Osteoporosis is defined by a clinically diagnosed fragility fracture or a bone mineral density (BMD) of at least 2.5 SD below the mean for young female adults, usually measured by dual-energy x-ray absorptiometry. Risk factors include age, female sex, post-menopause, hypogonadism or premature ovarian failure, history of cigarette smoking or alcohol consumption (3 or more drinks daily), rheumatoid arthritis, or medications including glucocorticoids, anticoagulants, anticonvulsants, and aromatase inhibitors.

This guideline update focuses on treatment with bisphosphonates (alendronate, risedronate, ibandronate, zoledronic acid) and denosumab. Denosumab, a human monoclonal antibody against RANK-ligand, approved by the Food and Drug Administration for treatment of osteoporosis, has been added to the list of allowed medications since publication of the 2008 guideline. Several therapies have been excluded from the update, including calcitonin, which is no longer widely used for osteoporosis treatment, and etidronate and pamidronate, neither of which are FDA-approved for the prevention of fractures or treatment of osteoporosis. It should be noted that the evidence continues to be insufficient regarding the effectiveness of therapies to prevent fractures or to treat osteoporosis in men.

Bottom line:

Clinicians should offer pharmacologic treatment with alendronate, risedronate, zoledronic acid, or denosumab to reduce the risk of hip and vertebral fractures in women who have known osteoporosis diagnosed as a T score less than –2.5 or those with a fragility fracture. Pharmacologic therapy should be used for 5 years; however, high risk patients may benefit from longer treatment. There is no benefit to bone density monitoring during the 5-year pharmacologic treatment period. In addition, bisphosphonates should be considered in men who have clinically recognized osteoporosis.

Reference:

Qaseem, A, Forciea, MA, McLean RM, Denberg TD. Treatment of Low Bone Density or Osteoporosis to Prevent Fractures in Men and Women: A Clinical Practice Guideline Update From the American College of Physicians. Ann Int Med. 2017;166(11):818-39.
 

Dr. Skolnik is professor of family and community medicine at Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, and associate director of the family medicine residency program at Abington (Pa.) Jefferson Health. Dr. Meizinger is a second year resident in the Family Medicine Residency Program at Abington Jefferson Health.

Osteoporosis is defined by a clinically diagnosed fragility fracture or a bone mineral density (BMD) of at least 2.5 SD below the mean for young female adults, usually measured by dual-energy x-ray absorptiometry. Risk factors include age, female sex, post-menopause, hypogonadism or premature ovarian failure, history of cigarette smoking or alcohol consumption (3 or more drinks daily), rheumatoid arthritis, or medications including glucocorticoids, anticoagulants, anticonvulsants, and aromatase inhibitors.

This guideline update focuses on treatment with bisphosphonates (alendronate, risedronate, ibandronate, zoledronic acid) and denosumab. Denosumab, a human monoclonal antibody against RANK-ligand, approved by the Food and Drug Administration for treatment of osteoporosis, has been added to the list of allowed medications since publication of the 2008 guideline. Several therapies have been excluded from the update, including calcitonin, which is no longer widely used for osteoporosis treatment, and etidronate and pamidronate, neither of which are FDA-approved for the prevention of fractures or treatment of osteoporosis. It should be noted that the evidence continues to be insufficient regarding the effectiveness of therapies to prevent fractures or to treat osteoporosis in men.

Bottom line:

Clinicians should offer pharmacologic treatment with alendronate, risedronate, zoledronic acid, or denosumab to reduce the risk of hip and vertebral fractures in women who have known osteoporosis diagnosed as a T score less than –2.5 or those with a fragility fracture. Pharmacologic therapy should be used for 5 years; however, high risk patients may benefit from longer treatment. There is no benefit to bone density monitoring during the 5-year pharmacologic treatment period. In addition, bisphosphonates should be considered in men who have clinically recognized osteoporosis.

Reference:

Qaseem, A, Forciea, MA, McLean RM, Denberg TD. Treatment of Low Bone Density or Osteoporosis to Prevent Fractures in Men and Women: A Clinical Practice Guideline Update From the American College of Physicians. Ann Int Med. 2017;166(11):818-39.
 

Dr. Skolnik is professor of family and community medicine at Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, and associate director of the family medicine residency program at Abington (Pa.) Jefferson Health. Dr. Meizinger is a second year resident in the Family Medicine Residency Program at Abington Jefferson Health.

Osteoporosis is defined by a clinically diagnosed fragility fracture or a bone mineral density (BMD) of at least 2.5 SD below the mean for young female adults, usually measured by dual-energy x-ray absorptiometry. Risk factors include age, female sex, post-menopause, hypogonadism or premature ovarian failure, history of cigarette smoking or alcohol consumption (3 or more drinks daily), rheumatoid arthritis, or medications including glucocorticoids, anticoagulants, anticonvulsants, and aromatase inhibitors.

This guideline update focuses on treatment with bisphosphonates (alendronate, risedronate, ibandronate, zoledronic acid) and denosumab. Denosumab, a human monoclonal antibody against RANK-ligand, approved by the Food and Drug Administration for treatment of osteoporosis, has been added to the list of allowed medications since publication of the 2008 guideline. Several therapies have been excluded from the update, including calcitonin, which is no longer widely used for osteoporosis treatment, and etidronate and pamidronate, neither of which are FDA-approved for the prevention of fractures or treatment of osteoporosis. It should be noted that the evidence continues to be insufficient regarding the effectiveness of therapies to prevent fractures or to treat osteoporosis in men.

Bottom line:

Clinicians should offer pharmacologic treatment with alendronate, risedronate, zoledronic acid, or denosumab to reduce the risk of hip and vertebral fractures in women who have known osteoporosis diagnosed as a T score less than –2.5 or those with a fragility fracture. Pharmacologic therapy should be used for 5 years; however, high risk patients may benefit from longer treatment. There is no benefit to bone density monitoring during the 5-year pharmacologic treatment period. In addition, bisphosphonates should be considered in men who have clinically recognized osteoporosis.

Reference:

Qaseem, A, Forciea, MA, McLean RM, Denberg TD. Treatment of Low Bone Density or Osteoporosis to Prevent Fractures in Men and Women: A Clinical Practice Guideline Update From the American College of Physicians. Ann Int Med. 2017;166(11):818-39.
 

Dr. Skolnik is professor of family and community medicine at Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, and associate director of the family medicine residency program at Abington (Pa.) Jefferson Health. Dr. Meizinger is a second year resident in the Family Medicine Residency Program at Abington Jefferson Health.

CHICAGO – Patients with advanced breast cancer whose aromatase inhibitor therapy was supplemented with a cycline-dependent kinase inhibitor had better progression-free survival with no drop in quality of life. Health-related quality of life for patients on the combination therapy was equivalent to that of patients on monotherapy in most aspects, but patients receiving both therapies had a sustained and clinically meaningful decrease in pain.

Also, the time to definitive deterioration by 10% or more of the global health status/quality of life scale score was similar between treatment arms (hazard ratio [HR] 0.944; 95% confidence interval [CI] 0.720-1.237).

The MONALEESA-2 trial had previously shown that the CDK 4/6 inhibitor ribociclib, when added to the aromatase inhibitor letrozole, significantly improved progression-free survival for postmenopausal patients with hormone receptor-positive, HER2 negative advanced breast cancer, when compared to letrozole in combination with placebo.

Sunil Verma, MD, reported on health-related quality of life and symptoms in the two arms of MONALEESA-2, reporting change from baseline, time to a definitive 10% deterioration, and the mean scores for on-treatment time compared to end of treatment on the global health status/quality of life subscale of the European Organization for Research and Treatment of Cancer 30-item core quality of life questionnaire (EORTC QLQ-30).

“During treatment, overall health-related quality of life was maintained from baseline and was similar in both arms,” said Dr. Verma, the study’s first author. Changes during treatment were not statistically significant, and did not reach the predetermined threshold for a clinically meaningful difference. The effect of such key symptoms as fatigue, nausea, and vomiting on quality of life was similar regardless of whether patients received ribociclib or placebo, he said; though symptom scores were slightly higher for patients in the active arm of the study, the results were not clinically significant.

Reporting validated, cancer-specific patient-reported outcomes from the trial, Dr. Verma, professor and head of the department of oncology at the University of Calgary, (Alta.), sought to “highlight the patient experience with a focus on health-related quality of life and symptoms,” he said during his presentation at the annual meeting of the American Society of Clinical Oncology.

“A clinically meaningful – more than 5-point – improvement from baseline in pain score was maintained up to and including cycle 15 in the ribociclib plus letrozole arm,” said Dr. Verma. The placebo arm had a mild, clinically insignificant improvement at most assessment points. For both treatment arms, pain scores increased a bit above baseline levels at the time of disease progression or end of therapy, he said.

Patients completed the EORTC 30-item core quality of life questionnaire at their screening visit, and then every 8 weeks for the first 18 months. Then, they completed the questionnaires every 12 weeks until they experienced disease progression, died, were lost to follow-up or withdrew from the study, or stopped treatment.

Statistical analysis of the questionnaire results took into account the patients’ baseline scores, treatments received, and how they were stratified. Investigators assessed both statistical significance and the clinical meaningfulness of changes, defined as a change of 5-10 points.

In MONALEESA-2, 334 patients each were allocated to the ribociclib + letrozole arm and the placebo + letrozole arm. Patients in both arms, said Dr. Verma, were very compliant with questionnaire completion. Over 90% of patients who were eligible completed questionnaire through cycle 19 of ribociclib or placebo. He explained that the overall numbers completing the questionnaire declined with time, as more patients had disease progression.

It’s important to include these measures, he said, because patients and their families care about “the quality of the time gained,” so patient-reported outcomes should be a part of risk-benefit assessments for new cancer therapies. “While delaying disease progression may help to maintain patient quality of life, the addition of novel treatments to existing therapies can add toxicities, which may diminish quality of life,” said Dr. Verma.

Dr. Verma reported financial relationships with multiple pharmaceutical companies, including Novartis, which funded the study.
 

koakes@frontlinemedcom.com

On Twitter @karioakes

CHICAGO – Patients with advanced breast cancer whose aromatase inhibitor therapy was supplemented with a cycline-dependent kinase inhibitor had better progression-free survival with no drop in quality of life. Health-related quality of life for patients on the combination therapy was equivalent to that of patients on monotherapy in most aspects, but patients receiving both therapies had a sustained and clinically meaningful decrease in pain.

Also, the time to definitive deterioration by 10% or more of the global health status/quality of life scale score was similar between treatment arms (hazard ratio [HR] 0.944; 95% confidence interval [CI] 0.720-1.237).

The MONALEESA-2 trial had previously shown that the CDK 4/6 inhibitor ribociclib, when added to the aromatase inhibitor letrozole, significantly improved progression-free survival for postmenopausal patients with hormone receptor-positive, HER2 negative advanced breast cancer, when compared to letrozole in combination with placebo.

Sunil Verma, MD, reported on health-related quality of life and symptoms in the two arms of MONALEESA-2, reporting change from baseline, time to a definitive 10% deterioration, and the mean scores for on-treatment time compared to end of treatment on the global health status/quality of life subscale of the European Organization for Research and Treatment of Cancer 30-item core quality of life questionnaire (EORTC QLQ-30).

“During treatment, overall health-related quality of life was maintained from baseline and was similar in both arms,” said Dr. Verma, the study’s first author. Changes during treatment were not statistically significant, and did not reach the predetermined threshold for a clinically meaningful difference. The effect of such key symptoms as fatigue, nausea, and vomiting on quality of life was similar regardless of whether patients received ribociclib or placebo, he said; though symptom scores were slightly higher for patients in the active arm of the study, the results were not clinically significant.

Reporting validated, cancer-specific patient-reported outcomes from the trial, Dr. Verma, professor and head of the department of oncology at the University of Calgary, (Alta.), sought to “highlight the patient experience with a focus on health-related quality of life and symptoms,” he said during his presentation at the annual meeting of the American Society of Clinical Oncology.

“A clinically meaningful – more than 5-point – improvement from baseline in pain score was maintained up to and including cycle 15 in the ribociclib plus letrozole arm,” said Dr. Verma. The placebo arm had a mild, clinically insignificant improvement at most assessment points. For both treatment arms, pain scores increased a bit above baseline levels at the time of disease progression or end of therapy, he said.

Patients completed the EORTC 30-item core quality of life questionnaire at their screening visit, and then every 8 weeks for the first 18 months. Then, they completed the questionnaires every 12 weeks until they experienced disease progression, died, were lost to follow-up or withdrew from the study, or stopped treatment.

Statistical analysis of the questionnaire results took into account the patients’ baseline scores, treatments received, and how they were stratified. Investigators assessed both statistical significance and the clinical meaningfulness of changes, defined as a change of 5-10 points.

In MONALEESA-2, 334 patients each were allocated to the ribociclib + letrozole arm and the placebo + letrozole arm. Patients in both arms, said Dr. Verma, were very compliant with questionnaire completion. Over 90% of patients who were eligible completed questionnaire through cycle 19 of ribociclib or placebo. He explained that the overall numbers completing the questionnaire declined with time, as more patients had disease progression.

It’s important to include these measures, he said, because patients and their families care about “the quality of the time gained,” so patient-reported outcomes should be a part of risk-benefit assessments for new cancer therapies. “While delaying disease progression may help to maintain patient quality of life, the addition of novel treatments to existing therapies can add toxicities, which may diminish quality of life,” said Dr. Verma.

Dr. Verma reported financial relationships with multiple pharmaceutical companies, including Novartis, which funded the study.
 

koakes@frontlinemedcom.com

On Twitter @karioakes

CHICAGO – Patients with advanced breast cancer whose aromatase inhibitor therapy was supplemented with a cycline-dependent kinase inhibitor had better progression-free survival with no drop in quality of life. Health-related quality of life for patients on the combination therapy was equivalent to that of patients on monotherapy in most aspects, but patients receiving both therapies had a sustained and clinically meaningful decrease in pain.

Also, the time to definitive deterioration by 10% or more of the global health status/quality of life scale score was similar between treatment arms (hazard ratio [HR] 0.944; 95% confidence interval [CI] 0.720-1.237).

The MONALEESA-2 trial had previously shown that the CDK 4/6 inhibitor ribociclib, when added to the aromatase inhibitor letrozole, significantly improved progression-free survival for postmenopausal patients with hormone receptor-positive, HER2 negative advanced breast cancer, when compared to letrozole in combination with placebo.

Sunil Verma, MD, reported on health-related quality of life and symptoms in the two arms of MONALEESA-2, reporting change from baseline, time to a definitive 10% deterioration, and the mean scores for on-treatment time compared to end of treatment on the global health status/quality of life subscale of the European Organization for Research and Treatment of Cancer 30-item core quality of life questionnaire (EORTC QLQ-30).

“During treatment, overall health-related quality of life was maintained from baseline and was similar in both arms,” said Dr. Verma, the study’s first author. Changes during treatment were not statistically significant, and did not reach the predetermined threshold for a clinically meaningful difference. The effect of such key symptoms as fatigue, nausea, and vomiting on quality of life was similar regardless of whether patients received ribociclib or placebo, he said; though symptom scores were slightly higher for patients in the active arm of the study, the results were not clinically significant.

Reporting validated, cancer-specific patient-reported outcomes from the trial, Dr. Verma, professor and head of the department of oncology at the University of Calgary, (Alta.), sought to “highlight the patient experience with a focus on health-related quality of life and symptoms,” he said during his presentation at the annual meeting of the American Society of Clinical Oncology.

“A clinically meaningful – more than 5-point – improvement from baseline in pain score was maintained up to and including cycle 15 in the ribociclib plus letrozole arm,” said Dr. Verma. The placebo arm had a mild, clinically insignificant improvement at most assessment points. For both treatment arms, pain scores increased a bit above baseline levels at the time of disease progression or end of therapy, he said.

Patients completed the EORTC 30-item core quality of life questionnaire at their screening visit, and then every 8 weeks for the first 18 months. Then, they completed the questionnaires every 12 weeks until they experienced disease progression, died, were lost to follow-up or withdrew from the study, or stopped treatment.

Statistical analysis of the questionnaire results took into account the patients’ baseline scores, treatments received, and how they were stratified. Investigators assessed both statistical significance and the clinical meaningfulness of changes, defined as a change of 5-10 points.

In MONALEESA-2, 334 patients each were allocated to the ribociclib + letrozole arm and the placebo + letrozole arm. Patients in both arms, said Dr. Verma, were very compliant with questionnaire completion. Over 90% of patients who were eligible completed questionnaire through cycle 19 of ribociclib or placebo. He explained that the overall numbers completing the questionnaire declined with time, as more patients had disease progression.

It’s important to include these measures, he said, because patients and their families care about “the quality of the time gained,” so patient-reported outcomes should be a part of risk-benefit assessments for new cancer therapies. “While delaying disease progression may help to maintain patient quality of life, the addition of novel treatments to existing therapies can add toxicities, which may diminish quality of life,” said Dr. Verma.

Dr. Verma reported financial relationships with multiple pharmaceutical companies, including Novartis, which funded the study.
 

koakes@frontlinemedcom.com

On Twitter @karioakes

THE CASE

A 26-year-old healthy male veteran with bipolar disorder and post-traumatic stress disorder was referred for a gastroenterology consultation after a routine laboratory evaluation revealed elevated levels of aspartate aminotransferase (AST), 1040 IU/L (normal range, 10-40 IU/L), and alanine aminotransferase (ALT), 334 IU/L (normal range, 7-56 IU/L). He had been taking divalproex and ziprasidone for the previous 2 years, during which time liver test results had been normal.

The patient reported no symptoms in the course of a detailed history. He had no family history of liver disease, drank alcohol infrequently, and didn’t use tobacco. He hadn’t received any blood transfusions and didn’t have tattoos.

The patient indicated that he had recently returned from military deployment and that a week before his laboratory tests, he’d resumed weight training. To boost his workout, he’d begun taking a nutritional supplement supplied by a friend. Further questioning revealed that the supplement was MuscleMeds’ Code Red, which contains 1,3-dimethylamylamine (DMAA). He denied using any other dietary supplements.

The physical examination was unremarkable and additional lab work was unrevealing. Lab results included normal levels of ceruloplasmin, alpha-1 antitrypsin, ferritin, iron, and transferrin. Viral hepatitis serologies revealed immunity to the hepatitis A and B virus. The patient tested negative for Epstein-Barr virus, cytomegalovirus, herpes simplex virus, human immunodeficiency virus, antinuclear antibody, anti-smooth muscle antibody, and antimitochondrial antibody. A toxicology screen was remarkable for cannabinoids. The remainder of the basic metabolic panel and complete blood count were within normal limits.

THE DIAGNOSIS

The patient’s AST and ALT levels prompted measurement of creatine phosphokinase (CPK), which was elevated at 34,270 IU/L (normal range, 22-198 IU/L). We diagnosed rhabdomyolysis in this patient, which can be associated with elevated levels of AST and ALT. When we contacted the patient about the diagnosis, he reported no muscle aches or pains, or other symptoms.

We instructed the patient to increase his fluid intake and refrain from further use of Code Red. Repeat liver tests one month after the initial consultation revealed significant improvement in AST (29 IU/L) and ALT (68 IU/L), as well as a decline in CPK to 743 IU/L.

DISCUSSION

Much debate has surrounded the safety and use of DMAA, also known as methylhexamine or Geranamine, in dietary supplements such as Code Red. Eli Lilly and Company developed and patented DMAA in the 1940s, then trademarked it under the name Forthane as an inhaled nasal decongestant in 1971.^1-3 United States Food and Drug Administration (FDA) approval for Forthane was withdrawn in 1983 at Lilly’s request.⁴ DMAA was reintroduced as a dietary supplement more than a decade ago after the FDA, in 2004, banned supplements containing ephedrine alkaloids, which have effects similar to DMAA.⁵

DMAA has been used to increase muscle mass, promote weight loss, and improve physical performance; it’s also been used as a recreational drug.^6-8 Several case reports have described poor outcomes in patients who consumed DMAA products. In 2012, the deaths of 2 military personnel who used DMAA prompted the FDA to warn manufacturers of DMAA-containing supplements to stop production, but such supplements remain easily available in the United States.⁶

DMAA’s validity as a dietary supplement is controversial. The claim that DMAA is naturally present in geraniums hasn’t been verified, leading some to question whether an inaccurate description of DMAA as a natural substance was employed to justify its use as a nutritional supplement.⁹ No published evidence exists to establish DMAA as a dietary ingredient.^10,11

A long list of potential adverse effects

DMAA is an indirect sympathomimetic with vasoconstricting and cardiovascular effects.¹² Animal studies have shown effects similar to ephedrine and amphetamines.^12-15 Marsh and colleagues reported that a single oral dose of 3 mg/kg in a human (210 mg/70 kg) moderately increases heart rate and blood pressure and can lead to confusion and concentration problems.¹⁶

Supplements containing DMAA are still readily available, despite a 2012 FDA warning to discontinue production.

Oral intake of DMAA affects the lungs at doses above 4 to 15 mg, the heart after 50 to 75 mg, and blood pressure after 100 mg.¹⁷ Because of the drug’s long half-life—24 hours based on urinary excretion rates—Venhuis and Kaste reported that there is a risk from repeated doses within 24 to 36 hours that can lead to steadily stronger pharmacologic effects.¹⁷

The use of DMAA has been cited in 5 cases of hemorrhagic stroke, a case of acute heart failure, and the deaths of 2 military personnel who experienced asystole during aerobic exercise.^7,8,18-20 These individuals ranged in age from 22 to 41 years.

Initial symptoms included severe headaches, palpitations, dizziness, twitching of extremities, nausea, vomiting, confusion, agitation, and chest pain. The 2 military personnel suffered leg cramps and dyspnea followed by loss of consciousness. Several individuals were hypertensive on presentation to the emergency department with blood pressures as high as 240/120 mm Hg.

