A new study of anxiety disorders among young adults aged 18-24 shows that the illnesses are less prevalent among African American and Hispanic young adults, compared with whites. Furthermore, anxiety disorders are 1.5 times as prevalent among married people in this age group, compared with their unmarried peers.

For their research, presented at the annual meeting of the American Academy of Child and Adolescent Psychiatry, Cristiane S. Duarte, PhD, MPH, of Columbia University, New York, and her colleagues looked at data from the 2012/2013 National Epidemiologic Survey on Alcohol and Related Conditions (NESARC), a nationally representative sample of U.S. households.

“We were trying to look specifically at young adulthood, which there’s emerging consensus to regard as a key developmental period,” said Dr. Duarte, whose research focuses on anxiety disorders in young adults. “It’s a period where several psychiatric disorders tend to become much more prevalent. Having untreated anxiety disorders at this age can put young adults at risk for worse outcomes down the line. If anxiety disorders can be resolved, a young adult’s trajectory can be quite different; it’s a time in life in which the right intervention can have a really big impact,” she said.

The NESARC III survey data used structured diagnostic interviews and DSM-5 criteria to assess anxiety disorders occurring in the past year. These included specific phobia, generalized anxiety disorder, social anxiety, panic disorder, and agoraphobia. 

For the most part, Dr. Duarte said, her group’s findings on anxiety disorders reflected earlier prevalence studies that had used DSM-IV criteria. Women were more likely than were men to report any past-year anxiety disorder (odds ratio, 2.26; 95% confidence interval, 1.80-2.84), as were people with lower personal and family incomes. Rates of anxiety disorders were highest in groups with the lowest personal and family incomes, and among people neither employed nor in an educational program.

Dr. Duarte said in an interview that the latter findings were generally anticipated. However, the finding that African Americans and Hispanics at this age had lower risk relative to whites (OR, 0.52; 95% CI, 0.40-0.67) and (OR, 0.63; 95% CI, 0.49-0.83) was interesting, because it appeared to mirror the lower relative prevalence seen among adults in those two groups, rather than the higher prevalence seen among children in the same groups. More research will be needed, she said, to verify and, if correct, understand this reversing trend in prevalence seen between childhood and adulthood.

The study’s most unexpected finding, Dr. Duarte said, was that married individuals aged 18-24 had higher prevalence of anxiety (OR, 1.54; 95% CI, 1.05-2.26). “Across the board, marriage is protective for many health and mental health conditions,” Dr. Duarte said, but she acknowledged that many factors could be in play. Marriage might not, in fact, be protective in this age group; the institution might be reflective of cultural factors promoting early marriage; or the findings could reflect a selection into marriage possibly related to existing anxiety disorders.

“To better understand this finding, we will need to consider several complexities which are part of young adulthood as a unique developmental period,” she said.

Dr. Duarte’s and her colleagues’ study was funded by the Youth Anxiety Center at New York–Presbyterian Hospital. Three coauthors reported research support from pharmaceutical manufacturers and royalties from commercial publishers. 

A new study of anxiety disorders among young adults aged 18-24 shows that the illnesses are less prevalent among African American and Hispanic young adults, compared with whites. Furthermore, anxiety disorders are 1.5 times as prevalent among married people in this age group, compared with their unmarried peers.

For their research, presented at the annual meeting of the American Academy of Child and Adolescent Psychiatry, Cristiane S. Duarte, PhD, MPH, of Columbia University, New York, and her colleagues looked at data from the 2012/2013 National Epidemiologic Survey on Alcohol and Related Conditions (NESARC), a nationally representative sample of U.S. households.

“We were trying to look specifically at young adulthood, which there’s emerging consensus to regard as a key developmental period,” said Dr. Duarte, whose research focuses on anxiety disorders in young adults. “It’s a period where several psychiatric disorders tend to become much more prevalent. Having untreated anxiety disorders at this age can put young adults at risk for worse outcomes down the line. If anxiety disorders can be resolved, a young adult’s trajectory can be quite different; it’s a time in life in which the right intervention can have a really big impact,” she said.

The NESARC III survey data used structured diagnostic interviews and DSM-5 criteria to assess anxiety disorders occurring in the past year. These included specific phobia, generalized anxiety disorder, social anxiety, panic disorder, and agoraphobia. 

For the most part, Dr. Duarte said, her group’s findings on anxiety disorders reflected earlier prevalence studies that had used DSM-IV criteria. Women were more likely than were men to report any past-year anxiety disorder (odds ratio, 2.26; 95% confidence interval, 1.80-2.84), as were people with lower personal and family incomes. Rates of anxiety disorders were highest in groups with the lowest personal and family incomes, and among people neither employed nor in an educational program.

Dr. Duarte said in an interview that the latter findings were generally anticipated. However, the finding that African Americans and Hispanics at this age had lower risk relative to whites (OR, 0.52; 95% CI, 0.40-0.67) and (OR, 0.63; 95% CI, 0.49-0.83) was interesting, because it appeared to mirror the lower relative prevalence seen among adults in those two groups, rather than the higher prevalence seen among children in the same groups. More research will be needed, she said, to verify and, if correct, understand this reversing trend in prevalence seen between childhood and adulthood.

The study’s most unexpected finding, Dr. Duarte said, was that married individuals aged 18-24 had higher prevalence of anxiety (OR, 1.54; 95% CI, 1.05-2.26). “Across the board, marriage is protective for many health and mental health conditions,” Dr. Duarte said, but she acknowledged that many factors could be in play. Marriage might not, in fact, be protective in this age group; the institution might be reflective of cultural factors promoting early marriage; or the findings could reflect a selection into marriage possibly related to existing anxiety disorders.

“To better understand this finding, we will need to consider several complexities which are part of young adulthood as a unique developmental period,” she said.

Dr. Duarte’s and her colleagues’ study was funded by the Youth Anxiety Center at New York–Presbyterian Hospital. Three coauthors reported research support from pharmaceutical manufacturers and royalties from commercial publishers. 

A new study of anxiety disorders among young adults aged 18-24 shows that the illnesses are less prevalent among African American and Hispanic young adults, compared with whites. Furthermore, anxiety disorders are 1.5 times as prevalent among married people in this age group, compared with their unmarried peers.

For their research, presented at the annual meeting of the American Academy of Child and Adolescent Psychiatry, Cristiane S. Duarte, PhD, MPH, of Columbia University, New York, and her colleagues looked at data from the 2012/2013 National Epidemiologic Survey on Alcohol and Related Conditions (NESARC), a nationally representative sample of U.S. households.

“We were trying to look specifically at young adulthood, which there’s emerging consensus to regard as a key developmental period,” said Dr. Duarte, whose research focuses on anxiety disorders in young adults. “It’s a period where several psychiatric disorders tend to become much more prevalent. Having untreated anxiety disorders at this age can put young adults at risk for worse outcomes down the line. If anxiety disorders can be resolved, a young adult’s trajectory can be quite different; it’s a time in life in which the right intervention can have a really big impact,” she said.

