection.1,4-7 Bacteria are the most common causative organisms that can infect the aorta, especially Staphylococcus, Enterococcus, Streptococcus, Salmonella, and spirochete Treponema pallidum (syphilis).1,2,4,8 The site of the primary infection remains unclear in some patients.2,3,5,6 Infection of the aorta can arise by several mechanisms: direct extension of a local infection to an existing intimal injury or atherosclerotic plaque (the most common mechanism), septic embolism from endocarditis, direct bacterial inoculation from traumatic contamination, contiguous infection extending to the aorta wall, or a distant source of bacteremia.2,3
Clinical manifestations of EA depend on the site and the extent of infection. The diagnosis should be considered in patients with atherosclerosis, fever, abdominal pain, and leukocytosis.2,4-8 The differential diagnosis for EA includes (1) noninfective causes of aortitis, including rheumatoid arthritis and systemic lupus erythematosus; (2) tuberculous aortitis; (3) syphilitic aortitis; and (4) idiopathic isolated aortitis. Establishing an early diagnosis of infectious aortitis is extremely important because this condition is associated with a high rate of morbidity and mortality secondary to aortic rupture.2-7
Imaging is critical for a reliable and quick diagnosis of acute aortic pathology. Noninvasive cross-sectional imaging modalities, such as contrast-enhanced computed tomography (CT), magnetic resonance imaging, nuclear medicine, or positron emission tomography, are used for both the initial diagnosis and follow-up of aortitis.1 CT is the primary imaging method in most medical centers because it is widely available with short acquisition time in critically ill patients.3 CT allows rapid detection of abnormalities in wall thickness, diameter, and density, and enhancement of periaortic structures, enabling reliable exclusion of other aortic pathologies that may resemble acute aortitis. Also, CT aids in planning the optimal therapeutic approach.1,3,5-8
This case illustrates EA associated with infection by K pneumoniae in a patient with poorly controlled type 2 DM (T2DM). In this single case, our patient presented to the Bay Pines Veterans Affairs Healthcare System (BPVAHS) in Florida with recent superficial soft tissue injury, severe hyperglycemia, worsening abdominal pain, and leukocytosis without fever or chills. The correct diagnosis of EA was confirmed by characteristic CT findings.
Case Presentation
A 72-year-old male with a history of T2DM, hypertension, atherosclerotic vascular disease, obstructive lung disease, and smoking 1.5 packs per day for 40 years presented with diabetic ketoacidosis, a urinary tract infection, and abdominal pain of 1-week duration that started to worsen the morning he arrived at the BPVAHS emergency department. He reported no nausea, vomiting, diarrhea, constipation, chest pain, shortness of breath, fever, chills, fatigue, or dysuria. He had a nonhealing laceration on his left medial foot that occurred 18 days before admission and was treated at an outside hospital.
The patient’s surgical history included a left common femoral endarterectomy and a left femoral popliteal above-knee reverse saphenous vein bypass 4 years ago for severe critical limb ischemia due to occlusion of his left superficial femoral artery with distal embolization to the first and fifth toes. About 6 months later, he developed disabling claudication in his left lower extremity due to distal popliteal artery occlusion and had another bypass surgery to the below-knee popliteal artery with a reverse saphenous vein graft harvested from the right thigh.
On initial examination, his vital signs were within normal limits except for a blood pressure of 177/87 mm Hg. His physical examination demonstrated a nondistended abdomen with normal bowel sounds, mild lower quadrant tenderness on the left more than on the right, intermittent abdominal pain located around umbilicus with radiation to the back, and a negative psoas sign. His left medial foot had a nonhealing laceration with black sutures in place, with minimal erythema in the surrounding tissue and scab formation. He also had mild costovertebral tenderness on the left.
Initial laboratory investigation results were notable for a glucose level of 609 mg/dL and a white blood cell count of 14.6 × 103 cells/mcL with 86.5% of neutrophils. A CT scan of his abdomen revealed extensive atherosclerosis of the abdominal aorta and periaortic aneurysmal fluid collection with multiple foci of gas (Figure 1). Additionally, the aneurysmal fluid collection involved the proximal segment of the left common femoral artery, suspicious for left femoral arteritis (Figure 2). The patient was started on broad-spectrum antibiotics, morphine, and an insulin drip. Both urine and blood cultures were positive for K pneumoniae susceptible to multiple antibiotics. He was transferred to a tertiary medical center and was referred for a vascular surgery consultation.
The patient underwent surgical resection of the infected infrarenal EA and infected left common femoral artery with right axillary-bifemoral bypass with an 8-mm PTFE (polytetrafluoroethylene) graft. During the surgery, excision of the wall of the left common femoral artery and infrarenal aorta revealed frank pus with purulent fluid, which was sent to cytology for analysis and culture. His intraoperative cultures grew K pneumoniae sensitive to multiple antibiotics, including ceftriaxone, sulfamethoxazole/trimethoprim, and ampicillin/sulbactam. The vascular surgery team recommended inpatient admission and administration of 6 weeks of IV antibiotics postoperatively with ceftriaxone, followed by outpatient oral suppression therapy after discharge. The patient tolerated the surgery well and was discharged after 6 weeks of IV ceftriaxone followed by outpatient oral suppression therapy. However, the patient was transferred back to BPVAHS for continued care and rehabilitation placement.
The patient’s subsequent course was complicated by multiple hospital admissions, including aspiration pneumonia, hypoglycemia, diarrhea, and anemia. On one of his CT abdomen/pelvic examinations, a cysticlike mass was noted in the pancreatic head with a possible pancreatic duodenal fistula (this mass was not mentioned on the initial presurgical CT, although it can be seen in retrospect (Figure 3). Gastroenterology was consulted.
An upper endoscopy was performed that confirmed the fistula at the second portion of the duodenum. Findings from an endoscopic ultrasonography performed at an outside institution were concerning for a main duct intraductal papillary mucinous neoplasm (IPMN) with fistula, with biopsy results pending.
Discussion
This case contributes to the evidence that poorly controlled T2DM can be a predisposing factor for multiple vascular complications, including the infection of the aortic wall with progression to EA. Klebsiella species are considered opportunistic, Gram-negative pathogens that may disseminate to other tissues, causing life-threatening infections, including pneumonia, UTIs, bacteremia, and sepsis.9K pneumoniae infections are particularly challenging in neonates, the elderly, and immunocompromised individuals.9 CT is sensitive and specific in the detection of this pathologic entity.1,3 In patients with a suspected infectious etiology, the presence of foci of gas on CT in solid organ tissues is usually associated with an anaerobic infection. Gas can also be produced by Gram-negative facultative anaerobes that can ferment glucose in necrotic tissues.9
Although any microorganism can infect the aorta, K pneumoniae cultured from the blood specimen, urine culture, and intraoperative specimens in our patient was responsible for the formed gas in the aortic wall. Occurrence of spontaneous gas by this microorganism is usually associated with conditions leading to either increased vulnerability to infections and/or enhanced bacterial virulence.9 Although a relationship between EA and T2DM has not been proved, it is well known that patients with T2DM have a defect in their host-defense mechanisms, making them more susceptible to infections such as EA. Furthermore, because patients with T2DM are prone to the development of Gram-negative sepsis, organisms such as K pneumoniae would tend to emerge. Patients with poorly controlled T2DM and the presence of an infectious source can be predisposed to infectious aortitis, eventually leading to a gas-forming infection of the aorta.5,7
We postulate that the hematogenous spread of bacteria from a laceration in the leg as well as the presence of the pancreaticoduodenal fistula was likely the cause of the infectious EA in this case, considering the patient’s underlying uncontrolled T2DM. The patient’s prior left lower extremity vascular graft also may have provided a nidus for spreading to the aorta. Other reported underlying diseases of EA include aortic atherosclerosis, T2DM, diverticulitis, colon cancer, underlying aneurysm, immune-compromised status, and the presence of a medical device or open surgery.4-7,9
To our knowledge, this is the first case of EA associated with a pancreaticoduodenal fistula related to intraductal papillary mucinous neoplasm (IPMN). Fistulation of a main duct IPMN is rare, occurring in just 6.6% of cases.10 It can occur both before and after malignant degeneration.
EA requires rapid diagnosis, antibiotic therapy, and consultation with a vascular surgeon for immediate resection of the infected artery and graft bypass. The initial treatment of suspected infectious aortitis is IV antibiotics with broad antimicrobial coverage of the most likely pathologic organisms, particularly staphylococcal species and Gram-negative rods. Surgical debridement and revascularization should be completed early because of the high mortality rate of this condition. The intent of surgery is to control sepsis and reconstruct the arterial vasculature. Patients should remain on parenteral or oral antibiotics for at least 6 weeks to ensure full clearance of the infection.8 They should be followed up closely with serial blood cultures and CT scans.8 The rarity of the disorder, low level of awareness, varying presentations, and lack of evidence delineating pathogenesis and causality contribute to the challenge of recognizing, diagnosing, and treating EA in patients with T2DM and inflammation.
Conclusions
This case report can help bring awareness of this rare and potentially life-threatening condition in patients with T2DM. Clinicians should be aware of the risk of AE, particularly in patients with several additional risk factors: recent skin/soft tissue trauma, prior vascular graft surgery, and an underlying pancreatic mass. CT is the imaging method of choice that helps to rapidly choose a necessary emergent treatment approach.
1. Litmanovich DE, Yıldırım A, Bankier AA. Insights into imaging of aortitis. Insights Imaging. 2012;3(6):545-560. doi:10.1007/s13244-012-0192-x
2. Lopes RJ, Almeida J, Dias PJ, Pinho P, Maciel MJ. Infectious thoracic aortitis: a literature review. Clin Cardiol. 2009;32(9):488-490. doi:10.1002/clc.20578
3. Murphy DJ, Keraliya AR, Agrawal MD, Aghayev A, Steigner ML. Cross-sectional imaging of aortic infections. Insights Imaging. 2016;7(6):801-818. doi:10.1007/s13244-016-0522-5
4. Md Noh MSF, Abdul Rashid AM, Ar A, B N, Mohammed Y, A RE. Emphysematous aortitis: report of two cases and CT imaging findings. BJR Case Rep. 2017;3(3):20170006. doi:10.1259/bjrcr.20170006
5. Harris C, Geffen J, Rizg K, et al. A rare report of infectious emphysematous aortitis secondary to Clostridium septicum without prior vascular intervention. Case Rep Vasc Med. 2017;2017:4984325. doi:10.1155/2017/4984325
6. Ito F, Inokuchi R, Matsumoto A, et al. Presence of periaortic gas in Clostridium septicum-infected aortic aneurysm aids in early diagnosis: a case report and systematic review of the literature. J Med Case Rep. 2017;11(1):268. doi:10.1186/s13256-017-1422-0
7. Urgiles S, Matos-Casano H, Win KZ, Berardo J, Bhatt U, Shah J. Emphysematous aortitis due to Clostridium septicum in an 89-year-old female with ileus. Case Rep Infect Dis. 2019;2019:1094837. doi:10.1155/2019/1094837
8. Foote EA, Postier RG, Greenfield RA, Bronze MS. Infectious aortitis. Curr Treat Options Cardiovasc Med. 2005;7(2):89-97. doi:10.1007/s11936-005-0010-6
9. Paczosa MK, Mecsas J. Klebsiella pneumoniae: going on the offense with a strong defense. Microbiol Mol Biol Rev. 2016;80(3):629-661. doi:10.1128/mmbr.00078-15
10. Kobayashi G, Fujita N, Noda Y, et al. Intraductal papillary mucinous neoplasms of the pancreas showing fistula formation into other organs. J Gastroenterol. 2010;45(10):1080-1089. doi:10.1007/s00535-010-0263-z
Patients with poorly controlled diabetes mellitus and an infectious source can be predisposed to infectious aortitis.
Patients with poorly controlled diabetes mellitus and an infectious source can be predisposed to infectious aortitis.
Aortitis is the all-encompassing term ascribed to the inflammatory process in the aortic wall that can be either infective or noninfective in origin, commonly autoimmune or inflammatory large-vessel vasculitis.1 Infectious aortitis, also known as bacterial, microbial, or cryptogenic aortitis, as well as mycotic or infected aneurysm, is a rare entity in the current antibiotic era but potentially a life-threatening disorder.2 The potential complications of infectious aortitis include emphysematous aortitis (EA), pseudoaneurysm, aortic rupture, septic emboli, and fistula formation (eg, aorto-enteric fistula).2,3
EA is a rare but serious inflammatory condition of the aorta with a nonspecific clinical presentation associated with high morbidity and mortality.2-6 The condition is characterized by a localized collection of gas and purulent exudate at the aortic wall.1,3 A few cases of EA have previously been reported; however, no known cases have been reported in the literature due to Klebsiella pneumoniae (K pneumoniae).
The pathophysiology of EA is the presence of underlying damage to the arterial wall caused by a hematogenously inoculated gas-producing organism.2,3 Most reported cases of EA are due to endovascular graft complications. Under normal circumstances, the aortic intima is highly resistant to infectious pathogens; however, certain risk factors, such as diabetes mellitus (DM), atherosclerotic disease, preexisting aneurysm, cystic medial necrosis, vascular malformation, presence of medical devices, surgery, or impaired immunity can alter the integrity of the aortic intimal layer and predispose the aortic intima to infection.1,4-7 Bacteria are the most common causative organisms that can infect the aorta, especially Staphylococcus, Enterococcus, Streptococcus, Salmonella, and spirochete Treponema pallidum (syphilis).1,2,4,8 The site of the primary infection remains unclear in some patients.2,3,5,6 Infection of the aorta can arise by several mechanisms: direct extension of a local infection to an existing intimal injury or atherosclerotic plaque (the most common mechanism), septic embolism from endocarditis, direct bacterial inoculation from traumatic contamination, contiguous infection extending to the aorta wall, or a distant source of bacteremia.2,3
Clinical manifestations of EA depend on the site and the extent of infection. The diagnosis should be considered in patients with atherosclerosis, fever, abdominal pain, and leukocytosis.2,4-8 The differential diagnosis for EA includes (1) noninfective causes of aortitis, including rheumatoid arthritis and systemic lupus erythematosus; (2) tuberculous aortitis; (3) syphilitic aortitis; and (4) idiopathic isolated aortitis. Establishing an early diagnosis of infectious aortitis is extremely important because this condition is associated with a high rate of morbidity and mortality secondary to aortic rupture.2-7
Imaging is critical for a reliable and quick diagnosis of acute aortic pathology. Noninvasive cross-sectional imaging modalities, such as contrast-enhanced computed tomography (CT), magnetic resonance imaging, nuclear medicine, or positron emission tomography, are used for both the initial diagnosis and follow-up of aortitis.1 CT is the primary imaging method in most medical centers because it is widely available with short acquisition time in critically ill patients.3 CT allows rapid detection of abnormalities in wall thickness, diameter, and density, and enhancement of periaortic structures, enabling reliable exclusion of other aortic pathologies that may resemble acute aortitis. Also, CT aids in planning the optimal therapeutic approach.1,3,5-8
This case illustrates EA associated with infection by K pneumoniae in a patient with poorly controlled type 2 DM (T2DM). In this single case, our patient presented to the Bay Pines Veterans Affairs Healthcare System (BPVAHS) in Florida with recent superficial soft tissue injury, severe hyperglycemia, worsening abdominal pain, and leukocytosis without fever or chills. The correct diagnosis of EA was confirmed by characteristic CT findings.
Case Presentation
A 72-year-old male with a history of T2DM, hypertension, atherosclerotic vascular disease, obstructive lung disease, and smoking 1.5 packs per day for 40 years presented with diabetic ketoacidosis, a urinary tract infection, and abdominal pain of 1-week duration that started to worsen the morning he arrived at the BPVAHS emergency department. He reported no nausea, vomiting, diarrhea, constipation, chest pain, shortness of breath, fever, chills, fatigue, or dysuria. He had a nonhealing laceration on his left medial foot that occurred 18 days before admission and was treated at an outside hospital.
The patient’s surgical history included a left common femoral endarterectomy and a left femoral popliteal above-knee reverse saphenous vein bypass 4 years ago for severe critical limb ischemia due to occlusion of his left superficial femoral artery with distal embolization to the first and fifth toes. About 6 months later, he developed disabling claudication in his left lower extremity due to distal popliteal artery occlusion and had another bypass surgery to the below-knee popliteal artery with a reverse saphenous vein graft harvested from the right thigh.
On initial examination, his vital signs were within normal limits except for a blood pressure of 177/87 mm Hg. His physical examination demonstrated a nondistended abdomen with normal bowel sounds, mild lower quadrant tenderness on the left more than on the right, intermittent abdominal pain located around umbilicus with radiation to the back, and a negative psoas sign. His left medial foot had a nonhealing laceration with black sutures in place, with minimal erythema in the surrounding tissue and scab formation. He also had mild costovertebral tenderness on the left.
Initial laboratory investigation results were notable for a glucose level of 609 mg/dL and a white blood cell count of 14.6 × 103 cells/mcL with 86.5% of neutrophils. A CT scan of his abdomen revealed extensive atherosclerosis of the abdominal aorta and periaortic aneurysmal fluid collection with multiple foci of gas (Figure 1). Additionally, the aneurysmal fluid collection involved the proximal segment of the left common femoral artery, suspicious for left femoral arteritis (Figure 2). The patient was started on broad-spectrum antibiotics, morphine, and an insulin drip. Both urine and blood cultures were positive for K pneumoniae susceptible to multiple antibiotics. He was transferred to a tertiary medical center and was referred for a vascular surgery consultation.
The patient underwent surgical resection of the infected infrarenal EA and infected left common femoral artery with right axillary-bifemoral bypass with an 8-mm PTFE (polytetrafluoroethylene) graft. During the surgery, excision of the wall of the left common femoral artery and infrarenal aorta revealed frank pus with purulent fluid, which was sent to cytology for analysis and culture. His intraoperative cultures grew K pneumoniae sensitive to multiple antibiotics, including ceftriaxone, sulfamethoxazole/trimethoprim, and ampicillin/sulbactam. The vascular surgery team recommended inpatient admission and administration of 6 weeks of IV antibiotics postoperatively with ceftriaxone, followed by outpatient oral suppression therapy after discharge. The patient tolerated the surgery well and was discharged after 6 weeks of IV ceftriaxone followed by outpatient oral suppression therapy. However, the patient was transferred back to BPVAHS for continued care and rehabilitation placement.
The patient’s subsequent course was complicated by multiple hospital admissions, including aspiration pneumonia, hypoglycemia, diarrhea, and anemia. On one of his CT abdomen/pelvic examinations, a cysticlike mass was noted in the pancreatic head with a possible pancreatic duodenal fistula (this mass was not mentioned on the initial presurgical CT, although it can be seen in retrospect (Figure 3). Gastroenterology was consulted.
An upper endoscopy was performed that confirmed the fistula at the second portion of the duodenum. Findings from an endoscopic ultrasonography performed at an outside institution were concerning for a main duct intraductal papillary mucinous neoplasm (IPMN) with fistula, with biopsy results pending.
Discussion
This case contributes to the evidence that poorly controlled T2DM can be a predisposing factor for multiple vascular complications, including the infection of the aortic wall with progression to EA. Klebsiella species are considered opportunistic, Gram-negative pathogens that may disseminate to other tissues, causing life-threatening infections, including pneumonia, UTIs, bacteremia, and sepsis.9K pneumoniae infections are particularly challenging in neonates, the elderly, and immunocompromised individuals.9 CT is sensitive and specific in the detection of this pathologic entity.1,3 In patients with a suspected infectious etiology, the presence of foci of gas on CT in solid organ tissues is usually associated with an anaerobic infection. Gas can also be produced by Gram-negative facultative anaerobes that can ferment glucose in necrotic tissues.9
Although any microorganism can infect the aorta, K pneumoniae cultured from the blood specimen, urine culture, and intraoperative specimens in our patient was responsible for the formed gas in the aortic wall. Occurrence of spontaneous gas by this microorganism is usually associated with conditions leading to either increased vulnerability to infections and/or enhanced bacterial virulence.9 Although a relationship between EA and T2DM has not been proved, it is well known that patients with T2DM have a defect in their host-defense mechanisms, making them more susceptible to infections such as EA. Furthermore, because patients with T2DM are prone to the development of Gram-negative sepsis, organisms such as K pneumoniae would tend to emerge. Patients with poorly controlled T2DM and the presence of an infectious source can be predisposed to infectious aortitis, eventually leading to a gas-forming infection of the aorta.5,7
We postulate that the hematogenous spread of bacteria from a laceration in the leg as well as the presence of the pancreaticoduodenal fistula was likely the cause of the infectious EA in this case, considering the patient’s underlying uncontrolled T2DM. The patient’s prior left lower extremity vascular graft also may have provided a nidus for spreading to the aorta. Other reported underlying diseases of EA include aortic atherosclerosis, T2DM, diverticulitis, colon cancer, underlying aneurysm, immune-compromised status, and the presence of a medical device or open surgery.4-7,9
To our knowledge, this is the first case of EA associated with a pancreaticoduodenal fistula related to intraductal papillary mucinous neoplasm (IPMN). Fistulation of a main duct IPMN is rare, occurring in just 6.6% of cases.10 It can occur both before and after malignant degeneration.
EA requires rapid diagnosis, antibiotic therapy, and consultation with a vascular surgeon for immediate resection of the infected artery and graft bypass. The initial treatment of suspected infectious aortitis is IV antibiotics with broad antimicrobial coverage of the most likely pathologic organisms, particularly staphylococcal species and Gram-negative rods. Surgical debridement and revascularization should be completed early because of the high mortality rate of this condition. The intent of surgery is to control sepsis and reconstruct the arterial vasculature. Patients should remain on parenteral or oral antibiotics for at least 6 weeks to ensure full clearance of the infection.8 They should be followed up closely with serial blood cultures and CT scans.8 The rarity of the disorder, low level of awareness, varying presentations, and lack of evidence delineating pathogenesis and causality contribute to the challenge of recognizing, diagnosing, and treating EA in patients with T2DM and inflammation.
Conclusions
This case report can help bring awareness of this rare and potentially life-threatening condition in patients with T2DM. Clinicians should be aware of the risk of AE, particularly in patients with several additional risk factors: recent skin/soft tissue trauma, prior vascular graft surgery, and an underlying pancreatic mass. CT is the imaging method of choice that helps to rapidly choose a necessary emergent treatment approach.
Aortitis is the all-encompassing term ascribed to the inflammatory process in the aortic wall that can be either infective or noninfective in origin, commonly autoimmune or inflammatory large-vessel vasculitis.1 Infectious aortitis, also known as bacterial, microbial, or cryptogenic aortitis, as well as mycotic or infected aneurysm, is a rare entity in the current antibiotic era but potentially a life-threatening disorder.2 The potential complications of infectious aortitis include emphysematous aortitis (EA), pseudoaneurysm, aortic rupture, septic emboli, and fistula formation (eg, aorto-enteric fistula).2,3
EA is a rare but serious inflammatory condition of the aorta with a nonspecific clinical presentation associated with high morbidity and mortality.2-6 The condition is characterized by a localized collection of gas and purulent exudate at the aortic wall.1,3 A few cases of EA have previously been reported; however, no known cases have been reported in the literature due to Klebsiella pneumoniae (K pneumoniae).
The pathophysiology of EA is the presence of underlying damage to the arterial wall caused by a hematogenously inoculated gas-producing organism.2,3 Most reported cases of EA are due to endovascular graft complications. Under normal circumstances, the aortic intima is highly resistant to infectious pathogens; however, certain risk factors, such as diabetes mellitus (DM), atherosclerotic disease, preexisting aneurysm, cystic medial necrosis, vascular malformation, presence of medical devices, surgery, or impaired immunity can alter the integrity of the aortic intimal layer and predispose the aortic intima to infection.1,4-7 Bacteria are the most common causative organisms that can infect the aorta, especially Staphylococcus, Enterococcus, Streptococcus, Salmonella, and spirochete Treponema pallidum (syphilis).1,2,4,8 The site of the primary infection remains unclear in some patients.2,3,5,6 Infection of the aorta can arise by several mechanisms: direct extension of a local infection to an existing intimal injury or atherosclerotic plaque (the most common mechanism), septic embolism from endocarditis, direct bacterial inoculation from traumatic contamination, contiguous infection extending to the aorta wall, or a distant source of bacteremia.2,3
Clinical manifestations of EA depend on the site and the extent of infection. The diagnosis should be considered in patients with atherosclerosis, fever, abdominal pain, and leukocytosis.2,4-8 The differential diagnosis for EA includes (1) noninfective causes of aortitis, including rheumatoid arthritis and systemic lupus erythematosus; (2) tuberculous aortitis; (3) syphilitic aortitis; and (4) idiopathic isolated aortitis. Establishing an early diagnosis of infectious aortitis is extremely important because this condition is associated with a high rate of morbidity and mortality secondary to aortic rupture.2-7
Imaging is critical for a reliable and quick diagnosis of acute aortic pathology. Noninvasive cross-sectional imaging modalities, such as contrast-enhanced computed tomography (CT), magnetic resonance imaging, nuclear medicine, or positron emission tomography, are used for both the initial diagnosis and follow-up of aortitis.1 CT is the primary imaging method in most medical centers because it is widely available with short acquisition time in critically ill patients.3 CT allows rapid detection of abnormalities in wall thickness, diameter, and density, and enhancement of periaortic structures, enabling reliable exclusion of other aortic pathologies that may resemble acute aortitis. Also, CT aids in planning the optimal therapeutic approach.1,3,5-8
This case illustrates EA associated with infection by K pneumoniae in a patient with poorly controlled type 2 DM (T2DM). In this single case, our patient presented to the Bay Pines Veterans Affairs Healthcare System (BPVAHS) in Florida with recent superficial soft tissue injury, severe hyperglycemia, worsening abdominal pain, and leukocytosis without fever or chills. The correct diagnosis of EA was confirmed by characteristic CT findings.