THE TAKEAWAY

Our patient presented with transaminitis and was found to have rhabdomyolysis after using DMAA. A few case reports have associated rhabdomyolysis with elevated liver function tests.^21,22 We suspect that DMAA use, which has been linked to adverse effects such as hypertension, tachycardia, and muscle aches, may also cause leakage of muscle enzymes and the development of rhabdomyolysis.

Although a single instance can’t prove causation, this case may illustrate additional adverse effects of DMAA beyond the already long list of risks, including hypertension, seizures, cerebral hemorrhage, arrhythmias, myocardial infarction, cardiomyopathy, and death.^7,8,18-20,23 It’s important for physicians to recognize that their patients may be using dietary supplements to increase strength, energy, or weight loss and to be aware of the potential adverse effects.

THE CASE

A 26-year-old healthy male veteran with bipolar disorder and post-traumatic stress disorder was referred for a gastroenterology consultation after a routine laboratory evaluation revealed elevated levels of aspartate aminotransferase (AST), 1040 IU/L (normal range, 10-40 IU/L), and alanine aminotransferase (ALT), 334 IU/L (normal range, 7-56 IU/L). He had been taking divalproex and ziprasidone for the previous 2 years, during which time liver test results had been normal.

The patient reported no symptoms in the course of a detailed history. He had no family history of liver disease, drank alcohol infrequently, and didn’t use tobacco. He hadn’t received any blood transfusions and didn’t have tattoos.

The patient indicated that he had recently returned from military deployment and that a week before his laboratory tests, he’d resumed weight training. To boost his workout, he’d begun taking a nutritional supplement supplied by a friend. Further questioning revealed that the supplement was MuscleMeds’ Code Red, which contains 1,3-dimethylamylamine (DMAA). He denied using any other dietary supplements.

The physical examination was unremarkable and additional lab work was unrevealing. Lab results included normal levels of ceruloplasmin, alpha-1 antitrypsin, ferritin, iron, and transferrin. Viral hepatitis serologies revealed immunity to the hepatitis A and B virus. The patient tested negative for Epstein-Barr virus, cytomegalovirus, herpes simplex virus, human immunodeficiency virus, antinuclear antibody, anti-smooth muscle antibody, and antimitochondrial antibody. A toxicology screen was remarkable for cannabinoids. The remainder of the basic metabolic panel and complete blood count were within normal limits.

THE DIAGNOSIS

The patient’s AST and ALT levels prompted measurement of creatine phosphokinase (CPK), which was elevated at 34,270 IU/L (normal range, 22-198 IU/L). We diagnosed rhabdomyolysis in this patient, which can be associated with elevated levels of AST and ALT. When we contacted the patient about the diagnosis, he reported no muscle aches or pains, or other symptoms.

We instructed the patient to increase his fluid intake and refrain from further use of Code Red. Repeat liver tests one month after the initial consultation revealed significant improvement in AST (29 IU/L) and ALT (68 IU/L), as well as a decline in CPK to 743 IU/L.

DISCUSSION

Much debate has surrounded the safety and use of DMAA, also known as methylhexamine or Geranamine, in dietary supplements such as Code Red. Eli Lilly and Company developed and patented DMAA in the 1940s, then trademarked it under the name Forthane as an inhaled nasal decongestant in 1971.^1-3 United States Food and Drug Administration (FDA) approval for Forthane was withdrawn in 1983 at Lilly’s request.⁴ DMAA was reintroduced as a dietary supplement more than a decade ago after the FDA, in 2004, banned supplements containing ephedrine alkaloids, which have effects similar to DMAA.⁵

DMAA has been used to increase muscle mass, promote weight loss, and improve physical performance; it’s also been used as a recreational drug.^6-8 Several case reports have described poor outcomes in patients who consumed DMAA products. In 2012, the deaths of 2 military personnel who used DMAA prompted the FDA to warn manufacturers of DMAA-containing supplements to stop production, but such supplements remain easily available in the United States.⁶

DMAA’s validity as a dietary supplement is controversial. The claim that DMAA is naturally present in geraniums hasn’t been verified, leading some to question whether an inaccurate description of DMAA as a natural substance was employed to justify its use as a nutritional supplement.⁹ No published evidence exists to establish DMAA as a dietary ingredient.^10,11

A long list of potential adverse effects

DMAA is an indirect sympathomimetic with vasoconstricting and cardiovascular effects.¹² Animal studies have shown effects similar to ephedrine and amphetamines.^12-15 Marsh and colleagues reported that a single oral dose of 3 mg/kg in a human (210 mg/70 kg) moderately increases heart rate and blood pressure and can lead to confusion and concentration problems.¹⁶

Supplements containing DMAA are still readily available, despite a 2012 FDA warning to discontinue production.

Oral intake of DMAA affects the lungs at doses above 4 to 15 mg, the heart after 50 to 75 mg, and blood pressure after 100 mg.¹⁷ Because of the drug’s long half-life—24 hours based on urinary excretion rates—Venhuis and Kaste reported that there is a risk from repeated doses within 24 to 36 hours that can lead to steadily stronger pharmacologic effects.¹⁷

The use of DMAA has been cited in 5 cases of hemorrhagic stroke, a case of acute heart failure, and the deaths of 2 military personnel who experienced asystole during aerobic exercise.^7,8,18-20 These individuals ranged in age from 22 to 41 years.

Initial symptoms included severe headaches, palpitations, dizziness, twitching of extremities, nausea, vomiting, confusion, agitation, and chest pain. The 2 military personnel suffered leg cramps and dyspnea followed by loss of consciousness. Several individuals were hypertensive on presentation to the emergency department with blood pressures as high as 240/120 mm Hg.

THE TAKEAWAY

Our patient presented with transaminitis and was found to have rhabdomyolysis after using DMAA. A few case reports have associated rhabdomyolysis with elevated liver function tests.^21,22 We suspect that DMAA use, which has been linked to adverse effects such as hypertension, tachycardia, and muscle aches, may also cause leakage of muscle enzymes and the development of rhabdomyolysis.

Although a single instance can’t prove causation, this case may illustrate additional adverse effects of DMAA beyond the already long list of risks, including hypertension, seizures, cerebral hemorrhage, arrhythmias, myocardial infarction, cardiomyopathy, and death.^7,8,18-20,23 It’s important for physicians to recognize that their patients may be using dietary supplements to increase strength, energy, or weight loss and to be aware of the potential adverse effects.

THE CASE

A 26-year-old healthy male veteran with bipolar disorder and post-traumatic stress disorder was referred for a gastroenterology consultation after a routine laboratory evaluation revealed elevated levels of aspartate aminotransferase (AST), 1040 IU/L (normal range, 10-40 IU/L), and alanine aminotransferase (ALT), 334 IU/L (normal range, 7-56 IU/L). He had been taking divalproex and ziprasidone for the previous 2 years, during which time liver test results had been normal.

The patient reported no symptoms in the course of a detailed history. He had no family history of liver disease, drank alcohol infrequently, and didn’t use tobacco. He hadn’t received any blood transfusions and didn’t have tattoos.

The patient indicated that he had recently returned from military deployment and that a week before his laboratory tests, he’d resumed weight training. To boost his workout, he’d begun taking a nutritional supplement supplied by a friend. Further questioning revealed that the supplement was MuscleMeds’ Code Red, which contains 1,3-dimethylamylamine (DMAA). He denied using any other dietary supplements.

The physical examination was unremarkable and additional lab work was unrevealing. Lab results included normal levels of ceruloplasmin, alpha-1 antitrypsin, ferritin, iron, and transferrin. Viral hepatitis serologies revealed immunity to the hepatitis A and B virus. The patient tested negative for Epstein-Barr virus, cytomegalovirus, herpes simplex virus, human immunodeficiency virus, antinuclear antibody, anti-smooth muscle antibody, and antimitochondrial antibody. A toxicology screen was remarkable for cannabinoids. The remainder of the basic metabolic panel and complete blood count were within normal limits.

THE DIAGNOSIS

The patient’s AST and ALT levels prompted measurement of creatine phosphokinase (CPK), which was elevated at 34,270 IU/L (normal range, 22-198 IU/L). We diagnosed rhabdomyolysis in this patient, which can be associated with elevated levels of AST and ALT. When we contacted the patient about the diagnosis, he reported no muscle aches or pains, or other symptoms.

We instructed the patient to increase his fluid intake and refrain from further use of Code Red. Repeat liver tests one month after the initial consultation revealed significant improvement in AST (29 IU/L) and ALT (68 IU/L), as well as a decline in CPK to 743 IU/L.

DISCUSSION

Much debate has surrounded the safety and use of DMAA, also known as methylhexamine or Geranamine, in dietary supplements such as Code Red. Eli Lilly and Company developed and patented DMAA in the 1940s, then trademarked it under the name Forthane as an inhaled nasal decongestant in 1971.^1-3 United States Food and Drug Administration (FDA) approval for Forthane was withdrawn in 1983 at Lilly’s request.⁴ DMAA was reintroduced as a dietary supplement more than a decade ago after the FDA, in 2004, banned supplements containing ephedrine alkaloids, which have effects similar to DMAA.⁵

DMAA has been used to increase muscle mass, promote weight loss, and improve physical performance; it’s also been used as a recreational drug.^6-8 Several case reports have described poor outcomes in patients who consumed DMAA products. In 2012, the deaths of 2 military personnel who used DMAA prompted the FDA to warn manufacturers of DMAA-containing supplements to stop production, but such supplements remain easily available in the United States.⁶

DMAA’s validity as a dietary supplement is controversial. The claim that DMAA is naturally present in geraniums hasn’t been verified, leading some to question whether an inaccurate description of DMAA as a natural substance was employed to justify its use as a nutritional supplement.⁹ No published evidence exists to establish DMAA as a dietary ingredient.^10,11

A long list of potential adverse effects

DMAA is an indirect sympathomimetic with vasoconstricting and cardiovascular effects.¹² Animal studies have shown effects similar to ephedrine and amphetamines.^12-15 Marsh and colleagues reported that a single oral dose of 3 mg/kg in a human (210 mg/70 kg) moderately increases heart rate and blood pressure and can lead to confusion and concentration problems.¹⁶

Supplements containing DMAA are still readily available, despite a 2012 FDA warning to discontinue production.

Oral intake of DMAA affects the lungs at doses above 4 to 15 mg, the heart after 50 to 75 mg, and blood pressure after 100 mg.¹⁷ Because of the drug’s long half-life—24 hours based on urinary excretion rates—Venhuis and Kaste reported that there is a risk from repeated doses within 24 to 36 hours that can lead to steadily stronger pharmacologic effects.¹⁷

The use of DMAA has been cited in 5 cases of hemorrhagic stroke, a case of acute heart failure, and the deaths of 2 military personnel who experienced asystole during aerobic exercise.^7,8,18-20 These individuals ranged in age from 22 to 41 years.

Initial symptoms included severe headaches, palpitations, dizziness, twitching of extremities, nausea, vomiting, confusion, agitation, and chest pain. The 2 military personnel suffered leg cramps and dyspnea followed by loss of consciousness. Several individuals were hypertensive on presentation to the emergency department with blood pressures as high as 240/120 mm Hg.

THE TAKEAWAY

Our patient presented with transaminitis and was found to have rhabdomyolysis after using DMAA. A few case reports have associated rhabdomyolysis with elevated liver function tests.^21,22 We suspect that DMAA use, which has been linked to adverse effects such as hypertension, tachycardia, and muscle aches, may also cause leakage of muscle enzymes and the development of rhabdomyolysis.

Although a single instance can’t prove causation, this case may illustrate additional adverse effects of DMAA beyond the already long list of risks, including hypertension, seizures, cerebral hemorrhage, arrhythmias, myocardial infarction, cardiomyopathy, and death.^7,8,18-20,23 It’s important for physicians to recognize that their patients may be using dietary supplements to increase strength, energy, or weight loss and to be aware of the potential adverse effects.

Updated Clinical Documentation & Coding resources now available

SHM’s Clinical Documentation & Coding for Hospitalists, formerly CODE-H, has been updated for 2017.

“[It’s] an exciting program that offers valuable insight into the coding and billing challenges of hospitalist services. Whether you are a new or seasoned physician, SHM’s Clinical Documentation & Coding for Hospitalists provides you with a solid foundation for documentation, identifies common problems, and offers strategies for success.” – Carol Pohlig, BSN, RN, CPC, ASC Senior Coding and Compliance Specialist

For more information, visit hospitalmedicine.org/codeh.

Registration now open for NP/PA Bootcamp

Whether you’re new to hospital medicine or need a refresher on the latest topics, this course from the AAPA and SHM is perfect for you and offers up to 34.75 AAPA Category 1 CME credits.

At the Adult Hospital Medicine Bootcamp, you will cover commonly encountered diagnoses and diseases of adult hospitalized patients while networking with other hospital-based practitioners. Plus, attend optional pre-courses on reimbursement, hands-on ultrasound or hospital medicine basics.

Join us at the ninth annual Adult Hospital Medicine Boot Camp, September 27 – October 1, 2017, in San Diego. To register and learn more visit: aapa.org/bootcamp.

Learn how your HMG stacks up with the State of Hospital Medicine report

Did you know that hospitalist compensation typically consists of 80% base pay and 20% supplemental income based on production and performance? SHM’s State of Hospital Medicine Report continues to be your best source of information about how hospital medicine groups (HMGs) operate.

Don’t miss the new additions to the report for the 2016 version, including:

• Percentage of the hospital’s total patient volume the HMG was responsible for caring for.

• Presence of medical hospitalists within the HMG focusing their practice in a specific medical subspecialty.

• Value of CME allowances for hospitalists.

• Utilization of prolonged service codes by hospitalists.

• Charge capture methodologies being used by HMGs.

• For academic HMGs, the dollar amount of financial support provided for non-clinical work.

Order your print or digital copy at hospitalmedicine.org/sohm.

Enhance your leadership skills at SHM’s Leadership Academy

SHM’s Leadership Academy is the only leadership program designed specifically for hospitalists. The 2017 meeting will be held October 23 – 26 at the JW Marriott Camelback Inn in Scottsdale, Ariz.

Course highlight: Leadership mastering teamwork

Developed in response to high demand from previous Leadership Academy attendees, this course focuses on strengthening teams and institutions. Participants learn how to critically assess program growth opportunities and develop operational plans; utilize the principles of SWARM intelligence; lead, manage, and motivate teams in complex hospital environments; and develop effective communication strategies.

Upon completion of this course, participants will be able to apply communication strategies that allow others to fully experience their message, lead teams in complex environments to achieve the best results, invest in themselves as leaders to optimize their professional growth and career path, and critically assess program growth opportunities and implement the necessary infrastructure for success.

To view the course schedule, faculty and more visit shmleadershipacademy.org/masteringteamwork.

Improve glycemic control efforts in your hospital with online resources & mentorship

SHM offers a variety of resources to improve glycemic control in your hospital. Glycemic Control Electronic Quality Improvement Programs (eQUIPS) are designed to enhance the efficiency and reliability of your quality improvement efforts to close the gap between best practices and methods for caring for the inpatient with hyperglycemia.

Benefits of SHM’s eQUIPS include:

• Data and performance tracking tools.

• Step-by-step instructions for improving glycemic control, preventing hypoglycemia, and optimizing care of inpatients with hyperglycemia and diabetes.

• An online community and library of tools and documents, including sample order sets and protocols, awareness campaigns, patient educational materials, and supplemental articles.

• Toolkit of clinical tools and interventions, research materials, literature reviews, case studies, teaching slide sets, and more.

SHM’s Glycemic Control Mentored Implementation program sites receive 1 year of individualized mentoring including:

• On-site mentoring and training for the entire care team to help members interpret needs and resource assessments, map system processes, and develop site-specific action and intervention plans.

• Monthly coaching calls with the mentor to develop, modify, and implement interventions, establish evaluation processes, and monitor performance over time.

• SHM-facilitated calls with live webinars with other sites in the collaborative to share success stories and experiences.

• Access to the online community to share ideas, documents, and other resources.

• Data collection and analysis tools to generate on-demand reports and benchmark against other program participants.

Learn more about all of SHM’s Glycemic Control offerings by watching the recorded webinar from June 28, 2017, at hospitalmedicine.org/gc.

Earn CME with SHM’s Learning Portal

SHM’s Learning Portal is the online learning destination for hospitalists, featuring all of SHM’s eLearning initiatives in one place. Members can access over 85 CME credits for free in the Learning Portal.

Featured topics currently include perioperative medicine, anticoagulation, quality improvement, cardiac arrhythmia, and antimicrobial stewardship.

Try out the most popular modules:

• The Role of the Medical Consultant.

• Pulmonary Risk Management in the Perioperative Setting.

• Perioperative Medication Management.

• Venous Thromboembolism Prophylaxis in Surgical Patients.

• Perioperative Cardiac Risk Assessment.

Not a member? Join today or pay a small fee per module. Visit shmlearningportal.org to learn more and earn CME credits today.
 

Brett Radler is communications specialist at the Society of Hospital Medicine.

Updated Clinical Documentation & Coding resources now available

SHM’s Clinical Documentation & Coding for Hospitalists, formerly CODE-H, has been updated for 2017.

“[It’s] an exciting program that offers valuable insight into the coding and billing challenges of hospitalist services. Whether you are a new or seasoned physician, SHM’s Clinical Documentation & Coding for Hospitalists provides you with a solid foundation for documentation, identifies common problems, and offers strategies for success.” – Carol Pohlig, BSN, RN, CPC, ASC Senior Coding and Compliance Specialist

For more information, visit hospitalmedicine.org/codeh.

Registration now open for NP/PA Bootcamp

Whether you’re new to hospital medicine or need a refresher on the latest topics, this course from the AAPA and SHM is perfect for you and offers up to 34.75 AAPA Category 1 CME credits.

At the Adult Hospital Medicine Bootcamp, you will cover commonly encountered diagnoses and diseases of adult hospitalized patients while networking with other hospital-based practitioners. Plus, attend optional pre-courses on reimbursement, hands-on ultrasound or hospital medicine basics.

Join us at the ninth annual Adult Hospital Medicine Boot Camp, September 27 – October 1, 2017, in San Diego. To register and learn more visit: aapa.org/bootcamp.

Learn how your HMG stacks up with the State of Hospital Medicine report

Did you know that hospitalist compensation typically consists of 80% base pay and 20% supplemental income based on production and performance? SHM’s State of Hospital Medicine Report continues to be your best source of information about how hospital medicine groups (HMGs) operate.

Don’t miss the new additions to the report for the 2016 version, including:

• Percentage of the hospital’s total patient volume the HMG was responsible for caring for.

• Presence of medical hospitalists within the HMG focusing their practice in a specific medical subspecialty.

• Value of CME allowances for hospitalists.

• Utilization of prolonged service codes by hospitalists.

• Charge capture methodologies being used by HMGs.

• For academic HMGs, the dollar amount of financial support provided for non-clinical work.

Order your print or digital copy at hospitalmedicine.org/sohm.

Enhance your leadership skills at SHM’s Leadership Academy

SHM’s Leadership Academy is the only leadership program designed specifically for hospitalists. The 2017 meeting will be held October 23 – 26 at the JW Marriott Camelback Inn in Scottsdale, Ariz.

Course highlight: Leadership mastering teamwork

Developed in response to high demand from previous Leadership Academy attendees, this course focuses on strengthening teams and institutions. Participants learn how to critically assess program growth opportunities and develop operational plans; utilize the principles of SWARM intelligence; lead, manage, and motivate teams in complex hospital environments; and develop effective communication strategies.

Upon completion of this course, participants will be able to apply communication strategies that allow others to fully experience their message, lead teams in complex environments to achieve the best results, invest in themselves as leaders to optimize their professional growth and career path, and critically assess program growth opportunities and implement the necessary infrastructure for success.

To view the course schedule, faculty and more visit shmleadershipacademy.org/masteringteamwork.

Improve glycemic control efforts in your hospital with online resources & mentorship

SHM offers a variety of resources to improve glycemic control in your hospital. Glycemic Control Electronic Quality Improvement Programs (eQUIPS) are designed to enhance the efficiency and reliability of your quality improvement efforts to close the gap between best practices and methods for caring for the inpatient with hyperglycemia.

Benefits of SHM’s eQUIPS include:

• Data and performance tracking tools.

• Step-by-step instructions for improving glycemic control, preventing hypoglycemia, and optimizing care of inpatients with hyperglycemia and diabetes.

• An online community and library of tools and documents, including sample order sets and protocols, awareness campaigns, patient educational materials, and supplemental articles.

• Toolkit of clinical tools and interventions, research materials, literature reviews, case studies, teaching slide sets, and more.

SHM’s Glycemic Control Mentored Implementation program sites receive 1 year of individualized mentoring including:

• On-site mentoring and training for the entire care team to help members interpret needs and resource assessments, map system processes, and develop site-specific action and intervention plans.

• Monthly coaching calls with the mentor to develop, modify, and implement interventions, establish evaluation processes, and monitor performance over time.

• SHM-facilitated calls with live webinars with other sites in the collaborative to share success stories and experiences.

• Access to the online community to share ideas, documents, and other resources.

• Data collection and analysis tools to generate on-demand reports and benchmark against other program participants.

Learn more about all of SHM’s Glycemic Control offerings by watching the recorded webinar from June 28, 2017, at hospitalmedicine.org/gc.

Earn CME with SHM’s Learning Portal

SHM’s Learning Portal is the online learning destination for hospitalists, featuring all of SHM’s eLearning initiatives in one place. Members can access over 85 CME credits for free in the Learning Portal.

Featured topics currently include perioperative medicine, anticoagulation, quality improvement, cardiac arrhythmia, and antimicrobial stewardship.

Try out the most popular modules:

• The Role of the Medical Consultant.

• Pulmonary Risk Management in the Perioperative Setting.

• Perioperative Medication Management.

• Venous Thromboembolism Prophylaxis in Surgical Patients.