The NESARC III survey data used structured diagnostic interviews and DSM-5 criteria to assess anxiety disorders occurring in the past year. These included specific phobia, generalized anxiety disorder, social anxiety, panic disorder, and agoraphobia. 

For the most part, Dr. Duarte said, her group’s findings on anxiety disorders reflected earlier prevalence studies that had used DSM-IV criteria. Women were more likely than were men to report any past-year anxiety disorder (odds ratio, 2.26; 95% confidence interval, 1.80-2.84), as were people with lower personal and family incomes. Rates of anxiety disorders were highest in groups with the lowest personal and family incomes, and among people neither employed nor in an educational program.

Dr. Duarte said in an interview that the latter findings were generally anticipated. However, the finding that African Americans and Hispanics at this age had lower risk relative to whites (OR, 0.52; 95% CI, 0.40-0.67) and (OR, 0.63; 95% CI, 0.49-0.83) was interesting, because it appeared to mirror the lower relative prevalence seen among adults in those two groups, rather than the higher prevalence seen among children in the same groups. More research will be needed, she said, to verify and, if correct, understand this reversing trend in prevalence seen between childhood and adulthood.

The study’s most unexpected finding, Dr. Duarte said, was that married individuals aged 18-24 had higher prevalence of anxiety (OR, 1.54; 95% CI, 1.05-2.26). “Across the board, marriage is protective for many health and mental health conditions,” Dr. Duarte said, but she acknowledged that many factors could be in play. Marriage might not, in fact, be protective in this age group; the institution might be reflective of cultural factors promoting early marriage; or the findings could reflect a selection into marriage possibly related to existing anxiety disorders.

“To better understand this finding, we will need to consider several complexities which are part of young adulthood as a unique developmental period,” she said.

Dr. Duarte’s and her colleagues’ study was funded by the Youth Anxiety Center at New York–Presbyterian Hospital. Three coauthors reported research support from pharmaceutical manufacturers and royalties from commercial publishers. 

COLUMBUS, OHIO – A study of vascular procedures at 35 Michigan hospitals has identified three risk factors for surgical site infection after lower-extremity bypass that hospitals and vascular surgery teams may be able to modify.

“Patients who had iodine-only skin antiseptic preparation, a high-peak intraoperative glucose, or long operative times were more likely to have substantially increased risk for surgical site infection (SSI),” Frank Davis, MD, of the University of Michigan said in reporting the study results at the annual meeting of the Midwestern Vascular Surgical Society. Those risk factors are modifiable, Dr. Davis said.

COLUMBUS, OHIO – A study of vascular procedures at 35 Michigan hospitals has identified three risk factors for surgical site infection after lower-extremity bypass that hospitals and vascular surgery teams may be able to modify.

“Patients who had iodine-only skin antiseptic preparation, a high-peak intraoperative glucose, or long operative times were more likely to have substantially increased risk for surgical site infection (SSI),” Frank Davis, MD, of the University of Michigan said in reporting the study results at the annual meeting of the Midwestern Vascular Surgical Society. Those risk factors are modifiable, Dr. Davis said.

COLUMBUS, OHIO – A study of vascular procedures at 35 Michigan hospitals has identified three risk factors for surgical site infection after lower-extremity bypass that hospitals and vascular surgery teams may be able to modify.

“Patients who had iodine-only skin antiseptic preparation, a high-peak intraoperative glucose, or long operative times were more likely to have substantially increased risk for surgical site infection (SSI),” Frank Davis, MD, of the University of Michigan said in reporting the study results at the annual meeting of the Midwestern Vascular Surgical Society. Those risk factors are modifiable, Dr. Davis said.

ATLANTA – Physicians are falling short on syphilis testing in both the prenatal period and at the time of delivery, suggest the findings of a study examining insurance claims from nearly 10,000 women who experienced stillbirths.

Overall, less than 10% of women in the study were tested for syphilis following a stillbirth delivery, while less than two-thirds of women who experienced a stillbirth had received prenatal syphilis testing.

jarun011/Thinkstock

[email protected]

ATLANTA – Physicians are falling short on syphilis testing in both the prenatal period and at the time of delivery, suggest the findings of a study examining insurance claims from nearly 10,000 women who experienced stillbirths.

Overall, less than 10% of women in the study were tested for syphilis following a stillbirth delivery, while less than two-thirds of women who experienced a stillbirth had received prenatal syphilis testing.

jarun011/Thinkstock

[email protected]

ATLANTA – Physicians are falling short on syphilis testing in both the prenatal period and at the time of delivery, suggest the findings of a study examining insurance claims from nearly 10,000 women who experienced stillbirths.

Overall, less than 10% of women in the study were tested for syphilis following a stillbirth delivery, while less than two-thirds of women who experienced a stillbirth had received prenatal syphilis testing.

jarun011/Thinkstock

[email protected]

NEWPORT BEACH, CALIF. – A patient with psoriasis can develop crippling psoriatic arthritis (PsA) within 5 to 10 years of diagnosis, but monitoring patients for signs of trouble can help prevent the onset of PsA, according to Alan Menter, MD.

Even a simple foot examination can make a huge difference, noted Dr. Menter, chief of the division of dermatology and director of the Psoriasis Research Institute at Baylor University Medical Center, Dallas. “At every visit, you and I should be looking for early signs of joint disease,” he said at the Skin Disease Education Foundation’s Women’s & Pediatric Dermatology Seminar. “We should not let these patients develop any joint disease because we have drugs that can prevent joint destruction.”

• Be on the lookout for “sausage fingers” and “sausage toes,” both signs of PsA. “You and I are very visual people, and we can see a swollen toe or finger very easily,” Dr. Menter said. “I take the shoes off every psoriasis patient at every visit and run my thumb and index finger down the Achilles. I look for a swollen Achilles – classic enthesitis.” In some cases, swollen big toes in psoriasis patients may be misdiagnosed as gout instead of PsA, he noted.

• Ask patients about how their joints feel when they wake up in the morning: Do they have swelling and tenderness? “That’s an early marker of psoriatic arthritis disease,” Dr. Menter said. In contrast, in a patient with osteoarthritis, “the more they use their joints, the worse it gets.”

• The severity of psoriasis has nothing to do with the severity of PsA. “You can have 50% of the body covered with psoriasis but no arthritis,” he said. “Or you can have someone with one patch of psoriasis on the scalp with devastating joint disease.”

• Be aware that there are five PsA subtypes that can occur in combination with each other:

1. Dactylitis. This is the form that causes the “sausage digit.”

2. Asymmetric oligoarthritis. This is the type most commonly seen on presentation, when there are few joints affected.

3. Symmetric arthritis. This form is more common in females and difficult to differentiate from rheumatoid arthritis.

4. Distal interphalangeal joint arthritis. This type is often linked to dactylitis and nail dystrophy.

5. Arthritis mutilans. This is more common in females, linked to long disease duration, and present in an estimated 5% of cases.
 

Dr. Menter suggested that dermatologists refer suspected cases of PsA to a rheumatologist. Since patients may have to wait 6-10 weeks for an appointment, he recommended that dermatologists consider NSAIDs, such as the over-the-counter naproxen and prescription meloxicam and celecoxib in the meantime. Dermatologists may also consider bringing up the use of methotrexate and biologics, he said.