Case Presentation
A 72-year-old male with a history of T2DM, hypertension, atherosclerotic vascular disease, obstructive lung disease, and smoking 1.5 packs per day for 40 years presented with diabetic ketoacidosis, a urinary tract infection, and abdominal pain of 1-week duration that started to worsen the morning he arrived at the BPVAHS emergency department. He reported no nausea, vomiting, diarrhea, constipation, chest pain, shortness of breath, fever, chills, fatigue, or dysuria. He had a nonhealing laceration on his left medial foot that occurred 18 days before admission and was treated at an outside hospital.
The patient’s surgical history included a left common femoral endarterectomy and a left femoral popliteal above-knee reverse saphenous vein bypass 4 years ago for severe critical limb ischemia due to occlusion of his left superficial femoral artery with distal embolization to the first and fifth toes. About 6 months later, he developed disabling claudication in his left lower extremity due to distal popliteal artery occlusion and had another bypass surgery to the below-knee popliteal artery with a reverse saphenous vein graft harvested from the right thigh.
On initial examination, his vital signs were within normal limits except for a blood pressure of 177/87 mm Hg. His physical examination demonstrated a nondistended abdomen with normal bowel sounds, mild lower quadrant tenderness on the left more than on the right, intermittent abdominal pain located around umbilicus with radiation to the back, and a negative psoas sign. His left medial foot had a nonhealing laceration with black sutures in place, with minimal erythema in the surrounding tissue and scab formation. He also had mild costovertebral tenderness on the left.
Initial laboratory investigation results were notable for a glucose level of 609 mg/dL and a white blood cell count of 14.6 × 103 cells/mcL with 86.5% of neutrophils. A CT scan of his abdomen revealed extensive atherosclerosis of the abdominal aorta and periaortic aneurysmal fluid collection with multiple foci of gas (Figure 1). Additionally, the aneurysmal fluid collection involved the proximal segment of the left common femoral artery, suspicious for left femoral arteritis (Figure 2). The patient was started on broad-spectrum antibiotics, morphine, and an insulin drip. Both urine and blood cultures were positive for K pneumoniae susceptible to multiple antibiotics. He was transferred to a tertiary medical center and was referred for a vascular surgery consultation.
The patient underwent surgical resection of the infected infrarenal EA and infected left common femoral artery with right axillary-bifemoral bypass with an 8-mm PTFE (polytetrafluoroethylene) graft. During the surgery, excision of the wall of the left common femoral artery and infrarenal aorta revealed frank pus with purulent fluid, which was sent to cytology for analysis and culture. His intraoperative cultures grew K pneumoniae sensitive to multiple antibiotics, including ceftriaxone, sulfamethoxazole/trimethoprim, and ampicillin/sulbactam. The vascular surgery team recommended inpatient admission and administration of 6 weeks of IV antibiotics postoperatively with ceftriaxone, followed by outpatient oral suppression therapy after discharge. The patient tolerated the surgery well and was discharged after 6 weeks of IV ceftriaxone followed by outpatient oral suppression therapy. However, the patient was transferred back to BPVAHS for continued care and rehabilitation placement.
The patient’s subsequent course was complicated by multiple hospital admissions, including aspiration pneumonia, hypoglycemia, diarrhea, and anemia. On one of his CT abdomen/pelvic examinations, a cysticlike mass was noted in the pancreatic head with a possible pancreatic duodenal fistula (this mass was not mentioned on the initial presurgical CT, although it can be seen in retrospect (Figure 3). Gastroenterology was consulted.
An upper endoscopy was performed that confirmed the fistula at the second portion of the duodenum. Findings from an endoscopic ultrasonography performed at an outside institution were concerning for a main duct intraductal papillary mucinous neoplasm (IPMN) with fistula, with biopsy results pending.
Discussion
This case contributes to the evidence that poorly controlled T2DM can be a predisposing factor for multiple vascular complications, including the infection of the aortic wall with progression to EA. Klebsiella species are considered opportunistic, Gram-negative pathogens that may disseminate to other tissues, causing life-threatening infections, including pneumonia, UTIs, bacteremia, and sepsis.9K pneumoniae infections are particularly challenging in neonates, the elderly, and immunocompromised individuals.9 CT is sensitive and specific in the detection of this pathologic entity.1,3 In patients with a suspected infectious etiology, the presence of foci of gas on CT in solid organ tissues is usually associated with an anaerobic infection. Gas can also be produced by Gram-negative facultative anaerobes that can ferment glucose in necrotic tissues.9
Although any microorganism can infect the aorta, K pneumoniae cultured from the blood specimen, urine culture, and intraoperative specimens in our patient was responsible for the formed gas in the aortic wall. Occurrence of spontaneous gas by this microorganism is usually associated with conditions leading to either increased vulnerability to infections and/or enhanced bacterial virulence.9 Although a relationship between EA and T2DM has not been proved, it is well known that patients with T2DM have a defect in their host-defense mechanisms, making them more susceptible to infections such as EA. Furthermore, because patients with T2DM are prone to the development of Gram-negative sepsis, organisms such as K pneumoniae would tend to emerge. Patients with poorly controlled T2DM and the presence of an infectious source can be predisposed to infectious aortitis, eventually leading to a gas-forming infection of the aorta.5,7
We postulate that the hematogenous spread of bacteria from a laceration in the leg as well as the presence of the pancreaticoduodenal fistula was likely the cause of the infectious EA in this case, considering the patient’s underlying uncontrolled T2DM. The patient’s prior left lower extremity vascular graft also may have provided a nidus for spreading to the aorta. Other reported underlying diseases of EA include aortic atherosclerosis, T2DM, diverticulitis, colon cancer, underlying aneurysm, immune-compromised status, and the presence of a medical device or open surgery.4-7,9
To our knowledge, this is the first case of EA associated with a pancreaticoduodenal fistula related to intraductal papillary mucinous neoplasm (IPMN). Fistulation of a main duct IPMN is rare, occurring in just 6.6% of cases.10 It can occur both before and after malignant degeneration.
EA requires rapid diagnosis, antibiotic therapy, and consultation with a vascular surgeon for immediate resection of the infected artery and graft bypass. The initial treatment of suspected infectious aortitis is IV antibiotics with broad antimicrobial coverage of the most likely pathologic organisms, particularly staphylococcal species and Gram-negative rods. Surgical debridement and revascularization should be completed early because of the high mortality rate of this condition. The intent of surgery is to control sepsis and reconstruct the arterial vasculature. Patients should remain on parenteral or oral antibiotics for at least 6 weeks to ensure full clearance of the infection.8 They should be followed up closely with serial blood cultures and CT scans.8 The rarity of the disorder, low level of awareness, varying presentations, and lack of evidence delineating pathogenesis and causality contribute to the challenge of recognizing, diagnosing, and treating EA in patients with T2DM and inflammation.
Conclusions
This case report can help bring awareness of this rare and potentially life-threatening condition in patients with T2DM. Clinicians should be aware of the risk of AE, particularly in patients with several additional risk factors: recent skin/soft tissue trauma, prior vascular graft surgery, and an underlying pancreatic mass. CT is the imaging method of choice that helps to rapidly choose a necessary emergent treatment approach.
1. Litmanovich DE, Yıldırım A, Bankier AA. Insights into imaging of aortitis. Insights Imaging. 2012;3(6):545-560. doi:10.1007/s13244-012-0192-x
2. Lopes RJ, Almeida J, Dias PJ, Pinho P, Maciel MJ. Infectious thoracic aortitis: a literature review. Clin Cardiol. 2009;32(9):488-490. doi:10.1002/clc.20578
3. Murphy DJ, Keraliya AR, Agrawal MD, Aghayev A, Steigner ML. Cross-sectional imaging of aortic infections. Insights Imaging. 2016;7(6):801-818. doi:10.1007/s13244-016-0522-5
4. Md Noh MSF, Abdul Rashid AM, Ar A, B N, Mohammed Y, A RE. Emphysematous aortitis: report of two cases and CT imaging findings. BJR Case Rep. 2017;3(3):20170006. doi:10.1259/bjrcr.20170006
5. Harris C, Geffen J, Rizg K, et al. A rare report of infectious emphysematous aortitis secondary to Clostridium septicum without prior vascular intervention. Case Rep Vasc Med. 2017;2017:4984325. doi:10.1155/2017/4984325
6. Ito F, Inokuchi R, Matsumoto A, et al. Presence of periaortic gas in Clostridium septicum-infected aortic aneurysm aids in early diagnosis: a case report and systematic review of the literature. J Med Case Rep. 2017;11(1):268. doi:10.1186/s13256-017-1422-0
7. Urgiles S, Matos-Casano H, Win KZ, Berardo J, Bhatt U, Shah J. Emphysematous aortitis due to Clostridium septicum in an 89-year-old female with ileus. Case Rep Infect Dis. 2019;2019:1094837. doi:10.1155/2019/1094837
8. Foote EA, Postier RG, Greenfield RA, Bronze MS. Infectious aortitis. Curr Treat Options Cardiovasc Med. 2005;7(2):89-97. doi:10.1007/s11936-005-0010-6
9. Paczosa MK, Mecsas J. Klebsiella pneumoniae: going on the offense with a strong defense. Microbiol Mol Biol Rev. 2016;80(3):629-661. doi:10.1128/mmbr.00078-15
10. Kobayashi G, Fujita N, Noda Y, et al. Intraductal papillary mucinous neoplasms of the pancreas showing fistula formation into other organs. J Gastroenterol. 2010;45(10):1080-1089. doi:10.1007/s00535-010-0263-z
1. Litmanovich DE, Yıldırım A, Bankier AA. Insights into imaging of aortitis. Insights Imaging. 2012;3(6):545-560. doi:10.1007/s13244-012-0192-x
2. Lopes RJ, Almeida J, Dias PJ, Pinho P, Maciel MJ. Infectious thoracic aortitis: a literature review. Clin Cardiol. 2009;32(9):488-490. doi:10.1002/clc.20578
3. Murphy DJ, Keraliya AR, Agrawal MD, Aghayev A, Steigner ML. Cross-sectional imaging of aortic infections. Insights Imaging. 2016;7(6):801-818. doi:10.1007/s13244-016-0522-5
4. Md Noh MSF, Abdul Rashid AM, Ar A, B N, Mohammed Y, A RE. Emphysematous aortitis: report of two cases and CT imaging findings. BJR Case Rep. 2017;3(3):20170006. doi:10.1259/bjrcr.20170006
5. Harris C, Geffen J, Rizg K, et al. A rare report of infectious emphysematous aortitis secondary to Clostridium septicum without prior vascular intervention. Case Rep Vasc Med. 2017;2017:4984325. doi:10.1155/2017/4984325
6. Ito F, Inokuchi R, Matsumoto A, et al. Presence of periaortic gas in Clostridium septicum-infected aortic aneurysm aids in early diagnosis: a case report and systematic review of the literature. J Med Case Rep. 2017;11(1):268. doi:10.1186/s13256-017-1422-0
7. Urgiles S, Matos-Casano H, Win KZ, Berardo J, Bhatt U, Shah J. Emphysematous aortitis due to Clostridium septicum in an 89-year-old female with ileus. Case Rep Infect Dis. 2019;2019:1094837. doi:10.1155/2019/1094837
8. Foote EA, Postier RG, Greenfield RA, Bronze MS. Infectious aortitis. Curr Treat Options Cardiovasc Med. 2005;7(2):89-97. doi:10.1007/s11936-005-0010-6
9. Paczosa MK, Mecsas J. Klebsiella pneumoniae: going on the offense with a strong defense. Microbiol Mol Biol Rev. 2016;80(3):629-661. doi:10.1128/mmbr.00078-15
10. Kobayashi G, Fujita N, Noda Y, et al. Intraductal papillary mucinous neoplasms of the pancreas showing fistula formation into other organs. J Gastroenterol. 2010;45(10):1080-1089. doi:10.1007/s00535-010-0263-z
Rosuvastatin-Induced Rhabdomyolysis, Pancreatitis, Transaminitis, and Acute Kidney Injury
Changing medications within a drug class requires considering the indication and dosage, possible adverse effects, and drug-drug interactions.
Attention should be paid to changing a tolerated medication to another within its class. Many drugs approved by the US Food and Drug Administration (FDA), have equivalent therapeutic properties as existing drugs. Rarely do such medications share the same potency and adverse effect (AE) profile.
Case Presentation
A 77-year-old man presented to the emergency department (ED) at the Raymond G. Murphy Medical Center in Albuquerque, New Mexico, with a 1-month history of progressive muscle weakness, which was so severe that he required assistance rising from chairs. The symptoms began when he switched from atorvastatin 40 mg daily to rosuvastatin 40 mg daily. A nephrology consultation was requested for an elevated plasma creatinine.
The patient reported strict adherence to his prescribed medications. In the days following the switch to rosuvastatin, he noticed that his urine turned black. He described the color as “like burnt coffee.” The color gradually cleared before his ED presentation. The patient stopped taking rosuvastatin the day prior to presentation and noted improvement of his symptoms. Review of symptoms was significant for lower extremity paresthesia and numbness the day he started rosuvastatin. He had no symptoms of decompensated heart failure and no recent exacerbations requiring alteration of his diuretic regimen.
The patient’s medical history was significant for traumatic brain injury with complex partial seizures, carpal tunnel syndrome, dyslipidemia, coronary artery disease with percutaneous intervention to the right coronary artery in the late 1990s, atrial fibrillation and ventricular tachycardia, status post implantable cardioverter defibrillator, heart failure with reduced ejection fraction (25%) attributed to ischemic cardiomyopathy, hypertension, lower urinary tract symptoms/prostatism, and previous bladder cancer. In the mid-1960s, the patient served in the US Army and had been deployed to South Korea. After the service, he worked for the local city government. He was retired for about 15 years. He reported no tobacco, alcohol, or recreational drug use and no tattoos. He did not require prior blood or blood product transfusions. None of his family members—parents, siblings, or children—had any history of kidney disease.
The patient’s outpatient medications included levetiracetam 750 mg twice daily, melatonin 9 mg at night, menthol 16%/methyl-salicylate 30% topically up to 4 times per day as needed, aspirin 81 mg once daily, fish oil 1000 mg twice daily, amiodarone 400 mg twice daily, hydralazine 20 mg 3 times daily, isosorbide mononitrate 60 mg daily, metoprolol succinate 100 mg daily, and tamsulosin 0.4 mg at night. His vital signs were stable: afebrile (97.5 ºF), normocardic (74 beats per minute), normotensive (118/78 mm Hg), and normoxic (98% on room air). On examination, he appeared elderly, somewhat frail, and chronically ill but in no acute distress. Affect was pleasant and appropriate, attention was high, and his thought process was logical. He had sparse, grey scalp hair. Extraocular movements were intact. Oral mucosa was pink and moist. His back was nontender, and there was no costovertebral tenderness bilaterally. The patient was in no respiratory distress, with a slightly hyperresonant chest to percussion bilaterally, very faint inspiratory basilar crepitant rales (that cleared with repeat inspiration), and was otherwise clear to auscultation throughout. An outline of an implanted pacemaker was evident on the chest under his left clavicle, with a laterally displaced apical impulse. The rate was normal and the rhythm was regular. Upper extremities demonstrated papyraceous skin but without cyanosis, clubbing, or edema. Radial pulses were slightly diminished. He had no lower extremity edema.
His laboratory values are provided in Table 1. Kidney function was stable months prior to admission. Of note, the blood urea nitrogen and plasma creatinine were increased from his baseline up to 47 and 5.89 mg/dL, respectively. The serum glutamic-oxaloacetic transaminase and serum glutamic pyruvic transaminase were 1051 U/L and 408 U/L, respectively. Plasma amylase and lipase levels also were elevated, 230 U/L and 892 U/L, respectively. Creatine kinase was 41,099 U/L. Urinalysis demonstrated a specific gravity of 1.017, pH of 5, and a large amount of blood (92 red blood cells/high power field).
A 12-lead electrocardiogram demonstrated a sinus rhythm, PR interval of 0.20 ms, narrow QRS with a leftward frontal axis deviation, R-transition between precordial leads V1 and V2, and flattening of the ST segments in III, V1-V3 (Figure 1). A portable chest X-ray demonstrated clear lung fields, no evidence of effusion in the costophrenic area. Ultrasonography was conducted at the time of the examination (Figure 2). The kidneys were smoothly contoured, each measuring > 10 cm; there was an exophytic cyst on the left. Otherwise, the cortices, perhaps slightly echogenic, did not appear diminished. The bladder was not abnormally enlarged.
Rosuvastatin-induced rhabdomyolysis, pancreatitis, transaminitis, and drug-induced acute kidney injury were considered high among the diagnostic differentials. The 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase inhibitor was stopped, and he was prescribed an acute renal insufficiency diet. All laboratory parameters improved with this change (Figure 3). Two months after presentation (and with rosuvastatin added to his list of adverse reactions), all symptoms resolved and his plasma creatinine reached a nadir of 1.22 mg/dL.
Discussion
Statin-class drugs inhibit the HMG-CoA reductase (Table 2). Upregulation of low-density lipoprotein cholesterol (LDL-C) receptors in the liver result in increased LDL-C uptake and cholesterol catabolism.1 Prescribed inhibitors of the HMG-CoA reductase—statins—are known to reduce mortality due to cardiovascular disease (CVD). Much like any other pharmaceutical agent with any measurable potency, HMG-CoA inhibitors can have AEs. Statin therapy has been associated with pancreatitis.2 Muscle toxicity is a complication of HMG-CoA reductase inhibitors, and statin-associated symptoms are a leading cause of nonadherence.3 Rosuvastatin had higher AE and drug reactions compared with that of atorvastatin and pitavastatin (35.6%, 8.7%, and 22.2%, respectively) in clinical trials for approval.4 We have reported concomitant adermatopathic dermatomyositis with statin-induced myopathy in a 48-year-old man from simvastatin (40 to 80 mg daily).1
Toxin-induced myopathy should be considered early in the differential diagnosis of weakness.5 All HMG-CoA inhibitors have been associated with acute kidney injury, particularly at high doses and also are known to induce myopathies, sometimes with inclusion bodies.1 Muscle-related AEs correlate with the potency of an HMG-CoA reductase inhibitor according to an analysis using the FDA AE Reporting System (AERS).6 Myalgia and rhabdomyolysis are well-known AEs of this class of medications. Furthermore, type II muscle atrophy—particularly in the proximal limb muscles—has been reported.5 Patients may have difficulty rising from chairs.1 Rosuvastatin had the strongest signal for muscular AEs (eg, myalgia, rhabdomyolysis, increased creatine phosphokinase level) from an FDA analysis of AERS.7
Rosuvastatin is the only HMG-CoA reductase inhibitor that causes dose-dependent increases in proteinuria and hematuria (Figure 4).8 Rosuvastatin at a 5-mg dose may induce 4 times the proteinuria as a placebo. Typically, other statins potentially reduce proteinuria (without hematuria). Proteinuria may be induced by rosuvastatin even at low doses.8 Proteinuria is attributed to how rosuvastatin impacts proximal tubular function.9 The drug is transported into the proximal tubule by the organic anion transporter-3. Acute kidney injury has been associated with several statins, including rosuvastatin.7,10 This may be associated with denuded tubular epithelia, active urinary sediment, acute tubular toxicity, vacuolated epithelial cells, and tubular cell casts. Unlike atorvastatin, the increase in proteinuria and hematuria also is dose dependent.
In patients with renal insufficiency (short of end-stage renal disease [ESRD]), most statins other than rosuvastatin are well tolerated and recommended for reduction of overall and CVD mortality risk. However, these benefits seem to diminish once ESRD is reached. Atorvastatin did not impact CVD mortality in patients with type 2 diabetes mellitus (T2DM) and ESRD (despite decreasing LDL-C).11 The AURORA study randomized 10 mg of statin vs placebo in 2776 maintenance dialysis patients aged 50 to 80 years. Rosuvastatin lowered the LDL-C but did not affect all-cause mortality (13.5 vs 14.0 events per 100 patient-years). Patients randomized to rosuvastatin had more than twice as many unclassified strokes (9 vs 4). Rosuvastatin, although efficacious in reducing LDL-C, had no impact on CVD mortality, nonfatal myocardial infarction, or nonfatal stroke.12 Post hoc analysis demonstrated that in patients with T2DM with ESRD the hazard ratio for hemorrhagic stroke was 5.2.13
Rosuvastatin ranked lower than lovastatin, pravastatin, simvastatin, atorvastatin, and fluvastatin with respect to reduction of all-cause mortality in trials of participants with or without prior coronary artery disease.14 AEs, such as rhabdomyolysis, proteinuria, nephropathy, renal failure, liver, and muscle toxicity are higher with rosuvastatin than other medications in its class.15
Conclusions
For patients with existing CVD, standard clinical practice is to encourage increased and regular physical activity, cholesterol-lowering diets, weight loss, and smoking cessation. Hypertension should be treated. Glycemia should be well controlled in the setting of T2DM. β-blockers may be beneficial in those with histories of myocardial infarction or heart failure with reduced systolic function. Statins are a valuable tool in the treatment of dyslipidemia.
Statin-induced muscle symptoms are a major reason for discontinuation and nonadherence.16 Statin-induced myalgia, myositis, and myopathy have been used interchangeably.17 Rhabdomyolysis, myalgia, increased creatine kinase, statin myopathy, and immune-mediated necrotizing myopathy are among the clinical phenotypes caused by statins.17 There are 33,695 serious cases—1808 deaths—reported with rosuvastatin in the FDA AERS as of June 30, 2021. Myalgia, pain in extremity, muscle spasms, pain, and arthralgia top the list of AEs. When statin-induced symptoms occur, adherence is rarely improved by dismissive clinicians.18
Drugs in the same class often have common therapeutic properties. Potencies and AE profiles are seldom uniform. The decision to add or change the brand of medication within a class should be balanced with considerations for the indication, duplications, simplification, AEs, appropriate dosage, and drug-drug interactions.
Acknowledgments
Brent Wagner is funded by a US Department of Veterans Affairs Merit Award (I01 BX001958), a National Institutes of Health R01 grant (DK-102085), Dialysis Clinic, Inc., and partially supported by the University of New Mexico Brain and Behavioral Health Institute (BBHI 2018-1008, 2020-21-002) and in part by the University of New Mexico’s Signature Program in Cardiovascular and Metabolic Disease (CVMD); and the University of New Mexico School of Medicine Research Allocation Committee (C-2459-RAC, New Mexico Medical Trust). Brent Wagner is an Associate Member to the University of New Mexico Health Sciences Center Autophagy, Inflammation, and Metabolism Center of Biomedical Research Excellence (AIM CoBRE) supported by NIH grant P20GM121176.
Funding
National Institutes of Health Grant R01 DK-102085, Dialysis Clinic Inc., VA Merit Award I01 BX001958, Center for Integrated Nanotechnologies User Agreement 2019AU0120, Brain & Behavioral Health Institute (grants 2018-1008, 2020-21-002), University of New Mexico’s Signature Program in Cardiovascular and Metabolic Disease (CVMD), the University of New Mexico School of Medicine Research Allocation Committee (C-2459-RAC, New Mexico Medical Trust) and a metabolomics voucher from the AIM Center (NIH P20GM121176).
1. Wagner B, Kagan-Hallet KS, Russell IJ. Concomitant presentation of adermatopathic dermatomyositis, statin myopathy, fibromyalgia syndrome, piriformis muscle myofascial pain and diabetic neuropathy. J Musculoskeletal Pain. 2003;11(2):25-30. doi:10.1300/J094v11n02_05
2. Collins R, Reith C, Emberson J, et al. Interpretation of the evidence for the efficacy and safety of statin therapy [published correction appears in Lancet. 2017 Feb 11;389(10069):602]. Lancet. 2016;388(10059):2532-2561. doi:10.1016/S0140-6736(16)31357-5
3. Stroes ES, Thompson PD, Corsini A, et al. Statin-associated muscle symptoms: impact on statin therapy-European Atherosclerosis Society Consensus Panel Statement on Assessment, Aetiology and Management. Eur Heart J. 2015;36(17):1012-1022. doi:10.1093/eurheartj/ehv043
4. Saku K, Zhang B, Noda K; PATROL Trial Investigators. Randomized head-to-head comparison of pitavastatin, atorvastatin, and rosuvastatin for safety and efficacy (quantity and quality of LDL): the PATROL trial. Circ J. 2011;75(6):1493-1505. doi:10.1253/circj.cj-10-1281
5. Wald JJ. The effects of toxins on muscle. Neurol Clin. 2000;18(3):695-718. doi:10.1016/s0733-8619(05)70219-x
6. Hoffman KB, Kraus C, Dimbil M, Golomb BA. A survey of the FDA’s AERS database regarding muscle and tendon adverse events linked to the statin drug class. PLoS One. 2012;7(8):e42866. doi:10.1371/journal.pone.0042866
7. Sakaeda T, Kadoyama K, Okuno Y. Statin-associated muscular and renal adverse events: data mining of the public version of the FDA adverse event reporting system. PLoS One. 2011;6(12):e28124. doi:10.1371/journal.pone.0028124
8. Tiwari A. An overview of statin-associated proteinuria. Drug Discov Today. 2006;11(9-10):458-464. doi:10.1016/j.drudis.2006.03.017
9. Verhulst A, Sayer R, De Broe ME, D’Haese PC, Brown CD. Human proximal tubular epithelium actively secretes but does not retain rosuvastatin. Mol Pharmacol. 2008;74(4):1084-1091. doi:10.1124/mol.108.047647
10. Jones PH, Davidson MH, Stein EA, et al. Comparison of the efficacy and safety of rosuvastatin versus atorvastatin, simvastatin, and pravastatin across doses (STELLAR* Trial). Am J Cardiol. 2003;92(2):152-160. doi:10.1016/s0002-9149(03)00530-7
11. Wanner C, Krane V, März W, et al. Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis [published correction appears in N Engl J Med. 2005 Oct 13;353(15):1640]. N Engl J Med. 2005;353(3):238-248. doi:10.1056/NEJMoa043545
12. Fellström BC, Jardine AG, Schmieder RE, et al. Rosuvastatin and cardiovascular events in patients undergoing hemodialysis [published correction appears in N Engl J Med. 2010 Apr 15;362(15):1450]. N Engl J Med. 2009;360(14):1395-1407. doi:10.1056/NEJMoa0810177
13. Holdaas H, Holme I, Schmieder RE, et al. Rosuvastatin in diabetic hemodialysis patients. J Am Soc Nephrol. 2011;22(7):1335-1341. doi:10.1681/ASN.2010090987
14. Naci H, Brugts JJ, Fleurence R, Tsoi B, Toor H, Ades AE. Comparative benefits of statins in the primary and secondary prevention of major coronary events and all-cause mortality: a network meta-analysis of placebo-controlled and active-comparator trials. Eur J Prev Cardiol. 2013;20(4):641-657. doi:10.1177/2047487313480435
15. Alsheikh-Ali AA, Ambrose MS, Kuvin JT, Karas RH. The safety of rosuvastatin as used in common clinical practice: a postmarketing analysis. Circulation. 2005;111(23):3051-3057. doi:10.1161/CIRCULATIONAHA.105.555482
16. Ward NC, Watts GF, Eckel RH. Statin toxicity. Circ Res. 2019;124(2):328-350. doi:10.1161/CIRCRESAHA.118.312782
17. Selva-O’Callaghan A, Alvarado-Cardenas M, Pinal-Fernández I, et al. Statin-induced myalgia and myositis: an update on pathogenesis and clinical recommendations. Expert Rev Clin Immunol. 2018;14(3):215-224. doi:10.1080/1744666X.2018.1440206
18. Koslik HJ, Meskimen AH, Golomb BA. Physicians’ Experiences as patients with statin side effects: a case series. Drug Saf Case Rep. 2017;4(1):3. doi:10.1007/s40800-017-0045-0
Changing medications within a drug class requires considering the indication and dosage, possible adverse effects, and drug-drug interactions.