• Perioperative Cardiac Risk Assessment.

Not a member? Join today or pay a small fee per module. Visit shmlearningportal.org to learn more and earn CME credits today.
 

Brett Radler is communications specialist at the Society of Hospital Medicine.

Updated Clinical Documentation & Coding resources now available

SHM’s Clinical Documentation & Coding for Hospitalists, formerly CODE-H, has been updated for 2017.

“[It’s] an exciting program that offers valuable insight into the coding and billing challenges of hospitalist services. Whether you are a new or seasoned physician, SHM’s Clinical Documentation & Coding for Hospitalists provides you with a solid foundation for documentation, identifies common problems, and offers strategies for success.” – Carol Pohlig, BSN, RN, CPC, ASC Senior Coding and Compliance Specialist

For more information, visit hospitalmedicine.org/codeh.

Registration now open for NP/PA Bootcamp

Whether you’re new to hospital medicine or need a refresher on the latest topics, this course from the AAPA and SHM is perfect for you and offers up to 34.75 AAPA Category 1 CME credits.

At the Adult Hospital Medicine Bootcamp, you will cover commonly encountered diagnoses and diseases of adult hospitalized patients while networking with other hospital-based practitioners. Plus, attend optional pre-courses on reimbursement, hands-on ultrasound or hospital medicine basics.

Join us at the ninth annual Adult Hospital Medicine Boot Camp, September 27 – October 1, 2017, in San Diego. To register and learn more visit: aapa.org/bootcamp.

Learn how your HMG stacks up with the State of Hospital Medicine report

Did you know that hospitalist compensation typically consists of 80% base pay and 20% supplemental income based on production and performance? SHM’s State of Hospital Medicine Report continues to be your best source of information about how hospital medicine groups (HMGs) operate.

Don’t miss the new additions to the report for the 2016 version, including:

• Percentage of the hospital’s total patient volume the HMG was responsible for caring for.

• Presence of medical hospitalists within the HMG focusing their practice in a specific medical subspecialty.

• Value of CME allowances for hospitalists.

• Utilization of prolonged service codes by hospitalists.

• Charge capture methodologies being used by HMGs.

• For academic HMGs, the dollar amount of financial support provided for non-clinical work.

Order your print or digital copy at hospitalmedicine.org/sohm.

Enhance your leadership skills at SHM’s Leadership Academy

SHM’s Leadership Academy is the only leadership program designed specifically for hospitalists. The 2017 meeting will be held October 23 – 26 at the JW Marriott Camelback Inn in Scottsdale, Ariz.

Course highlight: Leadership mastering teamwork

Developed in response to high demand from previous Leadership Academy attendees, this course focuses on strengthening teams and institutions. Participants learn how to critically assess program growth opportunities and develop operational plans; utilize the principles of SWARM intelligence; lead, manage, and motivate teams in complex hospital environments; and develop effective communication strategies.

Upon completion of this course, participants will be able to apply communication strategies that allow others to fully experience their message, lead teams in complex environments to achieve the best results, invest in themselves as leaders to optimize their professional growth and career path, and critically assess program growth opportunities and implement the necessary infrastructure for success.

To view the course schedule, faculty and more visit shmleadershipacademy.org/masteringteamwork.

Improve glycemic control efforts in your hospital with online resources & mentorship

SHM offers a variety of resources to improve glycemic control in your hospital. Glycemic Control Electronic Quality Improvement Programs (eQUIPS) are designed to enhance the efficiency and reliability of your quality improvement efforts to close the gap between best practices and methods for caring for the inpatient with hyperglycemia.

Benefits of SHM’s eQUIPS include:

• Data and performance tracking tools.

• Step-by-step instructions for improving glycemic control, preventing hypoglycemia, and optimizing care of inpatients with hyperglycemia and diabetes.

• An online community and library of tools and documents, including sample order sets and protocols, awareness campaigns, patient educational materials, and supplemental articles.

• Toolkit of clinical tools and interventions, research materials, literature reviews, case studies, teaching slide sets, and more.

SHM’s Glycemic Control Mentored Implementation program sites receive 1 year of individualized mentoring including:

• On-site mentoring and training for the entire care team to help members interpret needs and resource assessments, map system processes, and develop site-specific action and intervention plans.

• Monthly coaching calls with the mentor to develop, modify, and implement interventions, establish evaluation processes, and monitor performance over time.

• SHM-facilitated calls with live webinars with other sites in the collaborative to share success stories and experiences.

• Access to the online community to share ideas, documents, and other resources.

• Data collection and analysis tools to generate on-demand reports and benchmark against other program participants.

Learn more about all of SHM’s Glycemic Control offerings by watching the recorded webinar from June 28, 2017, at hospitalmedicine.org/gc.

Earn CME with SHM’s Learning Portal

SHM’s Learning Portal is the online learning destination for hospitalists, featuring all of SHM’s eLearning initiatives in one place. Members can access over 85 CME credits for free in the Learning Portal.

Featured topics currently include perioperative medicine, anticoagulation, quality improvement, cardiac arrhythmia, and antimicrobial stewardship.

Try out the most popular modules:

• The Role of the Medical Consultant.

• Pulmonary Risk Management in the Perioperative Setting.

• Perioperative Medication Management.

• Venous Thromboembolism Prophylaxis in Surgical Patients.

• Perioperative Cardiac Risk Assessment.

Not a member? Join today or pay a small fee per module. Visit shmlearningportal.org to learn more and earn CME credits today.
 

Brett Radler is communications specialist at the Society of Hospital Medicine.

Patients who suffer a stroke rarely have just one vascular risk factor. Therefore, the approach to secondary stroke prevention must be multifactorial. In fact, it has been estimated that 80% of recurrent strokes could be prevented through the application of a comprehensive, multifactorial approach that includes lifestyle modification and optimal medical management.¹ Such an achievement would save millions of people from disability and functional decline, as well as millions of dollars in related medical costs.

The initial approach to patients with stroke is focused on stabilization and a rapid work-up to identify the most likely etiology. Common causes of stroke include large artery atherosclerosis, cardiac emboli, and small vessel disease; less common causes include dissection, aortic emboli, and non-atherosclerotic vascular disease. If a complete diagnostic work-up is unrevealing, the stroke is said to be cryptogenic. Determining the correct etiology of a stroke is paramount to preventing secondary stroke (FIGURE^2-13).

Effective secondary prevention strategies designed to prevent a stroke or transient ischemic attack (TIA) in a patient with a known history of either event include lifestyle modifications, medications, and when appropriate, mechanical interventions. As a primary care physician (PCP), you are uniquely positioned to spearhead the prevention of secondary strokes: Not only are you at the forefront of prevention and the use of techniques such as motivational interviewing, but you also have longstanding relationships with many of your patients. In fact, the success of many interventions is improved by the informed, enduring, and trusting nature of relationships between patients and their PCPs.

In the first part of this 2-part series, we focused on subacute stroke management and outlined the recommended work-up for subacute stroke/TIA (see “Stroke: A road map to subacute management,” 2017;66:366-374). In this part, we focus on secondary prevention. The more common modifiable conditions encountered in primary care are discussed here, while many of the more rare etiologies (hypercoagulable states, sickle cell disease, and vasculitis) are outside the scope of this article.

Lifestyle interventions: Target tobacco use, obesity, alcohol intake

Lifestyle modifications can have a positive impact on many of America’s most prevalent diseases, and stroke is no exception.¹⁴ Many of the disease states identified as risk factors for stroke (type 2 diabetes, hypertension, dyslipidemia) are exacerbated by tobacco use, obesity, and excessive alcohol intake.

Does your patient smoke? Up to 25% of all strokes are directly attributable to cigarette smoking.¹⁵ Smoking raises an individual’s risk for stroke in a dose-dependent fashion.^15,16 One study demonstrated that, compared to never-smokers, women ages 15 to 49 years who smoked a half-pack per day had an odds ratio for ischemic stroke of 2.2; those who smoked 2 packs per day had an odds ratio of 9.1.¹⁷ After cessation, stroke risk generally returns to baseline within 5 years.¹⁶ Thus, smoking cessation is among the most significant steps a patient can take to reduce the risk of both primary and secondary stroke.

Is your patient overweight? While obesity in and of itself is a risk factor for stroke, a focus on nutrition and physical activity as mechanisms for weight loss is far superior to focusing on either element alone. Physical activity—consisting of at least 40 minutes of moderate intensity aerobic exercise 3 to 4 times per week—and a diet that emphasizes fruits and vegetables, whole grains, and healthy fats, have both independently demonstrated benefits in secondary stroke prevention and are important parts of American College of Cardiology (ACC)/American Heart Association (AHA) guidelines.^2,3

It’s estimated that 80% of recurrent strokes could be prevented through the application of a comprehensive, multifactorial approach that includes optimal medical management.

The Mediterranean Diet, which emphasizes consumption of fruits and vegetables, legumes, tree nuts, olive oil, and lean protein, has long been associated with cardiovascular benefit.¹⁸ One prospective, randomized, single-blinded trial involving approximately 600 patients that looked at secondary prevention of coronary heart disease found that following the diet significantly reduced mortality compared with a usual prudent post-infarct diet (number needed to treat [NNT]=30 over 4 years).¹⁹

Is alcohol consumption an issue? Chronic heavy alcohol intake contributes to the development of hemorrhagic and ischemic stroke through multiple mechanisms, including alcohol-induced hypertension, alcoholic cardiomyopathy, and atrial fibrillation (AF). Light or moderate alcohol consumption has a paradoxical mild protective effect on ischemic stroke, thought to possibly be mediated by an increase in high-density lipoprotein (HDL) level and mild antiplatelet effect.³

AHA/American Stroke Association (ASA) guidelines indicate that no more than one standard drink per day for women and 2 drinks per day for men is reasonable.³ Counsel patients who drink in excess of this about the benefits of decreasing alcohol intake or abstaining altogether.

Choosing medications to manage BP, cholesterol, and clotting

Optimize blood pressure control. Blood pressure (BP) plays a critical role in both the management and prevention of stroke and is considered to be the most important modifiable risk factor in both primary and secondary stroke prevention.²⁰ In the first 24 to 48 hours following a cerebral ischemic event that is not eligible for thrombolysis, permissive hypertension (treating BP only if it exceeds 220/120 mm Hg unless there is a concurrent medical illness that requires you do so) is appropriate, as hypotension or rapid fluctuations in BP can be harmful.²¹

This flexibility does not continue into the subacute phase of management (at a minimum, after the initial 48 hours) or into secondary prevention. Initiation and titration of oral agents to gradually achieve a BP <140/90 mm Hg or a reduction of 10/5 mm Hg for patients already within optimal range are the most widely recognized goals.^3,20 Patients with stroke secondary to small vessel disease may benefit from an even lower goal of <130/<80 mm Hg.¹¹ Encourage patients to monitor their BP at home for added accuracy and consistency.²²

Pharmacologic BP management is appropriate for patients who are consistently above optimal range despite attempting recommended lifestyle modifications. The data are relatively consistent with respect to the effects of different drug classes after a stroke: beta-blockers have no effect on any outcome; thiazide diuretics significantly reduce stroke and total vascular events; angiotensin-converting enzyme (ACE) inhibitors significantly reduce myocardial infarction (MI); and the combination of an ACE inhibitor and thiazide diuretic reduces stroke, MI, and combined vascular events.⁴

This has led many stroke specialists to recommend the combination of an ACE inhibitor or angiotensin II receptor blocker (ARB) and a thiazide diuretic as a first-line approach to secondary stroke prevention rather than a beta-blocker (assuming there is no additional indication for a beta-blocker). Similarly, there is ample evidence to show that the magnitude of BP reduction is proportional to the reduction in recurrent vascular events.³

Make use of statin therapy—regardless of LDL. The SPARCL (Stroke Prevention by Aggressive Reduction in Cholesterol Levels) trial⁵ explored the potential role of statin medication for secondary stroke prevention. Researchers randomly assigned almost 5000 participants who’d had a stroke or TIA one to 6 months before study entry (but had no known history of coronary artery disease) to placebo or a high-intensity statin (80 mg/d atorvastatin). The statin group demonstrated a 4.9-year absolute risk reduction in fatal or nonfatal recurrent stroke of 1.9% (NNT=53).

Given these findings and those from other studies, the AHA and ASA recommend treating patients with stroke or TIA presumed to be of atherosclerotic origin with high-intensity statin therapy, regardless of low-density lipoprotein (LDL) level.³ Of note, statins are not indicated for the secondary prevention of hemorrhagic stroke.

Select antiplatelet therapy based on ischemic stroke subtype. Investigators are still trying to determine the optimal antiplatelet for secondary stroke prevention; it is likely that the ideal choice depends largely on the etiology of the stroke. Trials that did not select patients based on subtype of ischemic stroke have not shown a long-term benefit from dual antiplatelet therapy (clopidogrel and aspirin),^23,24 and one double-blind, multicenter trial involving more than 3000 patients with recent stroke secondary to small vessel disease demonstrated harm from such therapy in terms of a significantly increased risk of bleeding and death.⁶

Smoking cessation is among the most significant steps a patient can take to reduce the risk of both primary and secondary stroke.

However, a 2011 study compared aggressive medical management (aspirin 325 mg/d plus clopidogrel 75 mg/d for 90 days) alone to aggressive medical management plus percutaneous transluminal angioplasty and stenting (PTAS). The study involved almost 500 patients who'd had a recent TIA or stroke attributed to intracranial atherosclerotic stenosis. The authors found that the 30-day rate of stroke or death was 14.7% in the PTAS group vs 5.8% in the medical management group.²⁵

Similarly, a randomized double-blind, placebo-controlled trial published in 2013 involving over 5000 patients in China found that short-term use of dual antiplatelets (clopidogrel and aspirin for the first 21 days after an ischemic event, followed by aspirin monotherapy for 90 days) had an absolute risk reduction of 3.5% without increasing the risk of major bleeding in patients with high-risk TIA or minor stroke.²⁶

All stroke patients who do not have an indication for oral anticoagulation should be placed on long-term daily aspirin (75-325 mg); research has shown that lower doses are as effective as higher doses but with a lower risk of adverse gastrointestinal effects, including bleeding.^3,20 Aspirin 81 mg/d is a common effective dose.

For patients who cannot tolerate aspirin due to allergy, clopidogrel 75 mg/d is a reasonable alternative. Long-term studies of aspirin vs clopidogrel⁷ and clopidogrel vs extended-release dipyridamole⁸ showed no difference in secondary stroke prevention. The International Stroke Trial²⁷ and Chinese Acute Stroke Trial²⁸ both indicate that aspirin should be started as soon as possible after the onset of an acute stroke.

This special population should probably get antiplatelets, too. One recent study explored the use of an antiplatelet vs anticoagulation therapy for stroke patients with carotid artery dissection. The CADISS (Cervical Artery Dissection in Stroke Study) trial²⁹ randomized 250 patients with extracranial carotid and vertebral artery dissection with onset of symptoms within the previous 7 days to either antiplatelet or anticoagulation therapy and found no difference in the primary outcomes of recurrent stroke or death. The study also demonstrated a low risk of recurrent stroke in this population, which was 2% at 3-month follow-up.

Most patients with cervical artery dissection, therefore, are now treated with antiplatelet therapy. That said, situations may still arise in which anticoagulation can be considered, and consultation with a neurologist for guidance on choice of therapy is recommended.

Is an anticoagulant in order? Which agent, when

The most common cause of cardioembolic stroke is AF, which accounts for at least 15% of ischemic strokes, a number that rises in those over the age of 80.^20,30,31 A meta-analysis of more than 28,000 patients with non-valvular AF demonstrated that warfarin reduced the risk of stroke by 64%.³²

All ischemic stroke patients who do not have an indication for oral anticoagulation should be placed on long-term daily aspirin.

The rate of intracerebral hemorrhages during oral anticoagulation ranges from 0.3% to 0.6% per year.³³ The risk of bleeding complications can be mitigated by keeping international normalized ratios ≤3.0, maintaining good BP control, and avoiding concurrent use of antiplatelets in the absence of a clear indication for them.³³

Several risk assessment scores, such as the HAS-BLED,³⁴ can help with estimating the risk of hemorrhagic complications, although these scores have their limitations.^35,36 Even in an older population (mean age 83 years) with a high risk for falls, warfarin provided a net benefit in a composite endpoint of out-of-hospital death or hospitalization for stroke, MI, or hemorrhage in a retrospective study of over 1200 Medicare beneficiaries.³⁷

AF is not the only cause of cardioembolic stroke to consider. Additional high-risk factors warranting anticoagulation include rheumatic mitral valve disease, the presence of mechanical aortic or mitral valves, known mural thrombus, and acute anterior ST segment elevation myocardial infarctions (STEMIs) with resulting anterior apical dyskinesis/akinesis and concurrent ischemic stroke/TIA.³ (The specific management of each of these situations is beyond the scope of this paper.)

The choice of anticoagulation agent is based on multiple factors, including cost, risk of non-reversible bleeding, drug interactions, renal function, and patient preference. Approved options currently include warfarin/­vitamin K antagonist therapy, apixaban, rivaroxaban, dabigatran and edoxaban.³ Choice of therapy will continue to evolve as reversal agents, such as idarucizumab, are developed. Idarucizumab, a reversal agent for dabigatran, received approval from the US Food and Drug Administration in October 2015.³⁸

When to start anticoagulation. There are limited data regarding the optimal timing of initiation of anticoagulation following a stroke; however, a recent multicenter prospective study supported the common practice of initiating anticoagulation therapy within 4 to 14 days of the event.³⁹ Individual patient factors must be taken into consideration, including the size of the stroke (the larger the stroke, the higher the risk for hemorrhagic transformation), BP control, any additional risk factors for bleeding, and the estimated risk of early recurrent stroke.

Bridging patients onto anticoagulation with unfractionated or low-molecular-weight heparin in the setting of acute stroke is not recommended.⁴⁰ Results from randomized controlled trials involving unfractionated heparin, heparinoids, and low-molecular-weight heparin have not reported any benefit to these agents over aspirin at preventing early stroke recurrence.^27,41,42

For immobile or hospitalized patients. Subcutaneous heparin for the prevention of deep vein thrombosis (DVT) during immobility and hospitalization is recommended.⁴³ Patients who cannot tolerate anticoagulation should be maintained on low-dose antiplatelet therapy. Experts do not recommend dual treatment with aspirin and anticoagulation in most cases. However, recent coronary artery stent placement does require temporary dual treatment, with duration dependent on the type of stent placed.

A role for glycemic control? Still to be determined

The specific role of diabetic management in secondary stroke prevention remains unclear. The 2008 ACCORD trial,⁴⁴ a randomized study involving over 10,000 patients with a median glycated hemoglobin level of 8.1%, investigated intensive hyperglycemic control (targeting a glycated hemoglobin level <6.0% vs <7.9%) as a means of decreasing cardiovascular risk. However, the trial ended 17 months early because of an increase in all-cause mortality in the intensive treatment arm compared with the standard management group. The same trial was also unable to demonstrate a decrease in stroke risk with a decrease in A1c.⁴⁴

More recently, the IRIS (Insulin Resistance Intervention after Stroke) trial⁴⁵ (2016) found a 2.8% absolute risk reduction in stroke or MI among participants who had a stroke or TIA in the previous 6 months who were treated with pioglitazone vs placebo over 4.8 years (NNT=36). Participants were required to have insulin resistance, but were excluded if they had diabetes. The authors did, however, report a notable increase in the risk of bone fractures requiring surgery or hospitalization in the pioglitazone arm (5.1% vs 3.2%; number needed to harm [NNH]=53).

Treat patients with stroke or TIA presumed to be of atherosclerotic origin with high-intensity statin therapy, regardless of low-density lipoprotein level.

The impact this single study should have on standard secondary prevention is not yet clear. The authors concluded, “It seems reasonable to consider individual treatment preference and risk of drug-related adverse events in addition to potential benefits when making patient-specific decisions regarding therapy.”⁴⁵

Determining whether mechanical interventions are needed

Almost all conditions leading to stroke warrant active medical management, but a few benefit from procedural intervention, as well.

Extracranial carotid atherosclerosis. Carotid endarterectomy or carotid artery stenting is recommended as secondary prevention for patients with a history of stroke or TIA who have ipsilateral high-grade extracranial carotid stenosis of 70% to 99% and, in some cases, 50% to 69%.^3,9,20 In patients with mild non-disabling stroke, the optimal timing for these procedures is within 2 weeks of the ischemic event. A delay of 6 weeks is generally preferred for moderate or larger strokes to allow for some healing of the injured brain.

The choice of procedure is based on risk profile, with the most important factor being age. For patients >70 years, endarterectomy is preferred because stenting is associated with an increased risk of stroke.^3,9,10 Experts do not recommend either procedure for patients who have had a severe disabling stroke. Generally speaking, these procedures have higher rates of success when they are performed in centers that perform a higher number of these procedures.¹⁰

Vertebrobasilar atherosclerosis. Due to generally good compensatory blood flow of the contralateral vertebral artery in the setting of vertebral artery stenosis, and an unacceptably high complication rate of angioplasty and stenting in the basilar artery, medical management is typically the first-line approach. If a patient has recurrent symptoms in the setting of optimal medical management and a focal lesion that is amenable to an endovascular intervention (most commonly a vertebral artery origin high-grade stenosis), angioplasty and stenting may be considered.¹⁰

Intracranial atherosclerosis. Similarly, medical management is the preferred strategy for intracranial atherosclerosis. Angioplasty and/or stenting are reserved for complex cases or recurrence despite adherence to secondary stroke prevention measures. Ideally, these patients should be managed with long-term aspirin 81 mg/d, adjunctive clopidogrel 75 mg/d for 90 days post stroke, a high-intensity statin, BP optimization, and any relevant lifestyle interventions.¹³

Patent foramen ovale. Research to date has not shown that closure of a patent foramen ovale (PFO) is superior to medical therapy for secondary stroke prevention in patients <60 years with cryptogenic stroke.^12,46,47 The decision to anticoagulate these patients should be based on the presence or absence of a DVT and not on a PFO alone. In patients with an identified DVT and a contraindication to oral anticoagulation, inferior vena cava filter placement should be considered. For patients with ongoing prothrombotic risk thought to increase the chances of future paradoxical embolism, closure of the PFO may be considered.