Dr. Menter disclosed relationships with multiple pharmaceutical companies, including AbbVie, Allergan, Amgen, Boehringer Ingelheim, Eli Lilly, Merck, Novartis, and Pfizer.

SDEF and this news organization are owned by Frontline Medical Communications.

NEWPORT BEACH, CALIF. – A patient with psoriasis can develop crippling psoriatic arthritis (PsA) within 5 to 10 years of diagnosis, but monitoring patients for signs of trouble can help prevent the onset of PsA, according to Alan Menter, MD.

Even a simple foot examination can make a huge difference, noted Dr. Menter, chief of the division of dermatology and director of the Psoriasis Research Institute at Baylor University Medical Center, Dallas. “At every visit, you and I should be looking for early signs of joint disease,” he said at the Skin Disease Education Foundation’s Women’s & Pediatric Dermatology Seminar. “We should not let these patients develop any joint disease because we have drugs that can prevent joint destruction.”

• Be on the lookout for “sausage fingers” and “sausage toes,” both signs of PsA. “You and I are very visual people, and we can see a swollen toe or finger very easily,” Dr. Menter said. “I take the shoes off every psoriasis patient at every visit and run my thumb and index finger down the Achilles. I look for a swollen Achilles – classic enthesitis.” In some cases, swollen big toes in psoriasis patients may be misdiagnosed as gout instead of PsA, he noted.

• Ask patients about how their joints feel when they wake up in the morning: Do they have swelling and tenderness? “That’s an early marker of psoriatic arthritis disease,” Dr. Menter said. In contrast, in a patient with osteoarthritis, “the more they use their joints, the worse it gets.”

• The severity of psoriasis has nothing to do with the severity of PsA. “You can have 50% of the body covered with psoriasis but no arthritis,” he said. “Or you can have someone with one patch of psoriasis on the scalp with devastating joint disease.”

• Be aware that there are five PsA subtypes that can occur in combination with each other:

1. Dactylitis. This is the form that causes the “sausage digit.”

2. Asymmetric oligoarthritis. This is the type most commonly seen on presentation, when there are few joints affected.

3. Symmetric arthritis. This form is more common in females and difficult to differentiate from rheumatoid arthritis.

4. Distal interphalangeal joint arthritis. This type is often linked to dactylitis and nail dystrophy.

5. Arthritis mutilans. This is more common in females, linked to long disease duration, and present in an estimated 5% of cases.
 

Dr. Menter suggested that dermatologists refer suspected cases of PsA to a rheumatologist. Since patients may have to wait 6-10 weeks for an appointment, he recommended that dermatologists consider NSAIDs, such as the over-the-counter naproxen and prescription meloxicam and celecoxib in the meantime. Dermatologists may also consider bringing up the use of methotrexate and biologics, he said.

Dr. Menter disclosed relationships with multiple pharmaceutical companies, including AbbVie, Allergan, Amgen, Boehringer Ingelheim, Eli Lilly, Merck, Novartis, and Pfizer.

SDEF and this news organization are owned by Frontline Medical Communications.

NEWPORT BEACH, CALIF. – A patient with psoriasis can develop crippling psoriatic arthritis (PsA) within 5 to 10 years of diagnosis, but monitoring patients for signs of trouble can help prevent the onset of PsA, according to Alan Menter, MD.

Even a simple foot examination can make a huge difference, noted Dr. Menter, chief of the division of dermatology and director of the Psoriasis Research Institute at Baylor University Medical Center, Dallas. “At every visit, you and I should be looking for early signs of joint disease,” he said at the Skin Disease Education Foundation’s Women’s & Pediatric Dermatology Seminar. “We should not let these patients develop any joint disease because we have drugs that can prevent joint destruction.”

• Be on the lookout for “sausage fingers” and “sausage toes,” both signs of PsA. “You and I are very visual people, and we can see a swollen toe or finger very easily,” Dr. Menter said. “I take the shoes off every psoriasis patient at every visit and run my thumb and index finger down the Achilles. I look for a swollen Achilles – classic enthesitis.” In some cases, swollen big toes in psoriasis patients may be misdiagnosed as gout instead of PsA, he noted.

• Ask patients about how their joints feel when they wake up in the morning: Do they have swelling and tenderness? “That’s an early marker of psoriatic arthritis disease,” Dr. Menter said. In contrast, in a patient with osteoarthritis, “the more they use their joints, the worse it gets.”

• The severity of psoriasis has nothing to do with the severity of PsA. “You can have 50% of the body covered with psoriasis but no arthritis,” he said. “Or you can have someone with one patch of psoriasis on the scalp with devastating joint disease.”

• Be aware that there are five PsA subtypes that can occur in combination with each other:

1. Dactylitis. This is the form that causes the “sausage digit.”

2. Asymmetric oligoarthritis. This is the type most commonly seen on presentation, when there are few joints affected.

3. Symmetric arthritis. This form is more common in females and difficult to differentiate from rheumatoid arthritis.

4. Distal interphalangeal joint arthritis. This type is often linked to dactylitis and nail dystrophy.

5. Arthritis mutilans. This is more common in females, linked to long disease duration, and present in an estimated 5% of cases.
 

Dr. Menter suggested that dermatologists refer suspected cases of PsA to a rheumatologist. Since patients may have to wait 6-10 weeks for an appointment, he recommended that dermatologists consider NSAIDs, such as the over-the-counter naproxen and prescription meloxicam and celecoxib in the meantime. Dermatologists may also consider bringing up the use of methotrexate and biologics, he said.

Dr. Menter disclosed relationships with multiple pharmaceutical companies, including AbbVie, Allergan, Amgen, Boehringer Ingelheim, Eli Lilly, Merck, Novartis, and Pfizer.

SDEF and this news organization are owned by Frontline Medical Communications.

A report on 11 infants in Brazil suggests the term “congenital Zika syndrome” be used to describe the abnormalities associated with Zika virus infection because microcephaly is only one clinical sign of this congenital malformation disorder. The report was published online ahead of print October 3 in JAMA Neurology.

“To our knowledge,” the researchers wrote, “most reports to date have focused on select aspects of the maternal or fetal infection and fetal effects.” To provide a fuller description, the researchers sought to characterize the prenatal evolution and perinatal outcomes of 11 neonates who had developmental abnormalities and neurologic damage associated with Zika infection.

Follow-Up of 11 Neonates

Amilcar Tanuri, MD, PhD, Professor of Genetics and Chief of the Laboratory of Molecular Virology at the Institute of Biology, Federal University of Rio de Janeiro, and coauthors observed 11 infants with congenital Zika infection from gestation to six months in the state of Paraíba, Brazil. Cases were referred between October 2015 and February 2016. Ten of 11 women included in the study presented with symptoms of Zika infection during the first half of pregnancy, and all 11 had laboratory evidence of infection in several tissues by serology or polymerase chain reaction. Brain damage was confirmed through intrauterine ultrasonography and was complemented by MRI. Histopathologic analysis was performed on the placenta and brain tissue from infants who died. The ZIKV genome was investigated in several tissues and sequenced for further phylogenetic analysis.