Changing medications within a drug class requires considering the indication and dosage, possible adverse effects, and drug-drug interactions.
Attention should be paid to changing a tolerated medication to another within its class. Many drugs approved by the US Food and Drug Administration (FDA), have equivalent therapeutic properties as existing drugs. Rarely do such medications share the same potency and adverse effect (AE) profile.
Case Presentation
A 77-year-old man presented to the emergency department (ED) at the Raymond G. Murphy Medical Center in Albuquerque, New Mexico, with a 1-month history of progressive muscle weakness, which was so severe that he required assistance rising from chairs. The symptoms began when he switched from atorvastatin 40 mg daily to rosuvastatin 40 mg daily. A nephrology consultation was requested for an elevated plasma creatinine.
The patient reported strict adherence to his prescribed medications. In the days following the switch to rosuvastatin, he noticed that his urine turned black. He described the color as “like burnt coffee.” The color gradually cleared before his ED presentation. The patient stopped taking rosuvastatin the day prior to presentation and noted improvement of his symptoms. Review of symptoms was significant for lower extremity paresthesia and numbness the day he started rosuvastatin. He had no symptoms of decompensated heart failure and no recent exacerbations requiring alteration of his diuretic regimen.
The patient’s medical history was significant for traumatic brain injury with complex partial seizures, carpal tunnel syndrome, dyslipidemia, coronary artery disease with percutaneous intervention to the right coronary artery in the late 1990s, atrial fibrillation and ventricular tachycardia, status post implantable cardioverter defibrillator, heart failure with reduced ejection fraction (25%) attributed to ischemic cardiomyopathy, hypertension, lower urinary tract symptoms/prostatism, and previous bladder cancer. In the mid-1960s, the patient served in the US Army and had been deployed to South Korea. After the service, he worked for the local city government. He was retired for about 15 years. He reported no tobacco, alcohol, or recreational drug use and no tattoos. He did not require prior blood or blood product transfusions. None of his family members—parents, siblings, or children—had any history of kidney disease.
The patient’s outpatient medications included levetiracetam 750 mg twice daily, melatonin 9 mg at night, menthol 16%/methyl-salicylate 30% topically up to 4 times per day as needed, aspirin 81 mg once daily, fish oil 1000 mg twice daily, amiodarone 400 mg twice daily, hydralazine 20 mg 3 times daily, isosorbide mononitrate 60 mg daily, metoprolol succinate 100 mg daily, and tamsulosin 0.4 mg at night. His vital signs were stable: afebrile (97.5 ºF), normocardic (74 beats per minute), normotensive (118/78 mm Hg), and normoxic (98% on room air). On examination, he appeared elderly, somewhat frail, and chronically ill but in no acute distress. Affect was pleasant and appropriate, attention was high, and his thought process was logical. He had sparse, grey scalp hair. Extraocular movements were intact. Oral mucosa was pink and moist. His back was nontender, and there was no costovertebral tenderness bilaterally. The patient was in no respiratory distress, with a slightly hyperresonant chest to percussion bilaterally, very faint inspiratory basilar crepitant rales (that cleared with repeat inspiration), and was otherwise clear to auscultation throughout. An outline of an implanted pacemaker was evident on the chest under his left clavicle, with a laterally displaced apical impulse. The rate was normal and the rhythm was regular. Upper extremities demonstrated papyraceous skin but without cyanosis, clubbing, or edema. Radial pulses were slightly diminished. He had no lower extremity edema.
His laboratory values are provided in Table 1. Kidney function was stable months prior to admission. Of note, the blood urea nitrogen and plasma creatinine were increased from his baseline up to 47 and 5.89 mg/dL, respectively. The serum glutamic-oxaloacetic transaminase and serum glutamic pyruvic transaminase were 1051 U/L and 408 U/L, respectively. Plasma amylase and lipase levels also were elevated, 230 U/L and 892 U/L, respectively. Creatine kinase was 41,099 U/L. Urinalysis demonstrated a specific gravity of 1.017, pH of 5, and a large amount of blood (92 red blood cells/high power field).
A 12-lead electrocardiogram demonstrated a sinus rhythm, PR interval of 0.20 ms, narrow QRS with a leftward frontal axis deviation, R-transition between precordial leads V1 and V2, and flattening of the ST segments in III, V1-V3 (Figure 1). A portable chest X-ray demonstrated clear lung fields, no evidence of effusion in the costophrenic area. Ultrasonography was conducted at the time of the examination (Figure 2). The kidneys were smoothly contoured, each measuring > 10 cm; there was an exophytic cyst on the left. Otherwise, the cortices, perhaps slightly echogenic, did not appear diminished. The bladder was not abnormally enlarged.
Rosuvastatin-induced rhabdomyolysis, pancreatitis, transaminitis, and drug-induced acute kidney injury were considered high among the diagnostic differentials. The 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase inhibitor was stopped, and he was prescribed an acute renal insufficiency diet. All laboratory parameters improved with this change (Figure 3). Two months after presentation (and with rosuvastatin added to his list of adverse reactions), all symptoms resolved and his plasma creatinine reached a nadir of 1.22 mg/dL.
Discussion
Statin-class drugs inhibit the HMG-CoA reductase (Table 2). Upregulation of low-density lipoprotein cholesterol (LDL-C) receptors in the liver result in increased LDL-C uptake and cholesterol catabolism.1 Prescribed inhibitors of the HMG-CoA reductase—statins—are known to reduce mortality due to cardiovascular disease (CVD). Much like any other pharmaceutical agent with any measurable potency, HMG-CoA inhibitors can have AEs. Statin therapy has been associated with pancreatitis.2 Muscle toxicity is a complication of HMG-CoA reductase inhibitors, and statin-associated symptoms are a leading cause of nonadherence.3 Rosuvastatin had higher AE and drug reactions compared with that of atorvastatin and pitavastatin (35.6%, 8.7%, and 22.2%, respectively) in clinical trials for approval.4 We have reported concomitant adermatopathic dermatomyositis with statin-induced myopathy in a 48-year-old man from simvastatin (40 to 80 mg daily).1
Toxin-induced myopathy should be considered early in the differential diagnosis of weakness.5 All HMG-CoA inhibitors have been associated with acute kidney injury, particularly at high doses and also are known to induce myopathies, sometimes with inclusion bodies.1 Muscle-related AEs correlate with the potency of an HMG-CoA reductase inhibitor according to an analysis using the FDA AE Reporting System (AERS).6 Myalgia and rhabdomyolysis are well-known AEs of this class of medications. Furthermore, type II muscle atrophy—particularly in the proximal limb muscles—has been reported.5 Patients may have difficulty rising from chairs.1 Rosuvastatin had the strongest signal for muscular AEs (eg, myalgia, rhabdomyolysis, increased creatine phosphokinase level) from an FDA analysis of AERS.7
Rosuvastatin is the only HMG-CoA reductase inhibitor that causes dose-dependent increases in proteinuria and hematuria (Figure 4).8 Rosuvastatin at a 5-mg dose may induce 4 times the proteinuria as a placebo. Typically, other statins potentially reduce proteinuria (without hematuria). Proteinuria may be induced by rosuvastatin even at low doses.8 Proteinuria is attributed to how rosuvastatin impacts proximal tubular function.9 The drug is transported into the proximal tubule by the organic anion transporter-3. Acute kidney injury has been associated with several statins, including rosuvastatin.7,10 This may be associated with denuded tubular epithelia, active urinary sediment, acute tubular toxicity, vacuolated epithelial cells, and tubular cell casts. Unlike atorvastatin, the increase in proteinuria and hematuria also is dose dependent.
In patients with renal insufficiency (short of end-stage renal disease [ESRD]), most statins other than rosuvastatin are well tolerated and recommended for reduction of overall and CVD mortality risk. However, these benefits seem to diminish once ESRD is reached. Atorvastatin did not impact CVD mortality in patients with type 2 diabetes mellitus (T2DM) and ESRD (despite decreasing LDL-C).11 The AURORA study randomized 10 mg of statin vs placebo in 2776 maintenance dialysis patients aged 50 to 80 years. Rosuvastatin lowered the LDL-C but did not affect all-cause mortality (13.5 vs 14.0 events per 100 patient-years). Patients randomized to rosuvastatin had more than twice as many unclassified strokes (9 vs 4). Rosuvastatin, although efficacious in reducing LDL-C, had no impact on CVD mortality, nonfatal myocardial infarction, or nonfatal stroke.12 Post hoc analysis demonstrated that in patients with T2DM with ESRD the hazard ratio for hemorrhagic stroke was 5.2.13
Rosuvastatin ranked lower than lovastatin, pravastatin, simvastatin, atorvastatin, and fluvastatin with respect to reduction of all-cause mortality in trials of participants with or without prior coronary artery disease.14 AEs, such as rhabdomyolysis, proteinuria, nephropathy, renal failure, liver, and muscle toxicity are higher with rosuvastatin than other medications in its class.15
Conclusions
For patients with existing CVD, standard clinical practice is to encourage increased and regular physical activity, cholesterol-lowering diets, weight loss, and smoking cessation. Hypertension should be treated. Glycemia should be well controlled in the setting of T2DM. β-blockers may be beneficial in those with histories of myocardial infarction or heart failure with reduced systolic function. Statins are a valuable tool in the treatment of dyslipidemia.
Statin-induced muscle symptoms are a major reason for discontinuation and nonadherence.16 Statin-induced myalgia, myositis, and myopathy have been used interchangeably.17 Rhabdomyolysis, myalgia, increased creatine kinase, statin myopathy, and immune-mediated necrotizing myopathy are among the clinical phenotypes caused by statins.17 There are 33,695 serious cases—1808 deaths—reported with rosuvastatin in the FDA AERS as of June 30, 2021. Myalgia, pain in extremity, muscle spasms, pain, and arthralgia top the list of AEs. When statin-induced symptoms occur, adherence is rarely improved by dismissive clinicians.18
Drugs in the same class often have common therapeutic properties. Potencies and AE profiles are seldom uniform. The decision to add or change the brand of medication within a class should be balanced with considerations for the indication, duplications, simplification, AEs, appropriate dosage, and drug-drug interactions.
Acknowledgments
Brent Wagner is funded by a US Department of Veterans Affairs Merit Award (I01 BX001958), a National Institutes of Health R01 grant (DK-102085), Dialysis Clinic, Inc., and partially supported by the University of New Mexico Brain and Behavioral Health Institute (BBHI 2018-1008, 2020-21-002) and in part by the University of New Mexico’s Signature Program in Cardiovascular and Metabolic Disease (CVMD); and the University of New Mexico School of Medicine Research Allocation Committee (C-2459-RAC, New Mexico Medical Trust). Brent Wagner is an Associate Member to the University of New Mexico Health Sciences Center Autophagy, Inflammation, and Metabolism Center of Biomedical Research Excellence (AIM CoBRE) supported by NIH grant P20GM121176.
Funding
National Institutes of Health Grant R01 DK-102085, Dialysis Clinic Inc., VA Merit Award I01 BX001958, Center for Integrated Nanotechnologies User Agreement 2019AU0120, Brain & Behavioral Health Institute (grants 2018-1008, 2020-21-002), University of New Mexico’s Signature Program in Cardiovascular and Metabolic Disease (CVMD), the University of New Mexico School of Medicine Research Allocation Committee (C-2459-RAC, New Mexico Medical Trust) and a metabolomics voucher from the AIM Center (NIH P20GM121176).
Attention should be paid to changing a tolerated medication to another within its class. Many drugs approved by the US Food and Drug Administration (FDA), have equivalent therapeutic properties as existing drugs. Rarely do such medications share the same potency and adverse effect (AE) profile.
Case Presentation
A 77-year-old man presented to the emergency department (ED) at the Raymond G. Murphy Medical Center in Albuquerque, New Mexico, with a 1-month history of progressive muscle weakness, which was so severe that he required assistance rising from chairs. The symptoms began when he switched from atorvastatin 40 mg daily to rosuvastatin 40 mg daily. A nephrology consultation was requested for an elevated plasma creatinine.
The patient reported strict adherence to his prescribed medications. In the days following the switch to rosuvastatin, he noticed that his urine turned black. He described the color as “like burnt coffee.” The color gradually cleared before his ED presentation. The patient stopped taking rosuvastatin the day prior to presentation and noted improvement of his symptoms. Review of symptoms was significant for lower extremity paresthesia and numbness the day he started rosuvastatin. He had no symptoms of decompensated heart failure and no recent exacerbations requiring alteration of his diuretic regimen.
The patient’s medical history was significant for traumatic brain injury with complex partial seizures, carpal tunnel syndrome, dyslipidemia, coronary artery disease with percutaneous intervention to the right coronary artery in the late 1990s, atrial fibrillation and ventricular tachycardia, status post implantable cardioverter defibrillator, heart failure with reduced ejection fraction (25%) attributed to ischemic cardiomyopathy, hypertension, lower urinary tract symptoms/prostatism, and previous bladder cancer. In the mid-1960s, the patient served in the US Army and had been deployed to South Korea. After the service, he worked for the local city government. He was retired for about 15 years. He reported no tobacco, alcohol, or recreational drug use and no tattoos. He did not require prior blood or blood product transfusions. None of his family members—parents, siblings, or children—had any history of kidney disease.
The patient’s outpatient medications included levetiracetam 750 mg twice daily, melatonin 9 mg at night, menthol 16%/methyl-salicylate 30% topically up to 4 times per day as needed, aspirin 81 mg once daily, fish oil 1000 mg twice daily, amiodarone 400 mg twice daily, hydralazine 20 mg 3 times daily, isosorbide mononitrate 60 mg daily, metoprolol succinate 100 mg daily, and tamsulosin 0.4 mg at night. His vital signs were stable: afebrile (97.5 ºF), normocardic (74 beats per minute), normotensive (118/78 mm Hg), and normoxic (98% on room air). On examination, he appeared elderly, somewhat frail, and chronically ill but in no acute distress. Affect was pleasant and appropriate, attention was high, and his thought process was logical. He had sparse, grey scalp hair. Extraocular movements were intact. Oral mucosa was pink and moist. His back was nontender, and there was no costovertebral tenderness bilaterally. The patient was in no respiratory distress, with a slightly hyperresonant chest to percussion bilaterally, very faint inspiratory basilar crepitant rales (that cleared with repeat inspiration), and was otherwise clear to auscultation throughout. An outline of an implanted pacemaker was evident on the chest under his left clavicle, with a laterally displaced apical impulse. The rate was normal and the rhythm was regular. Upper extremities demonstrated papyraceous skin but without cyanosis, clubbing, or edema. Radial pulses were slightly diminished. He had no lower extremity edema.
His laboratory values are provided in Table 1. Kidney function was stable months prior to admission. Of note, the blood urea nitrogen and plasma creatinine were increased from his baseline up to 47 and 5.89 mg/dL, respectively. The serum glutamic-oxaloacetic transaminase and serum glutamic pyruvic transaminase were 1051 U/L and 408 U/L, respectively. Plasma amylase and lipase levels also were elevated, 230 U/L and 892 U/L, respectively. Creatine kinase was 41,099 U/L. Urinalysis demonstrated a specific gravity of 1.017, pH of 5, and a large amount of blood (92 red blood cells/high power field).
A 12-lead electrocardiogram demonstrated a sinus rhythm, PR interval of 0.20 ms, narrow QRS with a leftward frontal axis deviation, R-transition between precordial leads V1 and V2, and flattening of the ST segments in III, V1-V3 (Figure 1). A portable chest X-ray demonstrated clear lung fields, no evidence of effusion in the costophrenic area. Ultrasonography was conducted at the time of the examination (Figure 2). The kidneys were smoothly contoured, each measuring > 10 cm; there was an exophytic cyst on the left. Otherwise, the cortices, perhaps slightly echogenic, did not appear diminished. The bladder was not abnormally enlarged.
Rosuvastatin-induced rhabdomyolysis, pancreatitis, transaminitis, and drug-induced acute kidney injury were considered high among the diagnostic differentials. The 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase inhibitor was stopped, and he was prescribed an acute renal insufficiency diet. All laboratory parameters improved with this change (Figure 3). Two months after presentation (and with rosuvastatin added to his list of adverse reactions), all symptoms resolved and his plasma creatinine reached a nadir of 1.22 mg/dL.
Discussion
Statin-class drugs inhibit the HMG-CoA reductase (Table 2). Upregulation of low-density lipoprotein cholesterol (LDL-C) receptors in the liver result in increased LDL-C uptake and cholesterol catabolism.1 Prescribed inhibitors of the HMG-CoA reductase—statins—are known to reduce mortality due to cardiovascular disease (CVD). Much like any other pharmaceutical agent with any measurable potency, HMG-CoA inhibitors can have AEs. Statin therapy has been associated with pancreatitis.2 Muscle toxicity is a complication of HMG-CoA reductase inhibitors, and statin-associated symptoms are a leading cause of nonadherence.3 Rosuvastatin had higher AE and drug reactions compared with that of atorvastatin and pitavastatin (35.6%, 8.7%, and 22.2%, respectively) in clinical trials for approval.4 We have reported concomitant adermatopathic dermatomyositis with statin-induced myopathy in a 48-year-old man from simvastatin (40 to 80 mg daily).1
Toxin-induced myopathy should be considered early in the differential diagnosis of weakness.5 All HMG-CoA inhibitors have been associated with acute kidney injury, particularly at high doses and also are known to induce myopathies, sometimes with inclusion bodies.1 Muscle-related AEs correlate with the potency of an HMG-CoA reductase inhibitor according to an analysis using the FDA AE Reporting System (AERS).6 Myalgia and rhabdomyolysis are well-known AEs of this class of medications. Furthermore, type II muscle atrophy—particularly in the proximal limb muscles—has been reported.5 Patients may have difficulty rising from chairs.1 Rosuvastatin had the strongest signal for muscular AEs (eg, myalgia, rhabdomyolysis, increased creatine phosphokinase level) from an FDA analysis of AERS.7
Rosuvastatin is the only HMG-CoA reductase inhibitor that causes dose-dependent increases in proteinuria and hematuria (Figure 4).8 Rosuvastatin at a 5-mg dose may induce 4 times the proteinuria as a placebo. Typically, other statins potentially reduce proteinuria (without hematuria). Proteinuria may be induced by rosuvastatin even at low doses.8 Proteinuria is attributed to how rosuvastatin impacts proximal tubular function.9 The drug is transported into the proximal tubule by the organic anion transporter-3. Acute kidney injury has been associated with several statins, including rosuvastatin.7,10 This may be associated with denuded tubular epithelia, active urinary sediment, acute tubular toxicity, vacuolated epithelial cells, and tubular cell casts. Unlike atorvastatin, the increase in proteinuria and hematuria also is dose dependent.
In patients with renal insufficiency (short of end-stage renal disease [ESRD]), most statins other than rosuvastatin are well tolerated and recommended for reduction of overall and CVD mortality risk. However, these benefits seem to diminish once ESRD is reached. Atorvastatin did not impact CVD mortality in patients with type 2 diabetes mellitus (T2DM) and ESRD (despite decreasing LDL-C).11 The AURORA study randomized 10 mg of statin vs placebo in 2776 maintenance dialysis patients aged 50 to 80 years. Rosuvastatin lowered the LDL-C but did not affect all-cause mortality (13.5 vs 14.0 events per 100 patient-years). Patients randomized to rosuvastatin had more than twice as many unclassified strokes (9 vs 4). Rosuvastatin, although efficacious in reducing LDL-C, had no impact on CVD mortality, nonfatal myocardial infarction, or nonfatal stroke.12 Post hoc analysis demonstrated that in patients with T2DM with ESRD the hazard ratio for hemorrhagic stroke was 5.2.13
Rosuvastatin ranked lower than lovastatin, pravastatin, simvastatin, atorvastatin, and fluvastatin with respect to reduction of all-cause mortality in trials of participants with or without prior coronary artery disease.14 AEs, such as rhabdomyolysis, proteinuria, nephropathy, renal failure, liver, and muscle toxicity are higher with rosuvastatin than other medications in its class.15
Conclusions
For patients with existing CVD, standard clinical practice is to encourage increased and regular physical activity, cholesterol-lowering diets, weight loss, and smoking cessation. Hypertension should be treated. Glycemia should be well controlled in the setting of T2DM. β-blockers may be beneficial in those with histories of myocardial infarction or heart failure with reduced systolic function. Statins are a valuable tool in the treatment of dyslipidemia.
Statin-induced muscle symptoms are a major reason for discontinuation and nonadherence.16 Statin-induced myalgia, myositis, and myopathy have been used interchangeably.17 Rhabdomyolysis, myalgia, increased creatine kinase, statin myopathy, and immune-mediated necrotizing myopathy are among the clinical phenotypes caused by statins.17 There are 33,695 serious cases—1808 deaths—reported with rosuvastatin in the FDA AERS as of June 30, 2021. Myalgia, pain in extremity, muscle spasms, pain, and arthralgia top the list of AEs. When statin-induced symptoms occur, adherence is rarely improved by dismissive clinicians.18
Drugs in the same class often have common therapeutic properties. Potencies and AE profiles are seldom uniform. The decision to add or change the brand of medication within a class should be balanced with considerations for the indication, duplications, simplification, AEs, appropriate dosage, and drug-drug interactions.
Acknowledgments
Brent Wagner is funded by a US Department of Veterans Affairs Merit Award (I01 BX001958), a National Institutes of Health R01 grant (DK-102085), Dialysis Clinic, Inc., and partially supported by the University of New Mexico Brain and Behavioral Health Institute (BBHI 2018-1008, 2020-21-002) and in part by the University of New Mexico’s Signature Program in Cardiovascular and Metabolic Disease (CVMD); and the University of New Mexico School of Medicine Research Allocation Committee (C-2459-RAC, New Mexico Medical Trust). Brent Wagner is an Associate Member to the University of New Mexico Health Sciences Center Autophagy, Inflammation, and Metabolism Center of Biomedical Research Excellence (AIM CoBRE) supported by NIH grant P20GM121176.
Funding
National Institutes of Health Grant R01 DK-102085, Dialysis Clinic Inc., VA Merit Award I01 BX001958, Center for Integrated Nanotechnologies User Agreement 2019AU0120, Brain & Behavioral Health Institute (grants 2018-1008, 2020-21-002), University of New Mexico’s Signature Program in Cardiovascular and Metabolic Disease (CVMD), the University of New Mexico School of Medicine Research Allocation Committee (C-2459-RAC, New Mexico Medical Trust) and a metabolomics voucher from the AIM Center (NIH P20GM121176).