CORRESPONDENCE
Stephen A. Martin, MD, EdM, Barre Family Health Center, 151 Worcester Road, Barre, MA 01005; stmartin@gmail.com.

Patients who suffer a stroke rarely have just one vascular risk factor. Therefore, the approach to secondary stroke prevention must be multifactorial. In fact, it has been estimated that 80% of recurrent strokes could be prevented through the application of a comprehensive, multifactorial approach that includes lifestyle modification and optimal medical management.¹ Such an achievement would save millions of people from disability and functional decline, as well as millions of dollars in related medical costs.

The initial approach to patients with stroke is focused on stabilization and a rapid work-up to identify the most likely etiology. Common causes of stroke include large artery atherosclerosis, cardiac emboli, and small vessel disease; less common causes include dissection, aortic emboli, and non-atherosclerotic vascular disease. If a complete diagnostic work-up is unrevealing, the stroke is said to be cryptogenic. Determining the correct etiology of a stroke is paramount to preventing secondary stroke (FIGURE^2-13).

Effective secondary prevention strategies designed to prevent a stroke or transient ischemic attack (TIA) in a patient with a known history of either event include lifestyle modifications, medications, and when appropriate, mechanical interventions. As a primary care physician (PCP), you are uniquely positioned to spearhead the prevention of secondary strokes: Not only are you at the forefront of prevention and the use of techniques such as motivational interviewing, but you also have longstanding relationships with many of your patients. In fact, the success of many interventions is improved by the informed, enduring, and trusting nature of relationships between patients and their PCPs.

In the first part of this 2-part series, we focused on subacute stroke management and outlined the recommended work-up for subacute stroke/TIA (see “Stroke: A road map to subacute management,” 2017;66:366-374). In this part, we focus on secondary prevention. The more common modifiable conditions encountered in primary care are discussed here, while many of the more rare etiologies (hypercoagulable states, sickle cell disease, and vasculitis) are outside the scope of this article.

Lifestyle interventions: Target tobacco use, obesity, alcohol intake

Lifestyle modifications can have a positive impact on many of America’s most prevalent diseases, and stroke is no exception.¹⁴ Many of the disease states identified as risk factors for stroke (type 2 diabetes, hypertension, dyslipidemia) are exacerbated by tobacco use, obesity, and excessive alcohol intake.

Does your patient smoke? Up to 25% of all strokes are directly attributable to cigarette smoking.¹⁵ Smoking raises an individual’s risk for stroke in a dose-dependent fashion.^15,16 One study demonstrated that, compared to never-smokers, women ages 15 to 49 years who smoked a half-pack per day had an odds ratio for ischemic stroke of 2.2; those who smoked 2 packs per day had an odds ratio of 9.1.¹⁷ After cessation, stroke risk generally returns to baseline within 5 years.¹⁶ Thus, smoking cessation is among the most significant steps a patient can take to reduce the risk of both primary and secondary stroke.

Is your patient overweight? While obesity in and of itself is a risk factor for stroke, a focus on nutrition and physical activity as mechanisms for weight loss is far superior to focusing on either element alone. Physical activity—consisting of at least 40 minutes of moderate intensity aerobic exercise 3 to 4 times per week—and a diet that emphasizes fruits and vegetables, whole grains, and healthy fats, have both independently demonstrated benefits in secondary stroke prevention and are important parts of American College of Cardiology (ACC)/American Heart Association (AHA) guidelines.^2,3

It’s estimated that 80% of recurrent strokes could be prevented through the application of a comprehensive, multifactorial approach that includes optimal medical management.

The Mediterranean Diet, which emphasizes consumption of fruits and vegetables, legumes, tree nuts, olive oil, and lean protein, has long been associated with cardiovascular benefit.¹⁸ One prospective, randomized, single-blinded trial involving approximately 600 patients that looked at secondary prevention of coronary heart disease found that following the diet significantly reduced mortality compared with a usual prudent post-infarct diet (number needed to treat [NNT]=30 over 4 years).¹⁹

Is alcohol consumption an issue? Chronic heavy alcohol intake contributes to the development of hemorrhagic and ischemic stroke through multiple mechanisms, including alcohol-induced hypertension, alcoholic cardiomyopathy, and atrial fibrillation (AF). Light or moderate alcohol consumption has a paradoxical mild protective effect on ischemic stroke, thought to possibly be mediated by an increase in high-density lipoprotein (HDL) level and mild antiplatelet effect.³

AHA/American Stroke Association (ASA) guidelines indicate that no more than one standard drink per day for women and 2 drinks per day for men is reasonable.³ Counsel patients who drink in excess of this about the benefits of decreasing alcohol intake or abstaining altogether.

Choosing medications to manage BP, cholesterol, and clotting

Optimize blood pressure control. Blood pressure (BP) plays a critical role in both the management and prevention of stroke and is considered to be the most important modifiable risk factor in both primary and secondary stroke prevention.²⁰ In the first 24 to 48 hours following a cerebral ischemic event that is not eligible for thrombolysis, permissive hypertension (treating BP only if it exceeds 220/120 mm Hg unless there is a concurrent medical illness that requires you do so) is appropriate, as hypotension or rapid fluctuations in BP can be harmful.²¹

This flexibility does not continue into the subacute phase of management (at a minimum, after the initial 48 hours) or into secondary prevention. Initiation and titration of oral agents to gradually achieve a BP <140/90 mm Hg or a reduction of 10/5 mm Hg for patients already within optimal range are the most widely recognized goals.^3,20 Patients with stroke secondary to small vessel disease may benefit from an even lower goal of <130/<80 mm Hg.¹¹ Encourage patients to monitor their BP at home for added accuracy and consistency.²²

Pharmacologic BP management is appropriate for patients who are consistently above optimal range despite attempting recommended lifestyle modifications. The data are relatively consistent with respect to the effects of different drug classes after a stroke: beta-blockers have no effect on any outcome; thiazide diuretics significantly reduce stroke and total vascular events; angiotensin-converting enzyme (ACE) inhibitors significantly reduce myocardial infarction (MI); and the combination of an ACE inhibitor and thiazide diuretic reduces stroke, MI, and combined vascular events.⁴

This has led many stroke specialists to recommend the combination of an ACE inhibitor or angiotensin II receptor blocker (ARB) and a thiazide diuretic as a first-line approach to secondary stroke prevention rather than a beta-blocker (assuming there is no additional indication for a beta-blocker). Similarly, there is ample evidence to show that the magnitude of BP reduction is proportional to the reduction in recurrent vascular events.³

Make use of statin therapy—regardless of LDL. The SPARCL (Stroke Prevention by Aggressive Reduction in Cholesterol Levels) trial⁵ explored the potential role of statin medication for secondary stroke prevention. Researchers randomly assigned almost 5000 participants who’d had a stroke or TIA one to 6 months before study entry (but had no known history of coronary artery disease) to placebo or a high-intensity statin (80 mg/d atorvastatin). The statin group demonstrated a 4.9-year absolute risk reduction in fatal or nonfatal recurrent stroke of 1.9% (NNT=53).

Given these findings and those from other studies, the AHA and ASA recommend treating patients with stroke or TIA presumed to be of atherosclerotic origin with high-intensity statin therapy, regardless of low-density lipoprotein (LDL) level.³ Of note, statins are not indicated for the secondary prevention of hemorrhagic stroke.

Select antiplatelet therapy based on ischemic stroke subtype. Investigators are still trying to determine the optimal antiplatelet for secondary stroke prevention; it is likely that the ideal choice depends largely on the etiology of the stroke. Trials that did not select patients based on subtype of ischemic stroke have not shown a long-term benefit from dual antiplatelet therapy (clopidogrel and aspirin),^23,24 and one double-blind, multicenter trial involving more than 3000 patients with recent stroke secondary to small vessel disease demonstrated harm from such therapy in terms of a significantly increased risk of bleeding and death.⁶

Smoking cessation is among the most significant steps a patient can take to reduce the risk of both primary and secondary stroke.

However, a 2011 study compared aggressive medical management (aspirin 325 mg/d plus clopidogrel 75 mg/d for 90 days) alone to aggressive medical management plus percutaneous transluminal angioplasty and stenting (PTAS). The study involved almost 500 patients who'd had a recent TIA or stroke attributed to intracranial atherosclerotic stenosis. The authors found that the 30-day rate of stroke or death was 14.7% in the PTAS group vs 5.8% in the medical management group.²⁵

Similarly, a randomized double-blind, placebo-controlled trial published in 2013 involving over 5000 patients in China found that short-term use of dual antiplatelets (clopidogrel and aspirin for the first 21 days after an ischemic event, followed by aspirin monotherapy for 90 days) had an absolute risk reduction of 3.5% without increasing the risk of major bleeding in patients with high-risk TIA or minor stroke.²⁶

All stroke patients who do not have an indication for oral anticoagulation should be placed on long-term daily aspirin (75-325 mg); research has shown that lower doses are as effective as higher doses but with a lower risk of adverse gastrointestinal effects, including bleeding.^3,20 Aspirin 81 mg/d is a common effective dose.

For patients who cannot tolerate aspirin due to allergy, clopidogrel 75 mg/d is a reasonable alternative. Long-term studies of aspirin vs clopidogrel⁷ and clopidogrel vs extended-release dipyridamole⁸ showed no difference in secondary stroke prevention. The International Stroke Trial²⁷ and Chinese Acute Stroke Trial²⁸ both indicate that aspirin should be started as soon as possible after the onset of an acute stroke.

This special population should probably get antiplatelets, too. One recent study explored the use of an antiplatelet vs anticoagulation therapy for stroke patients with carotid artery dissection. The CADISS (Cervical Artery Dissection in Stroke Study) trial²⁹ randomized 250 patients with extracranial carotid and vertebral artery dissection with onset of symptoms within the previous 7 days to either antiplatelet or anticoagulation therapy and found no difference in the primary outcomes of recurrent stroke or death. The study also demonstrated a low risk of recurrent stroke in this population, which was 2% at 3-month follow-up.

Most patients with cervical artery dissection, therefore, are now treated with antiplatelet therapy. That said, situations may still arise in which anticoagulation can be considered, and consultation with a neurologist for guidance on choice of therapy is recommended.

Is an anticoagulant in order? Which agent, when

The most common cause of cardioembolic stroke is AF, which accounts for at least 15% of ischemic strokes, a number that rises in those over the age of 80.^20,30,31 A meta-analysis of more than 28,000 patients with non-valvular AF demonstrated that warfarin reduced the risk of stroke by 64%.³²

All ischemic stroke patients who do not have an indication for oral anticoagulation should be placed on long-term daily aspirin.

The rate of intracerebral hemorrhages during oral anticoagulation ranges from 0.3% to 0.6% per year.³³ The risk of bleeding complications can be mitigated by keeping international normalized ratios ≤3.0, maintaining good BP control, and avoiding concurrent use of antiplatelets in the absence of a clear indication for them.³³

Several risk assessment scores, such as the HAS-BLED,³⁴ can help with estimating the risk of hemorrhagic complications, although these scores have their limitations.^35,36 Even in an older population (mean age 83 years) with a high risk for falls, warfarin provided a net benefit in a composite endpoint of out-of-hospital death or hospitalization for stroke, MI, or hemorrhage in a retrospective study of over 1200 Medicare beneficiaries.³⁷

AF is not the only cause of cardioembolic stroke to consider. Additional high-risk factors warranting anticoagulation include rheumatic mitral valve disease, the presence of mechanical aortic or mitral valves, known mural thrombus, and acute anterior ST segment elevation myocardial infarctions (STEMIs) with resulting anterior apical dyskinesis/akinesis and concurrent ischemic stroke/TIA.³ (The specific management of each of these situations is beyond the scope of this paper.)

The choice of anticoagulation agent is based on multiple factors, including cost, risk of non-reversible bleeding, drug interactions, renal function, and patient preference. Approved options currently include warfarin/­vitamin K antagonist therapy, apixaban, rivaroxaban, dabigatran and edoxaban.³ Choice of therapy will continue to evolve as reversal agents, such as idarucizumab, are developed. Idarucizumab, a reversal agent for dabigatran, received approval from the US Food and Drug Administration in October 2015.³⁸

When to start anticoagulation. There are limited data regarding the optimal timing of initiation of anticoagulation following a stroke; however, a recent multicenter prospective study supported the common practice of initiating anticoagulation therapy within 4 to 14 days of the event.³⁹ Individual patient factors must be taken into consideration, including the size of the stroke (the larger the stroke, the higher the risk for hemorrhagic transformation), BP control, any additional risk factors for bleeding, and the estimated risk of early recurrent stroke.

Bridging patients onto anticoagulation with unfractionated or low-molecular-weight heparin in the setting of acute stroke is not recommended.⁴⁰ Results from randomized controlled trials involving unfractionated heparin, heparinoids, and low-molecular-weight heparin have not reported any benefit to these agents over aspirin at preventing early stroke recurrence.^27,41,42

For immobile or hospitalized patients. Subcutaneous heparin for the prevention of deep vein thrombosis (DVT) during immobility and hospitalization is recommended.⁴³ Patients who cannot tolerate anticoagulation should be maintained on low-dose antiplatelet therapy. Experts do not recommend dual treatment with aspirin and anticoagulation in most cases. However, recent coronary artery stent placement does require temporary dual treatment, with duration dependent on the type of stent placed.

A role for glycemic control? Still to be determined

The specific role of diabetic management in secondary stroke prevention remains unclear. The 2008 ACCORD trial,⁴⁴ a randomized study involving over 10,000 patients with a median glycated hemoglobin level of 8.1%, investigated intensive hyperglycemic control (targeting a glycated hemoglobin level <6.0% vs <7.9%) as a means of decreasing cardiovascular risk. However, the trial ended 17 months early because of an increase in all-cause mortality in the intensive treatment arm compared with the standard management group. The same trial was also unable to demonstrate a decrease in stroke risk with a decrease in A1c.⁴⁴

More recently, the IRIS (Insulin Resistance Intervention after Stroke) trial⁴⁵ (2016) found a 2.8% absolute risk reduction in stroke or MI among participants who had a stroke or TIA in the previous 6 months who were treated with pioglitazone vs placebo over 4.8 years (NNT=36). Participants were required to have insulin resistance, but were excluded if they had diabetes. The authors did, however, report a notable increase in the risk of bone fractures requiring surgery or hospitalization in the pioglitazone arm (5.1% vs 3.2%; number needed to harm [NNH]=53).

Treat patients with stroke or TIA presumed to be of atherosclerotic origin with high-intensity statin therapy, regardless of low-density lipoprotein level.

The impact this single study should have on standard secondary prevention is not yet clear. The authors concluded, “It seems reasonable to consider individual treatment preference and risk of drug-related adverse events in addition to potential benefits when making patient-specific decisions regarding therapy.”⁴⁵

Determining whether mechanical interventions are needed

Almost all conditions leading to stroke warrant active medical management, but a few benefit from procedural intervention, as well.

Extracranial carotid atherosclerosis. Carotid endarterectomy or carotid artery stenting is recommended as secondary prevention for patients with a history of stroke or TIA who have ipsilateral high-grade extracranial carotid stenosis of 70% to 99% and, in some cases, 50% to 69%.^3,9,20 In patients with mild non-disabling stroke, the optimal timing for these procedures is within 2 weeks of the ischemic event. A delay of 6 weeks is generally preferred for moderate or larger strokes to allow for some healing of the injured brain.

The choice of procedure is based on risk profile, with the most important factor being age. For patients >70 years, endarterectomy is preferred because stenting is associated with an increased risk of stroke.^3,9,10 Experts do not recommend either procedure for patients who have had a severe disabling stroke. Generally speaking, these procedures have higher rates of success when they are performed in centers that perform a higher number of these procedures.¹⁰

Vertebrobasilar atherosclerosis. Due to generally good compensatory blood flow of the contralateral vertebral artery in the setting of vertebral artery stenosis, and an unacceptably high complication rate of angioplasty and stenting in the basilar artery, medical management is typically the first-line approach. If a patient has recurrent symptoms in the setting of optimal medical management and a focal lesion that is amenable to an endovascular intervention (most commonly a vertebral artery origin high-grade stenosis), angioplasty and stenting may be considered.¹⁰

Intracranial atherosclerosis. Similarly, medical management is the preferred strategy for intracranial atherosclerosis. Angioplasty and/or stenting are reserved for complex cases or recurrence despite adherence to secondary stroke prevention measures. Ideally, these patients should be managed with long-term aspirin 81 mg/d, adjunctive clopidogrel 75 mg/d for 90 days post stroke, a high-intensity statin, BP optimization, and any relevant lifestyle interventions.¹³

Patent foramen ovale. Research to date has not shown that closure of a patent foramen ovale (PFO) is superior to medical therapy for secondary stroke prevention in patients <60 years with cryptogenic stroke.^12,46,47 The decision to anticoagulate these patients should be based on the presence or absence of a DVT and not on a PFO alone. In patients with an identified DVT and a contraindication to oral anticoagulation, inferior vena cava filter placement should be considered. For patients with ongoing prothrombotic risk thought to increase the chances of future paradoxical embolism, closure of the PFO may be considered.

CORRESPONDENCE
Stephen A. Martin, MD, EdM, Barre Family Health Center, 151 Worcester Road, Barre, MA 01005; stmartin@gmail.com.

Patients who suffer a stroke rarely have just one vascular risk factor. Therefore, the approach to secondary stroke prevention must be multifactorial. In fact, it has been estimated that 80% of recurrent strokes could be prevented through the application of a comprehensive, multifactorial approach that includes lifestyle modification and optimal medical management.¹ Such an achievement would save millions of people from disability and functional decline, as well as millions of dollars in related medical costs.

The initial approach to patients with stroke is focused on stabilization and a rapid work-up to identify the most likely etiology. Common causes of stroke include large artery atherosclerosis, cardiac emboli, and small vessel disease; less common causes include dissection, aortic emboli, and non-atherosclerotic vascular disease. If a complete diagnostic work-up is unrevealing, the stroke is said to be cryptogenic. Determining the correct etiology of a stroke is paramount to preventing secondary stroke (FIGURE^2-13).

Effective secondary prevention strategies designed to prevent a stroke or transient ischemic attack (TIA) in a patient with a known history of either event include lifestyle modifications, medications, and when appropriate, mechanical interventions. As a primary care physician (PCP), you are uniquely positioned to spearhead the prevention of secondary strokes: Not only are you at the forefront of prevention and the use of techniques such as motivational interviewing, but you also have longstanding relationships with many of your patients. In fact, the success of many interventions is improved by the informed, enduring, and trusting nature of relationships between patients and their PCPs.

In the first part of this 2-part series, we focused on subacute stroke management and outlined the recommended work-up for subacute stroke/TIA (see “Stroke: A road map to subacute management,” 2017;66:366-374). In this part, we focus on secondary prevention. The more common modifiable conditions encountered in primary care are discussed here, while many of the more rare etiologies (hypercoagulable states, sickle cell disease, and vasculitis) are outside the scope of this article.

Lifestyle interventions: Target tobacco use, obesity, alcohol intake

Lifestyle modifications can have a positive impact on many of America’s most prevalent diseases, and stroke is no exception.¹⁴ Many of the disease states identified as risk factors for stroke (type 2 diabetes, hypertension, dyslipidemia) are exacerbated by tobacco use, obesity, and excessive alcohol intake.

Does your patient smoke? Up to 25% of all strokes are directly attributable to cigarette smoking.¹⁵ Smoking raises an individual’s risk for stroke in a dose-dependent fashion.^15,16 One study demonstrated that, compared to never-smokers, women ages 15 to 49 years who smoked a half-pack per day had an odds ratio for ischemic stroke of 2.2; those who smoked 2 packs per day had an odds ratio of 9.1.¹⁷ After cessation, stroke risk generally returns to baseline within 5 years.¹⁶ Thus, smoking cessation is among the most significant steps a patient can take to reduce the risk of both primary and secondary stroke.

Is your patient overweight? While obesity in and of itself is a risk factor for stroke, a focus on nutrition and physical activity as mechanisms for weight loss is far superior to focusing on either element alone. Physical activity—consisting of at least 40 minutes of moderate intensity aerobic exercise 3 to 4 times per week—and a diet that emphasizes fruits and vegetables, whole grains, and healthy fats, have both independently demonstrated benefits in secondary stroke prevention and are important parts of American College of Cardiology (ACC)/American Heart Association (AHA) guidelines.^2,3

It’s estimated that 80% of recurrent strokes could be prevented through the application of a comprehensive, multifactorial approach that includes optimal medical management.

The Mediterranean Diet, which emphasizes consumption of fruits and vegetables, legumes, tree nuts, olive oil, and lean protein, has long been associated with cardiovascular benefit.¹⁸ One prospective, randomized, single-blinded trial involving approximately 600 patients that looked at secondary prevention of coronary heart disease found that following the diet significantly reduced mortality compared with a usual prudent post-infarct diet (number needed to treat [NNT]=30 over 4 years).¹⁹

Is alcohol consumption an issue? Chronic heavy alcohol intake contributes to the development of hemorrhagic and ischemic stroke through multiple mechanisms, including alcohol-induced hypertension, alcoholic cardiomyopathy, and atrial fibrillation (AF). Light or moderate alcohol consumption has a paradoxical mild protective effect on ischemic stroke, thought to possibly be mediated by an increase in high-density lipoprotein (HDL) level and mild antiplatelet effect.³

AHA/American Stroke Association (ASA) guidelines indicate that no more than one standard drink per day for women and 2 drinks per day for men is reasonable.³ Counsel patients who drink in excess of this about the benefits of decreasing alcohol intake or abstaining altogether.