Of the 11 infants, seven (63.6%) were female, and the median maternal age at delivery was 25. Three of the neonates died, giving a perinatal mortality rate of 27.3%. Zika virus was identified in amniotic fluid, placenta, cord blood, and neonatal tissues collected post mortem in the three babies who died within 48 hours of delivery.

Brain damage and neurologic impairments were identified in all patients, including microcephaly, a reduction in cerebral volume, ventriculomegaly, cerebellar hypoplasia, lissencephaly with hydrocephalus, and fetal akinesia deformation sequence. Testing for other causes of microcephaly, such as genetic disorders and infections, was negative. The ZIKV virus genome was found in tissues of the mothers and their babies.

“Combined findings from clinical, laboratory, imaging, and pathologic examinations provided a more complete picture of the severe damage and developmental abnormalities caused by ZIKV infection than has been previously reported,” Dr. Tanuri and colleagues said.

Formulating a Plan of Action

“Although we have limited ways to stop emerging pathogens, we now have powerful techniques to quickly identify the culprit, such as polymerase chain reaction and whole genome sequencing,” said Raymond P. Roos, MD, Marjorie and Robert E. Straus Professor in Neurologic Science in the Department of Neurology at the University of Chicago, in an accompanying editorial. “We also have novel methods to control vectors and produce vaccines in an accelerated time frame.”

But many unanswered questions remain, said Dr. Roos. Among those questions is what neurologists can do about the Zika virus. “It would be valuable to have adult and pediatric neurologists network with the US Centers for Disease Control and Prevention to establish a surveillance system that could track Zika virus-induced Guillain-Barré syndrome (GBS) and CNS disease. This [cooperation] would facilitate the identification and characterization of disorders, the formation of a registry, and the mounting of comprehensive epidemiologic studies. This approach would also help to identify long-term sequelae of intrauterine infection and clarify effective treatments of the GBS syndrome.”

—Glenn S. Williams

Suggested Reading

Melo AS, Aguiar RS, Amorim MM, et al. Congenital Zika virus infection: beyond neonatal microcephaly. JAMA Neurol. 2016 Oct 3 [Epub ahead of print].

Roos RP. Zika virus-a public health emergency of international concern. JAMA Neurol. 2016 Oct 3 [Epub ahead of print].

A report on 11 infants in Brazil suggests the term “congenital Zika syndrome” be used to describe the abnormalities associated with Zika virus infection because microcephaly is only one clinical sign of this congenital malformation disorder. The report was published online ahead of print October 3 in JAMA Neurology.

“To our knowledge,” the researchers wrote, “most reports to date have focused on select aspects of the maternal or fetal infection and fetal effects.” To provide a fuller description, the researchers sought to characterize the prenatal evolution and perinatal outcomes of 11 neonates who had developmental abnormalities and neurologic damage associated with Zika infection.

Follow-Up of 11 Neonates

Amilcar Tanuri, MD, PhD, Professor of Genetics and Chief of the Laboratory of Molecular Virology at the Institute of Biology, Federal University of Rio de Janeiro, and coauthors observed 11 infants with congenital Zika infection from gestation to six months in the state of Paraíba, Brazil. Cases were referred between October 2015 and February 2016. Ten of 11 women included in the study presented with symptoms of Zika infection during the first half of pregnancy, and all 11 had laboratory evidence of infection in several tissues by serology or polymerase chain reaction. Brain damage was confirmed through intrauterine ultrasonography and was complemented by MRI. Histopathologic analysis was performed on the placenta and brain tissue from infants who died. The ZIKV genome was investigated in several tissues and sequenced for further phylogenetic analysis.

Of the 11 infants, seven (63.6%) were female, and the median maternal age at delivery was 25. Three of the neonates died, giving a perinatal mortality rate of 27.3%. Zika virus was identified in amniotic fluid, placenta, cord blood, and neonatal tissues collected post mortem in the three babies who died within 48 hours of delivery.

Brain damage and neurologic impairments were identified in all patients, including microcephaly, a reduction in cerebral volume, ventriculomegaly, cerebellar hypoplasia, lissencephaly with hydrocephalus, and fetal akinesia deformation sequence. Testing for other causes of microcephaly, such as genetic disorders and infections, was negative. The ZIKV virus genome was found in tissues of the mothers and their babies.

“Combined findings from clinical, laboratory, imaging, and pathologic examinations provided a more complete picture of the severe damage and developmental abnormalities caused by ZIKV infection than has been previously reported,” Dr. Tanuri and colleagues said.

Formulating a Plan of Action

“Although we have limited ways to stop emerging pathogens, we now have powerful techniques to quickly identify the culprit, such as polymerase chain reaction and whole genome sequencing,” said Raymond P. Roos, MD, Marjorie and Robert E. Straus Professor in Neurologic Science in the Department of Neurology at the University of Chicago, in an accompanying editorial. “We also have novel methods to control vectors and produce vaccines in an accelerated time frame.”

But many unanswered questions remain, said Dr. Roos. Among those questions is what neurologists can do about the Zika virus. “It would be valuable to have adult and pediatric neurologists network with the US Centers for Disease Control and Prevention to establish a surveillance system that could track Zika virus-induced Guillain-Barré syndrome (GBS) and CNS disease. This [cooperation] would facilitate the identification and characterization of disorders, the formation of a registry, and the mounting of comprehensive epidemiologic studies. This approach would also help to identify long-term sequelae of intrauterine infection and clarify effective treatments of the GBS syndrome.”

—Glenn S. Williams

Suggested Reading

Melo AS, Aguiar RS, Amorim MM, et al. Congenital Zika virus infection: beyond neonatal microcephaly. JAMA Neurol. 2016 Oct 3 [Epub ahead of print].

Roos RP. Zika virus-a public health emergency of international concern. JAMA Neurol. 2016 Oct 3 [Epub ahead of print].

A report on 11 infants in Brazil suggests the term “congenital Zika syndrome” be used to describe the abnormalities associated with Zika virus infection because microcephaly is only one clinical sign of this congenital malformation disorder. The report was published online ahead of print October 3 in JAMA Neurology.

“To our knowledge,” the researchers wrote, “most reports to date have focused on select aspects of the maternal or fetal infection and fetal effects.” To provide a fuller description, the researchers sought to characterize the prenatal evolution and perinatal outcomes of 11 neonates who had developmental abnormalities and neurologic damage associated with Zika infection.

Follow-Up of 11 Neonates

Amilcar Tanuri, MD, PhD, Professor of Genetics and Chief of the Laboratory of Molecular Virology at the Institute of Biology, Federal University of Rio de Janeiro, and coauthors observed 11 infants with congenital Zika infection from gestation to six months in the state of Paraíba, Brazil. Cases were referred between October 2015 and February 2016. Ten of 11 women included in the study presented with symptoms of Zika infection during the first half of pregnancy, and all 11 had laboratory evidence of infection in several tissues by serology or polymerase chain reaction. Brain damage was confirmed through intrauterine ultrasonography and was complemented by MRI. Histopathologic analysis was performed on the placenta and brain tissue from infants who died. The ZIKV genome was investigated in several tissues and sequenced for further phylogenetic analysis.