1. Wagner B, Kagan-Hallet KS, Russell IJ. Concomitant presentation of adermatopathic dermatomyositis, statin myopathy, fibromyalgia syndrome, piriformis muscle myofascial pain and diabetic neuropathy. J Musculoskeletal Pain. 2003;11(2):25-30. doi:10.1300/J094v11n02_05
2. Collins R, Reith C, Emberson J, et al. Interpretation of the evidence for the efficacy and safety of statin therapy [published correction appears in Lancet. 2017 Feb 11;389(10069):602]. Lancet. 2016;388(10059):2532-2561. doi:10.1016/S0140-6736(16)31357-5
3. Stroes ES, Thompson PD, Corsini A, et al. Statin-associated muscle symptoms: impact on statin therapy-European Atherosclerosis Society Consensus Panel Statement on Assessment, Aetiology and Management. Eur Heart J. 2015;36(17):1012-1022. doi:10.1093/eurheartj/ehv043
4. Saku K, Zhang B, Noda K; PATROL Trial Investigators. Randomized head-to-head comparison of pitavastatin, atorvastatin, and rosuvastatin for safety and efficacy (quantity and quality of LDL): the PATROL trial. Circ J. 2011;75(6):1493-1505. doi:10.1253/circj.cj-10-1281
5. Wald JJ. The effects of toxins on muscle. Neurol Clin. 2000;18(3):695-718. doi:10.1016/s0733-8619(05)70219-x
6. Hoffman KB, Kraus C, Dimbil M, Golomb BA. A survey of the FDA’s AERS database regarding muscle and tendon adverse events linked to the statin drug class. PLoS One. 2012;7(8):e42866. doi:10.1371/journal.pone.0042866
7. Sakaeda T, Kadoyama K, Okuno Y. Statin-associated muscular and renal adverse events: data mining of the public version of the FDA adverse event reporting system. PLoS One. 2011;6(12):e28124. doi:10.1371/journal.pone.0028124
8. Tiwari A. An overview of statin-associated proteinuria. Drug Discov Today. 2006;11(9-10):458-464. doi:10.1016/j.drudis.2006.03.017
9. Verhulst A, Sayer R, De Broe ME, D’Haese PC, Brown CD. Human proximal tubular epithelium actively secretes but does not retain rosuvastatin. Mol Pharmacol. 2008;74(4):1084-1091. doi:10.1124/mol.108.047647
10. Jones PH, Davidson MH, Stein EA, et al. Comparison of the efficacy and safety of rosuvastatin versus atorvastatin, simvastatin, and pravastatin across doses (STELLAR* Trial). Am J Cardiol. 2003;92(2):152-160. doi:10.1016/s0002-9149(03)00530-7
11. Wanner C, Krane V, März W, et al. Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis [published correction appears in N Engl J Med. 2005 Oct 13;353(15):1640]. N Engl J Med. 2005;353(3):238-248. doi:10.1056/NEJMoa043545
12. Fellström BC, Jardine AG, Schmieder RE, et al. Rosuvastatin and cardiovascular events in patients undergoing hemodialysis [published correction appears in N Engl J Med. 2010 Apr 15;362(15):1450]. N Engl J Med. 2009;360(14):1395-1407. doi:10.1056/NEJMoa0810177
13. Holdaas H, Holme I, Schmieder RE, et al. Rosuvastatin in diabetic hemodialysis patients. J Am Soc Nephrol. 2011;22(7):1335-1341. doi:10.1681/ASN.2010090987
14. Naci H, Brugts JJ, Fleurence R, Tsoi B, Toor H, Ades AE. Comparative benefits of statins in the primary and secondary prevention of major coronary events and all-cause mortality: a network meta-analysis of placebo-controlled and active-comparator trials. Eur J Prev Cardiol. 2013;20(4):641-657. doi:10.1177/2047487313480435
15. Alsheikh-Ali AA, Ambrose MS, Kuvin JT, Karas RH. The safety of rosuvastatin as used in common clinical practice: a postmarketing analysis. Circulation. 2005;111(23):3051-3057. doi:10.1161/CIRCULATIONAHA.105.555482
16. Ward NC, Watts GF, Eckel RH. Statin toxicity. Circ Res. 2019;124(2):328-350. doi:10.1161/CIRCRESAHA.118.312782
17. Selva-O’Callaghan A, Alvarado-Cardenas M, Pinal-Fernández I, et al. Statin-induced myalgia and myositis: an update on pathogenesis and clinical recommendations. Expert Rev Clin Immunol. 2018;14(3):215-224. doi:10.1080/1744666X.2018.1440206
18. Koslik HJ, Meskimen AH, Golomb BA. Physicians’ Experiences as patients with statin side effects: a case series. Drug Saf Case Rep. 2017;4(1):3. doi:10.1007/s40800-017-0045-0
1. Wagner B, Kagan-Hallet KS, Russell IJ. Concomitant presentation of adermatopathic dermatomyositis, statin myopathy, fibromyalgia syndrome, piriformis muscle myofascial pain and diabetic neuropathy. J Musculoskeletal Pain. 2003;11(2):25-30. doi:10.1300/J094v11n02_05
2. Collins R, Reith C, Emberson J, et al. Interpretation of the evidence for the efficacy and safety of statin therapy [published correction appears in Lancet. 2017 Feb 11;389(10069):602]. Lancet. 2016;388(10059):2532-2561. doi:10.1016/S0140-6736(16)31357-5
3. Stroes ES, Thompson PD, Corsini A, et al. Statin-associated muscle symptoms: impact on statin therapy-European Atherosclerosis Society Consensus Panel Statement on Assessment, Aetiology and Management. Eur Heart J. 2015;36(17):1012-1022. doi:10.1093/eurheartj/ehv043
4. Saku K, Zhang B, Noda K; PATROL Trial Investigators. Randomized head-to-head comparison of pitavastatin, atorvastatin, and rosuvastatin for safety and efficacy (quantity and quality of LDL): the PATROL trial. Circ J. 2011;75(6):1493-1505. doi:10.1253/circj.cj-10-1281
5. Wald JJ. The effects of toxins on muscle. Neurol Clin. 2000;18(3):695-718. doi:10.1016/s0733-8619(05)70219-x
6. Hoffman KB, Kraus C, Dimbil M, Golomb BA. A survey of the FDA’s AERS database regarding muscle and tendon adverse events linked to the statin drug class. PLoS One. 2012;7(8):e42866. doi:10.1371/journal.pone.0042866
7. Sakaeda T, Kadoyama K, Okuno Y. Statin-associated muscular and renal adverse events: data mining of the public version of the FDA adverse event reporting system. PLoS One. 2011;6(12):e28124. doi:10.1371/journal.pone.0028124
8. Tiwari A. An overview of statin-associated proteinuria. Drug Discov Today. 2006;11(9-10):458-464. doi:10.1016/j.drudis.2006.03.017
9. Verhulst A, Sayer R, De Broe ME, D’Haese PC, Brown CD. Human proximal tubular epithelium actively secretes but does not retain rosuvastatin. Mol Pharmacol. 2008;74(4):1084-1091. doi:10.1124/mol.108.047647
10. Jones PH, Davidson MH, Stein EA, et al. Comparison of the efficacy and safety of rosuvastatin versus atorvastatin, simvastatin, and pravastatin across doses (STELLAR* Trial). Am J Cardiol. 2003;92(2):152-160. doi:10.1016/s0002-9149(03)00530-7
11. Wanner C, Krane V, März W, et al. Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis [published correction appears in N Engl J Med. 2005 Oct 13;353(15):1640]. N Engl J Med. 2005;353(3):238-248. doi:10.1056/NEJMoa043545
12. Fellström BC, Jardine AG, Schmieder RE, et al. Rosuvastatin and cardiovascular events in patients undergoing hemodialysis [published correction appears in N Engl J Med. 2010 Apr 15;362(15):1450]. N Engl J Med. 2009;360(14):1395-1407. doi:10.1056/NEJMoa0810177
13. Holdaas H, Holme I, Schmieder RE, et al. Rosuvastatin in diabetic hemodialysis patients. J Am Soc Nephrol. 2011;22(7):1335-1341. doi:10.1681/ASN.2010090987
14. Naci H, Brugts JJ, Fleurence R, Tsoi B, Toor H, Ades AE. Comparative benefits of statins in the primary and secondary prevention of major coronary events and all-cause mortality: a network meta-analysis of placebo-controlled and active-comparator trials. Eur J Prev Cardiol. 2013;20(4):641-657. doi:10.1177/2047487313480435
15. Alsheikh-Ali AA, Ambrose MS, Kuvin JT, Karas RH. The safety of rosuvastatin as used in common clinical practice: a postmarketing analysis. Circulation. 2005;111(23):3051-3057. doi:10.1161/CIRCULATIONAHA.105.555482
16. Ward NC, Watts GF, Eckel RH. Statin toxicity. Circ Res. 2019;124(2):328-350. doi:10.1161/CIRCRESAHA.118.312782
17. Selva-O’Callaghan A, Alvarado-Cardenas M, Pinal-Fernández I, et al. Statin-induced myalgia and myositis: an update on pathogenesis and clinical recommendations. Expert Rev Clin Immunol. 2018;14(3):215-224. doi:10.1080/1744666X.2018.1440206
18. Koslik HJ, Meskimen AH, Golomb BA. Physicians’ Experiences as patients with statin side effects: a case series. Drug Saf Case Rep. 2017;4(1):3. doi:10.1007/s40800-017-0045-0
Pfizer seeks EUA expansion for COVID-19 booster
Pfizer and its European partner BioNTech on Nov. 9 asked the U.S. government to expand emergency use authorization (EUA) to allow everybody over 18 to receive their COVID-19 booster shots.
If the request is approved, He announced the goal last August but backed off after some scientists said younger people may not need boosters, especially with large parts of the world unvaccinated.
Pfizer is submitting a study of booster effects on 10,000 people to make its case, according to The Associated Press.
This would be Pfizer’s second attempt. In September, a Food and Drug Administration advisory panel turned down Pfizer’s idea of booster shots for everybody over 18.
However, the committee recommended Pfizer booster shots for people 65 and over, essential workers, and people with underlying health conditions.
The FDA and the Centers for Disease Control and Prevention authorized the Pfizer booster for those other groups and later authorization was granted for the same groups with Moderna and Johnson & Johnson boosters. People who got the two-shot Pfizer or Moderna vaccines should get a booster 6 months after the second dose and people who got the one-dose J&J vaccine should get a booster 2 months later.
The pro-booster argument has strengthened because new data have come in from Israel that confirm boosters provide protection as vaccine effectiveness wanes over time, The Washington Post reported. Also, health officials are worried about a post-holiday surge and because COVID-19 case counts and deaths are not dropping in every part of the country, though they are declining overall, according to the The Post report.
The regulatory path for a booster-for-all application is unclear. The Post, citing two unnamed officials, said the FDA probably won’t send the Pfizer application to the FDA advisory committee this time because the committee has already had extensive discussions about boosters. If the FDA gives the green light, CDC Director Rochelle Walensky, MD, would have to make updated recommendations on boosters, The Post article noted.
A version of this article first appeared on WebMD.com.
Pfizer and its European partner BioNTech on Nov. 9 asked the U.S. government to expand emergency use authorization (EUA) to allow everybody over 18 to receive their COVID-19 booster shots.
If the request is approved, He announced the goal last August but backed off after some scientists said younger people may not need boosters, especially with large parts of the world unvaccinated.
Pfizer is submitting a study of booster effects on 10,000 people to make its case, according to The Associated Press.
This would be Pfizer’s second attempt. In September, a Food and Drug Administration advisory panel turned down Pfizer’s idea of booster shots for everybody over 18.
However, the committee recommended Pfizer booster shots for people 65 and over, essential workers, and people with underlying health conditions.
The FDA and the Centers for Disease Control and Prevention authorized the Pfizer booster for those other groups and later authorization was granted for the same groups with Moderna and Johnson & Johnson boosters. People who got the two-shot Pfizer or Moderna vaccines should get a booster 6 months after the second dose and people who got the one-dose J&J vaccine should get a booster 2 months later.
The pro-booster argument has strengthened because new data have come in from Israel that confirm boosters provide protection as vaccine effectiveness wanes over time, The Washington Post reported. Also, health officials are worried about a post-holiday surge and because COVID-19 case counts and deaths are not dropping in every part of the country, though they are declining overall, according to the The Post report.
The regulatory path for a booster-for-all application is unclear. The Post, citing two unnamed officials, said the FDA probably won’t send the Pfizer application to the FDA advisory committee this time because the committee has already had extensive discussions about boosters. If the FDA gives the green light, CDC Director Rochelle Walensky, MD, would have to make updated recommendations on boosters, The Post article noted.
A version of this article first appeared on WebMD.com.
Pfizer and its European partner BioNTech on Nov. 9 asked the U.S. government to expand emergency use authorization (EUA) to allow everybody over 18 to receive their COVID-19 booster shots.
If the request is approved, He announced the goal last August but backed off after some scientists said younger people may not need boosters, especially with large parts of the world unvaccinated.
Pfizer is submitting a study of booster effects on 10,000 people to make its case, according to The Associated Press.
This would be Pfizer’s second attempt. In September, a Food and Drug Administration advisory panel turned down Pfizer’s idea of booster shots for everybody over 18.
However, the committee recommended Pfizer booster shots for people 65 and over, essential workers, and people with underlying health conditions.
The FDA and the Centers for Disease Control and Prevention authorized the Pfizer booster for those other groups and later authorization was granted for the same groups with Moderna and Johnson & Johnson boosters. People who got the two-shot Pfizer or Moderna vaccines should get a booster 6 months after the second dose and people who got the one-dose J&J vaccine should get a booster 2 months later.
The pro-booster argument has strengthened because new data have come in from Israel that confirm boosters provide protection as vaccine effectiveness wanes over time, The Washington Post reported. Also, health officials are worried about a post-holiday surge and because COVID-19 case counts and deaths are not dropping in every part of the country, though they are declining overall, according to the The Post report.
The regulatory path for a booster-for-all application is unclear. The Post, citing two unnamed officials, said the FDA probably won’t send the Pfizer application to the FDA advisory committee this time because the committee has already had extensive discussions about boosters. If the FDA gives the green light, CDC Director Rochelle Walensky, MD, would have to make updated recommendations on boosters, The Post article noted.
A version of this article first appeared on WebMD.com.
Gastric cancer prevalent in hereditary breast cancer patients
a prospective cohort study has shown.
“In short, what we are putting forward with these data is that pathogenic/likely pathogenic (P/LP) variants in the CDH1 gene confer a very high risk, at the very least, of occult early-stage gastric cancer in patients with HLBC,” said Jeremy Davis, MD, of the surgical oncology program, Center for Cancer Research at the National Cancer Institute.
“So patients that are referred to as ‘HLBC’ due to a CDH1 variant should at least undergo annual endoscopic surveillance but the real questions is whether or not they should also consider prophylactic total gastrectomy – as many patients in our study did,” he said.
The study, which was published online Oct. 13, 2021, in JAMA Surgery, included a cohort of 151 families totaling 283 patients with a CDH1 pathogenic or likely pathogenic (P/LP) variant. Analyses were conducted on three patient groups, which included those with HLBC and a family history of breast cancer but no gastric cancer, those with hereditary diffuse gastric cancer (HDGC) but no history of breast cancer, and those with a family history of both gastric and breast cancer in the mixed group. Of these, 15.5% had a history of HLBC, 16.2% had a history of HDGC, and 52.6% made up the mixed group.
“We examined the HLBC group with specific attention to CDH1 genotype and prevalence of occult gastric cancer,” the authors explained. The group consisted of 31 families with 19 CDH1 variants, 10 of which were also present in the HDGC and mixed groups.
Among this group of patients, almost 73% underwent one or more surveillance endoscopies and on endoscopy, occult signet ring cell carcinoma was detected in over one-third of patients.
The median age at the time of endoscopic carcinoma detection was only 33 years.
“Nearly all of the patients with HLBC (93.8%) ... who elected for risk-reducing total gastrectomy owing to their underlying CDH1 P/LP variant harbored occult signet ring cell gastric adenocarcinoma on final pathology,” investigators observed.
The median age at the time patients elected to undergo total gastrectomy was 50 years.
The prevalence of occult gastric cancer among asymptomatic patients in the HDGC group was similarly high, affecting almost 95% of this group of patients.
Some 18 out of 19 CDH1 P/LP variants were responsible for this high prevalence of occult gastric cancer, as the investigators pointed out.
“Hereditary cancer risk is informed by the presence of a germline gene variant more so than by family history of cancer,” the authors stressed. “[And we found that] germline CDH1 P/LP variants appear to have a highly penetrant gastric phenotype irrespective of family history.”
Given this finding, the authors stressed that it is “paramount” patients previously assigned a diagnosis of HLBC not be excluded from undergoing gastric cancer risk assessment and counseling.
Furthermore, “the mere presence of a germline CDH1 P/LP variant, regardless of family history, may be reason enough to consider prophylactic total gastrectomy,” the authors wrote.
Limitations of the study included the fact that the disease phenotype was established from family pedigrees which has the potential for recall bias by family members.
The study was supported in part by the Intramural Research Program of the National Cancer Institute. None of the authors had conflicts of interest to disclose.
a prospective cohort study has shown.
“In short, what we are putting forward with these data is that pathogenic/likely pathogenic (P/LP) variants in the CDH1 gene confer a very high risk, at the very least, of occult early-stage gastric cancer in patients with HLBC,” said Jeremy Davis, MD, of the surgical oncology program, Center for Cancer Research at the National Cancer Institute.
“So patients that are referred to as ‘HLBC’ due to a CDH1 variant should at least undergo annual endoscopic surveillance but the real questions is whether or not they should also consider prophylactic total gastrectomy – as many patients in our study did,” he said.
The study, which was published online Oct. 13, 2021, in JAMA Surgery, included a cohort of 151 families totaling 283 patients with a CDH1 pathogenic or likely pathogenic (P/LP) variant. Analyses were conducted on three patient groups, which included those with HLBC and a family history of breast cancer but no gastric cancer, those with hereditary diffuse gastric cancer (HDGC) but no history of breast cancer, and those with a family history of both gastric and breast cancer in the mixed group. Of these, 15.5% had a history of HLBC, 16.2% had a history of HDGC, and 52.6% made up the mixed group.
“We examined the HLBC group with specific attention to CDH1 genotype and prevalence of occult gastric cancer,” the authors explained. The group consisted of 31 families with 19 CDH1 variants, 10 of which were also present in the HDGC and mixed groups.
Among this group of patients, almost 73% underwent one or more surveillance endoscopies and on endoscopy, occult signet ring cell carcinoma was detected in over one-third of patients.
The median age at the time of endoscopic carcinoma detection was only 33 years.
“Nearly all of the patients with HLBC (93.8%) ... who elected for risk-reducing total gastrectomy owing to their underlying CDH1 P/LP variant harbored occult signet ring cell gastric adenocarcinoma on final pathology,” investigators observed.
The median age at the time patients elected to undergo total gastrectomy was 50 years.
The prevalence of occult gastric cancer among asymptomatic patients in the HDGC group was similarly high, affecting almost 95% of this group of patients.
Some 18 out of 19 CDH1 P/LP variants were responsible for this high prevalence of occult gastric cancer, as the investigators pointed out.
“Hereditary cancer risk is informed by the presence of a germline gene variant more so than by family history of cancer,” the authors stressed. “[And we found that] germline CDH1 P/LP variants appear to have a highly penetrant gastric phenotype irrespective of family history.”
Given this finding, the authors stressed that it is “paramount” patients previously assigned a diagnosis of HLBC not be excluded from undergoing gastric cancer risk assessment and counseling.
Furthermore, “the mere presence of a germline CDH1 P/LP variant, regardless of family history, may be reason enough to consider prophylactic total gastrectomy,” the authors wrote.
Limitations of the study included the fact that the disease phenotype was established from family pedigrees which has the potential for recall bias by family members.
The study was supported in part by the Intramural Research Program of the National Cancer Institute. None of the authors had conflicts of interest to disclose.
a prospective cohort study has shown.
“In short, what we are putting forward with these data is that pathogenic/likely pathogenic (P/LP) variants in the CDH1 gene confer a very high risk, at the very least, of occult early-stage gastric cancer in patients with HLBC,” said Jeremy Davis, MD, of the surgical oncology program, Center for Cancer Research at the National Cancer Institute.
“So patients that are referred to as ‘HLBC’ due to a CDH1 variant should at least undergo annual endoscopic surveillance but the real questions is whether or not they should also consider prophylactic total gastrectomy – as many patients in our study did,” he said.
The study, which was published online Oct. 13, 2021, in JAMA Surgery, included a cohort of 151 families totaling 283 patients with a CDH1 pathogenic or likely pathogenic (P/LP) variant. Analyses were conducted on three patient groups, which included those with HLBC and a family history of breast cancer but no gastric cancer, those with hereditary diffuse gastric cancer (HDGC) but no history of breast cancer, and those with a family history of both gastric and breast cancer in the mixed group. Of these, 15.5% had a history of HLBC, 16.2% had a history of HDGC, and 52.6% made up the mixed group.
“We examined the HLBC group with specific attention to CDH1 genotype and prevalence of occult gastric cancer,” the authors explained. The group consisted of 31 families with 19 CDH1 variants, 10 of which were also present in the HDGC and mixed groups.
Among this group of patients, almost 73% underwent one or more surveillance endoscopies and on endoscopy, occult signet ring cell carcinoma was detected in over one-third of patients.
The median age at the time of endoscopic carcinoma detection was only 33 years.
“Nearly all of the patients with HLBC (93.8%) ... who elected for risk-reducing total gastrectomy owing to their underlying CDH1 P/LP variant harbored occult signet ring cell gastric adenocarcinoma on final pathology,” investigators observed.
The median age at the time patients elected to undergo total gastrectomy was 50 years.
The prevalence of occult gastric cancer among asymptomatic patients in the HDGC group was similarly high, affecting almost 95% of this group of patients.
Some 18 out of 19 CDH1 P/LP variants were responsible for this high prevalence of occult gastric cancer, as the investigators pointed out.
“Hereditary cancer risk is informed by the presence of a germline gene variant more so than by family history of cancer,” the authors stressed. “[And we found that] germline CDH1 P/LP variants appear to have a highly penetrant gastric phenotype irrespective of family history.”
Given this finding, the authors stressed that it is “paramount” patients previously assigned a diagnosis of HLBC not be excluded from undergoing gastric cancer risk assessment and counseling.
Furthermore, “the mere presence of a germline CDH1 P/LP variant, regardless of family history, may be reason enough to consider prophylactic total gastrectomy,” the authors wrote.
Limitations of the study included the fact that the disease phenotype was established from family pedigrees which has the potential for recall bias by family members.
The study was supported in part by the Intramural Research Program of the National Cancer Institute. None of the authors had conflicts of interest to disclose.
FROM JAMA SURGERY
Chemotherapy with FOLFOX superior to TACE in liver cancer
Hepatic arterial infusion chemotherapy (HAIC) with FOLFOX led to superior patient outcomes and less toxicity than standard of care transarterial chemoembolization (TACE) for patients with large, unresectable hepatocellular carcinoma (HCC), a randomized, phase 3 trial has shown.
In a group of 315 patients with unresectable tumors at least 7 cm in diameter and no macrovascular invasion or extrahepatic spread, overall survival (OS) was 42% longer at 23.1 months for patients treated with FOLFOX-HAIC, compared with 16.1 months for TACE, at a hazard ratio of 0.58 (P < .001), Ming Shi, MD, Sun Yat-sen University, Guangzhou, China, and colleagues reported recently in the Journal of Clinical Oncology.
Similarly, median progression-free survival (PFS) was also longer for FOLFOX-HAIC patients at 9.6 months, compared with 5.4 months for TACE patients, as was median symptomatic PFS at 17.9 months, compared with 10.4 months, respectively (P < .001).
The frequency of grade 3-4 elevated liver ALT at 8% versus 19% (P = .005), elevated AST at 18% versus 28%, and hyperbilirubinemia at 1% versus 6% (P = .01) were all significantly higher in the TACE group than in the FOLFOX-HAIC group as was the overall incidence of serious adverse events at 30% versus 19%, respectively (P = .03).
The frequency of treatment delay and discontinuation of TACE because of adverse events were also higher than that in the FOLFOX-HAIC group.
“Transarterial chemoembolization (TACE) is the current standard of care for intermediate-stage hepatocellular carcinoma ... but the efficacy of TACE is largely dependent upon tumor size ... and for patients with particularly large tumors (>7 cm), the OS after TACE is only 11.2-13.2 months,” Dr. Shi and colleagues explained.
“Although the need for technical expertise may limit its generalizability, hepatic arterial infusion chemotherapy represents an appropriate frontline locoregional intervention in select patients with large unresectable hepatocellular carcinoma,” they observed.
TACE vs. HAIC
During TACE, a catheter was inserted into the celiac trunk or superior mesenteric artery for arteriography, after which a microcatheter was selectively placed into the feeding arteries of the tumors.
“Chemolipiodolization was performed using 50 mg of epirubicin and 50 mg of lobaplatin mixed with lipiodol,” the investigators noted, and subsequent embolization was done with the injection of polyvinyl alcohol particles.
TACE was repeated every 6 weeks.
HAIC in turn was divided into 3-week cycles during which a microcatheter was advanced into the hepatic artery on day 1 of each treatment cycle and FOLFOX was infused via the hepatic artery. FOLFOX consisted of oxaliplatin, 130 mg/m2; leucovorin, 400 mg/m2; and fluorouracil, 400 mg/m2, all given on day 1.
Subgroup analyses showed that HAIC provided a clinical benefit for PFS in most subgroups except females; those with a Child-Pug score of 6, and those who were negative for HBV.
The main drawback to the FOLFOX-HAIC regimen appears to be abdominal pain which some patients experienced when oxaliplatin was injected but which subsequently resolved when the injection was stopped.
As the authors pointed out, the overall response rate at 46% among patients treated with FOLFOX-HAIC was more than twice that with TACE at 18%.
“One possible reason is that FOLFOX-HAIC can provide stable local high concentrations of the chemotherapy agents in the tumor for more than 24 hours,” they speculated, “whereas most chemotherapeutic agents delivered through TACE ... will be released into the systemic circulation within less than 1 hour.”
Recently, drugs such as atezolizumab (Tecentriq, Roche) plus bevacizumab (Avastin, Genentech) have been shown to lead to high response rates in intermediate-stage HCC, as shown by the IMbrave 150 study.
“Therefore, in some latest practice guidelines and expert consensus statements, a switch of first-line treatment modality from TACE to systemic treatment is proposed for these patients,” the researchers noted.
Limitations of the study include its open-label design and the fact that more patients in the FOLFOX-HAIC group underwent hepatic resection whereas more patients in the TACE group crossed over to the other treatment arm.
Dr. Shi declared no conflicts of interest.
Hepatic arterial infusion chemotherapy (HAIC) with FOLFOX led to superior patient outcomes and less toxicity than standard of care transarterial chemoembolization (TACE) for patients with large, unresectable hepatocellular carcinoma (HCC), a randomized, phase 3 trial has shown.
In a group of 315 patients with unresectable tumors at least 7 cm in diameter and no macrovascular invasion or extrahepatic spread, overall survival (OS) was 42% longer at 23.1 months for patients treated with FOLFOX-HAIC, compared with 16.1 months for TACE, at a hazard ratio of 0.58 (P < .001), Ming Shi, MD, Sun Yat-sen University, Guangzhou, China, and colleagues reported recently in the Journal of Clinical Oncology.
Similarly, median progression-free survival (PFS) was also longer for FOLFOX-HAIC patients at 9.6 months, compared with 5.4 months for TACE patients, as was median symptomatic PFS at 17.9 months, compared with 10.4 months, respectively (P < .001).
The frequency of grade 3-4 elevated liver ALT at 8% versus 19% (P = .005), elevated AST at 18% versus 28%, and hyperbilirubinemia at 1% versus 6% (P = .01) were all significantly higher in the TACE group than in the FOLFOX-HAIC group as was the overall incidence of serious adverse events at 30% versus 19%, respectively (P = .03).