Choosing medications to manage BP, cholesterol, and clotting

Optimize blood pressure control. Blood pressure (BP) plays a critical role in both the management and prevention of stroke and is considered to be the most important modifiable risk factor in both primary and secondary stroke prevention.²⁰ In the first 24 to 48 hours following a cerebral ischemic event that is not eligible for thrombolysis, permissive hypertension (treating BP only if it exceeds 220/120 mm Hg unless there is a concurrent medical illness that requires you do so) is appropriate, as hypotension or rapid fluctuations in BP can be harmful.²¹

This flexibility does not continue into the subacute phase of management (at a minimum, after the initial 48 hours) or into secondary prevention. Initiation and titration of oral agents to gradually achieve a BP <140/90 mm Hg or a reduction of 10/5 mm Hg for patients already within optimal range are the most widely recognized goals.^3,20 Patients with stroke secondary to small vessel disease may benefit from an even lower goal of <130/<80 mm Hg.¹¹ Encourage patients to monitor their BP at home for added accuracy and consistency.²²

Pharmacologic BP management is appropriate for patients who are consistently above optimal range despite attempting recommended lifestyle modifications. The data are relatively consistent with respect to the effects of different drug classes after a stroke: beta-blockers have no effect on any outcome; thiazide diuretics significantly reduce stroke and total vascular events; angiotensin-converting enzyme (ACE) inhibitors significantly reduce myocardial infarction (MI); and the combination of an ACE inhibitor and thiazide diuretic reduces stroke, MI, and combined vascular events.⁴

This has led many stroke specialists to recommend the combination of an ACE inhibitor or angiotensin II receptor blocker (ARB) and a thiazide diuretic as a first-line approach to secondary stroke prevention rather than a beta-blocker (assuming there is no additional indication for a beta-blocker). Similarly, there is ample evidence to show that the magnitude of BP reduction is proportional to the reduction in recurrent vascular events.³

Make use of statin therapy—regardless of LDL. The SPARCL (Stroke Prevention by Aggressive Reduction in Cholesterol Levels) trial⁵ explored the potential role of statin medication for secondary stroke prevention. Researchers randomly assigned almost 5000 participants who’d had a stroke or TIA one to 6 months before study entry (but had no known history of coronary artery disease) to placebo or a high-intensity statin (80 mg/d atorvastatin). The statin group demonstrated a 4.9-year absolute risk reduction in fatal or nonfatal recurrent stroke of 1.9% (NNT=53).

Given these findings and those from other studies, the AHA and ASA recommend treating patients with stroke or TIA presumed to be of atherosclerotic origin with high-intensity statin therapy, regardless of low-density lipoprotein (LDL) level.³ Of note, statins are not indicated for the secondary prevention of hemorrhagic stroke.

Select antiplatelet therapy based on ischemic stroke subtype. Investigators are still trying to determine the optimal antiplatelet for secondary stroke prevention; it is likely that the ideal choice depends largely on the etiology of the stroke. Trials that did not select patients based on subtype of ischemic stroke have not shown a long-term benefit from dual antiplatelet therapy (clopidogrel and aspirin),^23,24 and one double-blind, multicenter trial involving more than 3000 patients with recent stroke secondary to small vessel disease demonstrated harm from such therapy in terms of a significantly increased risk of bleeding and death.⁶

Smoking cessation is among the most significant steps a patient can take to reduce the risk of both primary and secondary stroke.

However, a 2011 study compared aggressive medical management (aspirin 325 mg/d plus clopidogrel 75 mg/d for 90 days) alone to aggressive medical management plus percutaneous transluminal angioplasty and stenting (PTAS). The study involved almost 500 patients who'd had a recent TIA or stroke attributed to intracranial atherosclerotic stenosis. The authors found that the 30-day rate of stroke or death was 14.7% in the PTAS group vs 5.8% in the medical management group.²⁵

Similarly, a randomized double-blind, placebo-controlled trial published in 2013 involving over 5000 patients in China found that short-term use of dual antiplatelets (clopidogrel and aspirin for the first 21 days after an ischemic event, followed by aspirin monotherapy for 90 days) had an absolute risk reduction of 3.5% without increasing the risk of major bleeding in patients with high-risk TIA or minor stroke.²⁶

All stroke patients who do not have an indication for oral anticoagulation should be placed on long-term daily aspirin (75-325 mg); research has shown that lower doses are as effective as higher doses but with a lower risk of adverse gastrointestinal effects, including bleeding.^3,20 Aspirin 81 mg/d is a common effective dose.

For patients who cannot tolerate aspirin due to allergy, clopidogrel 75 mg/d is a reasonable alternative. Long-term studies of aspirin vs clopidogrel⁷ and clopidogrel vs extended-release dipyridamole⁸ showed no difference in secondary stroke prevention. The International Stroke Trial²⁷ and Chinese Acute Stroke Trial²⁸ both indicate that aspirin should be started as soon as possible after the onset of an acute stroke.

This special population should probably get antiplatelets, too. One recent study explored the use of an antiplatelet vs anticoagulation therapy for stroke patients with carotid artery dissection. The CADISS (Cervical Artery Dissection in Stroke Study) trial²⁹ randomized 250 patients with extracranial carotid and vertebral artery dissection with onset of symptoms within the previous 7 days to either antiplatelet or anticoagulation therapy and found no difference in the primary outcomes of recurrent stroke or death. The study also demonstrated a low risk of recurrent stroke in this population, which was 2% at 3-month follow-up.

Most patients with cervical artery dissection, therefore, are now treated with antiplatelet therapy. That said, situations may still arise in which anticoagulation can be considered, and consultation with a neurologist for guidance on choice of therapy is recommended.

Is an anticoagulant in order? Which agent, when

The most common cause of cardioembolic stroke is AF, which accounts for at least 15% of ischemic strokes, a number that rises in those over the age of 80.^20,30,31 A meta-analysis of more than 28,000 patients with non-valvular AF demonstrated that warfarin reduced the risk of stroke by 64%.³²

All ischemic stroke patients who do not have an indication for oral anticoagulation should be placed on long-term daily aspirin.

The rate of intracerebral hemorrhages during oral anticoagulation ranges from 0.3% to 0.6% per year.³³ The risk of bleeding complications can be mitigated by keeping international normalized ratios ≤3.0, maintaining good BP control, and avoiding concurrent use of antiplatelets in the absence of a clear indication for them.³³

Several risk assessment scores, such as the HAS-BLED,³⁴ can help with estimating the risk of hemorrhagic complications, although these scores have their limitations.^35,36 Even in an older population (mean age 83 years) with a high risk for falls, warfarin provided a net benefit in a composite endpoint of out-of-hospital death or hospitalization for stroke, MI, or hemorrhage in a retrospective study of over 1200 Medicare beneficiaries.³⁷

AF is not the only cause of cardioembolic stroke to consider. Additional high-risk factors warranting anticoagulation include rheumatic mitral valve disease, the presence of mechanical aortic or mitral valves, known mural thrombus, and acute anterior ST segment elevation myocardial infarctions (STEMIs) with resulting anterior apical dyskinesis/akinesis and concurrent ischemic stroke/TIA.³ (The specific management of each of these situations is beyond the scope of this paper.)

The choice of anticoagulation agent is based on multiple factors, including cost, risk of non-reversible bleeding, drug interactions, renal function, and patient preference. Approved options currently include warfarin/­vitamin K antagonist therapy, apixaban, rivaroxaban, dabigatran and edoxaban.³ Choice of therapy will continue to evolve as reversal agents, such as idarucizumab, are developed. Idarucizumab, a reversal agent for dabigatran, received approval from the US Food and Drug Administration in October 2015.³⁸

When to start anticoagulation. There are limited data regarding the optimal timing of initiation of anticoagulation following a stroke; however, a recent multicenter prospective study supported the common practice of initiating anticoagulation therapy within 4 to 14 days of the event.³⁹ Individual patient factors must be taken into consideration, including the size of the stroke (the larger the stroke, the higher the risk for hemorrhagic transformation), BP control, any additional risk factors for bleeding, and the estimated risk of early recurrent stroke.

Bridging patients onto anticoagulation with unfractionated or low-molecular-weight heparin in the setting of acute stroke is not recommended.⁴⁰ Results from randomized controlled trials involving unfractionated heparin, heparinoids, and low-molecular-weight heparin have not reported any benefit to these agents over aspirin at preventing early stroke recurrence.^27,41,42

For immobile or hospitalized patients. Subcutaneous heparin for the prevention of deep vein thrombosis (DVT) during immobility and hospitalization is recommended.⁴³ Patients who cannot tolerate anticoagulation should be maintained on low-dose antiplatelet therapy. Experts do not recommend dual treatment with aspirin and anticoagulation in most cases. However, recent coronary artery stent placement does require temporary dual treatment, with duration dependent on the type of stent placed.

A role for glycemic control? Still to be determined

The specific role of diabetic management in secondary stroke prevention remains unclear. The 2008 ACCORD trial,⁴⁴ a randomized study involving over 10,000 patients with a median glycated hemoglobin level of 8.1%, investigated intensive hyperglycemic control (targeting a glycated hemoglobin level <6.0% vs <7.9%) as a means of decreasing cardiovascular risk. However, the trial ended 17 months early because of an increase in all-cause mortality in the intensive treatment arm compared with the standard management group. The same trial was also unable to demonstrate a decrease in stroke risk with a decrease in A1c.⁴⁴

More recently, the IRIS (Insulin Resistance Intervention after Stroke) trial⁴⁵ (2016) found a 2.8% absolute risk reduction in stroke or MI among participants who had a stroke or TIA in the previous 6 months who were treated with pioglitazone vs placebo over 4.8 years (NNT=36). Participants were required to have insulin resistance, but were excluded if they had diabetes. The authors did, however, report a notable increase in the risk of bone fractures requiring surgery or hospitalization in the pioglitazone arm (5.1% vs 3.2%; number needed to harm [NNH]=53).

Treat patients with stroke or TIA presumed to be of atherosclerotic origin with high-intensity statin therapy, regardless of low-density lipoprotein level.

The impact this single study should have on standard secondary prevention is not yet clear. The authors concluded, “It seems reasonable to consider individual treatment preference and risk of drug-related adverse events in addition to potential benefits when making patient-specific decisions regarding therapy.”⁴⁵

Determining whether mechanical interventions are needed

Almost all conditions leading to stroke warrant active medical management, but a few benefit from procedural intervention, as well.

Extracranial carotid atherosclerosis. Carotid endarterectomy or carotid artery stenting is recommended as secondary prevention for patients with a history of stroke or TIA who have ipsilateral high-grade extracranial carotid stenosis of 70% to 99% and, in some cases, 50% to 69%.^3,9,20 In patients with mild non-disabling stroke, the optimal timing for these procedures is within 2 weeks of the ischemic event. A delay of 6 weeks is generally preferred for moderate or larger strokes to allow for some healing of the injured brain.

The choice of procedure is based on risk profile, with the most important factor being age. For patients >70 years, endarterectomy is preferred because stenting is associated with an increased risk of stroke.^3,9,10 Experts do not recommend either procedure for patients who have had a severe disabling stroke. Generally speaking, these procedures have higher rates of success when they are performed in centers that perform a higher number of these procedures.¹⁰

Vertebrobasilar atherosclerosis. Due to generally good compensatory blood flow of the contralateral vertebral artery in the setting of vertebral artery stenosis, and an unacceptably high complication rate of angioplasty and stenting in the basilar artery, medical management is typically the first-line approach. If a patient has recurrent symptoms in the setting of optimal medical management and a focal lesion that is amenable to an endovascular intervention (most commonly a vertebral artery origin high-grade stenosis), angioplasty and stenting may be considered.¹⁰

Intracranial atherosclerosis. Similarly, medical management is the preferred strategy for intracranial atherosclerosis. Angioplasty and/or stenting are reserved for complex cases or recurrence despite adherence to secondary stroke prevention measures. Ideally, these patients should be managed with long-term aspirin 81 mg/d, adjunctive clopidogrel 75 mg/d for 90 days post stroke, a high-intensity statin, BP optimization, and any relevant lifestyle interventions.¹³

Patent foramen ovale. Research to date has not shown that closure of a patent foramen ovale (PFO) is superior to medical therapy for secondary stroke prevention in patients <60 years with cryptogenic stroke.^12,46,47 The decision to anticoagulate these patients should be based on the presence or absence of a DVT and not on a PFO alone. In patients with an identified DVT and a contraindication to oral anticoagulation, inferior vena cava filter placement should be considered. For patients with ongoing prothrombotic risk thought to increase the chances of future paradoxical embolism, closure of the PFO may be considered.

CORRESPONDENCE
Stephen A. Martin, MD, EdM, Barre Family Health Center, 151 Worcester Road, Barre, MA 01005; stmartin@gmail.com.

Essure tubal microinserts were not designed to be removed. However, a small minority of women are requesting removal because of regret, complications, or the development of pelvic pain and other symptoms that may or may not be caused by the device.

Minimally invasive gynecologic surgeons have developed a variety of removal procedures and techniques for these women. There is general agreement that hysteroscopic removal is feasible only in the first 3 months following insertion of the device. After that, laparoscopic removal has become the norm. Small published reports and case series have documented the use of laparoscopic bilateral salpingectomy (BS) with and without hysterectomy, laparoscopic BS with cornuectomy, and laparoscopic salpingostomy, often followed by salpingectomy. There is not yet enough data to demonstrate that one method is superior to another, and we each have our own preferred approaches for preoperative imaging and removal.

Counseling, assessment, and consent

Dr. Cohen: We have to be frank with our patients that symptoms may or may not improve following Essure removal. In a recently published case series of 52 women who underwent Essure removal at our institution, three-quarters of the patients reported near or total improvement in the quality of life. However, a relatively high number – roughly 30% – reported some ongoing symptoms (J Minim Invasive Gynecol. 2017 Jun 6. doi: 10:1016/j.jmig.2017.05.015).

The most common indication for Essure removal in this series was pelvic pain (96%), followed by abnormal uterine bleeding (35%) and patient-reported allergic reaction (21%). The indications were not mutually exclusive.

Courtesy Dr. Sarah Cohen

Device structure and use of imaging

Essure is a 4-cm long device (0.8 mm in diameter) with two parts: an inner coil made of stainless steel and PET fibers, the latter of which induces the fibrosis responsible for tubal occlusion, and an outer coil made of nitinol, a nickel titanium alloy.

Dr. Cohen: While the exact mechanism is unclear, it’s possible that the PET fibers may be drivers of the systemic inflammatory-type symptoms that some women report. Nickel allergies are also possible albeit uncommon. They appear to manifest as rash, urticaria, and other symptoms characteristic of contact allergic reactions.

The brittle nature of the outer coil makes a grasp-and-pull approach disadvantageous, unless you’re removing coils early on hysteroscopically. In general, one must avoid fracturing the outer coil, or parts of the device will be left behind. Pulling too hard may also cause the outer coil to unravel and expand to be quite long, which further increases the risk of fracture.

Hysterosalpingogram (HSG) and ultrasound are typically first-line options for looking at coil position. A diagnostic hysteroscopy may also help identify coils, and intraoperative fluoroscopy may be useful for either the hysteroscopic or laparoscopic approach, if there’s any question about portions of the device not being recovered.

Dr. Levie: Ultrasound is often sufficient for operative planning, but, if it does not detect devices in the cornual region, then further imaging may be warranted.

It’s important to be aware that some devices that appear to have correct placement on ultrasound or HSG may actually be partially tracking subserosally. In these cases, the distal portion of the device may have tracked through the mucosal layer and along the muscularis but below the serosa in the fallopian tube, causing pain. Imaging won’t be helpful in making this diagnosis. It will be identified laparoscopically.

Dr. Yunker: When patients have completed the 3-month HSG (to confirm occlusion of the Fallopian tubes post placement), I will review the images myself rather than relying on the report. Without an HSG – and, in many cases, even when I have it in hand – I will order a plain film x-ray of the abdomen and pelvis to look for coils. In almost all cases, I also order an ultrasound, which is helpful in assessing for ovarian and uterine conditions.

I’ve found plain film imaging to be valuable for identifying additional or misplaced Essure inserts. I have found up to four in one tube. In interpreting x-rays, one must appreciate that the outer coil is not radio-opaque (other than the tiny marker at the end) and will not show up. Occasionally we’ll add hysteroscopy to see how much of a coil is trailing into the uterus, but the ultrasound and x-ray are usually enough.

Some patients ask about postremoval imaging. I do not routinely do this, but I’m not opposed to it.

Surgical techniques

Dr. Cohen: I advise dissecting around each coil without cutting the outer portion and removing the coil intact, resecting all the way down to the interstitial portion of the tube, then proceeding with bilateral salpingectomy to ensure contraception.

If the patient’s symptoms are systemic and possibly reflective of PET fiber reactions, a wedge resection of the cornua may provide more peace of mind that PET fibers will not be left in situ. This procedure can be approached similarly to myomectomy, with the use of hemostatic agents such as misoprostol or vasopressin and suture closure in multiple layers.

If there are multiple coils present in the cavity, one option, to avoid having to pull them all out from the abdominal side, is to transect and remove the intracavity portion of the device hysteroscopically then dissect and remove the tubal/interstitial potion laparoscopically. As a general rule, I send all the removed tissue to pathology.

Dr. Levie: In general, I do a linear salpingostomy after using a uterine manipulator and a grasper to first identify the site of the distal portion of the device. One can usually feel where the tubes bend onto the device.

A bit proximal to where I visually and mentally mark the distal end of the device, I make a 2-3 cm incision over the device. With a fine-tip grasper, I can usually release the distal portion of the inner coil. Using two graspers over the inner and outer coils together and a hand-over-hand motion, I pull without excess traction in the access of the tubes, and the proximal portion will usually follow and deliver fairly simply. If the proximal portion breaks, I advise looking for it hysteroscopically and delivering it through the uterus.

Some surgeons have recommended hysteroscopy at the beginning of the procedure with cutting (using scissors) at the proximal end of the outer coil to avoid its getting caught in the cornua.

Most patients continue to want permanent sterilization, so we proceed with salpingectomy. Sometimes, given underlying pathologies, we’ll decide on laparoscopic or vaginal hysterectomy as well or bilateral salpingectomy without doing the salpingostomy. When hysterectomy is part of the surgery, we don’t need to worry at all about broken devices.

When the device is removed separately from the fallopian tube, one should inspect it afterward to ensure that all four markers of the device – the markers that are recommended by the manufacturer for radiologic confirmation of proper placement – have been delivered.

Dr. Yunker: When everything looks normal on the ultrasound – and when the coils on either HSG and/or plain film x-ray appear to be in the appropriate position in the tubes – then removal of the coils and tubes only is an option.

The closer the coil is to the fimbriae, the easier it is to come straight across the tube as you would in a regular salpingectomy without concern of breaking or cutting the coil. However, the closer the coil is the uterine side, the deeper you’ll need to dissect into the cornual region of the uterus. A cornual wedge resection may be necessary in order to remove the coil intact.

Our procedure has evolved over the years and we have moved away from salpingectomy as a means to dissect out the coils. With the theoretical risk of retained coil fragments and PET fibers, we prefer to remove the coils and tubes en bloc.

Dr. Cohen is director of research and the fellowship program director of minimally invasive gynecologic surgery at Brigham and Women’s Hospital, Boston. She reported that she has no financial disclosures. Dr. Levie is professor and associate chairman of the department of obstetrics and gynecology and women’s health and director of the minimally invasive surgery fellowship at Montefiore Medical Center, New York. Dr. Levie reported that he is an investigator in two studies involving Essure and sat on the Essure medical advisory board for Bayer but did not receive personal renumeration. Dr. Yunker is an assistant professor of obstetrics and gynecology at Vanderbilt University, Nashville. She reported that she is a consultant for Olympus.

Essure tubal microinserts were not designed to be removed. However, a small minority of women are requesting removal because of regret, complications, or the development of pelvic pain and other symptoms that may or may not be caused by the device.

Minimally invasive gynecologic surgeons have developed a variety of removal procedures and techniques for these women. There is general agreement that hysteroscopic removal is feasible only in the first 3 months following insertion of the device. After that, laparoscopic removal has become the norm. Small published reports and case series have documented the use of laparoscopic bilateral salpingectomy (BS) with and without hysterectomy, laparoscopic BS with cornuectomy, and laparoscopic salpingostomy, often followed by salpingectomy. There is not yet enough data to demonstrate that one method is superior to another, and we each have our own preferred approaches for preoperative imaging and removal.

Counseling, assessment, and consent

Dr. Cohen: We have to be frank with our patients that symptoms may or may not improve following Essure removal. In a recently published case series of 52 women who underwent Essure removal at our institution, three-quarters of the patients reported near or total improvement in the quality of life. However, a relatively high number – roughly 30% – reported some ongoing symptoms (J Minim Invasive Gynecol. 2017 Jun 6. doi: 10:1016/j.jmig.2017.05.015).

The most common indication for Essure removal in this series was pelvic pain (96%), followed by abnormal uterine bleeding (35%) and patient-reported allergic reaction (21%). The indications were not mutually exclusive.

Courtesy Dr. Sarah Cohen

Device structure and use of imaging

Essure is a 4-cm long device (0.8 mm in diameter) with two parts: an inner coil made of stainless steel and PET fibers, the latter of which induces the fibrosis responsible for tubal occlusion, and an outer coil made of nitinol, a nickel titanium alloy.

Dr. Cohen: While the exact mechanism is unclear, it’s possible that the PET fibers may be drivers of the systemic inflammatory-type symptoms that some women report. Nickel allergies are also possible albeit uncommon. They appear to manifest as rash, urticaria, and other symptoms characteristic of contact allergic reactions.

The brittle nature of the outer coil makes a grasp-and-pull approach disadvantageous, unless you’re removing coils early on hysteroscopically. In general, one must avoid fracturing the outer coil, or parts of the device will be left behind. Pulling too hard may also cause the outer coil to unravel and expand to be quite long, which further increases the risk of fracture.