Of the 11 infants, seven (63.6%) were female, and the median maternal age at delivery was 25. Three of the neonates died, giving a perinatal mortality rate of 27.3%. Zika virus was identified in amniotic fluid, placenta, cord blood, and neonatal tissues collected post mortem in the three babies who died within 48 hours of delivery.

Brain damage and neurologic impairments were identified in all patients, including microcephaly, a reduction in cerebral volume, ventriculomegaly, cerebellar hypoplasia, lissencephaly with hydrocephalus, and fetal akinesia deformation sequence. Testing for other causes of microcephaly, such as genetic disorders and infections, was negative. The ZIKV virus genome was found in tissues of the mothers and their babies.

“Combined findings from clinical, laboratory, imaging, and pathologic examinations provided a more complete picture of the severe damage and developmental abnormalities caused by ZIKV infection than has been previously reported,” Dr. Tanuri and colleagues said.

Formulating a Plan of Action

“Although we have limited ways to stop emerging pathogens, we now have powerful techniques to quickly identify the culprit, such as polymerase chain reaction and whole genome sequencing,” said Raymond P. Roos, MD, Marjorie and Robert E. Straus Professor in Neurologic Science in the Department of Neurology at the University of Chicago, in an accompanying editorial. “We also have novel methods to control vectors and produce vaccines in an accelerated time frame.”

But many unanswered questions remain, said Dr. Roos. Among those questions is what neurologists can do about the Zika virus. “It would be valuable to have adult and pediatric neurologists network with the US Centers for Disease Control and Prevention to establish a surveillance system that could track Zika virus-induced Guillain-Barré syndrome (GBS) and CNS disease. This [cooperation] would facilitate the identification and characterization of disorders, the formation of a registry, and the mounting of comprehensive epidemiologic studies. This approach would also help to identify long-term sequelae of intrauterine infection and clarify effective treatments of the GBS syndrome.”

—Glenn S. Williams

Suggested Reading

Melo AS, Aguiar RS, Amorim MM, et al. Congenital Zika virus infection: beyond neonatal microcephaly. JAMA Neurol. 2016 Oct 3 [Epub ahead of print].

Roos RP. Zika virus-a public health emergency of international concern. JAMA Neurol. 2016 Oct 3 [Epub ahead of print].

A device that closes the left atrial appendage to prevent stroke in patients with nonvalvular atrial fibrillation showed a 95.6% procedural success rate in a study of real-world experience since it was approved by the FDA in 2015, according to a report presented at the Transcatheter Cardiovascular Therapeutics annual meeting and published simultaneously in the Journal of the American College of Cardiology.

The study was based on data collected by Boston Scientific, the manufacturer of the Watchman device, regarding 3,822 consecutive patients who underwent the implantation during a 14-month period. The “excellent” procedural success rate, together with low short-term complication rates, are especially “remarkable” because 71% of the interventional cardiologists and electrophysiologists who performed these procedures had no experience with the device prior to FDA approval, said Vivek Y. Reddy, MD, of Mount Sinai Medical Center, New York.

A device that closes the left atrial appendage to prevent stroke in patients with nonvalvular atrial fibrillation showed a 95.6% procedural success rate in a study of real-world experience since it was approved by the FDA in 2015, according to a report presented at the Transcatheter Cardiovascular Therapeutics annual meeting and published simultaneously in the Journal of the American College of Cardiology.

The study was based on data collected by Boston Scientific, the manufacturer of the Watchman device, regarding 3,822 consecutive patients who underwent the implantation during a 14-month period. The “excellent” procedural success rate, together with low short-term complication rates, are especially “remarkable” because 71% of the interventional cardiologists and electrophysiologists who performed these procedures had no experience with the device prior to FDA approval, said Vivek Y. Reddy, MD, of Mount Sinai Medical Center, New York.

A device that closes the left atrial appendage to prevent stroke in patients with nonvalvular atrial fibrillation showed a 95.6% procedural success rate in a study of real-world experience since it was approved by the FDA in 2015, according to a report presented at the Transcatheter Cardiovascular Therapeutics annual meeting and published simultaneously in the Journal of the American College of Cardiology.

The study was based on data collected by Boston Scientific, the manufacturer of the Watchman device, regarding 3,822 consecutive patients who underwent the implantation during a 14-month period. The “excellent” procedural success rate, together with low short-term complication rates, are especially “remarkable” because 71% of the interventional cardiologists and electrophysiologists who performed these procedures had no experience with the device prior to FDA approval, said Vivek Y. Reddy, MD, of Mount Sinai Medical Center, New York.

A home-based intervention designed to address cognitive impairment in cancer survivors led to significant improvements in perceived cognitive impairment, anxiety, stress, and quality of life, compared with usual care.

The intervention, a computerized neurocognitive learning program, “targets cognitive domains including visual precision, divided attention, working memory, field of view, and visual processing speed, which are frequently affected in patients with cancer,” wrote Victoria J. Bray, MD, of the University of Sydney, and coauthors.

Investigators evaluated the program in a randomized controlled trial of 242 adult cancer survivors. The majority were female (95%) and had been treated for breast cancer (89%). The mean time since completion of chemotherapy was 27 months (6-60 months).

The program used, Insight From Posit Science, involved four 40-minute sessions a week for 15 weeks.

At the end of the 15-week intervention, the 121 patients in the intervention group showed significantly less perceived cognitive impairment, according to the Functional Assessment of Cancer Therapy Cognitive Function questionnaire, than the 121 patients in the standard care control group. This improvement persisted at the 6-month follow-up (J Clin Oncol. 2016 Oct 31. doi: 10.1200/JCO.2016.67.8201).

Participants in the intervention group also reported significantly better perceived cognitive abilities, and significantly less impact on their quality of life from cognitive impairment. They also reported having fewer comments from others on their cognitive impairment after the intervention finished, although this difference between the two groups disappeared by 6 months.

The authors saw no significant differences between the two groups in neuropsychological function during the follow-up; however, they stressed this result should be interpreted with caution because of missing data at both the 15-week and 6-month follow-up.

The intervention was also associated with significantly less anxiety, depression,and fatigue at the end of the 15-week period but not at the 6-month follow-up. Participants did show significant improvements in perceived stress at both follow-up points, compared with those in the control group.

Overall, only 27% of participants finished the program in the recommended 15-week time frame, and 14% never started the program.

The authors said there was a large unmet need for effective treatment options for cancer survivors experiencing cognitive symptoms after cancer treatment, even though previous research had suggested that cognitive rehabilitation strategies were feasible.

“Our large RCT [randomized controlled trial] adds weight to this evidence, confirming that the use of Insight led to an improvement in cognitive symptoms,” they wrote, pointing out the advantage of this relatively inexpensive, home-based treatment approach. “The program has the potential to provide a new treatment option for patients with cancer with cognitive symptoms, where previously none existed.”