The frequency of treatment delay and discontinuation of TACE because of adverse events were also higher than that in the FOLFOX-HAIC group.
“Transarterial chemoembolization (TACE) is the current standard of care for intermediate-stage hepatocellular carcinoma ... but the efficacy of TACE is largely dependent upon tumor size ... and for patients with particularly large tumors (>7 cm), the OS after TACE is only 11.2-13.2 months,” Dr. Shi and colleagues explained.
“Although the need for technical expertise may limit its generalizability, hepatic arterial infusion chemotherapy represents an appropriate frontline locoregional intervention in select patients with large unresectable hepatocellular carcinoma,” they observed.
TACE vs. HAIC
During TACE, a catheter was inserted into the celiac trunk or superior mesenteric artery for arteriography, after which a microcatheter was selectively placed into the feeding arteries of the tumors.
“Chemolipiodolization was performed using 50 mg of epirubicin and 50 mg of lobaplatin mixed with lipiodol,” the investigators noted, and subsequent embolization was done with the injection of polyvinyl alcohol particles.
TACE was repeated every 6 weeks.
HAIC in turn was divided into 3-week cycles during which a microcatheter was advanced into the hepatic artery on day 1 of each treatment cycle and FOLFOX was infused via the hepatic artery. FOLFOX consisted of oxaliplatin, 130 mg/m2; leucovorin, 400 mg/m2; and fluorouracil, 400 mg/m2, all given on day 1.
Subgroup analyses showed that HAIC provided a clinical benefit for PFS in most subgroups except females; those with a Child-Pug score of 6, and those who were negative for HBV.
The main drawback to the FOLFOX-HAIC regimen appears to be abdominal pain which some patients experienced when oxaliplatin was injected but which subsequently resolved when the injection was stopped.
As the authors pointed out, the overall response rate at 46% among patients treated with FOLFOX-HAIC was more than twice that with TACE at 18%.
“One possible reason is that FOLFOX-HAIC can provide stable local high concentrations of the chemotherapy agents in the tumor for more than 24 hours,” they speculated, “whereas most chemotherapeutic agents delivered through TACE ... will be released into the systemic circulation within less than 1 hour.”
Recently, drugs such as atezolizumab (Tecentriq, Roche) plus bevacizumab (Avastin, Genentech) have been shown to lead to high response rates in intermediate-stage HCC, as shown by the IMbrave 150 study.
“Therefore, in some latest practice guidelines and expert consensus statements, a switch of first-line treatment modality from TACE to systemic treatment is proposed for these patients,” the researchers noted.
Limitations of the study include its open-label design and the fact that more patients in the FOLFOX-HAIC group underwent hepatic resection whereas more patients in the TACE group crossed over to the other treatment arm.
Dr. Shi declared no conflicts of interest.
Hepatic arterial infusion chemotherapy (HAIC) with FOLFOX led to superior patient outcomes and less toxicity than standard of care transarterial chemoembolization (TACE) for patients with large, unresectable hepatocellular carcinoma (HCC), a randomized, phase 3 trial has shown.
In a group of 315 patients with unresectable tumors at least 7 cm in diameter and no macrovascular invasion or extrahepatic spread, overall survival (OS) was 42% longer at 23.1 months for patients treated with FOLFOX-HAIC, compared with 16.1 months for TACE, at a hazard ratio of 0.58 (P < .001), Ming Shi, MD, Sun Yat-sen University, Guangzhou, China, and colleagues reported recently in the Journal of Clinical Oncology.
Similarly, median progression-free survival (PFS) was also longer for FOLFOX-HAIC patients at 9.6 months, compared with 5.4 months for TACE patients, as was median symptomatic PFS at 17.9 months, compared with 10.4 months, respectively (P < .001).
The frequency of grade 3-4 elevated liver ALT at 8% versus 19% (P = .005), elevated AST at 18% versus 28%, and hyperbilirubinemia at 1% versus 6% (P = .01) were all significantly higher in the TACE group than in the FOLFOX-HAIC group as was the overall incidence of serious adverse events at 30% versus 19%, respectively (P = .03).
The frequency of treatment delay and discontinuation of TACE because of adverse events were also higher than that in the FOLFOX-HAIC group.
“Transarterial chemoembolization (TACE) is the current standard of care for intermediate-stage hepatocellular carcinoma ... but the efficacy of TACE is largely dependent upon tumor size ... and for patients with particularly large tumors (>7 cm), the OS after TACE is only 11.2-13.2 months,” Dr. Shi and colleagues explained.
“Although the need for technical expertise may limit its generalizability, hepatic arterial infusion chemotherapy represents an appropriate frontline locoregional intervention in select patients with large unresectable hepatocellular carcinoma,” they observed.
TACE vs. HAIC
During TACE, a catheter was inserted into the celiac trunk or superior mesenteric artery for arteriography, after which a microcatheter was selectively placed into the feeding arteries of the tumors.
“Chemolipiodolization was performed using 50 mg of epirubicin and 50 mg of lobaplatin mixed with lipiodol,” the investigators noted, and subsequent embolization was done with the injection of polyvinyl alcohol particles.
TACE was repeated every 6 weeks.
HAIC in turn was divided into 3-week cycles during which a microcatheter was advanced into the hepatic artery on day 1 of each treatment cycle and FOLFOX was infused via the hepatic artery. FOLFOX consisted of oxaliplatin, 130 mg/m2; leucovorin, 400 mg/m2; and fluorouracil, 400 mg/m2, all given on day 1.
Subgroup analyses showed that HAIC provided a clinical benefit for PFS in most subgroups except females; those with a Child-Pug score of 6, and those who were negative for HBV.
The main drawback to the FOLFOX-HAIC regimen appears to be abdominal pain which some patients experienced when oxaliplatin was injected but which subsequently resolved when the injection was stopped.
As the authors pointed out, the overall response rate at 46% among patients treated with FOLFOX-HAIC was more than twice that with TACE at 18%.
“One possible reason is that FOLFOX-HAIC can provide stable local high concentrations of the chemotherapy agents in the tumor for more than 24 hours,” they speculated, “whereas most chemotherapeutic agents delivered through TACE ... will be released into the systemic circulation within less than 1 hour.”
Recently, drugs such as atezolizumab (Tecentriq, Roche) plus bevacizumab (Avastin, Genentech) have been shown to lead to high response rates in intermediate-stage HCC, as shown by the IMbrave 150 study.
“Therefore, in some latest practice guidelines and expert consensus statements, a switch of first-line treatment modality from TACE to systemic treatment is proposed for these patients,” the researchers noted.
Limitations of the study include its open-label design and the fact that more patients in the FOLFOX-HAIC group underwent hepatic resection whereas more patients in the TACE group crossed over to the other treatment arm.
Dr. Shi declared no conflicts of interest.
FROM THE JOURNAL OF CLINICAL ONCOLOGY
Success in closing racial survival gap in lung and breast cancer
When barriers to completing radiation therapy were identified and addressed in a cohort of patients with early-stage lung and breast cancer, 5-year survival rates improved for all patients and closed the racial disparity gap, researchers reported at the annual meeting of the American Society for Radiation Oncology (ASTRO).
The findings come from the ACCURE clinical trial. This is the first prospective study designed to erase gaps in cancer treatment completion and survival among Black and White patient populations, explained lead author Matthew A. Manning, MD, a radiation oncologist and chief of oncology at Cone Health in Greensboro, N.C.
“Thousands of studies have looked at racial disparities in health care, but until recently, very few studies have implemented interventions to eliminate those disparities,” he said.
“This study shows that the implementation of ‘systems-change’ can eliminate racial disparities in cancer survival while improving survival for all,” he added.
“These results add to a growing body of evidence that health care disparities in cancer outcomes are eliminated or minimized by providing supportive, timely, and guideline-directed care,” said Lannis Hall, MD, MPH, director of radiation oncology, Siteman Cancer Center, and associate professor of radiation oncology at Washington University School of Medicine, St. Louis, who was approached for comment
“This research supports that access to care and timely treatment completion is critical to eliminating health care disparities,” she told this news organization. The system-based intervention in this trial was designed to reduce treatment delays and provide a supportive matrix for patients confronting real-world difficulties like transportation issues, childcare complications, and work absence, she explained.
Eliminating racial disparities
Previous findings from the ACCURE trial showed that it eliminated Black-White disparities in treatment completion rates, which was the study’s primary endpoint (Cancer Med. 2019;8:1095-1102). “It also improved treatment for all patients,” said Dr. Manning. “The current study is a follow-up on the survival of eligible patients treated during the ACCURE enrollment as compared to historical data.”
ACCURE was a multi-institutional trial designed to test a community-created intervention to reduce racial disparities. The intervention involved multiple changes to the way patients were supported while receiving cancer treatment and had four components:
- an electronic health record with automatic alerts to flag missed appointments or unmet milestones in expected care
- a nurse navigator trained in race-specific barriers to help patients overcome obstacles to care when alerts are flagged
- a physician champion to engage health care teams with race-related feedback on treatment completion
- regular health equity education training sessions for staff
The cohort was comprised of 1,413 patients with lung and breast cancer (stage 0-II) who were diagnosed from 2013-2015, and survival was compared to historical cases – 2,016 patients who had been treated from 2007-2011.
The results showed a significant improvement in survival for both Black and White patients with breast and lung cancer over time, and the racial gap in survival was reduced.
The 5-year survival rate for breast cancer increased from 91% for White patients and 89% in Black patients in historical cases, to 94% for both during the study period.
For patients with lung cancer, the 5-year survival rate improved from 43% in White patients and 37% in Black patients to 56% and 54%, respectively.
A subgroup analysis showed that patients with lung cancer who underwent surgery had 5-year survival rates of 78.5% for White and 70.1% for Black patients, whereas for those who underwent stereotactic body radiation therapy (SBRT) the rates were 41.9% and 50% respectively.
“We’ve shown it’s possible to eliminate disparities in cancer treatment completion and that this change has the potential to close cancer survival gaps downstream,” said Dr. Manning. “But we think the application can be much broader.”
The ACCURE study was sponsored by the National Institutes of Health. Dr. Manning and Dr. Hall have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
When barriers to completing radiation therapy were identified and addressed in a cohort of patients with early-stage lung and breast cancer, 5-year survival rates improved for all patients and closed the racial disparity gap, researchers reported at the annual meeting of the American Society for Radiation Oncology (ASTRO).
The findings come from the ACCURE clinical trial. This is the first prospective study designed to erase gaps in cancer treatment completion and survival among Black and White patient populations, explained lead author Matthew A. Manning, MD, a radiation oncologist and chief of oncology at Cone Health in Greensboro, N.C.
“Thousands of studies have looked at racial disparities in health care, but until recently, very few studies have implemented interventions to eliminate those disparities,” he said.
“This study shows that the implementation of ‘systems-change’ can eliminate racial disparities in cancer survival while improving survival for all,” he added.
“These results add to a growing body of evidence that health care disparities in cancer outcomes are eliminated or minimized by providing supportive, timely, and guideline-directed care,” said Lannis Hall, MD, MPH, director of radiation oncology, Siteman Cancer Center, and associate professor of radiation oncology at Washington University School of Medicine, St. Louis, who was approached for comment
“This research supports that access to care and timely treatment completion is critical to eliminating health care disparities,” she told this news organization. The system-based intervention in this trial was designed to reduce treatment delays and provide a supportive matrix for patients confronting real-world difficulties like transportation issues, childcare complications, and work absence, she explained.
Eliminating racial disparities
Previous findings from the ACCURE trial showed that it eliminated Black-White disparities in treatment completion rates, which was the study’s primary endpoint (Cancer Med. 2019;8:1095-1102). “It also improved treatment for all patients,” said Dr. Manning. “The current study is a follow-up on the survival of eligible patients treated during the ACCURE enrollment as compared to historical data.”
ACCURE was a multi-institutional trial designed to test a community-created intervention to reduce racial disparities. The intervention involved multiple changes to the way patients were supported while receiving cancer treatment and had four components:
- an electronic health record with automatic alerts to flag missed appointments or unmet milestones in expected care
- a nurse navigator trained in race-specific barriers to help patients overcome obstacles to care when alerts are flagged
- a physician champion to engage health care teams with race-related feedback on treatment completion
- regular health equity education training sessions for staff
The cohort was comprised of 1,413 patients with lung and breast cancer (stage 0-II) who were diagnosed from 2013-2015, and survival was compared to historical cases – 2,016 patients who had been treated from 2007-2011.
The results showed a significant improvement in survival for both Black and White patients with breast and lung cancer over time, and the racial gap in survival was reduced.
The 5-year survival rate for breast cancer increased from 91% for White patients and 89% in Black patients in historical cases, to 94% for both during the study period.
For patients with lung cancer, the 5-year survival rate improved from 43% in White patients and 37% in Black patients to 56% and 54%, respectively.
A subgroup analysis showed that patients with lung cancer who underwent surgery had 5-year survival rates of 78.5% for White and 70.1% for Black patients, whereas for those who underwent stereotactic body radiation therapy (SBRT) the rates were 41.9% and 50% respectively.
“We’ve shown it’s possible to eliminate disparities in cancer treatment completion and that this change has the potential to close cancer survival gaps downstream,” said Dr. Manning. “But we think the application can be much broader.”
The ACCURE study was sponsored by the National Institutes of Health. Dr. Manning and Dr. Hall have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
When barriers to completing radiation therapy were identified and addressed in a cohort of patients with early-stage lung and breast cancer, 5-year survival rates improved for all patients and closed the racial disparity gap, researchers reported at the annual meeting of the American Society for Radiation Oncology (ASTRO).
The findings come from the ACCURE clinical trial. This is the first prospective study designed to erase gaps in cancer treatment completion and survival among Black and White patient populations, explained lead author Matthew A. Manning, MD, a radiation oncologist and chief of oncology at Cone Health in Greensboro, N.C.
“Thousands of studies have looked at racial disparities in health care, but until recently, very few studies have implemented interventions to eliminate those disparities,” he said.
“This study shows that the implementation of ‘systems-change’ can eliminate racial disparities in cancer survival while improving survival for all,” he added.
“These results add to a growing body of evidence that health care disparities in cancer outcomes are eliminated or minimized by providing supportive, timely, and guideline-directed care,” said Lannis Hall, MD, MPH, director of radiation oncology, Siteman Cancer Center, and associate professor of radiation oncology at Washington University School of Medicine, St. Louis, who was approached for comment
“This research supports that access to care and timely treatment completion is critical to eliminating health care disparities,” she told this news organization. The system-based intervention in this trial was designed to reduce treatment delays and provide a supportive matrix for patients confronting real-world difficulties like transportation issues, childcare complications, and work absence, she explained.
Eliminating racial disparities
Previous findings from the ACCURE trial showed that it eliminated Black-White disparities in treatment completion rates, which was the study’s primary endpoint (Cancer Med. 2019;8:1095-1102). “It also improved treatment for all patients,” said Dr. Manning. “The current study is a follow-up on the survival of eligible patients treated during the ACCURE enrollment as compared to historical data.”
ACCURE was a multi-institutional trial designed to test a community-created intervention to reduce racial disparities. The intervention involved multiple changes to the way patients were supported while receiving cancer treatment and had four components:
- an electronic health record with automatic alerts to flag missed appointments or unmet milestones in expected care
- a nurse navigator trained in race-specific barriers to help patients overcome obstacles to care when alerts are flagged
- a physician champion to engage health care teams with race-related feedback on treatment completion
- regular health equity education training sessions for staff
The cohort was comprised of 1,413 patients with lung and breast cancer (stage 0-II) who were diagnosed from 2013-2015, and survival was compared to historical cases – 2,016 patients who had been treated from 2007-2011.
The results showed a significant improvement in survival for both Black and White patients with breast and lung cancer over time, and the racial gap in survival was reduced.
The 5-year survival rate for breast cancer increased from 91% for White patients and 89% in Black patients in historical cases, to 94% for both during the study period.
For patients with lung cancer, the 5-year survival rate improved from 43% in White patients and 37% in Black patients to 56% and 54%, respectively.
A subgroup analysis showed that patients with lung cancer who underwent surgery had 5-year survival rates of 78.5% for White and 70.1% for Black patients, whereas for those who underwent stereotactic body radiation therapy (SBRT) the rates were 41.9% and 50% respectively.
“We’ve shown it’s possible to eliminate disparities in cancer treatment completion and that this change has the potential to close cancer survival gaps downstream,” said Dr. Manning. “But we think the application can be much broader.”
The ACCURE study was sponsored by the National Institutes of Health. Dr. Manning and Dr. Hall have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM ASTRO 2021
What does it mean to be a trustworthy male ally?
“If you want to be trusted, be trustworthy” – Stephen Covey
A few years ago, while working in my office, a female colleague stopped by for a casual chat. During the course of the conversation, she noticed that I did not have any diplomas or certificates hanging on my office walls. Instead, there were clusters of pictures drawn by my children, family photos, and a white board with my “to-do” list. The only wall art was a print of Banksy’s “The Thinker Monkey,” which depicts a monkey with its fist to its chin similar to Rodin’s famous sculpture, “Le Penseur.”
When asked why I didn’t hang any diplomas or awards, I replied that I preferred to keep my office atmosphere light and fun, and to focus on future goals rather than past accomplishments. I could see her jaw tense. Her frustration appeared deep, but it was for reasons beyond just my self-righteous tone. She said, “You know, I appreciate your focus on future goals, but it’s a pretty privileged position to not have to worry about sharing your accomplishments publicly.”
What followed was a discussion that was generative, enlightening, uncomfortable, and necessary. I had never considered what I chose to hang (or not hang) on my office walls as a privilege, and that was exactly the point. She described numerous episodes when her accomplishments were overlooked or (worse) attributed to a male colleague because she was a woman. I began to understand that graceful self-promotion is not optional for many women in medicine, it is a necessary skill.
This is just one example of how my privilege as a male in medicine contributed to my ignorance of the gender inequities that my female coworkers have faced throughout their careers. My colleague showed a lot of grace by taking the time to help me navigate my male privilege in a constructive manner. I decided to learn more about gender inequities, and eventually determined that I was woefully inadequate as a male ally, not by refusal but by ignorance. I wanted to start earning my colleague’s trust that I would be an ally that she could count on.
Trustworthiness
I wanted to be a trustworthy ally, but what does that entail? Perhaps we can learn from medical education. Trust is a complex construct that is increasingly used as a framework for assessing medical students and residents, such as with entrustable professional activities (EPAs).1,2 Multiple studies have examined the characteristics that make a learner “trustworthy” when determining how much supervision is required.3-8 Ten Cate and Chen performed an interpretivist, narrative review to synthesize the medical education literature on learner trustworthiness in the past 15 years,9 developing five major themes that contribute to trustworthiness: Humility, Capability, Agency, Reliability, and Integrity. Let’s examine each of these through the lens of male allyship.
Humility
Humility involves knowing one’s limits, asking for help, and being receptive to feedback.9 The first thing men need to do is to put their egos in check and recognize that women do not need rescuing; they need partnership. Systemic inequities have led to men holding the majority of leadership positions and significant sociopolitical capital, and correcting these inequities is more feasible when those in leadership and positions of power contribute. Women don’t need knights in shining armor, they need collaborative activism.
Humility also means a willingness to admit fallibility and to ask for help. Men often don’t know what they don’t know (see my foibles in the opening). As David G. Smith, PhD, and W. Brad Johnson, PhD, write in their book, “Good Guys,” “There are no perfect allies. As you work to become a better ally for the women around you, you will undoubtedly make a mistake.”10 Men must accept feedback on their shortcomings as allies without feeling as though they are losing their sociopolitical standing. Allyship for women does not mean there is a devaluing of men. We must escape a “zero-sum” mindset. Mistakes are where growth happens, but only if we approach our missteps with humility.
Capability
Capability entails having the necessary knowledge, skills, and attitudes to be a strong ally. Allyship is not intuitive for most men for several reasons. Many men do not experience the same biases or systemic inequities that women do, and therefore perceive them less frequently. I want to acknowledge that men can be victims of other systemic biases such as those against one’s race, ethnicity, gender identity, sexual orientation, religion, or any number of factors. Men who face inequities for these other reasons may be more cognizant of the biases women face. Even so, allyship is a skill that few men have been explicitly taught. Even if taught, few standard or organized mechanisms for feedback on allyship capability exist. How, then, can men become capable allies?
Just like in medical education, men must become self-directed learners who seek to build capability and receive feedback on their performance as allies. Men should seek allyship training through local women-in-medicine programs or organizations, or through the increasing number of national education options such as the recent ADVANCE PHM Gender Equity Symposium. As with learning any skill, men should go to the literature, seeking knowledge from experts in the field. I recommend starting with “Good Guys: How Men Can Be Better Allies for Women in the Workplace10 or “Athena Rising: How and Why Men Should Mentor Women.”11 Both books, by Dr. Smith and Dr. Johnson, are great entry points into the gender allyship literature. Seek out other resources from local experts on gender equity and allyship. Both aforementioned books were recommended to me by a friend and gender equity expert; without her guidance I would not have known where to start.
Agency
Agency involves being proactive and engaged rather than passive or apathetic. Men must be enthusiastic allies who seek out opportunities to mentor and sponsor women rather than waiting for others to ask. Agency requires being curious and passionate about improving. Most men in medicine are not openly and explicitly misogynistic or sexist, but many are only passive when it comes to gender equity and allyship. Trustworthy allyship entails turning passive support into active change. Not sure how to start? A good first step is to ask female colleagues questions such as, “What can I do to be a better ally for you in the workplace?” or “What are some things at work that are most challenging to you, but I might not notice because I’m a man?” Curiosity is the springboard toward agency.
Reliability
Reliability means being conscientious, accountable, and doing what we say we will do. Nothing undermines trustworthiness faster than making a commitment and not following through. Allyship cannot be a show or an attempt to get public plaudits. It is a longitudinal commitment to supporting women through individual mentorship and sponsorship, and to work toward institutional and systems change.
Reliability also means taking an equitable approach to what Dr. Smith and Dr. Johnson call “office housework.” They define this as “administrative work that is necessary but undervalued, unlikely to lead to promotion, and disproportionately assigned to women.”10 In medicine, these tasks include organizing meetings, taking notes, planning social events, and remembering to celebrate colleagues’ achievements and milestones. Men should take on more of these tasks and advocate for change when the distribution of office housework in their workplace is inequitably directed toward women.
Integrity
Integrity involves honesty, professionalism, and benevolence. It is about making the morally correct choice even if there is potential risk. When men see gender inequity, they have an obligation to speak up. Whether it is overtly misogynistic behavior, subtle sexism, use of gendered language, inequitable distribution of office housework, lack of inclusivity and recognition for women, or another form of inequity, men must act with integrity and make it clear that they are partnering with women for change. Integrity means being an ally even when women are not present, and advocating that women be “at the table” for important conversations.
Beyond the individual
Allyship cannot end with individual actions; systems changes that build trustworthy institutions are necessary. Organizational leaders must approach gender conversations with humility to critically examine inequities and agency to implement meaningful changes. Workplace cultures and institutional policies should be reviewed with an eye toward system-level integrity and reliability for promoting and supporting women. Ongoing faculty and staff development programs must provide men with the knowledge, skills, and attitudes (capability) to be strong allies. We have a long history of male-dominated institutions that are unfair or (worse) unsafe for women. Many systems are designed in a way that disadvantages women. These systems must be redesigned through an equity lens to start building trust with women in medicine.
Becoming trustworthy is a process
Even the best male allies have room to improve their trustworthiness. Many men (myself included) have a LOT of room to improve, but they should not get discouraged by the amount of ground to be gained. Steady, deliberate improvement in men’s humility, capability, agency, reliability, and integrity can build the foundation of trust with female colleagues. Trust takes time. It takes effort. It takes vulnerability. It is an ongoing, developmental process that requires deliberate practice, frequent reflection, and feedback from our female colleagues.
Dr. Kinnear is associate professor of internal medicine and pediatrics in the Division of Hospital Medicine at Cincinnati Children’s Hospital Medical Center and University of Cincinnati Medical Center. He is associate program director for the Med-Peds and Internal Medicine residency programs.
References
1. Ten Cate O. Nuts and bolts of entrustable professional activities. J Grad Med Educ. 2013 Mar;5(1):157-8. doi: 10.4300/JGME-D-12-00380.1.
2. Ten Cate O. Entrustment decisions: Bringing the patient into the assessment equation. Acad Med. 2017 Jun;92(6):736-8. doi: 10.1097/ACM.0000000000001623.
3. Kennedy TJT et al. Point-of-care assessment of medical trainee competence for independent clinical work. Acad Med. 2008 Oct;83(10 Suppl):S89-92. doi: 10.1097/ACM.0b013e318183c8b7.
4. Choo KJ et al. How do supervising physicians decide to entrust residents with unsupervised tasks? A qualitative analysis. J Hosp Med. 2014 Mar;9(3):169-75. doi: 10.1002/jhm.2150.
5. Hauer KE et al. How clinical supervisors develop trust in their trainees: A qualitative study. Med Educ. 2015 Aug;49(8):783-95. doi: 10.1111/medu.12745.
6. Sterkenburg A et al. When do supervising physicians decide to entrust residents with unsupervised tasks? Acad Med. 2010 Sep;85(9):1408-17. doi: 10.1097/ACM.0b013e3181eab0ec.
7. Sheu L et al. How supervisor experience influences trust, supervision, and trainee learning: A qualitative study. Acad Med. 2017 Sep;92(9):1320-7. doi: 10.1097/ACM.0000000000001560.
8. Pingree EW et al. Encouraging entrustment: A qualitative study of resident behaviors that promote entrustment. Acad Med. 2020 Nov;95(11):1718-25. doi: 10.1097/ACM.0000000000003487.
9. Ten Cate O, Chen HC. The ingredients of a rich entrustment decision. Med Teach. 2020 Dec;42(12):1413-20. doi: 10.1080/0142159X.2020.1817348.
10. Smith DG, Johnson WB. Good guys: How men can be better allies for women in the workplace: Harvard Business School Publishing Corporation 2020.