Hysterosalpingogram (HSG) and ultrasound are typically first-line options for looking at coil position. A diagnostic hysteroscopy may also help identify coils, and intraoperative fluoroscopy may be useful for either the hysteroscopic or laparoscopic approach, if there’s any question about portions of the device not being recovered.

Dr. Levie: Ultrasound is often sufficient for operative planning, but, if it does not detect devices in the cornual region, then further imaging may be warranted.

It’s important to be aware that some devices that appear to have correct placement on ultrasound or HSG may actually be partially tracking subserosally. In these cases, the distal portion of the device may have tracked through the mucosal layer and along the muscularis but below the serosa in the fallopian tube, causing pain. Imaging won’t be helpful in making this diagnosis. It will be identified laparoscopically.

Dr. Yunker: When patients have completed the 3-month HSG (to confirm occlusion of the Fallopian tubes post placement), I will review the images myself rather than relying on the report. Without an HSG – and, in many cases, even when I have it in hand – I will order a plain film x-ray of the abdomen and pelvis to look for coils. In almost all cases, I also order an ultrasound, which is helpful in assessing for ovarian and uterine conditions.

I’ve found plain film imaging to be valuable for identifying additional or misplaced Essure inserts. I have found up to four in one tube. In interpreting x-rays, one must appreciate that the outer coil is not radio-opaque (other than the tiny marker at the end) and will not show up. Occasionally we’ll add hysteroscopy to see how much of a coil is trailing into the uterus, but the ultrasound and x-ray are usually enough.

Some patients ask about postremoval imaging. I do not routinely do this, but I’m not opposed to it.

Surgical techniques

Dr. Cohen: I advise dissecting around each coil without cutting the outer portion and removing the coil intact, resecting all the way down to the interstitial portion of the tube, then proceeding with bilateral salpingectomy to ensure contraception.

If the patient’s symptoms are systemic and possibly reflective of PET fiber reactions, a wedge resection of the cornua may provide more peace of mind that PET fibers will not be left in situ. This procedure can be approached similarly to myomectomy, with the use of hemostatic agents such as misoprostol or vasopressin and suture closure in multiple layers.

If there are multiple coils present in the cavity, one option, to avoid having to pull them all out from the abdominal side, is to transect and remove the intracavity portion of the device hysteroscopically then dissect and remove the tubal/interstitial potion laparoscopically. As a general rule, I send all the removed tissue to pathology.

Dr. Levie: In general, I do a linear salpingostomy after using a uterine manipulator and a grasper to first identify the site of the distal portion of the device. One can usually feel where the tubes bend onto the device.

A bit proximal to where I visually and mentally mark the distal end of the device, I make a 2-3 cm incision over the device. With a fine-tip grasper, I can usually release the distal portion of the inner coil. Using two graspers over the inner and outer coils together and a hand-over-hand motion, I pull without excess traction in the access of the tubes, and the proximal portion will usually follow and deliver fairly simply. If the proximal portion breaks, I advise looking for it hysteroscopically and delivering it through the uterus.

Some surgeons have recommended hysteroscopy at the beginning of the procedure with cutting (using scissors) at the proximal end of the outer coil to avoid its getting caught in the cornua.

Most patients continue to want permanent sterilization, so we proceed with salpingectomy. Sometimes, given underlying pathologies, we’ll decide on laparoscopic or vaginal hysterectomy as well or bilateral salpingectomy without doing the salpingostomy. When hysterectomy is part of the surgery, we don’t need to worry at all about broken devices.

When the device is removed separately from the fallopian tube, one should inspect it afterward to ensure that all four markers of the device – the markers that are recommended by the manufacturer for radiologic confirmation of proper placement – have been delivered.

Dr. Yunker: When everything looks normal on the ultrasound – and when the coils on either HSG and/or plain film x-ray appear to be in the appropriate position in the tubes – then removal of the coils and tubes only is an option.

The closer the coil is to the fimbriae, the easier it is to come straight across the tube as you would in a regular salpingectomy without concern of breaking or cutting the coil. However, the closer the coil is the uterine side, the deeper you’ll need to dissect into the cornual region of the uterus. A cornual wedge resection may be necessary in order to remove the coil intact.

Our procedure has evolved over the years and we have moved away from salpingectomy as a means to dissect out the coils. With the theoretical risk of retained coil fragments and PET fibers, we prefer to remove the coils and tubes en bloc.

Dr. Cohen is director of research and the fellowship program director of minimally invasive gynecologic surgery at Brigham and Women’s Hospital, Boston. She reported that she has no financial disclosures. Dr. Levie is professor and associate chairman of the department of obstetrics and gynecology and women’s health and director of the minimally invasive surgery fellowship at Montefiore Medical Center, New York. Dr. Levie reported that he is an investigator in two studies involving Essure and sat on the Essure medical advisory board for Bayer but did not receive personal renumeration. Dr. Yunker is an assistant professor of obstetrics and gynecology at Vanderbilt University, Nashville. She reported that she is a consultant for Olympus.

Essure tubal microinserts were not designed to be removed. However, a small minority of women are requesting removal because of regret, complications, or the development of pelvic pain and other symptoms that may or may not be caused by the device.

Minimally invasive gynecologic surgeons have developed a variety of removal procedures and techniques for these women. There is general agreement that hysteroscopic removal is feasible only in the first 3 months following insertion of the device. After that, laparoscopic removal has become the norm. Small published reports and case series have documented the use of laparoscopic bilateral salpingectomy (BS) with and without hysterectomy, laparoscopic BS with cornuectomy, and laparoscopic salpingostomy, often followed by salpingectomy. There is not yet enough data to demonstrate that one method is superior to another, and we each have our own preferred approaches for preoperative imaging and removal.

Counseling, assessment, and consent

Dr. Cohen: We have to be frank with our patients that symptoms may or may not improve following Essure removal. In a recently published case series of 52 women who underwent Essure removal at our institution, three-quarters of the patients reported near or total improvement in the quality of life. However, a relatively high number – roughly 30% – reported some ongoing symptoms (J Minim Invasive Gynecol. 2017 Jun 6. doi: 10:1016/j.jmig.2017.05.015).

The most common indication for Essure removal in this series was pelvic pain (96%), followed by abnormal uterine bleeding (35%) and patient-reported allergic reaction (21%). The indications were not mutually exclusive.

Courtesy Dr. Sarah Cohen

Device structure and use of imaging

Essure is a 4-cm long device (0.8 mm in diameter) with two parts: an inner coil made of stainless steel and PET fibers, the latter of which induces the fibrosis responsible for tubal occlusion, and an outer coil made of nitinol, a nickel titanium alloy.

Dr. Cohen: While the exact mechanism is unclear, it’s possible that the PET fibers may be drivers of the systemic inflammatory-type symptoms that some women report. Nickel allergies are also possible albeit uncommon. They appear to manifest as rash, urticaria, and other symptoms characteristic of contact allergic reactions.

The brittle nature of the outer coil makes a grasp-and-pull approach disadvantageous, unless you’re removing coils early on hysteroscopically. In general, one must avoid fracturing the outer coil, or parts of the device will be left behind. Pulling too hard may also cause the outer coil to unravel and expand to be quite long, which further increases the risk of fracture.

Hysterosalpingogram (HSG) and ultrasound are typically first-line options for looking at coil position. A diagnostic hysteroscopy may also help identify coils, and intraoperative fluoroscopy may be useful for either the hysteroscopic or laparoscopic approach, if there’s any question about portions of the device not being recovered.

Dr. Levie: Ultrasound is often sufficient for operative planning, but, if it does not detect devices in the cornual region, then further imaging may be warranted.

It’s important to be aware that some devices that appear to have correct placement on ultrasound or HSG may actually be partially tracking subserosally. In these cases, the distal portion of the device may have tracked through the mucosal layer and along the muscularis but below the serosa in the fallopian tube, causing pain. Imaging won’t be helpful in making this diagnosis. It will be identified laparoscopically.

Dr. Yunker: When patients have completed the 3-month HSG (to confirm occlusion of the Fallopian tubes post placement), I will review the images myself rather than relying on the report. Without an HSG – and, in many cases, even when I have it in hand – I will order a plain film x-ray of the abdomen and pelvis to look for coils. In almost all cases, I also order an ultrasound, which is helpful in assessing for ovarian and uterine conditions.

I’ve found plain film imaging to be valuable for identifying additional or misplaced Essure inserts. I have found up to four in one tube. In interpreting x-rays, one must appreciate that the outer coil is not radio-opaque (other than the tiny marker at the end) and will not show up. Occasionally we’ll add hysteroscopy to see how much of a coil is trailing into the uterus, but the ultrasound and x-ray are usually enough.

Some patients ask about postremoval imaging. I do not routinely do this, but I’m not opposed to it.

Surgical techniques

Dr. Cohen: I advise dissecting around each coil without cutting the outer portion and removing the coil intact, resecting all the way down to the interstitial portion of the tube, then proceeding with bilateral salpingectomy to ensure contraception.

If the patient’s symptoms are systemic and possibly reflective of PET fiber reactions, a wedge resection of the cornua may provide more peace of mind that PET fibers will not be left in situ. This procedure can be approached similarly to myomectomy, with the use of hemostatic agents such as misoprostol or vasopressin and suture closure in multiple layers.

If there are multiple coils present in the cavity, one option, to avoid having to pull them all out from the abdominal side, is to transect and remove the intracavity portion of the device hysteroscopically then dissect and remove the tubal/interstitial potion laparoscopically. As a general rule, I send all the removed tissue to pathology.

Dr. Levie: In general, I do a linear salpingostomy after using a uterine manipulator and a grasper to first identify the site of the distal portion of the device. One can usually feel where the tubes bend onto the device.

A bit proximal to where I visually and mentally mark the distal end of the device, I make a 2-3 cm incision over the device. With a fine-tip grasper, I can usually release the distal portion of the inner coil. Using two graspers over the inner and outer coils together and a hand-over-hand motion, I pull without excess traction in the access of the tubes, and the proximal portion will usually follow and deliver fairly simply. If the proximal portion breaks, I advise looking for it hysteroscopically and delivering it through the uterus.

Some surgeons have recommended hysteroscopy at the beginning of the procedure with cutting (using scissors) at the proximal end of the outer coil to avoid its getting caught in the cornua.

Most patients continue to want permanent sterilization, so we proceed with salpingectomy. Sometimes, given underlying pathologies, we’ll decide on laparoscopic or vaginal hysterectomy as well or bilateral salpingectomy without doing the salpingostomy. When hysterectomy is part of the surgery, we don’t need to worry at all about broken devices.

When the device is removed separately from the fallopian tube, one should inspect it afterward to ensure that all four markers of the device – the markers that are recommended by the manufacturer for radiologic confirmation of proper placement – have been delivered.

Dr. Yunker: When everything looks normal on the ultrasound – and when the coils on either HSG and/or plain film x-ray appear to be in the appropriate position in the tubes – then removal of the coils and tubes only is an option.

The closer the coil is to the fimbriae, the easier it is to come straight across the tube as you would in a regular salpingectomy without concern of breaking or cutting the coil. However, the closer the coil is the uterine side, the deeper you’ll need to dissect into the cornual region of the uterus. A cornual wedge resection may be necessary in order to remove the coil intact.

Our procedure has evolved over the years and we have moved away from salpingectomy as a means to dissect out the coils. With the theoretical risk of retained coil fragments and PET fibers, we prefer to remove the coils and tubes en bloc.

Dr. Cohen is director of research and the fellowship program director of minimally invasive gynecologic surgery at Brigham and Women’s Hospital, Boston. She reported that she has no financial disclosures. Dr. Levie is professor and associate chairman of the department of obstetrics and gynecology and women’s health and director of the minimally invasive surgery fellowship at Montefiore Medical Center, New York. Dr. Levie reported that he is an investigator in two studies involving Essure and sat on the Essure medical advisory board for Bayer but did not receive personal renumeration. Dr. Yunker is an assistant professor of obstetrics and gynecology at Vanderbilt University, Nashville. She reported that she is a consultant for Olympus.

Despite recent negative lay press and a boxed safety warning from the Food and Drug Administration, Essure tubal microinserts continue to be a popular method of permanent contraception. It is imperative for patients to understand that this method of contraception cannot be reversed, and thereafter, the only method to achieve pregnancy would be via in vitro fertilization. Furthermore, preoperatively, patients must be counseled that placement of the Essure tubal microinserts may be associated with pelvic pain, abnormal bleeding, and even allergic reaction.

Even with our best effort to properly inform our patients as to the risks and benefits of permanent sterilization via Essure tubal microinserts, secondary to undesired side effects, patients desire their removal. This can be a challenging endeavor for the practitioner, especially if the women is not interested in hysterectomy.

Dr. Miller is clinical associate professor at the University of Illinois at Chicago and past president of the AAGL. He is a reproductive endocrinologist and minimally invasive gynecologic surgeon in metropolitan Chicago; director of minimally invasive gynecologic surgery at Advocate Lutheran General Hospital, Park Ridge, Ill.; and the medical editor of this column. He reported having no financial disclosures related to this column.

Despite recent negative lay press and a boxed safety warning from the Food and Drug Administration, Essure tubal microinserts continue to be a popular method of permanent contraception. It is imperative for patients to understand that this method of contraception cannot be reversed, and thereafter, the only method to achieve pregnancy would be via in vitro fertilization. Furthermore, preoperatively, patients must be counseled that placement of the Essure tubal microinserts may be associated with pelvic pain, abnormal bleeding, and even allergic reaction.

Even with our best effort to properly inform our patients as to the risks and benefits of permanent sterilization via Essure tubal microinserts, secondary to undesired side effects, patients desire their removal. This can be a challenging endeavor for the practitioner, especially if the women is not interested in hysterectomy.

Dr. Miller is clinical associate professor at the University of Illinois at Chicago and past president of the AAGL. He is a reproductive endocrinologist and minimally invasive gynecologic surgeon in metropolitan Chicago; director of minimally invasive gynecologic surgery at Advocate Lutheran General Hospital, Park Ridge, Ill.; and the medical editor of this column. He reported having no financial disclosures related to this column.

Despite recent negative lay press and a boxed safety warning from the Food and Drug Administration, Essure tubal microinserts continue to be a popular method of permanent contraception. It is imperative for patients to understand that this method of contraception cannot be reversed, and thereafter, the only method to achieve pregnancy would be via in vitro fertilization. Furthermore, preoperatively, patients must be counseled that placement of the Essure tubal microinserts may be associated with pelvic pain, abnormal bleeding, and even allergic reaction.

Even with our best effort to properly inform our patients as to the risks and benefits of permanent sterilization via Essure tubal microinserts, secondary to undesired side effects, patients desire their removal. This can be a challenging endeavor for the practitioner, especially if the women is not interested in hysterectomy.

Dr. Miller is clinical associate professor at the University of Illinois at Chicago and past president of the AAGL. He is a reproductive endocrinologist and minimally invasive gynecologic surgeon in metropolitan Chicago; director of minimally invasive gynecologic surgery at Advocate Lutheran General Hospital, Park Ridge, Ill.; and the medical editor of this column. He reported having no financial disclosures related to this column.

Over the last 2 decades, there has been a growing interest in establishing a rich evidence base for treatment of psychiatric illness in pregnancy and the postpartum period. It seems as if a week does not go by when we don’t find multiple publications in the scientific literature describing a new finding or confirmation or inconsistency with existing data – whether it is a small prospective cohort study or an elegant analysis of a large administrative database. The goals of these reports center on refining our knowledge of safe treatments for perinatal psychiatric disorders.

Despite these strides, my colleagues and I frequently see a divergence between recommendations in the literature and what is done clinically by those who treat women around reproductive associated psychiatric disturbance – premenstrual dysphoric disorder or psychiatric disorder during pregnancy and the postpartum period. In some cases, scientific evidence has not filtered into day to day practice and some physicians continue to follow practices that, while outdated, make intuitive sense. In other clinical situations, limited evidence is being applied too broadly or data are too sparse to clearly inform practice. Regardless of the reason, we frequently see patients in clinical situations in which we are forced to rethink the clinical rationale for advice they have received or the clinical path taken.

1. Discontinuation of antidepressants proximate to conception

Despite multiple studies supporting the high risk for relapse of major depression in women on maintenance antidepressant therapy with a history of recurrent depressive illness, it is still quite common for clinicians to routinely advise women to stop antidepressants while planning a pregnancy or after documentation of a pregnancy, regardless of the severity of the underlying illness. This runs counter to data showing high rates of relapse in women who stop antidepressants proximate to conception, the safety of antidepressants in pregnancy, and the harm to the mother and fetus when depression during pregnancy is untreated.

2. Use of a lower dose of antidepressants during pregnancy

It makes intuitive sense to use the smallest dose of medicine like antidepressant during pregnancy. However, multiple studies show that, at least in nonpregnant patients, the dose that gets patients well is typically the dose that keeps them well. One of the quickest paths to relapse in depression is a reduction in the antidepressant dose after someone has gotten well. This is even more relevant in pregnant patients because pregnancy itself dilutes the plasma level of the antidepressant given the rapidly expanding plasma volume seen in pregnancy. One can debate whether clinicians should empirically increase the dose of antidepressant during pregnancy to sustain plasma level of medication, but lowering the dose of this medication proximate or during pregnancy makes little sense.

3. A switch to sertraline in pregnancy/post partum

Another scenario that my colleagues and I often see is a pregnant patient whose depression was previously well controlled with a particular antidepressant, but whose physician, once she decides to conceive or becomes pregnant, switched her to sertraline.

The idea, which has been around for a long time, is that sertraline is the safest antidepressant for pregnant women because it has robust reproductive safety data and has particularly modest amounts of medication (if detected at all) in the plasma of infants of mothers who breastfeed while using the medicine. While we certainly have more safety data on SSRIs that were manufactured earlier, as compared with antidepressants that became available later, we have now accumulated data that fails to demonstrate a clear signal for teratogenicity across many antidepressants manufactured over the last 2 decades. Identifying an antidepressant for a given patient to which she will respond can be a challenging course for the patient. Achieving euthymia and subsequently switching to sertraline or another medication may only put her at risk for recurrence of depression and its attendant morbidity.

©Purestock/Thinkstock

4. A change to a Category B label drug

This is another example of switching a patient to a potentially less effective drug in a somewhat misguided effort at finding a treatment that is safer in pregnancy. While the Food and Drug Administration’s drug category label system was a step forward, or at least a well intentioned effort to give women and their clinicians clearer insight into the reproductive safety of a medication, ultimately, the incomplete nature of the information caused the agency to transition to a new system (see the Pregnancy Labeling and Lactation Rule). Switching a woman to a category B medicine with sparse reproductive safety data instead of a category C medicine, which may not be unsafe but has raised some concerns in animal models, is not a better choice. The new labeling system is a step forward.

5. Discontinuation of lithium during pregnancy

Like discontinuation of antidepressants, the discontinuation of lithium during attempts to conceive in a woman whose illness has been well controlled, is associated with a high risk of relapse. In earlier work, it was sometimes recommended that discontinuation of lithium be considered after a long period of wellness. We have learned over time that this can be a risky move. Even women with a remote history of bipolar disorder appear to be at high risk of relapse when a mood stabilizer is stopped. Exquisite response to medicine does not imply less severe illness. Women who have bipolar disorder who have sustained euthymia on lithium should consider maintaining the safest possible regimen before, during, and after pregnancy despite the known small teratogenic risk associated with fetal exposure to this agent.

6. Try supplements or alternative therapies

Out of a desire to avoid any medication with incomplete reproductive safety data, some women and clinicians make the intuitive leap that “alternative treatments” can mitigate relapse in pregnancy, and they stop pharmacological treatments and switch to supplements or alternative therapies, including acupuncture, massage, or light therapy. Unfortunately, data supporting this clinical maneuver are sparse. Frequently, we see women with past histories of severe depression who have stopped antidepressants and who have started supplements as a substitute and who then relapse. Then, they try to restore euthymia with antidepressants and psychotherapy, and the road to restoration of well-being can be long.

Data on efficacy of alternative therapies continues to evolve and is an exciting and important area of research. However, where these treatments are best employed in the algorithm for treating depression in pregnancy, or at other times, has yet to be adequately defined.
 

7. Stop breastfeeding or defer antidepressant treatment

Many women continue to be counseled to either stop breastfeeding while using antidepressants or to defer treatment with antidepressants if they wish to breastfeed. Not uncommonly, we see women who are suffering from postpartum depression and who are engaged in psychotherapy but who have deferred treatment with antidepressants despite residual depressive symptoms that impair functioning. Clinicians should keep in mind that data supporting evidence of toxicity in newborns of women using antidepressants while breastfeeding are extremely sparse. Unfortunately, some women with postpartum depression are deferring treatment because they were counseled that it is not compatible with their desire to breastfeed.

8. Use of non-benzodiazepine sedative-hypnotics

Insomnia is a common problem in pregnancy, especially when coupled with comorbid anxiety, and, increasingly, it is being treated with non-benzodiazepine sedative-hypnotics. Clinicians should keep in mind that a known small risk may be better than an unknown risk. If a pregnant woman has severe insomnia, she may benefit from a low dose of a benzodiazepine, such as lorazepam or clonazepam, as opposed to a medication such as zolpidem for which reproductive safety data are particularly limited.

9. Pumping and dumping breast milk

Many women are advised to set an alarm to “pump and dump” their breast milk to minimize their baby’s exposure to antidepressants during breastfeeding. Early literature to pump and dump breast milk at peak antidepressant concentration was of great analytic and theoretical interest but has scant clinical application. As an author of many of those early publications, I can say that we never intended for women to sacrifice precious sleep to dump breast milk with the idea that limiting exposure to trace amounts of antidepressants would have beneficial effects over the long term.