A home-based intervention designed to address cognitive impairment in cancer survivors led to significant improvements in perceived cognitive impairment, anxiety, stress, and quality of life, compared with usual care.

The intervention, a computerized neurocognitive learning program, “targets cognitive domains including visual precision, divided attention, working memory, field of view, and visual processing speed, which are frequently affected in patients with cancer,” wrote Victoria J. Bray, MD, of the University of Sydney, and coauthors.

Investigators evaluated the program in a randomized controlled trial of 242 adult cancer survivors. The majority were female (95%) and had been treated for breast cancer (89%). The mean time since completion of chemotherapy was 27 months (6-60 months).

The program used, Insight From Posit Science, involved four 40-minute sessions a week for 15 weeks.

At the end of the 15-week intervention, the 121 patients in the intervention group showed significantly less perceived cognitive impairment, according to the Functional Assessment of Cancer Therapy Cognitive Function questionnaire, than the 121 patients in the standard care control group. This improvement persisted at the 6-month follow-up (J Clin Oncol. 2016 Oct 31. doi: 10.1200/JCO.2016.67.8201).

Participants in the intervention group also reported significantly better perceived cognitive abilities, and significantly less impact on their quality of life from cognitive impairment. They also reported having fewer comments from others on their cognitive impairment after the intervention finished, although this difference between the two groups disappeared by 6 months.

The authors saw no significant differences between the two groups in neuropsychological function during the follow-up; however, they stressed this result should be interpreted with caution because of missing data at both the 15-week and 6-month follow-up.

The intervention was also associated with significantly less anxiety, depression,and fatigue at the end of the 15-week period but not at the 6-month follow-up. Participants did show significant improvements in perceived stress at both follow-up points, compared with those in the control group.

Overall, only 27% of participants finished the program in the recommended 15-week time frame, and 14% never started the program.

The authors said there was a large unmet need for effective treatment options for cancer survivors experiencing cognitive symptoms after cancer treatment, even though previous research had suggested that cognitive rehabilitation strategies were feasible.

“Our large RCT [randomized controlled trial] adds weight to this evidence, confirming that the use of Insight led to an improvement in cognitive symptoms,” they wrote, pointing out the advantage of this relatively inexpensive, home-based treatment approach. “The program has the potential to provide a new treatment option for patients with cancer with cognitive symptoms, where previously none existed.”

A home-based intervention designed to address cognitive impairment in cancer survivors led to significant improvements in perceived cognitive impairment, anxiety, stress, and quality of life, compared with usual care.

The intervention, a computerized neurocognitive learning program, “targets cognitive domains including visual precision, divided attention, working memory, field of view, and visual processing speed, which are frequently affected in patients with cancer,” wrote Victoria J. Bray, MD, of the University of Sydney, and coauthors.

Investigators evaluated the program in a randomized controlled trial of 242 adult cancer survivors. The majority were female (95%) and had been treated for breast cancer (89%). The mean time since completion of chemotherapy was 27 months (6-60 months).

The program used, Insight From Posit Science, involved four 40-minute sessions a week for 15 weeks.

At the end of the 15-week intervention, the 121 patients in the intervention group showed significantly less perceived cognitive impairment, according to the Functional Assessment of Cancer Therapy Cognitive Function questionnaire, than the 121 patients in the standard care control group. This improvement persisted at the 6-month follow-up (J Clin Oncol. 2016 Oct 31. doi: 10.1200/JCO.2016.67.8201).

Participants in the intervention group also reported significantly better perceived cognitive abilities, and significantly less impact on their quality of life from cognitive impairment. They also reported having fewer comments from others on their cognitive impairment after the intervention finished, although this difference between the two groups disappeared by 6 months.

The authors saw no significant differences between the two groups in neuropsychological function during the follow-up; however, they stressed this result should be interpreted with caution because of missing data at both the 15-week and 6-month follow-up.

The intervention was also associated with significantly less anxiety, depression,and fatigue at the end of the 15-week period but not at the 6-month follow-up. Participants did show significant improvements in perceived stress at both follow-up points, compared with those in the control group.

Overall, only 27% of participants finished the program in the recommended 15-week time frame, and 14% never started the program.

The authors said there was a large unmet need for effective treatment options for cancer survivors experiencing cognitive symptoms after cancer treatment, even though previous research had suggested that cognitive rehabilitation strategies were feasible.

“Our large RCT [randomized controlled trial] adds weight to this evidence, confirming that the use of Insight led to an improvement in cognitive symptoms,” they wrote, pointing out the advantage of this relatively inexpensive, home-based treatment approach. “The program has the potential to provide a new treatment option for patients with cancer with cognitive symptoms, where previously none existed.”

Innovations are dominating the early part of the 21st century and the impact on cardiovascular medicine has been especially remarkable. Keeping up and evaluating the relevance of these innovations and the role in patient care is a constant challenge and opportunity for providers and scientists alike.

This Cleveland Clinic Journal of Medicine supplement on cardiovascular disease presents healthcare providers with evidenced-based reviews of important innovations and a glimpse into their potential for an exciting future.

In this supplement, Amar Krishnaswamy, MD, and colleagues look to new frontiers in valve replacement therapies. The success of transcatheter aortic valve replacement has led to extending the technique to the mitral valve. While technical challenges exist with transcatheter mitral valve replacement, methods to overcome these challenges are feasible. The authors review the various valve devices currently under development and examine their potential implications in practice.

The introduction of stents in percutaneous coronary interventions has been one of the most revolutionary innovations in cardiovascular medicine, resulting in impressive outcomes during the past few decades. Despite the dramatic advancement, persistent rates of restenosis and thrombosis continue to cause substantial morbidity and mortality. Stephen Ellis, MD, and Haris Riaz, MD, discuss the evolution of stent design from bare-metal stents through drug-eluting stents and their impact on outcomes. The evolution continues with the development of bioresorbable polymers and stents without polymers. The authors consider the promise of these innovations, especially bioresorbable stents, to further reduce restenosis and stent thrombosis.

Erich Kiehl, MD, and Daniel Cantillon, MD, present information about the latest innovation in cardiac pacing—leadless pacemakers. The first leadless pacemaker was approved earlier this year. In over 50 years of use of transvenous pacemakers, long-term complications have primarily involved the endovascular leads and surgical pocket. The authors discuss the promise of leadless cardiac pacing using catheter-based delivery of a self-contained device in the right ventricle to favorably reduce these complications, as well the current limitation of single-chamber pacing and possible future directions.

Innovations in monoclonal antibody therapy have resulted in a new class of biologic drugs to lower low-density-lipoprotein (LDL) in the blood—PCSK9 inhibitors. These new biologics target the overexpression of the PCSK9 protein in the liver, thereby increasing LDL receptors available to metabolize and remove LDL from the blood. Khendi White, MD, Chaitra Mohan, MD, and Michael Rocco, MD, discuss potential candidates for recently approved PCSK9 inhibitor therapy.