11. Johnson WB, Smith D. Athena rising: How and why men should mentor women: Routledge 2016.
“If you want to be trusted, be trustworthy” – Stephen Covey
A few years ago, while working in my office, a female colleague stopped by for a casual chat. During the course of the conversation, she noticed that I did not have any diplomas or certificates hanging on my office walls. Instead, there were clusters of pictures drawn by my children, family photos, and a white board with my “to-do” list. The only wall art was a print of Banksy’s “The Thinker Monkey,” which depicts a monkey with its fist to its chin similar to Rodin’s famous sculpture, “Le Penseur.”
When asked why I didn’t hang any diplomas or awards, I replied that I preferred to keep my office atmosphere light and fun, and to focus on future goals rather than past accomplishments. I could see her jaw tense. Her frustration appeared deep, but it was for reasons beyond just my self-righteous tone. She said, “You know, I appreciate your focus on future goals, but it’s a pretty privileged position to not have to worry about sharing your accomplishments publicly.”
What followed was a discussion that was generative, enlightening, uncomfortable, and necessary. I had never considered what I chose to hang (or not hang) on my office walls as a privilege, and that was exactly the point. She described numerous episodes when her accomplishments were overlooked or (worse) attributed to a male colleague because she was a woman. I began to understand that graceful self-promotion is not optional for many women in medicine, it is a necessary skill.
This is just one example of how my privilege as a male in medicine contributed to my ignorance of the gender inequities that my female coworkers have faced throughout their careers. My colleague showed a lot of grace by taking the time to help me navigate my male privilege in a constructive manner. I decided to learn more about gender inequities, and eventually determined that I was woefully inadequate as a male ally, not by refusal but by ignorance. I wanted to start earning my colleague’s trust that I would be an ally that she could count on.
Trustworthiness
I wanted to be a trustworthy ally, but what does that entail? Perhaps we can learn from medical education. Trust is a complex construct that is increasingly used as a framework for assessing medical students and residents, such as with entrustable professional activities (EPAs).1,2 Multiple studies have examined the characteristics that make a learner “trustworthy” when determining how much supervision is required.3-8 Ten Cate and Chen performed an interpretivist, narrative review to synthesize the medical education literature on learner trustworthiness in the past 15 years,9 developing five major themes that contribute to trustworthiness: Humility, Capability, Agency, Reliability, and Integrity. Let’s examine each of these through the lens of male allyship.
Humility
Humility involves knowing one’s limits, asking for help, and being receptive to feedback.9 The first thing men need to do is to put their egos in check and recognize that women do not need rescuing; they need partnership. Systemic inequities have led to men holding the majority of leadership positions and significant sociopolitical capital, and correcting these inequities is more feasible when those in leadership and positions of power contribute. Women don’t need knights in shining armor, they need collaborative activism.
Humility also means a willingness to admit fallibility and to ask for help. Men often don’t know what they don’t know (see my foibles in the opening). As David G. Smith, PhD, and W. Brad Johnson, PhD, write in their book, “Good Guys,” “There are no perfect allies. As you work to become a better ally for the women around you, you will undoubtedly make a mistake.”10 Men must accept feedback on their shortcomings as allies without feeling as though they are losing their sociopolitical standing. Allyship for women does not mean there is a devaluing of men. We must escape a “zero-sum” mindset. Mistakes are where growth happens, but only if we approach our missteps with humility.
Capability
Capability entails having the necessary knowledge, skills, and attitudes to be a strong ally. Allyship is not intuitive for most men for several reasons. Many men do not experience the same biases or systemic inequities that women do, and therefore perceive them less frequently. I want to acknowledge that men can be victims of other systemic biases such as those against one’s race, ethnicity, gender identity, sexual orientation, religion, or any number of factors. Men who face inequities for these other reasons may be more cognizant of the biases women face. Even so, allyship is a skill that few men have been explicitly taught. Even if taught, few standard or organized mechanisms for feedback on allyship capability exist. How, then, can men become capable allies?
Just like in medical education, men must become self-directed learners who seek to build capability and receive feedback on their performance as allies. Men should seek allyship training through local women-in-medicine programs or organizations, or through the increasing number of national education options such as the recent ADVANCE PHM Gender Equity Symposium. As with learning any skill, men should go to the literature, seeking knowledge from experts in the field. I recommend starting with “Good Guys: How Men Can Be Better Allies for Women in the Workplace10 or “Athena Rising: How and Why Men Should Mentor Women.”11 Both books, by Dr. Smith and Dr. Johnson, are great entry points into the gender allyship literature. Seek out other resources from local experts on gender equity and allyship. Both aforementioned books were recommended to me by a friend and gender equity expert; without her guidance I would not have known where to start.
Agency
Agency involves being proactive and engaged rather than passive or apathetic. Men must be enthusiastic allies who seek out opportunities to mentor and sponsor women rather than waiting for others to ask. Agency requires being curious and passionate about improving. Most men in medicine are not openly and explicitly misogynistic or sexist, but many are only passive when it comes to gender equity and allyship. Trustworthy allyship entails turning passive support into active change. Not sure how to start? A good first step is to ask female colleagues questions such as, “What can I do to be a better ally for you in the workplace?” or “What are some things at work that are most challenging to you, but I might not notice because I’m a man?” Curiosity is the springboard toward agency.
Reliability
Reliability means being conscientious, accountable, and doing what we say we will do. Nothing undermines trustworthiness faster than making a commitment and not following through. Allyship cannot be a show or an attempt to get public plaudits. It is a longitudinal commitment to supporting women through individual mentorship and sponsorship, and to work toward institutional and systems change.
Reliability also means taking an equitable approach to what Dr. Smith and Dr. Johnson call “office housework.” They define this as “administrative work that is necessary but undervalued, unlikely to lead to promotion, and disproportionately assigned to women.”10 In medicine, these tasks include organizing meetings, taking notes, planning social events, and remembering to celebrate colleagues’ achievements and milestones. Men should take on more of these tasks and advocate for change when the distribution of office housework in their workplace is inequitably directed toward women.
Integrity
Integrity involves honesty, professionalism, and benevolence. It is about making the morally correct choice even if there is potential risk. When men see gender inequity, they have an obligation to speak up. Whether it is overtly misogynistic behavior, subtle sexism, use of gendered language, inequitable distribution of office housework, lack of inclusivity and recognition for women, or another form of inequity, men must act with integrity and make it clear that they are partnering with women for change. Integrity means being an ally even when women are not present, and advocating that women be “at the table” for important conversations.
Beyond the individual
Allyship cannot end with individual actions; systems changes that build trustworthy institutions are necessary. Organizational leaders must approach gender conversations with humility to critically examine inequities and agency to implement meaningful changes. Workplace cultures and institutional policies should be reviewed with an eye toward system-level integrity and reliability for promoting and supporting women. Ongoing faculty and staff development programs must provide men with the knowledge, skills, and attitudes (capability) to be strong allies. We have a long history of male-dominated institutions that are unfair or (worse) unsafe for women. Many systems are designed in a way that disadvantages women. These systems must be redesigned through an equity lens to start building trust with women in medicine.
Becoming trustworthy is a process
Even the best male allies have room to improve their trustworthiness. Many men (myself included) have a LOT of room to improve, but they should not get discouraged by the amount of ground to be gained. Steady, deliberate improvement in men’s humility, capability, agency, reliability, and integrity can build the foundation of trust with female colleagues. Trust takes time. It takes effort. It takes vulnerability. It is an ongoing, developmental process that requires deliberate practice, frequent reflection, and feedback from our female colleagues.
Dr. Kinnear is associate professor of internal medicine and pediatrics in the Division of Hospital Medicine at Cincinnati Children’s Hospital Medical Center and University of Cincinnati Medical Center. He is associate program director for the Med-Peds and Internal Medicine residency programs.
References
1. Ten Cate O. Nuts and bolts of entrustable professional activities. J Grad Med Educ. 2013 Mar;5(1):157-8. doi: 10.4300/JGME-D-12-00380.1.
2. Ten Cate O. Entrustment decisions: Bringing the patient into the assessment equation. Acad Med. 2017 Jun;92(6):736-8. doi: 10.1097/ACM.0000000000001623.
3. Kennedy TJT et al. Point-of-care assessment of medical trainee competence for independent clinical work. Acad Med. 2008 Oct;83(10 Suppl):S89-92. doi: 10.1097/ACM.0b013e318183c8b7.
4. Choo KJ et al. How do supervising physicians decide to entrust residents with unsupervised tasks? A qualitative analysis. J Hosp Med. 2014 Mar;9(3):169-75. doi: 10.1002/jhm.2150.
5. Hauer KE et al. How clinical supervisors develop trust in their trainees: A qualitative study. Med Educ. 2015 Aug;49(8):783-95. doi: 10.1111/medu.12745.
6. Sterkenburg A et al. When do supervising physicians decide to entrust residents with unsupervised tasks? Acad Med. 2010 Sep;85(9):1408-17. doi: 10.1097/ACM.0b013e3181eab0ec.
7. Sheu L et al. How supervisor experience influences trust, supervision, and trainee learning: A qualitative study. Acad Med. 2017 Sep;92(9):1320-7. doi: 10.1097/ACM.0000000000001560.
8. Pingree EW et al. Encouraging entrustment: A qualitative study of resident behaviors that promote entrustment. Acad Med. 2020 Nov;95(11):1718-25. doi: 10.1097/ACM.0000000000003487.
9. Ten Cate O, Chen HC. The ingredients of a rich entrustment decision. Med Teach. 2020 Dec;42(12):1413-20. doi: 10.1080/0142159X.2020.1817348.
10. Smith DG, Johnson WB. Good guys: How men can be better allies for women in the workplace: Harvard Business School Publishing Corporation 2020.
11. Johnson WB, Smith D. Athena rising: How and why men should mentor women: Routledge 2016.
“If you want to be trusted, be trustworthy” – Stephen Covey
A few years ago, while working in my office, a female colleague stopped by for a casual chat. During the course of the conversation, she noticed that I did not have any diplomas or certificates hanging on my office walls. Instead, there were clusters of pictures drawn by my children, family photos, and a white board with my “to-do” list. The only wall art was a print of Banksy’s “The Thinker Monkey,” which depicts a monkey with its fist to its chin similar to Rodin’s famous sculpture, “Le Penseur.”
When asked why I didn’t hang any diplomas or awards, I replied that I preferred to keep my office atmosphere light and fun, and to focus on future goals rather than past accomplishments. I could see her jaw tense. Her frustration appeared deep, but it was for reasons beyond just my self-righteous tone. She said, “You know, I appreciate your focus on future goals, but it’s a pretty privileged position to not have to worry about sharing your accomplishments publicly.”
What followed was a discussion that was generative, enlightening, uncomfortable, and necessary. I had never considered what I chose to hang (or not hang) on my office walls as a privilege, and that was exactly the point. She described numerous episodes when her accomplishments were overlooked or (worse) attributed to a male colleague because she was a woman. I began to understand that graceful self-promotion is not optional for many women in medicine, it is a necessary skill.
This is just one example of how my privilege as a male in medicine contributed to my ignorance of the gender inequities that my female coworkers have faced throughout their careers. My colleague showed a lot of grace by taking the time to help me navigate my male privilege in a constructive manner. I decided to learn more about gender inequities, and eventually determined that I was woefully inadequate as a male ally, not by refusal but by ignorance. I wanted to start earning my colleague’s trust that I would be an ally that she could count on.
Trustworthiness
I wanted to be a trustworthy ally, but what does that entail? Perhaps we can learn from medical education. Trust is a complex construct that is increasingly used as a framework for assessing medical students and residents, such as with entrustable professional activities (EPAs).1,2 Multiple studies have examined the characteristics that make a learner “trustworthy” when determining how much supervision is required.3-8 Ten Cate and Chen performed an interpretivist, narrative review to synthesize the medical education literature on learner trustworthiness in the past 15 years,9 developing five major themes that contribute to trustworthiness: Humility, Capability, Agency, Reliability, and Integrity. Let’s examine each of these through the lens of male allyship.
Humility
Humility involves knowing one’s limits, asking for help, and being receptive to feedback.9 The first thing men need to do is to put their egos in check and recognize that women do not need rescuing; they need partnership. Systemic inequities have led to men holding the majority of leadership positions and significant sociopolitical capital, and correcting these inequities is more feasible when those in leadership and positions of power contribute. Women don’t need knights in shining armor, they need collaborative activism.
Humility also means a willingness to admit fallibility and to ask for help. Men often don’t know what they don’t know (see my foibles in the opening). As David G. Smith, PhD, and W. Brad Johnson, PhD, write in their book, “Good Guys,” “There are no perfect allies. As you work to become a better ally for the women around you, you will undoubtedly make a mistake.”10 Men must accept feedback on their shortcomings as allies without feeling as though they are losing their sociopolitical standing. Allyship for women does not mean there is a devaluing of men. We must escape a “zero-sum” mindset. Mistakes are where growth happens, but only if we approach our missteps with humility.
Capability
Capability entails having the necessary knowledge, skills, and attitudes to be a strong ally. Allyship is not intuitive for most men for several reasons. Many men do not experience the same biases or systemic inequities that women do, and therefore perceive them less frequently. I want to acknowledge that men can be victims of other systemic biases such as those against one’s race, ethnicity, gender identity, sexual orientation, religion, or any number of factors. Men who face inequities for these other reasons may be more cognizant of the biases women face. Even so, allyship is a skill that few men have been explicitly taught. Even if taught, few standard or organized mechanisms for feedback on allyship capability exist. How, then, can men become capable allies?
Just like in medical education, men must become self-directed learners who seek to build capability and receive feedback on their performance as allies. Men should seek allyship training through local women-in-medicine programs or organizations, or through the increasing number of national education options such as the recent ADVANCE PHM Gender Equity Symposium. As with learning any skill, men should go to the literature, seeking knowledge from experts in the field. I recommend starting with “Good Guys: How Men Can Be Better Allies for Women in the Workplace10 or “Athena Rising: How and Why Men Should Mentor Women.”11 Both books, by Dr. Smith and Dr. Johnson, are great entry points into the gender allyship literature. Seek out other resources from local experts on gender equity and allyship. Both aforementioned books were recommended to me by a friend and gender equity expert; without her guidance I would not have known where to start.
Agency
Agency involves being proactive and engaged rather than passive or apathetic. Men must be enthusiastic allies who seek out opportunities to mentor and sponsor women rather than waiting for others to ask. Agency requires being curious and passionate about improving. Most men in medicine are not openly and explicitly misogynistic or sexist, but many are only passive when it comes to gender equity and allyship. Trustworthy allyship entails turning passive support into active change. Not sure how to start? A good first step is to ask female colleagues questions such as, “What can I do to be a better ally for you in the workplace?” or “What are some things at work that are most challenging to you, but I might not notice because I’m a man?” Curiosity is the springboard toward agency.
Reliability
Reliability means being conscientious, accountable, and doing what we say we will do. Nothing undermines trustworthiness faster than making a commitment and not following through. Allyship cannot be a show or an attempt to get public plaudits. It is a longitudinal commitment to supporting women through individual mentorship and sponsorship, and to work toward institutional and systems change.
Reliability also means taking an equitable approach to what Dr. Smith and Dr. Johnson call “office housework.” They define this as “administrative work that is necessary but undervalued, unlikely to lead to promotion, and disproportionately assigned to women.”10 In medicine, these tasks include organizing meetings, taking notes, planning social events, and remembering to celebrate colleagues’ achievements and milestones. Men should take on more of these tasks and advocate for change when the distribution of office housework in their workplace is inequitably directed toward women.
Integrity
Integrity involves honesty, professionalism, and benevolence. It is about making the morally correct choice even if there is potential risk. When men see gender inequity, they have an obligation to speak up. Whether it is overtly misogynistic behavior, subtle sexism, use of gendered language, inequitable distribution of office housework, lack of inclusivity and recognition for women, or another form of inequity, men must act with integrity and make it clear that they are partnering with women for change. Integrity means being an ally even when women are not present, and advocating that women be “at the table” for important conversations.
Beyond the individual
Allyship cannot end with individual actions; systems changes that build trustworthy institutions are necessary. Organizational leaders must approach gender conversations with humility to critically examine inequities and agency to implement meaningful changes. Workplace cultures and institutional policies should be reviewed with an eye toward system-level integrity and reliability for promoting and supporting women. Ongoing faculty and staff development programs must provide men with the knowledge, skills, and attitudes (capability) to be strong allies. We have a long history of male-dominated institutions that are unfair or (worse) unsafe for women. Many systems are designed in a way that disadvantages women. These systems must be redesigned through an equity lens to start building trust with women in medicine.
Becoming trustworthy is a process
Even the best male allies have room to improve their trustworthiness. Many men (myself included) have a LOT of room to improve, but they should not get discouraged by the amount of ground to be gained. Steady, deliberate improvement in men’s humility, capability, agency, reliability, and integrity can build the foundation of trust with female colleagues. Trust takes time. It takes effort. It takes vulnerability. It is an ongoing, developmental process that requires deliberate practice, frequent reflection, and feedback from our female colleagues.
Dr. Kinnear is associate professor of internal medicine and pediatrics in the Division of Hospital Medicine at Cincinnati Children’s Hospital Medical Center and University of Cincinnati Medical Center. He is associate program director for the Med-Peds and Internal Medicine residency programs.
References
1. Ten Cate O. Nuts and bolts of entrustable professional activities. J Grad Med Educ. 2013 Mar;5(1):157-8. doi: 10.4300/JGME-D-12-00380.1.
2. Ten Cate O. Entrustment decisions: Bringing the patient into the assessment equation. Acad Med. 2017 Jun;92(6):736-8. doi: 10.1097/ACM.0000000000001623.
3. Kennedy TJT et al. Point-of-care assessment of medical trainee competence for independent clinical work. Acad Med. 2008 Oct;83(10 Suppl):S89-92. doi: 10.1097/ACM.0b013e318183c8b7.
4. Choo KJ et al. How do supervising physicians decide to entrust residents with unsupervised tasks? A qualitative analysis. J Hosp Med. 2014 Mar;9(3):169-75. doi: 10.1002/jhm.2150.
5. Hauer KE et al. How clinical supervisors develop trust in their trainees: A qualitative study. Med Educ. 2015 Aug;49(8):783-95. doi: 10.1111/medu.12745.
6. Sterkenburg A et al. When do supervising physicians decide to entrust residents with unsupervised tasks? Acad Med. 2010 Sep;85(9):1408-17. doi: 10.1097/ACM.0b013e3181eab0ec.
7. Sheu L et al. How supervisor experience influences trust, supervision, and trainee learning: A qualitative study. Acad Med. 2017 Sep;92(9):1320-7. doi: 10.1097/ACM.0000000000001560.
8. Pingree EW et al. Encouraging entrustment: A qualitative study of resident behaviors that promote entrustment. Acad Med. 2020 Nov;95(11):1718-25. doi: 10.1097/ACM.0000000000003487.
9. Ten Cate O, Chen HC. The ingredients of a rich entrustment decision. Med Teach. 2020 Dec;42(12):1413-20. doi: 10.1080/0142159X.2020.1817348.
10. Smith DG, Johnson WB. Good guys: How men can be better allies for women in the workplace: Harvard Business School Publishing Corporation 2020.
11. Johnson WB, Smith D. Athena rising: How and why men should mentor women: Routledge 2016.
A pediatrician’s guide to screening for and treating depression
On Oct. 19, the American Academy of Pediatrics, the American Academy of Child and Adolescent Psychiatry, and the Children’s Hospital Association jointly declared a “national emergency in children’s mental health,” calling upon policy makers to take actions that could help address “soaring rates” of anxiety and depression.
Knowing that increasing the work force or creating new programs will come slowly if at all, they called for the integration of mental health care into primary care pediatrics and efforts to reduce the risk of suicide in children and adolescents.
Our clinical experience suggests that adolescent depression, which can lead to profoundly impaired function, impaired development, and even suicide, is a major concern in your practice. We hope to do our part by reviewing the screening, diagnosis, and management of depression that can reasonably happen in the pediatrician’s office.
Depression
Depression affects as many as 20% of adolescents, with girls experiencing major depressive disorder (MDD) twice as often as boys. The incidence of depression increases fourfold after puberty, and there is substantial evidence, but no clear cause, that it has increased by nearly 50% over the past decade, rising from a rate of 8% of U.S. adolescents in 2007 to 13% in 2017.1 In that same time period, the rate of completed suicides among U.S. youth aged 10-24 increased 57.4%, after being stable for the prior decade.2 Adolescent depression is also linked to increased substance use and high-risk behaviors such as drunk driving. In 2020, mental health–related emergency department visits by adolescents aged 12-17 increased by 31%. Visits for suicide attempts among adolescent girls in 2021 jumped by 51% from 2019.3 Clearly, MDD in adolescence is a common, potentially life-threatening problem
.
Screening and assessment
At annual checkups with patients 12 and older or at sick visits of patients with emotional, sleep, or vague somatic concerns, it should be standard practice to screen for depression. The Patient Health Questionnaire 9 modified for Adolescents (PHQ9-A) is a reliable, validated, and free screening instrument that your patients can fill out in the waiting room. (The PHQ9 can be used for your patients who are 18 and older.) It takes only 5 minutes to complete and is very easy to score. It establishes whether your patient meets DSM-5 criteria for MDD, and the degree of severity (5-9 is mild, 10-14 is moderate, 15-19 is moderately severe, and 20-27 is severe). It also screens for thoughts about suicide and past suicide attempts. You might add the more comprehensive parent-completed Pediatric Symptom Checklist, which includes a depression screen.4
These screening instruments can be completed electronically prior to or at the visit and should have a preamble explaining why depression screening is relevant. If screening is positive, interview your adolescent patients alone. This will give you the time to gather more detail about how impaired their function is at school, with friends, and in family relationships. Have they been missing school? Have their grades changed? Are they failing to hand in homework? Have they withdrawn from sports or activities? Are they less likely to hang out with friends? Do they participate in family activities? Have others noticed any changes? You should also check for associated anxiety symptoms (ruminative worries, panic attacks) and drug and alcohol use. Of course, you should ask about any suicidal thoughts (from vague morbid thoughts to specific plans, with intent and factors that have prevented them) and actual attempts. Remember, asking about suicidal thoughts and attempts will not cause or worsen them. On the contrary, your patients may feel shame, but will be relieved to not be alone with these thoughts. And this knowledge will be essential as you decide what to do next. When you meet with the parents, ask them about a family history of depression or suicide attempts, and then offer supportive interventions.
Supportive interventions
For all adolescents with depression, supportive interventions are helpful, and for those with mild symptoms, they are often adequate treatment. This begins with education for your patient and their parents about depression. It is an illness, not a problem of character or discipline. Advise your patients that adequate, restful sleep every night is critical to recovery. Regular exercise (daily is best, but at least three times weekly for 30 minutes) is often effective in mild to moderate depression. Patience and compassion for feelings of sadness, irritability, or disinterest are important at home, and maintaining connections with those people who offer support (friends, coaches, parents, etc.) is essential. They should also be told that “depression lies.” Feelings of guilt and self-reproach are a normal part of the illness, not facts. Organizations such as the National Alliance on Mental Illness (NAMI) and the American Academy of Child and Adolescent Psychiatry (AACAP) offer written materials through their websites that are very helpful educational resources. Connect them with sources of counseling support (through school, for example). For those with mild, brief, and uncomplicated depression, supportive interventions alone should offer relief within 4-6 weeks. It is hard to predict the trajectory of depression, so follow-up visits are relevant to determine if they are improving or worsening.
Psychotherapy
For your patients with moderate depression, or with hopelessness or suicidality, a referral for evidence-based psychotherapy is indicated. Both cognitive behavioral therapy and interpersonal therapy have demonstrated efficacy in treating depression in adolescents. If there is a history of trauma or high family conflict, supportive psychotherapy that will enhance communication skills within the family is very important to recovery. Identify various sources for high-quality psychotherapy services (individual, family, and group) in your community. While this may sound easier said than done, online services such as Psychology Today’s therapist locator can help. If your local university has a graduate program in social work or psychology, connect with them as they may have easier access to high-quality services through their training programs. If there is a group practice of therapists in your community, invite them to meet with your team to learn about whether they use evidence-based therapies and can support families as well as individual youth.
Pharmacologic options
For those adolescents with moderate to severe depression, psychotherapy alone is usually inadequate. Indeed, they may be so impaired that they simply cannot meaningfully engage in the work of psychotherapy. These patients require psychopharmacologic treatment first. First-line treatment is with selective serotonin reuptake inhibitors (SSRIs) (both fluoxetine and escitalopram are approved for use in adolescent depression). While many pediatricians remain reluctant about initiating SSRI treatment of depression since the Food and Drug Administration’s 2004 boxed warning was issued, the risks of untreated severe depression are more marked than are the risks of SSRI treatment. As prescription rates dipped in the following decade, rates of suicide attempts in adolescents with severe depression climbed. Subsequent research on the nature of the risk of “increased suicidality” indicated it is substantially lower than originally thought.
The AAP’s Guidelines for Adolescent Depression in Primary Care offer reassuring guidance: They recommend that pediatricians initiate treatment at a very low dose of SSRI (5 mg of fluoxetine, 12.5 mg of sertraline, or 5 mg of escitalopram) and aim to get to a therapeutic dose within 4 weeks.5 Educate the patient and parent about likely side effects (gastrointestinal upset, sleep disruption, akathisia or restlessness, and activation), which indicate the dose should be held steady until the side effects subside. Patients should be seen weekly until they get to a therapeutic dose, then biweekly to monitor for response. At these regular check-ins, the PHQ9A can follow symptom severity. You should monitor changes in function and for any change in suicidal thoughts. If your patient does not respond with at least energy improvement within 4 weeks, you should cross-taper to a different SSRI.
Managing risk
Suicidal thoughts are a common symptom of depression and an important marker of severity. Adolescents have more limited impulse control than do adults, elevating their risk for impulsively acting on these thoughts. Adolescents who are using alcohol or other substances, or who have a history of impulsivity, are at higher risk. Further compounding the degree of risk are a history of suicide attempts, impulsive aggression or psychotic symptoms, or a family history of completed suicide. In managing risk, it is critical that you assess and discuss these risk factors and discuss the need to have a safety plan.