10. Failure to bring up contraception use

We continue to see a 50% unplanned pregnancy rate across sociodemographic groups in the United States. This is a critical statistic because it may affect how treatment is managed. Bringing up the topic of reliable contraception prior to pregnancy allows for planned pregnancy and affords us the time to discuss treatment options and the ability to plot a more thoughtful and safe clinical course. However, often, contraception is not discussed.

One of our goals as clinicians is to, first, do no harm and that continues to be a challenge because the data in perinatal psychiatry is still inconsistent in some areas and there are evidence gaps in others. Nevertheless, our task is to take the best available data along with the patient’s wishes and knowledge of her past clinical history and to then translate that into the best care for the individual.

Dr. Cohen is the director of the Ammon-Pinizzotto Center for Women’s Mental Health at Massachusetts General Hospital in Boston, which provides information resources and conducts clinical care and research in reproductive mental health. He has been a consultant to manufacturers of psychiatric medications.

Over the last 2 decades, there has been a growing interest in establishing a rich evidence base for treatment of psychiatric illness in pregnancy and the postpartum period. It seems as if a week does not go by when we don’t find multiple publications in the scientific literature describing a new finding or confirmation or inconsistency with existing data – whether it is a small prospective cohort study or an elegant analysis of a large administrative database. The goals of these reports center on refining our knowledge of safe treatments for perinatal psychiatric disorders.

Despite these strides, my colleagues and I frequently see a divergence between recommendations in the literature and what is done clinically by those who treat women around reproductive associated psychiatric disturbance – premenstrual dysphoric disorder or psychiatric disorder during pregnancy and the postpartum period. In some cases, scientific evidence has not filtered into day to day practice and some physicians continue to follow practices that, while outdated, make intuitive sense. In other clinical situations, limited evidence is being applied too broadly or data are too sparse to clearly inform practice. Regardless of the reason, we frequently see patients in clinical situations in which we are forced to rethink the clinical rationale for advice they have received or the clinical path taken.

1. Discontinuation of antidepressants proximate to conception

Despite multiple studies supporting the high risk for relapse of major depression in women on maintenance antidepressant therapy with a history of recurrent depressive illness, it is still quite common for clinicians to routinely advise women to stop antidepressants while planning a pregnancy or after documentation of a pregnancy, regardless of the severity of the underlying illness. This runs counter to data showing high rates of relapse in women who stop antidepressants proximate to conception, the safety of antidepressants in pregnancy, and the harm to the mother and fetus when depression during pregnancy is untreated.

2. Use of a lower dose of antidepressants during pregnancy

It makes intuitive sense to use the smallest dose of medicine like antidepressant during pregnancy. However, multiple studies show that, at least in nonpregnant patients, the dose that gets patients well is typically the dose that keeps them well. One of the quickest paths to relapse in depression is a reduction in the antidepressant dose after someone has gotten well. This is even more relevant in pregnant patients because pregnancy itself dilutes the plasma level of the antidepressant given the rapidly expanding plasma volume seen in pregnancy. One can debate whether clinicians should empirically increase the dose of antidepressant during pregnancy to sustain plasma level of medication, but lowering the dose of this medication proximate or during pregnancy makes little sense.

3. A switch to sertraline in pregnancy/post partum

Another scenario that my colleagues and I often see is a pregnant patient whose depression was previously well controlled with a particular antidepressant, but whose physician, once she decides to conceive or becomes pregnant, switched her to sertraline.

The idea, which has been around for a long time, is that sertraline is the safest antidepressant for pregnant women because it has robust reproductive safety data and has particularly modest amounts of medication (if detected at all) in the plasma of infants of mothers who breastfeed while using the medicine. While we certainly have more safety data on SSRIs that were manufactured earlier, as compared with antidepressants that became available later, we have now accumulated data that fails to demonstrate a clear signal for teratogenicity across many antidepressants manufactured over the last 2 decades. Identifying an antidepressant for a given patient to which she will respond can be a challenging course for the patient. Achieving euthymia and subsequently switching to sertraline or another medication may only put her at risk for recurrence of depression and its attendant morbidity.

©Purestock/Thinkstock

4. A change to a Category B label drug

This is another example of switching a patient to a potentially less effective drug in a somewhat misguided effort at finding a treatment that is safer in pregnancy. While the Food and Drug Administration’s drug category label system was a step forward, or at least a well intentioned effort to give women and their clinicians clearer insight into the reproductive safety of a medication, ultimately, the incomplete nature of the information caused the agency to transition to a new system (see the Pregnancy Labeling and Lactation Rule). Switching a woman to a category B medicine with sparse reproductive safety data instead of a category C medicine, which may not be unsafe but has raised some concerns in animal models, is not a better choice. The new labeling system is a step forward.

5. Discontinuation of lithium during pregnancy

Like discontinuation of antidepressants, the discontinuation of lithium during attempts to conceive in a woman whose illness has been well controlled, is associated with a high risk of relapse. In earlier work, it was sometimes recommended that discontinuation of lithium be considered after a long period of wellness. We have learned over time that this can be a risky move. Even women with a remote history of bipolar disorder appear to be at high risk of relapse when a mood stabilizer is stopped. Exquisite response to medicine does not imply less severe illness. Women who have bipolar disorder who have sustained euthymia on lithium should consider maintaining the safest possible regimen before, during, and after pregnancy despite the known small teratogenic risk associated with fetal exposure to this agent.

6. Try supplements or alternative therapies

Out of a desire to avoid any medication with incomplete reproductive safety data, some women and clinicians make the intuitive leap that “alternative treatments” can mitigate relapse in pregnancy, and they stop pharmacological treatments and switch to supplements or alternative therapies, including acupuncture, massage, or light therapy. Unfortunately, data supporting this clinical maneuver are sparse. Frequently, we see women with past histories of severe depression who have stopped antidepressants and who have started supplements as a substitute and who then relapse. Then, they try to restore euthymia with antidepressants and psychotherapy, and the road to restoration of well-being can be long.

Data on efficacy of alternative therapies continues to evolve and is an exciting and important area of research. However, where these treatments are best employed in the algorithm for treating depression in pregnancy, or at other times, has yet to be adequately defined.
 

7. Stop breastfeeding or defer antidepressant treatment

Many women continue to be counseled to either stop breastfeeding while using antidepressants or to defer treatment with antidepressants if they wish to breastfeed. Not uncommonly, we see women who are suffering from postpartum depression and who are engaged in psychotherapy but who have deferred treatment with antidepressants despite residual depressive symptoms that impair functioning. Clinicians should keep in mind that data supporting evidence of toxicity in newborns of women using antidepressants while breastfeeding are extremely sparse. Unfortunately, some women with postpartum depression are deferring treatment because they were counseled that it is not compatible with their desire to breastfeed.

8. Use of non-benzodiazepine sedative-hypnotics

Insomnia is a common problem in pregnancy, especially when coupled with comorbid anxiety, and, increasingly, it is being treated with non-benzodiazepine sedative-hypnotics. Clinicians should keep in mind that a known small risk may be better than an unknown risk. If a pregnant woman has severe insomnia, she may benefit from a low dose of a benzodiazepine, such as lorazepam or clonazepam, as opposed to a medication such as zolpidem for which reproductive safety data are particularly limited.

9. Pumping and dumping breast milk

Many women are advised to set an alarm to “pump and dump” their breast milk to minimize their baby’s exposure to antidepressants during breastfeeding. Early literature to pump and dump breast milk at peak antidepressant concentration was of great analytic and theoretical interest but has scant clinical application. As an author of many of those early publications, I can say that we never intended for women to sacrifice precious sleep to dump breast milk with the idea that limiting exposure to trace amounts of antidepressants would have beneficial effects over the long term.

10. Failure to bring up contraception use

We continue to see a 50% unplanned pregnancy rate across sociodemographic groups in the United States. This is a critical statistic because it may affect how treatment is managed. Bringing up the topic of reliable contraception prior to pregnancy allows for planned pregnancy and affords us the time to discuss treatment options and the ability to plot a more thoughtful and safe clinical course. However, often, contraception is not discussed.

One of our goals as clinicians is to, first, do no harm and that continues to be a challenge because the data in perinatal psychiatry is still inconsistent in some areas and there are evidence gaps in others. Nevertheless, our task is to take the best available data along with the patient’s wishes and knowledge of her past clinical history and to then translate that into the best care for the individual.

Dr. Cohen is the director of the Ammon-Pinizzotto Center for Women’s Mental Health at Massachusetts General Hospital in Boston, which provides information resources and conducts clinical care and research in reproductive mental health. He has been a consultant to manufacturers of psychiatric medications.

Over the last 2 decades, there has been a growing interest in establishing a rich evidence base for treatment of psychiatric illness in pregnancy and the postpartum period. It seems as if a week does not go by when we don’t find multiple publications in the scientific literature describing a new finding or confirmation or inconsistency with existing data – whether it is a small prospective cohort study or an elegant analysis of a large administrative database. The goals of these reports center on refining our knowledge of safe treatments for perinatal psychiatric disorders.

Despite these strides, my colleagues and I frequently see a divergence between recommendations in the literature and what is done clinically by those who treat women around reproductive associated psychiatric disturbance – premenstrual dysphoric disorder or psychiatric disorder during pregnancy and the postpartum period. In some cases, scientific evidence has not filtered into day to day practice and some physicians continue to follow practices that, while outdated, make intuitive sense. In other clinical situations, limited evidence is being applied too broadly or data are too sparse to clearly inform practice. Regardless of the reason, we frequently see patients in clinical situations in which we are forced to rethink the clinical rationale for advice they have received or the clinical path taken.

1. Discontinuation of antidepressants proximate to conception

Despite multiple studies supporting the high risk for relapse of major depression in women on maintenance antidepressant therapy with a history of recurrent depressive illness, it is still quite common for clinicians to routinely advise women to stop antidepressants while planning a pregnancy or after documentation of a pregnancy, regardless of the severity of the underlying illness. This runs counter to data showing high rates of relapse in women who stop antidepressants proximate to conception, the safety of antidepressants in pregnancy, and the harm to the mother and fetus when depression during pregnancy is untreated.

2. Use of a lower dose of antidepressants during pregnancy

It makes intuitive sense to use the smallest dose of medicine like antidepressant during pregnancy. However, multiple studies show that, at least in nonpregnant patients, the dose that gets patients well is typically the dose that keeps them well. One of the quickest paths to relapse in depression is a reduction in the antidepressant dose after someone has gotten well. This is even more relevant in pregnant patients because pregnancy itself dilutes the plasma level of the antidepressant given the rapidly expanding plasma volume seen in pregnancy. One can debate whether clinicians should empirically increase the dose of antidepressant during pregnancy to sustain plasma level of medication, but lowering the dose of this medication proximate or during pregnancy makes little sense.

3. A switch to sertraline in pregnancy/post partum

Another scenario that my colleagues and I often see is a pregnant patient whose depression was previously well controlled with a particular antidepressant, but whose physician, once she decides to conceive or becomes pregnant, switched her to sertraline.

The idea, which has been around for a long time, is that sertraline is the safest antidepressant for pregnant women because it has robust reproductive safety data and has particularly modest amounts of medication (if detected at all) in the plasma of infants of mothers who breastfeed while using the medicine. While we certainly have more safety data on SSRIs that were manufactured earlier, as compared with antidepressants that became available later, we have now accumulated data that fails to demonstrate a clear signal for teratogenicity across many antidepressants manufactured over the last 2 decades. Identifying an antidepressant for a given patient to which she will respond can be a challenging course for the patient. Achieving euthymia and subsequently switching to sertraline or another medication may only put her at risk for recurrence of depression and its attendant morbidity.

©Purestock/Thinkstock

4. A change to a Category B label drug

This is another example of switching a patient to a potentially less effective drug in a somewhat misguided effort at finding a treatment that is safer in pregnancy. While the Food and Drug Administration’s drug category label system was a step forward, or at least a well intentioned effort to give women and their clinicians clearer insight into the reproductive safety of a medication, ultimately, the incomplete nature of the information caused the agency to transition to a new system (see the Pregnancy Labeling and Lactation Rule). Switching a woman to a category B medicine with sparse reproductive safety data instead of a category C medicine, which may not be unsafe but has raised some concerns in animal models, is not a better choice. The new labeling system is a step forward.

5. Discontinuation of lithium during pregnancy

Like discontinuation of antidepressants, the discontinuation of lithium during attempts to conceive in a woman whose illness has been well controlled, is associated with a high risk of relapse. In earlier work, it was sometimes recommended that discontinuation of lithium be considered after a long period of wellness. We have learned over time that this can be a risky move. Even women with a remote history of bipolar disorder appear to be at high risk of relapse when a mood stabilizer is stopped. Exquisite response to medicine does not imply less severe illness. Women who have bipolar disorder who have sustained euthymia on lithium should consider maintaining the safest possible regimen before, during, and after pregnancy despite the known small teratogenic risk associated with fetal exposure to this agent.

6. Try supplements or alternative therapies

Out of a desire to avoid any medication with incomplete reproductive safety data, some women and clinicians make the intuitive leap that “alternative treatments” can mitigate relapse in pregnancy, and they stop pharmacological treatments and switch to supplements or alternative therapies, including acupuncture, massage, or light therapy. Unfortunately, data supporting this clinical maneuver are sparse. Frequently, we see women with past histories of severe depression who have stopped antidepressants and who have started supplements as a substitute and who then relapse. Then, they try to restore euthymia with antidepressants and psychotherapy, and the road to restoration of well-being can be long.

Data on efficacy of alternative therapies continues to evolve and is an exciting and important area of research. However, where these treatments are best employed in the algorithm for treating depression in pregnancy, or at other times, has yet to be adequately defined.
 

7. Stop breastfeeding or defer antidepressant treatment

Many women continue to be counseled to either stop breastfeeding while using antidepressants or to defer treatment with antidepressants if they wish to breastfeed. Not uncommonly, we see women who are suffering from postpartum depression and who are engaged in psychotherapy but who have deferred treatment with antidepressants despite residual depressive symptoms that impair functioning. Clinicians should keep in mind that data supporting evidence of toxicity in newborns of women using antidepressants while breastfeeding are extremely sparse. Unfortunately, some women with postpartum depression are deferring treatment because they were counseled that it is not compatible with their desire to breastfeed.

8. Use of non-benzodiazepine sedative-hypnotics

Insomnia is a common problem in pregnancy, especially when coupled with comorbid anxiety, and, increasingly, it is being treated with non-benzodiazepine sedative-hypnotics. Clinicians should keep in mind that a known small risk may be better than an unknown risk. If a pregnant woman has severe insomnia, she may benefit from a low dose of a benzodiazepine, such as lorazepam or clonazepam, as opposed to a medication such as zolpidem for which reproductive safety data are particularly limited.

9. Pumping and dumping breast milk

Many women are advised to set an alarm to “pump and dump” their breast milk to minimize their baby’s exposure to antidepressants during breastfeeding. Early literature to pump and dump breast milk at peak antidepressant concentration was of great analytic and theoretical interest but has scant clinical application. As an author of many of those early publications, I can say that we never intended for women to sacrifice precious sleep to dump breast milk with the idea that limiting exposure to trace amounts of antidepressants would have beneficial effects over the long term.

10. Failure to bring up contraception use

We continue to see a 50% unplanned pregnancy rate across sociodemographic groups in the United States. This is a critical statistic because it may affect how treatment is managed. Bringing up the topic of reliable contraception prior to pregnancy allows for planned pregnancy and affords us the time to discuss treatment options and the ability to plot a more thoughtful and safe clinical course. However, often, contraception is not discussed.

One of our goals as clinicians is to, first, do no harm and that continues to be a challenge because the data in perinatal psychiatry is still inconsistent in some areas and there are evidence gaps in others. Nevertheless, our task is to take the best available data along with the patient’s wishes and knowledge of her past clinical history and to then translate that into the best care for the individual.

Dr. Cohen is the director of the Ammon-Pinizzotto Center for Women’s Mental Health at Massachusetts General Hospital in Boston, which provides information resources and conducts clinical care and research in reproductive mental health. He has been a consultant to manufacturers of psychiatric medications.

Human papillomavirus (HPV) is the most prevalent sexually transmitted disease globally. It is causally related to the development of several malignancies, including cervical, anal, and oropharyngeal ones, because of its integration and dysregulation of the genome of infected cells. Fortunately, vaccination is available to prevent development of HPV-related diseases. Understanding this virus, its carcinogenic role, and the importance of prevention through vaccination are critically important for ob.gyns. This column reviews the fundamentals of HPV biology, epidemiology, and carcinogenesis.

Viral anatomy

HPV are members of the A genus of the family Papovaviridae. They contain between 7,800 and 7,900 base pairs. They are nonenveloped, double-stranded DNA viruses with a circular structure. The viral DNA is contained within an icosahedral capsid that measures 45 nm-55 nm. The HPV genome has three critical regions: the long control region, otherwise known as the upstream regulatory region; the early region; and the late region.¹

Capsid proteins are similar between groups. Therefore, HPV are categorized into “types” and “subtypes” based on the extent of DNA similarity. There are more than 100 types of HPV in humans.² The type of HPV is determined by the gene sequences of E6/E7 and L1 and must show more than 10% difference between types. The gene sequences between different subtypes differ by 2%-5%.

National Cancer Institute

Epidemiology of HPV infection

HPV are widely distributed among mammalian species but are species specific. Their tissue affinity varies by type. HPV types 1, 2, and 4 cause common or plantar warts. HPV types 6 and 11 cause condyloma acuminata (genital warts) and low grade dysplasia. HPV types 16 and 18 – in addition to 31 and 52 – are of particular interest to oncologists because they are associated with lower genital tract high grade dysplasia and invasive carcinoma. Infection with HPV 16 is present in about half of invasive cervical cancers, with HPV type 18 present in 20% of cervical cancers. Adenocarcinomas of the cervix are more commonly associated with HPV 18. Anal cancer and oropharyngeal cancer are more commonly associated with HPV 16.³

HPV infections are acquired through cutaneous touching (including hand to genital) and HPV positivity is most commonly present within the first 10 years after sexual debut.⁴ However, most individuals who acquire HPV do so as a transient infection, which is cleared without sequelae. Those who fail to rapidly clear HPV infection, and in whom it becomes chronic, face an increasing risk of development of dysplasia and invasive carcinoma. The incidence of HPV infection increases again at menopause, but, for these older women, the new finding of HPV detection may be related to reactivation of an earlier infection rather than exclusively new exposure to the virus.⁵

Diagnosis and testing

HPV infection can be detected through DNA testing, RNA testing, and cellular markers.⁶

HPV DNA testing was the original form of testing offered. It improved the sensitivity over cytology alone in the detection of precursors to malignancy but had relatively poor specificity, resulting in a high false positive rate and unnecessary referral to colposcopy. The various tests approved by the Food and Drug Administration – Hybrid Capture 2 (HC2), Cervista, and Cobas 4800 – differ in the number and nature of HPV types that they detect.

HPV RNA testing has developed and involves measuring the expression of E6 and E7 RNA. This testing is FDA approved and has the potential to improve upon the specificity of DNA testing procedures by decreasing false positives.

Measurement of cellular markers is currently considered experimental/exploratory and is not yet FDA approved for diagnostic purposes in screening or confirmation of HPV infection or coexisting dysplasia. It involves measuring the downstream cellular targets (such as p16) of E6 or E7 activity.
 

The mechanism of carcinogenesis

The early region of the HPV genome is downstream from the upstream regulatory region. It codes for proteins involved in viral infection and replication. The two most important genes in the early region are E6 and E7. When integrated into the human genome of the lower genital tract cell, the viral genes E6 and E7 negatively interfere with cell cycle control and mechanisms to halt dysregulation.⁷

E6 and E7 are considered oncogenes because they cause loss of function of the critical tumor suppressor proteins p53 and the retinoblastoma protein. The p53 protein is typically responsible for controlling cell cycling through the G0/G1 to S phases. It involves stalling cellular mitosis in order to facilitate DNA repair mechanisms in the case of damaged cells, thereby preventing replication of DNA aberrations. The retinoblastoma protein also functions to inhibit cells that have acquired DNA damage from cycling and induces apoptosis in DNA damaged cells. When protein products of E6 and E7 negatively interact with these two tumor suppressor proteins they overcome the cell’s safeguard arrest response.

In the presence of other carcinogens, such as products of tobacco exposure, the increased DNA damage sustained by the genital tract cell is allowed to go relatively unchecked by the HPV coinfection, which has disabled tumor suppressor function. This facilitates immortality of the damaged cell, amplification of additional DNA mutations, and unchecked cellular growth and dysplastic transformation. E6 and E7 are strongly expressed in invasive genital tract lesions to support its important role in carcinogenesis.

HIV coinfection is another factor that promotes carcinogenesis following HPV infection because it inhibits clearance of the virus through T-cell mediated immunosuppression and directly enhances expression of E6 and E7 proteins in the HIV and HPV coinfected cell.⁸ For these reasons, HIV-positive women are less likely to clear HPV infection and more likely to develop high grade dysplasia or invasive carcinomas.
 

Prevention and vaccination

HPV vaccinations utilize virus-like particles (VLPs). These VLPs are capsid particles generated from the L1 region of the HPV DNA. The capsid proteins coded for by L1 are highly immunogenic. VLPs are recombinant proteins created in benign biologic systems (such as yeast) and contain no inner DNA core (effectively empty viral capsids) and therefore are not infectious. The L1 gene is incorporated into a plasmid, which is inserted into the nucleus of a eukaryotic cell. Transcription and translation of the L1 gene takes place, creating capsid proteins that self-assemble into VLPs. These VLPs are retrieved and inoculated into candidate patients to illicit an immune response.