Ellen Brinza, MS, and Heather Gornik, MD, discuss new findings in our understanding of fibromuscular dysplasia (FMD). This uncommon nonatherosclerotic disease leads to narrowing, dissection, or aneurysm of medium-sized arteries. FMD is caused by abnormal development of the arterial cell wall and can cause symptoms if narrowing or a tear decreases blood flow through the artery. The authors discuss evaluation, management, and surveillance strategies as well as important lifestyle modifications and appropriate treatment of symptoms.

We hope this presentation of recent innovations in cardiovascular medicine is useful and informative to you and your clinical practice.

Innovations are dominating the early part of the 21st century and the impact on cardiovascular medicine has been especially remarkable. Keeping up and evaluating the relevance of these innovations and the role in patient care is a constant challenge and opportunity for providers and scientists alike.

This Cleveland Clinic Journal of Medicine supplement on cardiovascular disease presents healthcare providers with evidenced-based reviews of important innovations and a glimpse into their potential for an exciting future.

In this supplement, Amar Krishnaswamy, MD, and colleagues look to new frontiers in valve replacement therapies. The success of transcatheter aortic valve replacement has led to extending the technique to the mitral valve. While technical challenges exist with transcatheter mitral valve replacement, methods to overcome these challenges are feasible. The authors review the various valve devices currently under development and examine their potential implications in practice.

The introduction of stents in percutaneous coronary interventions has been one of the most revolutionary innovations in cardiovascular medicine, resulting in impressive outcomes during the past few decades. Despite the dramatic advancement, persistent rates of restenosis and thrombosis continue to cause substantial morbidity and mortality. Stephen Ellis, MD, and Haris Riaz, MD, discuss the evolution of stent design from bare-metal stents through drug-eluting stents and their impact on outcomes. The evolution continues with the development of bioresorbable polymers and stents without polymers. The authors consider the promise of these innovations, especially bioresorbable stents, to further reduce restenosis and stent thrombosis.

Erich Kiehl, MD, and Daniel Cantillon, MD, present information about the latest innovation in cardiac pacing—leadless pacemakers. The first leadless pacemaker was approved earlier this year. In over 50 years of use of transvenous pacemakers, long-term complications have primarily involved the endovascular leads and surgical pocket. The authors discuss the promise of leadless cardiac pacing using catheter-based delivery of a self-contained device in the right ventricle to favorably reduce these complications, as well the current limitation of single-chamber pacing and possible future directions.

Innovations in monoclonal antibody therapy have resulted in a new class of biologic drugs to lower low-density-lipoprotein (LDL) in the blood—PCSK9 inhibitors. These new biologics target the overexpression of the PCSK9 protein in the liver, thereby increasing LDL receptors available to metabolize and remove LDL from the blood. Khendi White, MD, Chaitra Mohan, MD, and Michael Rocco, MD, discuss potential candidates for recently approved PCSK9 inhibitor therapy.

Ellen Brinza, MS, and Heather Gornik, MD, discuss new findings in our understanding of fibromuscular dysplasia (FMD). This uncommon nonatherosclerotic disease leads to narrowing, dissection, or aneurysm of medium-sized arteries. FMD is caused by abnormal development of the arterial cell wall and can cause symptoms if narrowing or a tear decreases blood flow through the artery. The authors discuss evaluation, management, and surveillance strategies as well as important lifestyle modifications and appropriate treatment of symptoms.

We hope this presentation of recent innovations in cardiovascular medicine is useful and informative to you and your clinical practice.

Innovations are dominating the early part of the 21st century and the impact on cardiovascular medicine has been especially remarkable. Keeping up and evaluating the relevance of these innovations and the role in patient care is a constant challenge and opportunity for providers and scientists alike.

This Cleveland Clinic Journal of Medicine supplement on cardiovascular disease presents healthcare providers with evidenced-based reviews of important innovations and a glimpse into their potential for an exciting future.

In this supplement, Amar Krishnaswamy, MD, and colleagues look to new frontiers in valve replacement therapies. The success of transcatheter aortic valve replacement has led to extending the technique to the mitral valve. While technical challenges exist with transcatheter mitral valve replacement, methods to overcome these challenges are feasible. The authors review the various valve devices currently under development and examine their potential implications in practice.

The introduction of stents in percutaneous coronary interventions has been one of the most revolutionary innovations in cardiovascular medicine, resulting in impressive outcomes during the past few decades. Despite the dramatic advancement, persistent rates of restenosis and thrombosis continue to cause substantial morbidity and mortality. Stephen Ellis, MD, and Haris Riaz, MD, discuss the evolution of stent design from bare-metal stents through drug-eluting stents and their impact on outcomes. The evolution continues with the development of bioresorbable polymers and stents without polymers. The authors consider the promise of these innovations, especially bioresorbable stents, to further reduce restenosis and stent thrombosis.

Erich Kiehl, MD, and Daniel Cantillon, MD, present information about the latest innovation in cardiac pacing—leadless pacemakers. The first leadless pacemaker was approved earlier this year. In over 50 years of use of transvenous pacemakers, long-term complications have primarily involved the endovascular leads and surgical pocket. The authors discuss the promise of leadless cardiac pacing using catheter-based delivery of a self-contained device in the right ventricle to favorably reduce these complications, as well the current limitation of single-chamber pacing and possible future directions.

Innovations in monoclonal antibody therapy have resulted in a new class of biologic drugs to lower low-density-lipoprotein (LDL) in the blood—PCSK9 inhibitors. These new biologics target the overexpression of the PCSK9 protein in the liver, thereby increasing LDL receptors available to metabolize and remove LDL from the blood. Khendi White, MD, Chaitra Mohan, MD, and Michael Rocco, MD, discuss potential candidates for recently approved PCSK9 inhibitor therapy.

Ellen Brinza, MS, and Heather Gornik, MD, discuss new findings in our understanding of fibromuscular dysplasia (FMD). This uncommon nonatherosclerotic disease leads to narrowing, dissection, or aneurysm of medium-sized arteries. FMD is caused by abnormal development of the arterial cell wall and can cause symptoms if narrowing or a tear decreases blood flow through the artery. The authors discuss evaluation, management, and surveillance strategies as well as important lifestyle modifications and appropriate treatment of symptoms.

We hope this presentation of recent innovations in cardiovascular medicine is useful and informative to you and your clinical practice.

In the last 10 years, we have seen a revolution in transcatheter therapies for structural heart disease. The most widely embraced, transcatheter aortic valve replacement (TAVR) was originally intended for patients in whom surgery was considered impossible, but it has now been established as an excellent alternative to surgical aortic valve replacement in patients at high or intermediate risk.^1–3 As TAVR has become established, with well-designed devices and acceptable safety and efficacy, it has inspired operators and inventors to push the envelope of innovation to transcatheter mitral valve replacement (TMVR).

This review summarizes the newest data available for the TMVR devices currently being tested in patients with native mitral regurgitation, bioprosthetic degeneration, and degenerative mitral stenosis.