This planning should include both patient and parent. Help the parent to identify lethal means at home (guns, rope, medications, and knives or box cutters) and make plans to secure or remove them. It includes helping your patient list those strategies that can be helpful if they are feeling more distressed (distracting with music or television, exercise, or connecting with select friends). A safety plan is not a promise or a contract to not do something, rather it is a practical set of strategies the patient and family can employ if they are feeling worse. It depends on the adolescent having a secure, trusting connection with the adults at home and with your office.
If your patient fails to improve, if the diagnosis appears complicated, or if you feel the patient is not safe, you should refer to child psychiatry or, if needed, a local emergency department. If you cannot find access to a psychiatrist, start with your state’s child psychiatric consultation hotline for access to telephone support: www.nncpap.org.
Although the suggestions outlined above are grounded in evidence and need, treating moderate to severe depression is likely a new challenge for many pediatricians. Managing the risk of suicide can be stressful, without a doubt. In our own work as child psychiatrists, we recognize that there is no single, reliable method to predict suicide and therefore no specific approach to ensuring prevention. We appreciate this burden of worry when treating a severely depressed adolescent, and follow the rule, “never worry alone” – share your concerns with parents and/or a mental health consultant (hopefully co-located in your office), or obtain a second opinion, even consult a child psychiatrist on a hotline. Offering supportive care for those with mild depression can prevent it from becoming severe, and beginning treatment for those with severe depression can make a profound difference in the course of a young person’s illness.
Dr. Swick is physician in chief at Ohana, Center for Child and Adolescent Behavioral Health, Community Hospital of the Monterey (Calif.) Peninsula. Dr. Jellinek is professor emeritus of psychiatry and pediatrics, Harvard Medical School, Boston. Email them at [email protected].
References
1. Pew Research Center. National Survey on Drug Use and Health (2017).
2. Curtin SC. Natl Vital Stat Rep. 2020 Sep;69(11):1-10.
3. Yard E et al. MMWR Morb Mortal Wkly Rep. 2021 Jun 18;70(24):888-94.
4. Jellinek M et al. J Pediatr. 2021 Jun;233:220-6.e1.
5. Zuckerbrot RA et al. Pediatrics. 2018 Mar;141(3):e20174081.
On Oct. 19, the American Academy of Pediatrics, the American Academy of Child and Adolescent Psychiatry, and the Children’s Hospital Association jointly declared a “national emergency in children’s mental health,” calling upon policy makers to take actions that could help address “soaring rates” of anxiety and depression.
Knowing that increasing the work force or creating new programs will come slowly if at all, they called for the integration of mental health care into primary care pediatrics and efforts to reduce the risk of suicide in children and adolescents.
Our clinical experience suggests that adolescent depression, which can lead to profoundly impaired function, impaired development, and even suicide, is a major concern in your practice. We hope to do our part by reviewing the screening, diagnosis, and management of depression that can reasonably happen in the pediatrician’s office.
Depression
Depression affects as many as 20% of adolescents, with girls experiencing major depressive disorder (MDD) twice as often as boys. The incidence of depression increases fourfold after puberty, and there is substantial evidence, but no clear cause, that it has increased by nearly 50% over the past decade, rising from a rate of 8% of U.S. adolescents in 2007 to 13% in 2017.1 In that same time period, the rate of completed suicides among U.S. youth aged 10-24 increased 57.4%, after being stable for the prior decade.2 Adolescent depression is also linked to increased substance use and high-risk behaviors such as drunk driving. In 2020, mental health–related emergency department visits by adolescents aged 12-17 increased by 31%. Visits for suicide attempts among adolescent girls in 2021 jumped by 51% from 2019.3 Clearly, MDD in adolescence is a common, potentially life-threatening problem
.
Screening and assessment
At annual checkups with patients 12 and older or at sick visits of patients with emotional, sleep, or vague somatic concerns, it should be standard practice to screen for depression. The Patient Health Questionnaire 9 modified for Adolescents (PHQ9-A) is a reliable, validated, and free screening instrument that your patients can fill out in the waiting room. (The PHQ9 can be used for your patients who are 18 and older.) It takes only 5 minutes to complete and is very easy to score. It establishes whether your patient meets DSM-5 criteria for MDD, and the degree of severity (5-9 is mild, 10-14 is moderate, 15-19 is moderately severe, and 20-27 is severe). It also screens for thoughts about suicide and past suicide attempts. You might add the more comprehensive parent-completed Pediatric Symptom Checklist, which includes a depression screen.4
These screening instruments can be completed electronically prior to or at the visit and should have a preamble explaining why depression screening is relevant. If screening is positive, interview your adolescent patients alone. This will give you the time to gather more detail about how impaired their function is at school, with friends, and in family relationships. Have they been missing school? Have their grades changed? Are they failing to hand in homework? Have they withdrawn from sports or activities? Are they less likely to hang out with friends? Do they participate in family activities? Have others noticed any changes? You should also check for associated anxiety symptoms (ruminative worries, panic attacks) and drug and alcohol use. Of course, you should ask about any suicidal thoughts (from vague morbid thoughts to specific plans, with intent and factors that have prevented them) and actual attempts. Remember, asking about suicidal thoughts and attempts will not cause or worsen them. On the contrary, your patients may feel shame, but will be relieved to not be alone with these thoughts. And this knowledge will be essential as you decide what to do next. When you meet with the parents, ask them about a family history of depression or suicide attempts, and then offer supportive interventions.
Supportive interventions
For all adolescents with depression, supportive interventions are helpful, and for those with mild symptoms, they are often adequate treatment. This begins with education for your patient and their parents about depression. It is an illness, not a problem of character or discipline. Advise your patients that adequate, restful sleep every night is critical to recovery. Regular exercise (daily is best, but at least three times weekly for 30 minutes) is often effective in mild to moderate depression. Patience and compassion for feelings of sadness, irritability, or disinterest are important at home, and maintaining connections with those people who offer support (friends, coaches, parents, etc.) is essential. They should also be told that “depression lies.” Feelings of guilt and self-reproach are a normal part of the illness, not facts. Organizations such as the National Alliance on Mental Illness (NAMI) and the American Academy of Child and Adolescent Psychiatry (AACAP) offer written materials through their websites that are very helpful educational resources. Connect them with sources of counseling support (through school, for example). For those with mild, brief, and uncomplicated depression, supportive interventions alone should offer relief within 4-6 weeks. It is hard to predict the trajectory of depression, so follow-up visits are relevant to determine if they are improving or worsening.
Psychotherapy
For your patients with moderate depression, or with hopelessness or suicidality, a referral for evidence-based psychotherapy is indicated. Both cognitive behavioral therapy and interpersonal therapy have demonstrated efficacy in treating depression in adolescents. If there is a history of trauma or high family conflict, supportive psychotherapy that will enhance communication skills within the family is very important to recovery. Identify various sources for high-quality psychotherapy services (individual, family, and group) in your community. While this may sound easier said than done, online services such as Psychology Today’s therapist locator can help. If your local university has a graduate program in social work or psychology, connect with them as they may have easier access to high-quality services through their training programs. If there is a group practice of therapists in your community, invite them to meet with your team to learn about whether they use evidence-based therapies and can support families as well as individual youth.
Pharmacologic options
For those adolescents with moderate to severe depression, psychotherapy alone is usually inadequate. Indeed, they may be so impaired that they simply cannot meaningfully engage in the work of psychotherapy. These patients require psychopharmacologic treatment first. First-line treatment is with selective serotonin reuptake inhibitors (SSRIs) (both fluoxetine and escitalopram are approved for use in adolescent depression). While many pediatricians remain reluctant about initiating SSRI treatment of depression since the Food and Drug Administration’s 2004 boxed warning was issued, the risks of untreated severe depression are more marked than are the risks of SSRI treatment. As prescription rates dipped in the following decade, rates of suicide attempts in adolescents with severe depression climbed. Subsequent research on the nature of the risk of “increased suicidality” indicated it is substantially lower than originally thought.
The AAP’s Guidelines for Adolescent Depression in Primary Care offer reassuring guidance: They recommend that pediatricians initiate treatment at a very low dose of SSRI (5 mg of fluoxetine, 12.5 mg of sertraline, or 5 mg of escitalopram) and aim to get to a therapeutic dose within 4 weeks.5 Educate the patient and parent about likely side effects (gastrointestinal upset, sleep disruption, akathisia or restlessness, and activation), which indicate the dose should be held steady until the side effects subside. Patients should be seen weekly until they get to a therapeutic dose, then biweekly to monitor for response. At these regular check-ins, the PHQ9A can follow symptom severity. You should monitor changes in function and for any change in suicidal thoughts. If your patient does not respond with at least energy improvement within 4 weeks, you should cross-taper to a different SSRI.
Managing risk
Suicidal thoughts are a common symptom of depression and an important marker of severity. Adolescents have more limited impulse control than do adults, elevating their risk for impulsively acting on these thoughts. Adolescents who are using alcohol or other substances, or who have a history of impulsivity, are at higher risk. Further compounding the degree of risk are a history of suicide attempts, impulsive aggression or psychotic symptoms, or a family history of completed suicide. In managing risk, it is critical that you assess and discuss these risk factors and discuss the need to have a safety plan.
This planning should include both patient and parent. Help the parent to identify lethal means at home (guns, rope, medications, and knives or box cutters) and make plans to secure or remove them. It includes helping your patient list those strategies that can be helpful if they are feeling more distressed (distracting with music or television, exercise, or connecting with select friends). A safety plan is not a promise or a contract to not do something, rather it is a practical set of strategies the patient and family can employ if they are feeling worse. It depends on the adolescent having a secure, trusting connection with the adults at home and with your office.
If your patient fails to improve, if the diagnosis appears complicated, or if you feel the patient is not safe, you should refer to child psychiatry or, if needed, a local emergency department. If you cannot find access to a psychiatrist, start with your state’s child psychiatric consultation hotline for access to telephone support: www.nncpap.org.
Although the suggestions outlined above are grounded in evidence and need, treating moderate to severe depression is likely a new challenge for many pediatricians. Managing the risk of suicide can be stressful, without a doubt. In our own work as child psychiatrists, we recognize that there is no single, reliable method to predict suicide and therefore no specific approach to ensuring prevention. We appreciate this burden of worry when treating a severely depressed adolescent, and follow the rule, “never worry alone” – share your concerns with parents and/or a mental health consultant (hopefully co-located in your office), or obtain a second opinion, even consult a child psychiatrist on a hotline. Offering supportive care for those with mild depression can prevent it from becoming severe, and beginning treatment for those with severe depression can make a profound difference in the course of a young person’s illness.
Dr. Swick is physician in chief at Ohana, Center for Child and Adolescent Behavioral Health, Community Hospital of the Monterey (Calif.) Peninsula. Dr. Jellinek is professor emeritus of psychiatry and pediatrics, Harvard Medical School, Boston. Email them at [email protected].
References
1. Pew Research Center. National Survey on Drug Use and Health (2017).
2. Curtin SC. Natl Vital Stat Rep. 2020 Sep;69(11):1-10.
3. Yard E et al. MMWR Morb Mortal Wkly Rep. 2021 Jun 18;70(24):888-94.
4. Jellinek M et al. J Pediatr. 2021 Jun;233:220-6.e1.
5. Zuckerbrot RA et al. Pediatrics. 2018 Mar;141(3):e20174081.
On Oct. 19, the American Academy of Pediatrics, the American Academy of Child and Adolescent Psychiatry, and the Children’s Hospital Association jointly declared a “national emergency in children’s mental health,” calling upon policy makers to take actions that could help address “soaring rates” of anxiety and depression.
Knowing that increasing the work force or creating new programs will come slowly if at all, they called for the integration of mental health care into primary care pediatrics and efforts to reduce the risk of suicide in children and adolescents.
Our clinical experience suggests that adolescent depression, which can lead to profoundly impaired function, impaired development, and even suicide, is a major concern in your practice. We hope to do our part by reviewing the screening, diagnosis, and management of depression that can reasonably happen in the pediatrician’s office.
Depression
Depression affects as many as 20% of adolescents, with girls experiencing major depressive disorder (MDD) twice as often as boys. The incidence of depression increases fourfold after puberty, and there is substantial evidence, but no clear cause, that it has increased by nearly 50% over the past decade, rising from a rate of 8% of U.S. adolescents in 2007 to 13% in 2017.1 In that same time period, the rate of completed suicides among U.S. youth aged 10-24 increased 57.4%, after being stable for the prior decade.2 Adolescent depression is also linked to increased substance use and high-risk behaviors such as drunk driving. In 2020, mental health–related emergency department visits by adolescents aged 12-17 increased by 31%. Visits for suicide attempts among adolescent girls in 2021 jumped by 51% from 2019.3 Clearly, MDD in adolescence is a common, potentially life-threatening problem
.
Screening and assessment
At annual checkups with patients 12 and older or at sick visits of patients with emotional, sleep, or vague somatic concerns, it should be standard practice to screen for depression. The Patient Health Questionnaire 9 modified for Adolescents (PHQ9-A) is a reliable, validated, and free screening instrument that your patients can fill out in the waiting room. (The PHQ9 can be used for your patients who are 18 and older.) It takes only 5 minutes to complete and is very easy to score. It establishes whether your patient meets DSM-5 criteria for MDD, and the degree of severity (5-9 is mild, 10-14 is moderate, 15-19 is moderately severe, and 20-27 is severe). It also screens for thoughts about suicide and past suicide attempts. You might add the more comprehensive parent-completed Pediatric Symptom Checklist, which includes a depression screen.4
These screening instruments can be completed electronically prior to or at the visit and should have a preamble explaining why depression screening is relevant. If screening is positive, interview your adolescent patients alone. This will give you the time to gather more detail about how impaired their function is at school, with friends, and in family relationships. Have they been missing school? Have their grades changed? Are they failing to hand in homework? Have they withdrawn from sports or activities? Are they less likely to hang out with friends? Do they participate in family activities? Have others noticed any changes? You should also check for associated anxiety symptoms (ruminative worries, panic attacks) and drug and alcohol use. Of course, you should ask about any suicidal thoughts (from vague morbid thoughts to specific plans, with intent and factors that have prevented them) and actual attempts. Remember, asking about suicidal thoughts and attempts will not cause or worsen them. On the contrary, your patients may feel shame, but will be relieved to not be alone with these thoughts. And this knowledge will be essential as you decide what to do next. When you meet with the parents, ask them about a family history of depression or suicide attempts, and then offer supportive interventions.
Supportive interventions
For all adolescents with depression, supportive interventions are helpful, and for those with mild symptoms, they are often adequate treatment. This begins with education for your patient and their parents about depression. It is an illness, not a problem of character or discipline. Advise your patients that adequate, restful sleep every night is critical to recovery. Regular exercise (daily is best, but at least three times weekly for 30 minutes) is often effective in mild to moderate depression. Patience and compassion for feelings of sadness, irritability, or disinterest are important at home, and maintaining connections with those people who offer support (friends, coaches, parents, etc.) is essential. They should also be told that “depression lies.” Feelings of guilt and self-reproach are a normal part of the illness, not facts. Organizations such as the National Alliance on Mental Illness (NAMI) and the American Academy of Child and Adolescent Psychiatry (AACAP) offer written materials through their websites that are very helpful educational resources. Connect them with sources of counseling support (through school, for example). For those with mild, brief, and uncomplicated depression, supportive interventions alone should offer relief within 4-6 weeks. It is hard to predict the trajectory of depression, so follow-up visits are relevant to determine if they are improving or worsening.
Psychotherapy
For your patients with moderate depression, or with hopelessness or suicidality, a referral for evidence-based psychotherapy is indicated. Both cognitive behavioral therapy and interpersonal therapy have demonstrated efficacy in treating depression in adolescents. If there is a history of trauma or high family conflict, supportive psychotherapy that will enhance communication skills within the family is very important to recovery. Identify various sources for high-quality psychotherapy services (individual, family, and group) in your community. While this may sound easier said than done, online services such as Psychology Today’s therapist locator can help. If your local university has a graduate program in social work or psychology, connect with them as they may have easier access to high-quality services through their training programs. If there is a group practice of therapists in your community, invite them to meet with your team to learn about whether they use evidence-based therapies and can support families as well as individual youth.
Pharmacologic options
For those adolescents with moderate to severe depression, psychotherapy alone is usually inadequate. Indeed, they may be so impaired that they simply cannot meaningfully engage in the work of psychotherapy. These patients require psychopharmacologic treatment first. First-line treatment is with selective serotonin reuptake inhibitors (SSRIs) (both fluoxetine and escitalopram are approved for use in adolescent depression). While many pediatricians remain reluctant about initiating SSRI treatment of depression since the Food and Drug Administration’s 2004 boxed warning was issued, the risks of untreated severe depression are more marked than are the risks of SSRI treatment. As prescription rates dipped in the following decade, rates of suicide attempts in adolescents with severe depression climbed. Subsequent research on the nature of the risk of “increased suicidality” indicated it is substantially lower than originally thought.
The AAP’s Guidelines for Adolescent Depression in Primary Care offer reassuring guidance: They recommend that pediatricians initiate treatment at a very low dose of SSRI (5 mg of fluoxetine, 12.5 mg of sertraline, or 5 mg of escitalopram) and aim to get to a therapeutic dose within 4 weeks.5 Educate the patient and parent about likely side effects (gastrointestinal upset, sleep disruption, akathisia or restlessness, and activation), which indicate the dose should be held steady until the side effects subside. Patients should be seen weekly until they get to a therapeutic dose, then biweekly to monitor for response. At these regular check-ins, the PHQ9A can follow symptom severity. You should monitor changes in function and for any change in suicidal thoughts. If your patient does not respond with at least energy improvement within 4 weeks, you should cross-taper to a different SSRI.
Managing risk
Suicidal thoughts are a common symptom of depression and an important marker of severity. Adolescents have more limited impulse control than do adults, elevating their risk for impulsively acting on these thoughts. Adolescents who are using alcohol or other substances, or who have a history of impulsivity, are at higher risk. Further compounding the degree of risk are a history of suicide attempts, impulsive aggression or psychotic symptoms, or a family history of completed suicide. In managing risk, it is critical that you assess and discuss these risk factors and discuss the need to have a safety plan.
This planning should include both patient and parent. Help the parent to identify lethal means at home (guns, rope, medications, and knives or box cutters) and make plans to secure or remove them. It includes helping your patient list those strategies that can be helpful if they are feeling more distressed (distracting with music or television, exercise, or connecting with select friends). A safety plan is not a promise or a contract to not do something, rather it is a practical set of strategies the patient and family can employ if they are feeling worse. It depends on the adolescent having a secure, trusting connection with the adults at home and with your office.
If your patient fails to improve, if the diagnosis appears complicated, or if you feel the patient is not safe, you should refer to child psychiatry or, if needed, a local emergency department. If you cannot find access to a psychiatrist, start with your state’s child psychiatric consultation hotline for access to telephone support: www.nncpap.org.
Although the suggestions outlined above are grounded in evidence and need, treating moderate to severe depression is likely a new challenge for many pediatricians. Managing the risk of suicide can be stressful, without a doubt. In our own work as child psychiatrists, we recognize that there is no single, reliable method to predict suicide and therefore no specific approach to ensuring prevention. We appreciate this burden of worry when treating a severely depressed adolescent, and follow the rule, “never worry alone” – share your concerns with parents and/or a mental health consultant (hopefully co-located in your office), or obtain a second opinion, even consult a child psychiatrist on a hotline. Offering supportive care for those with mild depression can prevent it from becoming severe, and beginning treatment for those with severe depression can make a profound difference in the course of a young person’s illness.
Dr. Swick is physician in chief at Ohana, Center for Child and Adolescent Behavioral Health, Community Hospital of the Monterey (Calif.) Peninsula. Dr. Jellinek is professor emeritus of psychiatry and pediatrics, Harvard Medical School, Boston. Email them at [email protected].
References
1. Pew Research Center. National Survey on Drug Use and Health (2017).
2. Curtin SC. Natl Vital Stat Rep. 2020 Sep;69(11):1-10.
3. Yard E et al. MMWR Morb Mortal Wkly Rep. 2021 Jun 18;70(24):888-94.
4. Jellinek M et al. J Pediatr. 2021 Jun;233:220-6.e1.
5. Zuckerbrot RA et al. Pediatrics. 2018 Mar;141(3):e20174081.
A house divided cannot stand
The United States of America are not united. Politics have polarized the competing monologues and the policy making around vaccines, masks, children returning to school, what children are taught in school, and whether the federal government (or the National Football League) can or should create universal mandates enforcing one extreme of any of those policy disputes. Public health and health care have become so entangled in polarized politics that the role of science has often been pushed aside.
Polarization is not a novel event in the history of governments. The partition of India in 1947 divided most of its Hindu and Muslim inhabitants into separate countries, but that hasn’t stopped the recent resurgence of Hindu nationalism in India. The Thirty Years’ War in Europe sought to decide whether Catholics or Protestants would dominate Western Christianity. Those two sides decided in 1648 that coexistence was wiser than continuing into the abyss of mutual annihilation. Current conflicts between Israelis and Palestinians, between Shia and Sunni Arab states, between China and the Uyghurs, and within Sudan and Ethiopia together demonstrate that polarization to the point of genocide can occur regardless of religion, race, and nationality.
Abraham Lincoln, a lawyer in Illinois with a habit of losing elections, was nominated in 1858 to be the Republican nominee in the U.S. Senate race. His speech accepting the nomination spoke a truth that resonated across the nation and across time. It is known as the House Divided speech. He said: “A house divided against itself cannot stand. I believe this government cannot endure, permanently half slave and half free. I do not expect the Union to be dissolved – I do not expect the house to fall – but I do expect it will cease to be divided. It will become all one thing or all the other.”
The Republican Lincoln, supported by antislavery groups, lost that election to the Democrat Stephen A. Douglas, whose party espoused popular sovereignty and local decision-making about slavery. Lincoln’s acceptance speech propelled him 2 years later to be nominated for and elected President of the United States. Lincoln’s first inaugural address as the President of the United States on March 4, 1861, focused on the issue of division and secession. This time, Lincoln placed much more emphasis on preserving the Union. He specifically renounced any federal efforts to use force to abolish slavery in the states that permitted it. He declared: “I have no purpose, directly or indirectly, to interfere with the institution of slavery in the States where it exists. I believe I have no lawful right to do so, and I have no inclination to do so.”
President Lincoln’s approach might not meet muster in today’s cancel culture. He was facing a precariously divided nation not unlike the current day, so his speech contains insights and wisdom important for today. Lincoln saw government as “a majority held in restraint by constitutional checks and limitations.” I am loath to further quote out of context or paraphrase his masterful words. Go read the original, in its balanced entirety.
I have written previous columns about the importance of taking time to reflect on one’s life and one’s career. Reflection is both a wellness check and a moral compass check. Some call it mindfulness. I lean toward calling it thankfulness and gratitude. Hence, November is a convenient time for pediatricians if flu and respiratory syncytial virus seasons haven’t started.
The Gettysburg Address extols the virtue of dedication. Lincoln’s second inaugural address promotes mercy and forgiveness. His Farewell Address to Springfield in 1861 in a single paragraph captures grief, faith, and hope. Those speeches are my perennial favorites. But this year it is the two aforementioned addresses that must be mined for wisdom.
I advocate vaccine and mask mandates, but I am not enamored with the idea of President Biden using the unchecked power of the executive branch to promulgate a single federal regulation that overreaches into every moderate-size business nationwide. The 1861 inaugural address concurs. Lincoln’s prophecy that division will be solved when one side ultimately wins is not the model I seek. It hasn’t worked for gun control. It hasn’t worked for abortion as we approach the 50th anniversary of Roe v. Wade. The present 50+1 vote majority in the U.S. Senate does not have a mandate to overhaul society, especially when those majorities are transient. One should have the courage to seek change, but beware of creating large divisions with small majorities.
Facebook profits when you meditate in the echo chambers of large, outraged groups. Avoid that. Hebrew tradition has some reflection occurring in groups of two or three, rather than solo. Truth is revealed in community. Voltaire said: “Cherish those who seek the truth but beware of those who find it.” As a scientist, my experience is that humility, skepticism, and a dedication to finding truth have served me well for a lifetime.
Dr. Powell is a retired pediatric hospitalist and clinical ethics consultant living in St. Louis. Email him at [email protected].
The United States of America are not united. Politics have polarized the competing monologues and the policy making around vaccines, masks, children returning to school, what children are taught in school, and whether the federal government (or the National Football League) can or should create universal mandates enforcing one extreme of any of those policy disputes. Public health and health care have become so entangled in polarized politics that the role of science has often been pushed aside.
Polarization is not a novel event in the history of governments. The partition of India in 1947 divided most of its Hindu and Muslim inhabitants into separate countries, but that hasn’t stopped the recent resurgence of Hindu nationalism in India. The Thirty Years’ War in Europe sought to decide whether Catholics or Protestants would dominate Western Christianity. Those two sides decided in 1648 that coexistence was wiser than continuing into the abyss of mutual annihilation. Current conflicts between Israelis and Palestinians, between Shia and Sunni Arab states, between China and the Uyghurs, and within Sudan and Ethiopia together demonstrate that polarization to the point of genocide can occur regardless of religion, race, and nationality.
Abraham Lincoln, a lawyer in Illinois with a habit of losing elections, was nominated in 1858 to be the Republican nominee in the U.S. Senate race. His speech accepting the nomination spoke a truth that resonated across the nation and across time. It is known as the House Divided speech. He said: “A house divided against itself cannot stand. I believe this government cannot endure, permanently half slave and half free. I do not expect the Union to be dissolved – I do not expect the house to fall – but I do expect it will cease to be divided. It will become all one thing or all the other.”