Quadrivalent, nine-valent, and bivalent vaccines are available worldwide. However, only the nine-valent vaccine – protective against types 6, 11, 16, 18, 31, 33, 45, 52, and 58 – is available in the United States. This theoretically provides more comprehensive coverage against cervical cancer–causing HPV types, as 70% of cervical cancer is attributable to HPV 16 and 18, but an additional 20% is attributable to HPV 31, 33, 45, 52, and 58. This vaccine also provides protection against the HPV strains that cause genital warts and low-grade dysplastic changes.⁹

HPV, in most instances, is a transient virus with no sequelae. However, if not cleared from the cells of the lower genital tract, anus, or oropharynx it can result in the breakdown of cellular correction strategies and culminate in invasive carcinoma. Fortunately, highly effective and safe vaccinations are available and should be broadly prescribed.

Dr. Rossi is an assistant professor in the division of gynecologic oncology at the University of North Carolina at Chapel Hill. She reported having no relevant financial disclosures.

References

1. Cancer Epidemiol Biomarkers Prev. 1995 Jun;4(4):415-28.

2. Gynecol Oncol. 2011 Apr;121(1):32-42.

3. Cancer Epidemiol Biomarkers Prev. 2008 Jul;17(7):1611-22.

4. JAMA. 2007 Feb 28;297(8):813-9.

5. J Infect Dis. 2013; 207(2): 272-80.

6. J Natl Cancer Inst. 2011 Mar 2;103(5):368-83.

7. J Natl Cancer Inst. 2000 May 3;92(9):690-8.

8. Lancet. 2002 Jan 12;359(9301):108-13.

9. Obstet Gynecol 2017;129:e173–8.

Human papillomavirus (HPV) is the most prevalent sexually transmitted disease globally. It is causally related to the development of several malignancies, including cervical, anal, and oropharyngeal ones, because of its integration and dysregulation of the genome of infected cells. Fortunately, vaccination is available to prevent development of HPV-related diseases. Understanding this virus, its carcinogenic role, and the importance of prevention through vaccination are critically important for ob.gyns. This column reviews the fundamentals of HPV biology, epidemiology, and carcinogenesis.

Viral anatomy

HPV are members of the A genus of the family Papovaviridae. They contain between 7,800 and 7,900 base pairs. They are nonenveloped, double-stranded DNA viruses with a circular structure. The viral DNA is contained within an icosahedral capsid that measures 45 nm-55 nm. The HPV genome has three critical regions: the long control region, otherwise known as the upstream regulatory region; the early region; and the late region.¹

Capsid proteins are similar between groups. Therefore, HPV are categorized into “types” and “subtypes” based on the extent of DNA similarity. There are more than 100 types of HPV in humans.² The type of HPV is determined by the gene sequences of E6/E7 and L1 and must show more than 10% difference between types. The gene sequences between different subtypes differ by 2%-5%.

National Cancer Institute

Epidemiology of HPV infection

HPV are widely distributed among mammalian species but are species specific. Their tissue affinity varies by type. HPV types 1, 2, and 4 cause common or plantar warts. HPV types 6 and 11 cause condyloma acuminata (genital warts) and low grade dysplasia. HPV types 16 and 18 – in addition to 31 and 52 – are of particular interest to oncologists because they are associated with lower genital tract high grade dysplasia and invasive carcinoma. Infection with HPV 16 is present in about half of invasive cervical cancers, with HPV type 18 present in 20% of cervical cancers. Adenocarcinomas of the cervix are more commonly associated with HPV 18. Anal cancer and oropharyngeal cancer are more commonly associated with HPV 16.³

HPV infections are acquired through cutaneous touching (including hand to genital) and HPV positivity is most commonly present within the first 10 years after sexual debut.⁴ However, most individuals who acquire HPV do so as a transient infection, which is cleared without sequelae. Those who fail to rapidly clear HPV infection, and in whom it becomes chronic, face an increasing risk of development of dysplasia and invasive carcinoma. The incidence of HPV infection increases again at menopause, but, for these older women, the new finding of HPV detection may be related to reactivation of an earlier infection rather than exclusively new exposure to the virus.⁵

Diagnosis and testing

HPV infection can be detected through DNA testing, RNA testing, and cellular markers.⁶

HPV DNA testing was the original form of testing offered. It improved the sensitivity over cytology alone in the detection of precursors to malignancy but had relatively poor specificity, resulting in a high false positive rate and unnecessary referral to colposcopy. The various tests approved by the Food and Drug Administration – Hybrid Capture 2 (HC2), Cervista, and Cobas 4800 – differ in the number and nature of HPV types that they detect.

HPV RNA testing has developed and involves measuring the expression of E6 and E7 RNA. This testing is FDA approved and has the potential to improve upon the specificity of DNA testing procedures by decreasing false positives.

Measurement of cellular markers is currently considered experimental/exploratory and is not yet FDA approved for diagnostic purposes in screening or confirmation of HPV infection or coexisting dysplasia. It involves measuring the downstream cellular targets (such as p16) of E6 or E7 activity.
 

The mechanism of carcinogenesis

The early region of the HPV genome is downstream from the upstream regulatory region. It codes for proteins involved in viral infection and replication. The two most important genes in the early region are E6 and E7. When integrated into the human genome of the lower genital tract cell, the viral genes E6 and E7 negatively interfere with cell cycle control and mechanisms to halt dysregulation.⁷

E6 and E7 are considered oncogenes because they cause loss of function of the critical tumor suppressor proteins p53 and the retinoblastoma protein. The p53 protein is typically responsible for controlling cell cycling through the G0/G1 to S phases. It involves stalling cellular mitosis in order to facilitate DNA repair mechanisms in the case of damaged cells, thereby preventing replication of DNA aberrations. The retinoblastoma protein also functions to inhibit cells that have acquired DNA damage from cycling and induces apoptosis in DNA damaged cells. When protein products of E6 and E7 negatively interact with these two tumor suppressor proteins they overcome the cell’s safeguard arrest response.

In the presence of other carcinogens, such as products of tobacco exposure, the increased DNA damage sustained by the genital tract cell is allowed to go relatively unchecked by the HPV coinfection, which has disabled tumor suppressor function. This facilitates immortality of the damaged cell, amplification of additional DNA mutations, and unchecked cellular growth and dysplastic transformation. E6 and E7 are strongly expressed in invasive genital tract lesions to support its important role in carcinogenesis.

HIV coinfection is another factor that promotes carcinogenesis following HPV infection because it inhibits clearance of the virus through T-cell mediated immunosuppression and directly enhances expression of E6 and E7 proteins in the HIV and HPV coinfected cell.⁸ For these reasons, HIV-positive women are less likely to clear HPV infection and more likely to develop high grade dysplasia or invasive carcinomas.
 

Prevention and vaccination

HPV vaccinations utilize virus-like particles (VLPs). These VLPs are capsid particles generated from the L1 region of the HPV DNA. The capsid proteins coded for by L1 are highly immunogenic. VLPs are recombinant proteins created in benign biologic systems (such as yeast) and contain no inner DNA core (effectively empty viral capsids) and therefore are not infectious. The L1 gene is incorporated into a plasmid, which is inserted into the nucleus of a eukaryotic cell. Transcription and translation of the L1 gene takes place, creating capsid proteins that self-assemble into VLPs. These VLPs are retrieved and inoculated into candidate patients to illicit an immune response.

Quadrivalent, nine-valent, and bivalent vaccines are available worldwide. However, only the nine-valent vaccine – protective against types 6, 11, 16, 18, 31, 33, 45, 52, and 58 – is available in the United States. This theoretically provides more comprehensive coverage against cervical cancer–causing HPV types, as 70% of cervical cancer is attributable to HPV 16 and 18, but an additional 20% is attributable to HPV 31, 33, 45, 52, and 58. This vaccine also provides protection against the HPV strains that cause genital warts and low-grade dysplastic changes.⁹

HPV, in most instances, is a transient virus with no sequelae. However, if not cleared from the cells of the lower genital tract, anus, or oropharynx it can result in the breakdown of cellular correction strategies and culminate in invasive carcinoma. Fortunately, highly effective and safe vaccinations are available and should be broadly prescribed.

Dr. Rossi is an assistant professor in the division of gynecologic oncology at the University of North Carolina at Chapel Hill. She reported having no relevant financial disclosures.

References

1. Cancer Epidemiol Biomarkers Prev. 1995 Jun;4(4):415-28.

2. Gynecol Oncol. 2011 Apr;121(1):32-42.

3. Cancer Epidemiol Biomarkers Prev. 2008 Jul;17(7):1611-22.

4. JAMA. 2007 Feb 28;297(8):813-9.

5. J Infect Dis. 2013; 207(2): 272-80.

6. J Natl Cancer Inst. 2011 Mar 2;103(5):368-83.

7. J Natl Cancer Inst. 2000 May 3;92(9):690-8.

8. Lancet. 2002 Jan 12;359(9301):108-13.

9. Obstet Gynecol 2017;129:e173–8.

Human papillomavirus (HPV) is the most prevalent sexually transmitted disease globally. It is causally related to the development of several malignancies, including cervical, anal, and oropharyngeal ones, because of its integration and dysregulation of the genome of infected cells. Fortunately, vaccination is available to prevent development of HPV-related diseases. Understanding this virus, its carcinogenic role, and the importance of prevention through vaccination are critically important for ob.gyns. This column reviews the fundamentals of HPV biology, epidemiology, and carcinogenesis.

Viral anatomy

HPV are members of the A genus of the family Papovaviridae. They contain between 7,800 and 7,900 base pairs. They are nonenveloped, double-stranded DNA viruses with a circular structure. The viral DNA is contained within an icosahedral capsid that measures 45 nm-55 nm. The HPV genome has three critical regions: the long control region, otherwise known as the upstream regulatory region; the early region; and the late region.¹

Capsid proteins are similar between groups. Therefore, HPV are categorized into “types” and “subtypes” based on the extent of DNA similarity. There are more than 100 types of HPV in humans.² The type of HPV is determined by the gene sequences of E6/E7 and L1 and must show more than 10% difference between types. The gene sequences between different subtypes differ by 2%-5%.

National Cancer Institute

Epidemiology of HPV infection

HPV are widely distributed among mammalian species but are species specific. Their tissue affinity varies by type. HPV types 1, 2, and 4 cause common or plantar warts. HPV types 6 and 11 cause condyloma acuminata (genital warts) and low grade dysplasia. HPV types 16 and 18 – in addition to 31 and 52 – are of particular interest to oncologists because they are associated with lower genital tract high grade dysplasia and invasive carcinoma. Infection with HPV 16 is present in about half of invasive cervical cancers, with HPV type 18 present in 20% of cervical cancers. Adenocarcinomas of the cervix are more commonly associated with HPV 18. Anal cancer and oropharyngeal cancer are more commonly associated with HPV 16.³

HPV infections are acquired through cutaneous touching (including hand to genital) and HPV positivity is most commonly present within the first 10 years after sexual debut.⁴ However, most individuals who acquire HPV do so as a transient infection, which is cleared without sequelae. Those who fail to rapidly clear HPV infection, and in whom it becomes chronic, face an increasing risk of development of dysplasia and invasive carcinoma. The incidence of HPV infection increases again at menopause, but, for these older women, the new finding of HPV detection may be related to reactivation of an earlier infection rather than exclusively new exposure to the virus.⁵

Diagnosis and testing

HPV infection can be detected through DNA testing, RNA testing, and cellular markers.⁶

HPV DNA testing was the original form of testing offered. It improved the sensitivity over cytology alone in the detection of precursors to malignancy but had relatively poor specificity, resulting in a high false positive rate and unnecessary referral to colposcopy. The various tests approved by the Food and Drug Administration – Hybrid Capture 2 (HC2), Cervista, and Cobas 4800 – differ in the number and nature of HPV types that they detect.

HPV RNA testing has developed and involves measuring the expression of E6 and E7 RNA. This testing is FDA approved and has the potential to improve upon the specificity of DNA testing procedures by decreasing false positives.

Measurement of cellular markers is currently considered experimental/exploratory and is not yet FDA approved for diagnostic purposes in screening or confirmation of HPV infection or coexisting dysplasia. It involves measuring the downstream cellular targets (such as p16) of E6 or E7 activity.
 

The mechanism of carcinogenesis

The early region of the HPV genome is downstream from the upstream regulatory region. It codes for proteins involved in viral infection and replication. The two most important genes in the early region are E6 and E7. When integrated into the human genome of the lower genital tract cell, the viral genes E6 and E7 negatively interfere with cell cycle control and mechanisms to halt dysregulation.⁷

E6 and E7 are considered oncogenes because they cause loss of function of the critical tumor suppressor proteins p53 and the retinoblastoma protein. The p53 protein is typically responsible for controlling cell cycling through the G0/G1 to S phases. It involves stalling cellular mitosis in order to facilitate DNA repair mechanisms in the case of damaged cells, thereby preventing replication of DNA aberrations. The retinoblastoma protein also functions to inhibit cells that have acquired DNA damage from cycling and induces apoptosis in DNA damaged cells. When protein products of E6 and E7 negatively interact with these two tumor suppressor proteins they overcome the cell’s safeguard arrest response.

In the presence of other carcinogens, such as products of tobacco exposure, the increased DNA damage sustained by the genital tract cell is allowed to go relatively unchecked by the HPV coinfection, which has disabled tumor suppressor function. This facilitates immortality of the damaged cell, amplification of additional DNA mutations, and unchecked cellular growth and dysplastic transformation. E6 and E7 are strongly expressed in invasive genital tract lesions to support its important role in carcinogenesis.

HIV coinfection is another factor that promotes carcinogenesis following HPV infection because it inhibits clearance of the virus through T-cell mediated immunosuppression and directly enhances expression of E6 and E7 proteins in the HIV and HPV coinfected cell.⁸ For these reasons, HIV-positive women are less likely to clear HPV infection and more likely to develop high grade dysplasia or invasive carcinomas.
 

Prevention and vaccination

HPV vaccinations utilize virus-like particles (VLPs). These VLPs are capsid particles generated from the L1 region of the HPV DNA. The capsid proteins coded for by L1 are highly immunogenic. VLPs are recombinant proteins created in benign biologic systems (such as yeast) and contain no inner DNA core (effectively empty viral capsids) and therefore are not infectious. The L1 gene is incorporated into a plasmid, which is inserted into the nucleus of a eukaryotic cell. Transcription and translation of the L1 gene takes place, creating capsid proteins that self-assemble into VLPs. These VLPs are retrieved and inoculated into candidate patients to illicit an immune response.

Quadrivalent, nine-valent, and bivalent vaccines are available worldwide. However, only the nine-valent vaccine – protective against types 6, 11, 16, 18, 31, 33, 45, 52, and 58 – is available in the United States. This theoretically provides more comprehensive coverage against cervical cancer–causing HPV types, as 70% of cervical cancer is attributable to HPV 16 and 18, but an additional 20% is attributable to HPV 31, 33, 45, 52, and 58. This vaccine also provides protection against the HPV strains that cause genital warts and low-grade dysplastic changes.⁹

HPV, in most instances, is a transient virus with no sequelae. However, if not cleared from the cells of the lower genital tract, anus, or oropharynx it can result in the breakdown of cellular correction strategies and culminate in invasive carcinoma. Fortunately, highly effective and safe vaccinations are available and should be broadly prescribed.

Dr. Rossi is an assistant professor in the division of gynecologic oncology at the University of North Carolina at Chapel Hill. She reported having no relevant financial disclosures.

References

1. Cancer Epidemiol Biomarkers Prev. 1995 Jun;4(4):415-28.

2. Gynecol Oncol. 2011 Apr;121(1):32-42.

3. Cancer Epidemiol Biomarkers Prev. 2008 Jul;17(7):1611-22.

4. JAMA. 2007 Feb 28;297(8):813-9.

5. J Infect Dis. 2013; 207(2): 272-80.

6. J Natl Cancer Inst. 2011 Mar 2;103(5):368-83.

7. J Natl Cancer Inst. 2000 May 3;92(9):690-8.

8. Lancet. 2002 Jan 12;359(9301):108-13.

9. Obstet Gynecol 2017;129:e173–8.

Photo by Graham Colm

The US Food and Drug Administration (FDA) has allowed marketing of the ClearLLab Reagent Panel, a combination of conjugated antibody cocktails designed to aid the detection of hematopoietic neoplasia.

This includes chronic and acute leukemias, non-Hodgkin lymphoma, myeloma, myelodysplastic syndromes, and myeloproliferative neoplasms.

The ClearLLab reagents are intended for in vitro diagnostic use to identify various cell populations by immunophenotyping on an FC 500 flow cytometer.

The reagents are directed against B, T, and myeloid lineage antigens and intended to identify relevant leukocyte surface molecules.

ClearLLab provides 2 T-cell tubes, 2 B-cell tubes, and a myeloid tube, each consisting of pre-mixed 4- to 5-color cocktails. Together, this totals 18 markers as directly conjugated antibodies.

The reagents can be used with peripheral whole blood, bone marrow, and lymph node specimens.

The results obtained via testing with the ClearLLab reagents should be interpreted along with additional clinical and laboratory findings, according to Beckman Coulter, Inc., the company that will be marketing the reagents.

The FDA reviewed data for the ClearLLab reagents through the de novo premarket review pathway, a regulatory pathway for novel, low-to-moderate-risk devices that are not substantially equivalent to an already legally marketed device.

The FDA’s clearance of the ClearLLab reagents was supported by a study designed to demonstrate the reagents’ performance, which was conducted on 279 samples at 4 independent clinical sites.

Results with the ClearLLab reagents were compared to results with alternative detection methods used at the sites.

The ClearLLab results aligned with the study sites’ final diagnosis 93.4% of the time and correctly detected abnormalities 84.2% of the time.

Along with its clearance of the ClearLLab reagents, the FDA is establishing criteria, called special controls, which clarify the agency’s expectations in assuring the reagents’ accuracy, reliability, and clinical relevance.

These special controls, when met along with general controls, provide reasonable assurance of safety and effectiveness for the ClearLLab reagents and similar tools.

The special controls also describe the least burdensome regulatory pathway for future developers of similar diagnostic tests.

Photo by Graham Colm

The US Food and Drug Administration (FDA) has allowed marketing of the ClearLLab Reagent Panel, a combination of conjugated antibody cocktails designed to aid the detection of hematopoietic neoplasia.

This includes chronic and acute leukemias, non-Hodgkin lymphoma, myeloma, myelodysplastic syndromes, and myeloproliferative neoplasms.

The ClearLLab reagents are intended for in vitro diagnostic use to identify various cell populations by immunophenotyping on an FC 500 flow cytometer.

The reagents are directed against B, T, and myeloid lineage antigens and intended to identify relevant leukocyte surface molecules.

ClearLLab provides 2 T-cell tubes, 2 B-cell tubes, and a myeloid tube, each consisting of pre-mixed 4- to 5-color cocktails. Together, this totals 18 markers as directly conjugated antibodies.

The reagents can be used with peripheral whole blood, bone marrow, and lymph node specimens.

The results obtained via testing with the ClearLLab reagents should be interpreted along with additional clinical and laboratory findings, according to Beckman Coulter, Inc., the company that will be marketing the reagents.

The FDA reviewed data for the ClearLLab reagents through the de novo premarket review pathway, a regulatory pathway for novel, low-to-moderate-risk devices that are not substantially equivalent to an already legally marketed device.

The FDA’s clearance of the ClearLLab reagents was supported by a study designed to demonstrate the reagents’ performance, which was conducted on 279 samples at 4 independent clinical sites.

Results with the ClearLLab reagents were compared to results with alternative detection methods used at the sites.

The ClearLLab results aligned with the study sites’ final diagnosis 93.4% of the time and correctly detected abnormalities 84.2% of the time.

Along with its clearance of the ClearLLab reagents, the FDA is establishing criteria, called special controls, which clarify the agency’s expectations in assuring the reagents’ accuracy, reliability, and clinical relevance.

These special controls, when met along with general controls, provide reasonable assurance of safety and effectiveness for the ClearLLab reagents and similar tools.

The special controls also describe the least burdensome regulatory pathway for future developers of similar diagnostic tests.

Photo by Graham Colm

The US Food and Drug Administration (FDA) has allowed marketing of the ClearLLab Reagent Panel, a combination of conjugated antibody cocktails designed to aid the detection of hematopoietic neoplasia.

This includes chronic and acute leukemias, non-Hodgkin lymphoma, myeloma, myelodysplastic syndromes, and myeloproliferative neoplasms.

The ClearLLab reagents are intended for in vitro diagnostic use to identify various cell populations by immunophenotyping on an FC 500 flow cytometer.

The reagents are directed against B, T, and myeloid lineage antigens and intended to identify relevant leukocyte surface molecules.

ClearLLab provides 2 T-cell tubes, 2 B-cell tubes, and a myeloid tube, each consisting of pre-mixed 4- to 5-color cocktails. Together, this totals 18 markers as directly conjugated antibodies.

The reagents can be used with peripheral whole blood, bone marrow, and lymph node specimens.

The results obtained via testing with the ClearLLab reagents should be interpreted along with additional clinical and laboratory findings, according to Beckman Coulter, Inc., the company that will be marketing the reagents.

The FDA reviewed data for the ClearLLab reagents through the de novo premarket review pathway, a regulatory pathway for novel, low-to-moderate-risk devices that are not substantially equivalent to an already legally marketed device.

The FDA’s clearance of the ClearLLab reagents was supported by a study designed to demonstrate the reagents’ performance, which was conducted on 279 samples at 4 independent clinical sites.

Results with the ClearLLab reagents were compared to results with alternative detection methods used at the sites.

The ClearLLab results aligned with the study sites’ final diagnosis 93.4% of the time and correctly detected abnormalities 84.2% of the time.

Along with its clearance of the ClearLLab reagents, the FDA is establishing criteria, called special controls, which clarify the agency’s expectations in assuring the reagents’ accuracy, reliability, and clinical relevance.

These special controls, when met along with general controls, provide reasonable assurance of safety and effectiveness for the ClearLLab reagents and similar tools.

The special controls also describe the least burdensome regulatory pathway for future developers of similar diagnostic tests.