The Republican Lincoln, supported by antislavery groups, lost that election to the Democrat Stephen A. Douglas, whose party espoused popular sovereignty and local decision-making about slavery. Lincoln’s acceptance speech propelled him 2 years later to be nominated for and elected President of the United States. Lincoln’s first inaugural address as the President of the United States on March 4, 1861, focused on the issue of division and secession. This time, Lincoln placed much more emphasis on preserving the Union. He specifically renounced any federal efforts to use force to abolish slavery in the states that permitted it. He declared: “I have no purpose, directly or indirectly, to interfere with the institution of slavery in the States where it exists. I believe I have no lawful right to do so, and I have no inclination to do so.”
President Lincoln’s approach might not meet muster in today’s cancel culture. He was facing a precariously divided nation not unlike the current day, so his speech contains insights and wisdom important for today. Lincoln saw government as “a majority held in restraint by constitutional checks and limitations.” I am loath to further quote out of context or paraphrase his masterful words. Go read the original, in its balanced entirety.
I have written previous columns about the importance of taking time to reflect on one’s life and one’s career. Reflection is both a wellness check and a moral compass check. Some call it mindfulness. I lean toward calling it thankfulness and gratitude. Hence, November is a convenient time for pediatricians if flu and respiratory syncytial virus seasons haven’t started.
The Gettysburg Address extols the virtue of dedication. Lincoln’s second inaugural address promotes mercy and forgiveness. His Farewell Address to Springfield in 1861 in a single paragraph captures grief, faith, and hope. Those speeches are my perennial favorites. But this year it is the two aforementioned addresses that must be mined for wisdom.
I advocate vaccine and mask mandates, but I am not enamored with the idea of President Biden using the unchecked power of the executive branch to promulgate a single federal regulation that overreaches into every moderate-size business nationwide. The 1861 inaugural address concurs. Lincoln’s prophecy that division will be solved when one side ultimately wins is not the model I seek. It hasn’t worked for gun control. It hasn’t worked for abortion as we approach the 50th anniversary of Roe v. Wade. The present 50+1 vote majority in the U.S. Senate does not have a mandate to overhaul society, especially when those majorities are transient. One should have the courage to seek change, but beware of creating large divisions with small majorities.
Facebook profits when you meditate in the echo chambers of large, outraged groups. Avoid that. Hebrew tradition has some reflection occurring in groups of two or three, rather than solo. Truth is revealed in community. Voltaire said: “Cherish those who seek the truth but beware of those who find it.” As a scientist, my experience is that humility, skepticism, and a dedication to finding truth have served me well for a lifetime.
Dr. Powell is a retired pediatric hospitalist and clinical ethics consultant living in St. Louis. Email him at [email protected].
The United States of America are not united. Politics have polarized the competing monologues and the policy making around vaccines, masks, children returning to school, what children are taught in school, and whether the federal government (or the National Football League) can or should create universal mandates enforcing one extreme of any of those policy disputes. Public health and health care have become so entangled in polarized politics that the role of science has often been pushed aside.
Polarization is not a novel event in the history of governments. The partition of India in 1947 divided most of its Hindu and Muslim inhabitants into separate countries, but that hasn’t stopped the recent resurgence of Hindu nationalism in India. The Thirty Years’ War in Europe sought to decide whether Catholics or Protestants would dominate Western Christianity. Those two sides decided in 1648 that coexistence was wiser than continuing into the abyss of mutual annihilation. Current conflicts between Israelis and Palestinians, between Shia and Sunni Arab states, between China and the Uyghurs, and within Sudan and Ethiopia together demonstrate that polarization to the point of genocide can occur regardless of religion, race, and nationality.
Abraham Lincoln, a lawyer in Illinois with a habit of losing elections, was nominated in 1858 to be the Republican nominee in the U.S. Senate race. His speech accepting the nomination spoke a truth that resonated across the nation and across time. It is known as the House Divided speech. He said: “A house divided against itself cannot stand. I believe this government cannot endure, permanently half slave and half free. I do not expect the Union to be dissolved – I do not expect the house to fall – but I do expect it will cease to be divided. It will become all one thing or all the other.”
The Republican Lincoln, supported by antislavery groups, lost that election to the Democrat Stephen A. Douglas, whose party espoused popular sovereignty and local decision-making about slavery. Lincoln’s acceptance speech propelled him 2 years later to be nominated for and elected President of the United States. Lincoln’s first inaugural address as the President of the United States on March 4, 1861, focused on the issue of division and secession. This time, Lincoln placed much more emphasis on preserving the Union. He specifically renounced any federal efforts to use force to abolish slavery in the states that permitted it. He declared: “I have no purpose, directly or indirectly, to interfere with the institution of slavery in the States where it exists. I believe I have no lawful right to do so, and I have no inclination to do so.”
President Lincoln’s approach might not meet muster in today’s cancel culture. He was facing a precariously divided nation not unlike the current day, so his speech contains insights and wisdom important for today. Lincoln saw government as “a majority held in restraint by constitutional checks and limitations.” I am loath to further quote out of context or paraphrase his masterful words. Go read the original, in its balanced entirety.
I have written previous columns about the importance of taking time to reflect on one’s life and one’s career. Reflection is both a wellness check and a moral compass check. Some call it mindfulness. I lean toward calling it thankfulness and gratitude. Hence, November is a convenient time for pediatricians if flu and respiratory syncytial virus seasons haven’t started.
The Gettysburg Address extols the virtue of dedication. Lincoln’s second inaugural address promotes mercy and forgiveness. His Farewell Address to Springfield in 1861 in a single paragraph captures grief, faith, and hope. Those speeches are my perennial favorites. But this year it is the two aforementioned addresses that must be mined for wisdom.
I advocate vaccine and mask mandates, but I am not enamored with the idea of President Biden using the unchecked power of the executive branch to promulgate a single federal regulation that overreaches into every moderate-size business nationwide. The 1861 inaugural address concurs. Lincoln’s prophecy that division will be solved when one side ultimately wins is not the model I seek. It hasn’t worked for gun control. It hasn’t worked for abortion as we approach the 50th anniversary of Roe v. Wade. The present 50+1 vote majority in the U.S. Senate does not have a mandate to overhaul society, especially when those majorities are transient. One should have the courage to seek change, but beware of creating large divisions with small majorities.
Facebook profits when you meditate in the echo chambers of large, outraged groups. Avoid that. Hebrew tradition has some reflection occurring in groups of two or three, rather than solo. Truth is revealed in community. Voltaire said: “Cherish those who seek the truth but beware of those who find it.” As a scientist, my experience is that humility, skepticism, and a dedication to finding truth have served me well for a lifetime.
Dr. Powell is a retired pediatric hospitalist and clinical ethics consultant living in St. Louis. Email him at [email protected].
Hormone blocker sticker shock – again – as patients lose cheaper drug option
In 2020, he’d fought to get insurance to cover a lower-priced version of a drug his then-8-year-old needed. She’d been diagnosed with central precocious puberty, a rare condition marked by early onset of sexual development – often years earlier than one’s peers. KHN and NPR wrote about Dr. Taksali and his family as part of the Bill of the Month series.
The girl’s doctors and the Taksalis decided to put her puberty on pause with a hormone-blocking drug implant that would be placed under the skin in her arm and release a little bit of the medication each day.
Dr. Taksali, an orthopedic surgeon, learned there were two nearly identical drug products made by Endo Pharmaceuticals, both containing 50 mg of the hormone blocker histrelin. One cost more than eight times more than the other. He wanted to use the cheaper one, Vantas, which costs about $4,800 per implant. But his insurer would not initially cover it, instead preferring Supprelin LA, which is approved by the Food and Drug Administration to treat central precocious puberty, and costs about $43,000.
Vantas can be prescribed off label for the condition, and after much back-and-forth dialogue, Dr. Taksali finally got the insurer to cover it.
Then this summer, it was time to replace the implant.
“I thought we would just get a Vantas replacement,” Dr. Taksali said. “In my mind, I was like: ‘Well, she got it the first time, and we’ve already kind of fought the battle with the insurance company and, you know, got it approved.”
But during a virtual appointment with his daughter’s doctor, he learned they couldn’t get Vantas. No one could. There was a Vantas shortage.
Endo cited a manufacturing problem. Batches of Vantas weren’t coming out right and couldn’t be released to the public, the company’s vice president of corporate affairs, Heather Zoumas Lubeski, said in an email. Vantas and Supprelin were made in the same facility, but the problem affected only Vantas, she wrote, stressing that the drugs are “not identical products.”
In August, Endo’s president and CEO, Blaise Coleman, told investors Supprelin was doing particularly well for the company. Revenue had grown by 79%, compared with the same quarter the year before. The growth was driven in part, Mr. Coleman explained, “by stronger-than-expected demand resulting from expanded patient awareness and a competitor product shortage,” he said.
What competitor product shortage? Could that be Vantas?
Asked about this, Ms. Zoumas Lubeski said Mr. Coleman wasn’t referring to Vantas. Since Vantas isn’t approved to treat central precocious puberty, it can’t technically be considered a competitor to Supprelin. Mr. Coleman was referring to the rival product Lupron Depot-Ped, not an implant, but an injection made by AbbVie, Ms. Zoumas Lubeski said.
Dr. Taksali was skeptical.
“It’s all very curious, like, huh, you know, when this particular option went away and your profits went up nearly 80% from the more expensive drug,” he said.
Then, in September, Endo told the FDA it stopped making Vantas for good.
Ms. Zoumas Lubeski said that, when Endo investigated its Vantas manufacturing problem, it wasn’t able to find “a suitable corrective action that resolves the issue.”
“As a result, and after analysis of the market for the availability of alternative therapies, we made the difficult decision to discontinue the supply of this product,” she said via email. “Endo is committed to maintaining the highest quality standards for all of its products.”
Dr. Taksali said he felt resigned to giving his daughter Supprelin even before the shortage turned into a discontinuation. Ultimately, he won’t pay much more out-of-pocket, but his insurance will pay the rest. And that could raise his business’s premiums.
The FDA cannot force Endo to keep making the drug or set a lower price for the remaining one. It doesn’t have the authority. That decision lies with Endo Pharmaceuticals. A drugmaker discontinuing a product isn’t anything new, said Erin Fox, who directs drug information and support services at University of Utah Health hospitals.
“The FDA has very little leverage because there is no requirement for any company to make any drug, no matter how lifesaving,” she said. “We have a capitalist society. We have a free market. And so any company can discontinue anything ... at any time for any reason.”
Still, companies are supposed to tell the FDA about potential shortages and discontinuations ahead of time so it can minimize the impact on public health. It can help a firm resolve a manufacturing issue, decide whether it’s safe to extend an expiration date or help a company making an alternative product to ramp up production.
“The FDA expects that manufacturers will notify the agency before a meaningful disruption in their own supply occurs,” FDA spokesperson Jeremy Kahn wrote in an email. “When the FDA does not receive timely, informative notifications, the agency’s ability to respond appropriately is limited.”
But the rules are somewhat flexible. A company is required to notify the FDA of an upcoming drug supply disruption 6 months before it affects consumers or “as soon as practicable” after that. But their true deadline is 5 business days after manufacturing stops, according to the FDA website.
“They’re supposed to tell the FDA, but even if they don’t, there’s no penalty,” Ms. Fox said. “There’s no teeth in that law. ... Their name can go on the FDA naughty list. That’s pretty much it.”
In rare cases, the FDA will send a noncompliance letter to the drugmaker and require it to explain itself. This has happened only five times since 2015. There is no such letter about Vantas, suggesting that Endo met the FDA’s requirements for notification.
Concerned about potential drug shortages caused by COVID-19 in March 2020, a bipartisan group of legislators introduced the Preventing Drug Shortages Act, which aimed to increase transparency around shortages. But the legislation gained no traction.
As a result of limited FDA power, the intricacies of drug shortages remain opaque, Ms. Fox said. Companies don’t have to make the reasons for shortages public. That sets the Vantas shortage and discontinuation apart from many others. The company is saying more about what happened than most do.
“Many companies will actually just put drugs on temporarily unavailable or long-term backorder, and sometimes that can last years before the company finally makes a decision” on whether to discontinue a product, she said. “It can take a long time, and so it can be frustrating to not know – or to kind of stake your hopes on a product coming back to the market once it’s been in shortage for so long.”
It’s hard to know exactly how many children will be affected by the Vantas discontinuation because data about off-label use is hard to come by.
Erica Eugster, MD, a professor of pediatrics at Indiana University, Indianapolis, said central precocious puberty patients weren’t her first thought when she learned of the Vantas discontinuation.
“I immediately thought about our transgender population,” she said. “They’re the ones that are really going to suffer from this.”
No medications have been FDA approved to treat patients with gender dysphoria, the medical term for when the sex assigned at birth doesn’t match someone’s gender identity, causing them psychological distress. As a result, any drug to stop puberty in this population would be off label, making it difficult for families to get health insurance coverage. Vantas had been a lower-cost option.
The number of transgender patients receiving histrelin implants rose significantly from 2004 to 2016, according to a study published in the Journal of Pediatric Endocrinology and Metabolism.
KHN (Kaiser Health News) is a national newsroom that produces in-depth journalism about health issues. Together with Policy Analysis and Polling, KHN is one of the three major operating programs at KFF (Kaiser Family Foundation). KFF is an endowed nonprofit organization providing information on health issues to the nation.
In 2020, he’d fought to get insurance to cover a lower-priced version of a drug his then-8-year-old needed. She’d been diagnosed with central precocious puberty, a rare condition marked by early onset of sexual development – often years earlier than one’s peers. KHN and NPR wrote about Dr. Taksali and his family as part of the Bill of the Month series.
The girl’s doctors and the Taksalis decided to put her puberty on pause with a hormone-blocking drug implant that would be placed under the skin in her arm and release a little bit of the medication each day.
Dr. Taksali, an orthopedic surgeon, learned there were two nearly identical drug products made by Endo Pharmaceuticals, both containing 50 mg of the hormone blocker histrelin. One cost more than eight times more than the other. He wanted to use the cheaper one, Vantas, which costs about $4,800 per implant. But his insurer would not initially cover it, instead preferring Supprelin LA, which is approved by the Food and Drug Administration to treat central precocious puberty, and costs about $43,000.
Vantas can be prescribed off label for the condition, and after much back-and-forth dialogue, Dr. Taksali finally got the insurer to cover it.
Then this summer, it was time to replace the implant.
“I thought we would just get a Vantas replacement,” Dr. Taksali said. “In my mind, I was like: ‘Well, she got it the first time, and we’ve already kind of fought the battle with the insurance company and, you know, got it approved.”
But during a virtual appointment with his daughter’s doctor, he learned they couldn’t get Vantas. No one could. There was a Vantas shortage.
Endo cited a manufacturing problem. Batches of Vantas weren’t coming out right and couldn’t be released to the public, the company’s vice president of corporate affairs, Heather Zoumas Lubeski, said in an email. Vantas and Supprelin were made in the same facility, but the problem affected only Vantas, she wrote, stressing that the drugs are “not identical products.”
In August, Endo’s president and CEO, Blaise Coleman, told investors Supprelin was doing particularly well for the company. Revenue had grown by 79%, compared with the same quarter the year before. The growth was driven in part, Mr. Coleman explained, “by stronger-than-expected demand resulting from expanded patient awareness and a competitor product shortage,” he said.
What competitor product shortage? Could that be Vantas?
Asked about this, Ms. Zoumas Lubeski said Mr. Coleman wasn’t referring to Vantas. Since Vantas isn’t approved to treat central precocious puberty, it can’t technically be considered a competitor to Supprelin. Mr. Coleman was referring to the rival product Lupron Depot-Ped, not an implant, but an injection made by AbbVie, Ms. Zoumas Lubeski said.
Dr. Taksali was skeptical.
“It’s all very curious, like, huh, you know, when this particular option went away and your profits went up nearly 80% from the more expensive drug,” he said.
Then, in September, Endo told the FDA it stopped making Vantas for good.
Ms. Zoumas Lubeski said that, when Endo investigated its Vantas manufacturing problem, it wasn’t able to find “a suitable corrective action that resolves the issue.”
“As a result, and after analysis of the market for the availability of alternative therapies, we made the difficult decision to discontinue the supply of this product,” she said via email. “Endo is committed to maintaining the highest quality standards for all of its products.”
Dr. Taksali said he felt resigned to giving his daughter Supprelin even before the shortage turned into a discontinuation. Ultimately, he won’t pay much more out-of-pocket, but his insurance will pay the rest. And that could raise his business’s premiums.
The FDA cannot force Endo to keep making the drug or set a lower price for the remaining one. It doesn’t have the authority. That decision lies with Endo Pharmaceuticals. A drugmaker discontinuing a product isn’t anything new, said Erin Fox, who directs drug information and support services at University of Utah Health hospitals.
“The FDA has very little leverage because there is no requirement for any company to make any drug, no matter how lifesaving,” she said. “We have a capitalist society. We have a free market. And so any company can discontinue anything ... at any time for any reason.”
Still, companies are supposed to tell the FDA about potential shortages and discontinuations ahead of time so it can minimize the impact on public health. It can help a firm resolve a manufacturing issue, decide whether it’s safe to extend an expiration date or help a company making an alternative product to ramp up production.
“The FDA expects that manufacturers will notify the agency before a meaningful disruption in their own supply occurs,” FDA spokesperson Jeremy Kahn wrote in an email. “When the FDA does not receive timely, informative notifications, the agency’s ability to respond appropriately is limited.”
But the rules are somewhat flexible. A company is required to notify the FDA of an upcoming drug supply disruption 6 months before it affects consumers or “as soon as practicable” after that. But their true deadline is 5 business days after manufacturing stops, according to the FDA website.
“They’re supposed to tell the FDA, but even if they don’t, there’s no penalty,” Ms. Fox said. “There’s no teeth in that law. ... Their name can go on the FDA naughty list. That’s pretty much it.”
In rare cases, the FDA will send a noncompliance letter to the drugmaker and require it to explain itself. This has happened only five times since 2015. There is no such letter about Vantas, suggesting that Endo met the FDA’s requirements for notification.
Concerned about potential drug shortages caused by COVID-19 in March 2020, a bipartisan group of legislators introduced the Preventing Drug Shortages Act, which aimed to increase transparency around shortages. But the legislation gained no traction.
As a result of limited FDA power, the intricacies of drug shortages remain opaque, Ms. Fox said. Companies don’t have to make the reasons for shortages public. That sets the Vantas shortage and discontinuation apart from many others. The company is saying more about what happened than most do.
“Many companies will actually just put drugs on temporarily unavailable or long-term backorder, and sometimes that can last years before the company finally makes a decision” on whether to discontinue a product, she said. “It can take a long time, and so it can be frustrating to not know – or to kind of stake your hopes on a product coming back to the market once it’s been in shortage for so long.”
It’s hard to know exactly how many children will be affected by the Vantas discontinuation because data about off-label use is hard to come by.
Erica Eugster, MD, a professor of pediatrics at Indiana University, Indianapolis, said central precocious puberty patients weren’t her first thought when she learned of the Vantas discontinuation.
“I immediately thought about our transgender population,” she said. “They’re the ones that are really going to suffer from this.”
No medications have been FDA approved to treat patients with gender dysphoria, the medical term for when the sex assigned at birth doesn’t match someone’s gender identity, causing them psychological distress. As a result, any drug to stop puberty in this population would be off label, making it difficult for families to get health insurance coverage. Vantas had been a lower-cost option.
The number of transgender patients receiving histrelin implants rose significantly from 2004 to 2016, according to a study published in the Journal of Pediatric Endocrinology and Metabolism.
KHN (Kaiser Health News) is a national newsroom that produces in-depth journalism about health issues. Together with Policy Analysis and Polling, KHN is one of the three major operating programs at KFF (Kaiser Family Foundation). KFF is an endowed nonprofit organization providing information on health issues to the nation.
In 2020, he’d fought to get insurance to cover a lower-priced version of a drug his then-8-year-old needed. She’d been diagnosed with central precocious puberty, a rare condition marked by early onset of sexual development – often years earlier than one’s peers. KHN and NPR wrote about Dr. Taksali and his family as part of the Bill of the Month series.
The girl’s doctors and the Taksalis decided to put her puberty on pause with a hormone-blocking drug implant that would be placed under the skin in her arm and release a little bit of the medication each day.
Dr. Taksali, an orthopedic surgeon, learned there were two nearly identical drug products made by Endo Pharmaceuticals, both containing 50 mg of the hormone blocker histrelin. One cost more than eight times more than the other. He wanted to use the cheaper one, Vantas, which costs about $4,800 per implant. But his insurer would not initially cover it, instead preferring Supprelin LA, which is approved by the Food and Drug Administration to treat central precocious puberty, and costs about $43,000.
Vantas can be prescribed off label for the condition, and after much back-and-forth dialogue, Dr. Taksali finally got the insurer to cover it.
Then this summer, it was time to replace the implant.
“I thought we would just get a Vantas replacement,” Dr. Taksali said. “In my mind, I was like: ‘Well, she got it the first time, and we’ve already kind of fought the battle with the insurance company and, you know, got it approved.”
But during a virtual appointment with his daughter’s doctor, he learned they couldn’t get Vantas. No one could. There was a Vantas shortage.
Endo cited a manufacturing problem. Batches of Vantas weren’t coming out right and couldn’t be released to the public, the company’s vice president of corporate affairs, Heather Zoumas Lubeski, said in an email. Vantas and Supprelin were made in the same facility, but the problem affected only Vantas, she wrote, stressing that the drugs are “not identical products.”
In August, Endo’s president and CEO, Blaise Coleman, told investors Supprelin was doing particularly well for the company. Revenue had grown by 79%, compared with the same quarter the year before. The growth was driven in part, Mr. Coleman explained, “by stronger-than-expected demand resulting from expanded patient awareness and a competitor product shortage,” he said.
What competitor product shortage? Could that be Vantas?
Asked about this, Ms. Zoumas Lubeski said Mr. Coleman wasn’t referring to Vantas. Since Vantas isn’t approved to treat central precocious puberty, it can’t technically be considered a competitor to Supprelin. Mr. Coleman was referring to the rival product Lupron Depot-Ped, not an implant, but an injection made by AbbVie, Ms. Zoumas Lubeski said.
Dr. Taksali was skeptical.
“It’s all very curious, like, huh, you know, when this particular option went away and your profits went up nearly 80% from the more expensive drug,” he said.
Then, in September, Endo told the FDA it stopped making Vantas for good.
Ms. Zoumas Lubeski said that, when Endo investigated its Vantas manufacturing problem, it wasn’t able to find “a suitable corrective action that resolves the issue.”
“As a result, and after analysis of the market for the availability of alternative therapies, we made the difficult decision to discontinue the supply of this product,” she said via email. “Endo is committed to maintaining the highest quality standards for all of its products.”
Dr. Taksali said he felt resigned to giving his daughter Supprelin even before the shortage turned into a discontinuation. Ultimately, he won’t pay much more out-of-pocket, but his insurance will pay the rest. And that could raise his business’s premiums.
The FDA cannot force Endo to keep making the drug or set a lower price for the remaining one. It doesn’t have the authority. That decision lies with Endo Pharmaceuticals. A drugmaker discontinuing a product isn’t anything new, said Erin Fox, who directs drug information and support services at University of Utah Health hospitals.
“The FDA has very little leverage because there is no requirement for any company to make any drug, no matter how lifesaving,” she said. “We have a capitalist society. We have a free market. And so any company can discontinue anything ... at any time for any reason.”
Still, companies are supposed to tell the FDA about potential shortages and discontinuations ahead of time so it can minimize the impact on public health. It can help a firm resolve a manufacturing issue, decide whether it’s safe to extend an expiration date or help a company making an alternative product to ramp up production.
“The FDA expects that manufacturers will notify the agency before a meaningful disruption in their own supply occurs,” FDA spokesperson Jeremy Kahn wrote in an email. “When the FDA does not receive timely, informative notifications, the agency’s ability to respond appropriately is limited.”
But the rules are somewhat flexible. A company is required to notify the FDA of an upcoming drug supply disruption 6 months before it affects consumers or “as soon as practicable” after that. But their true deadline is 5 business days after manufacturing stops, according to the FDA website.
“They’re supposed to tell the FDA, but even if they don’t, there’s no penalty,” Ms. Fox said. “There’s no teeth in that law. ... Their name can go on the FDA naughty list. That’s pretty much it.”
In rare cases, the FDA will send a noncompliance letter to the drugmaker and require it to explain itself. This has happened only five times since 2015. There is no such letter about Vantas, suggesting that Endo met the FDA’s requirements for notification.
Concerned about potential drug shortages caused by COVID-19 in March 2020, a bipartisan group of legislators introduced the Preventing Drug Shortages Act, which aimed to increase transparency around shortages. But the legislation gained no traction.
As a result of limited FDA power, the intricacies of drug shortages remain opaque, Ms. Fox said. Companies don’t have to make the reasons for shortages public. That sets the Vantas shortage and discontinuation apart from many others. The company is saying more about what happened than most do.
“Many companies will actually just put drugs on temporarily unavailable or long-term backorder, and sometimes that can last years before the company finally makes a decision” on whether to discontinue a product, she said. “It can take a long time, and so it can be frustrating to not know – or to kind of stake your hopes on a product coming back to the market once it’s been in shortage for so long.”
It’s hard to know exactly how many children will be affected by the Vantas discontinuation because data about off-label use is hard to come by.
Erica Eugster, MD, a professor of pediatrics at Indiana University, Indianapolis, said central precocious puberty patients weren’t her first thought when she learned of the Vantas discontinuation.
“I immediately thought about our transgender population,” she said. “They’re the ones that are really going to suffer from this.”
No medications have been FDA approved to treat patients with gender dysphoria, the medical term for when the sex assigned at birth doesn’t match someone’s gender identity, causing them psychological distress. As a result, any drug to stop puberty in this population would be off label, making it difficult for families to get health insurance coverage. Vantas had been a lower-cost option.
The number of transgender patients receiving histrelin implants rose significantly from 2004 to 2016, according to a study published in the Journal of Pediatric Endocrinology and Metabolism.
KHN (Kaiser Health News) is a national newsroom that produces in-depth journalism about health issues. Together with Policy Analysis and Polling, KHN is one of the three major operating programs at KFF (Kaiser Family Foundation). KFF is an endowed nonprofit organization providing information on health issues to the nation.