THE MITRAL VALVE: THE NEW FRONTIER

Whereas the pathologic mechanisms of aortic stenosis generally all result in the same anatomic consequence (ie, calcification of the valve leaflets and commissures resulting in reduced mobility), mitral valve regurgitation is much more heterogeneous. Primary (degenerative) mitral regurgitation is caused by intrinsic valve pathology such as myxomatous degeneration, chordal detachment, fibroelastic deficiency, endocarditis, and other conditions that prevent the leaflets from coapting properly. In contrast, in secondary or functional mitral regurgitation, the leaflets are normal but do not coapt properly because of apical tethering to a dilated left ventricle, reduced closing forces with left ventricular dysfunction, or annular dilation as the result of either left ventricular or left atrial dilation.

Surgical mitral valve repair is safe and effective in patients with degenerative mitral regurgitation caused by leaflet prolapse and flail. However, some patients cannot undergo surgery because they have comorbid conditions that place them at extreme risk.⁴ For example, most patients with functional mitral regurgitation due to ischemic or dilated cardiomyopathy have significant surgical risk and multiple comorbidities, and in this group surgical repair has limited efficacy.⁵ A sizeable proportion of patients with mitral regurgitation may not be offered surgery because their risk is too high.⁶ Therefore, alternatives to the current surgical treatments have the potential to benefit a large number of patients.

Similarly, many patients with degenerative mitral stenosis caused by calcification of the mitral annulus also cannot undergo cardiac surgery because of prohibitively high risk. While rheumatic disease is the most common cause of mitral stenosis worldwide, degenerative mitral stenosis may be the cause in up to one-fourth of patients overall and up to 60% of patients older than 80 years.⁷ In the latter group, not only do old age and comorbidities such as diabetes mellitus and chronic kidney disease pose surgical risks, the technical challenge of surgically implanting a prosthetic mitral valve in the setting of a calcified annulus may be significant.⁸

The mitral valve is, therefore, the perfect new frontier for percutaneous valve replacement therapies, and TMVR is emerging as a potential option for patients with mitral regurgitation and degenerative mitral stenosis. The currently available percutaneous treatment options for mitral regurgitation include edge-to-edge leaflet repair, direct and indirect annuloplasty, spacers, and left ventricular remodeling devices (Table 1).^9,10 As surgical mitral valve repair is strongly preferred over mitral valve replacement, the percutaneous procedures and the devices that are used are engineered to approximate the current standard surgical techniques. However, given the complex pathologies involved, surgical repair often requires the use of multiple repair techniques in the same patient. Therefore, percutaneous repair may also require more than one type of device in the same patient and may not be anatomically feasible in many patients. Replacing the entire valve may obviate some of these challenges.

Reprinted with permission from Wolters Kluwer Health, Inc. (Sud K, et al. Degenerated mitral stenosis: unmet need for percutaneous interventions. Circulation 2016; 133:1594–1604).

Compared with the aortic valve, the mitral valve poses a greater challenge to percutaneous treatment due to its structure and dynamic relationship with the left ventricle. Some specific challenges facing the development of TMVR are that the mitral valve is large, it is difficult to access, it is asymmetrical, it lacks an anatomically well-defined annulus to which to anchor the replacement valve, its geometry changes throughout the cardiac cycle, and placing a replacement valve in it entails the risk of left ventricular outflow tract obstruction. Despite these challenges, a number of devices are undergoing preclinical testing, a few are in phase 1 clinical trials, and registries are being kept. Depending on the specific device, an antegrade transseptal approach to the mitral valve (via the femoral vein) or a retrograde transapical approach (via direct left ventricular access) may be used (Figure 1).

NATIVE MITRAL VALVE REGURGITATION

For degenerative mitral regurgitation, the standard of care is cardiac surgery at a hospital experienced with mitral valve repair, and with very low rates of mortality and morbidity. For patients in whom the surgical risk is prohibitive, percutaneous edge-to-edge leaflet repair using the MitraClip (Abbott Vascular, Minneapolis, MN) is the best option if the anatomy permits. If the mitral valve pathology is not amenable to MitraClip repair, the patient may be evaluated for TMVR under a clinical trial protocol.

For functional mitral regurgitation, the decisions are more complex. If the patient has chronic atrial fibrillation, electrical cardioversion and antiarrhythmic drug therapy may restore and maintain sinus rhythm, though if the left atrium is large, sinus rhythm may not be possible. If the patient has left ventricular dysfunction, guideline-directed medical therapy should be optimized; this reduces the risk of exacerbations, hospitalizations, and death and may also reduce the degree of regurgitation. If the patient has severe left ventricular dysfunction and a wide QRS duration, cardiac resynchronization therapy (biventricular pacing) may also be beneficial and reduce functional mitral regurgitation. If symptoms and severe functional mitral regurgitation persist despite these measures and the patient’s surgical risk is deemed to be extreme, options include MitraClip placement as part of the randomized Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy (COAPT) trial, which compares guideline-directed medical therapy with guideline-directed therapy plus MitraClip. Another option is enrollment in a clinical trial or registry of TMVR.

At this writing, six TMVR devices have been implanted in humans:

• Fortis (Edwards Lifesciences, Irvine, CA)
• Tendyne (Tendyne Holding Inc, Roseville, MN)
• NaviGate (NaviGate Cardiac Structures, Inc, Lake Forest, CA)
• Intrepid (Medtronic, Minneapolis, MN)
• CardiAQ (Edwards Lifesciences, Irvine, CA)
• Tiara (Neovasc Inc, Richmond, BC).

Most of the early experience with these valves has not yet been published, but some data have been presented at national and international meetings.

The Fortis valve

Courtesy of Edwards Lifesciences.

The Fortis valve consists of a self-expanding nitinol frame and leaflets made of bovine pericardium and is implanted via a transapical approach.

The device was successfully implanted in three patients in Quebec City, Canada, and at 6 months, all had improved significantly in functional class and none had needed to be hospitalized.¹¹ Echocardiographic assessment demonstrated trace or less mitral regurgitation and a mean transvalvular gradient less than 4 mm Hg in all.

Bapat and colleagues¹² attempted to implant the device in 13 patients in Europe and Canada. The average left ventricular ejection fraction was 34%, and 12 of 13 patients (92%) had functional mitral regurgitation. Procedural success was achieved in 10 patients, but five patients died within 30 days. While the deaths were due to nonvalvular issues (multi­organ failure, septic shock, intestinal ischemia after failed valve implantation and conversion to open surgery, malnutrition leading to respiratory failure, and valve thrombosis), the trial is currently on hold as more data are collected and reviewed. Among the eight patients who survived the first month, all were still alive at 6 months, and echocardiography demonstrated no or trivial mitral regurgitation in six patients (80%) and mild regurgitation in two patients (20%); the average mitral gradient was 4 mm Hg, and there was no change in mean left ventricular ejection fraction.

The Tendyne valve

Reprinted from EuroIntervention (Perpetua EM, et al. The Tendyne transcatheter mitral valve implantation system. EuroIntervention 2015; 11:W78-W79.) © 2015 with permission from Europa Digital Publishing.

The Tendyne valve is a self-expanding prosthesis with porcine pericardial leaflets. It is delivered transapically and is held in place by a tether from the valve to the left ventricular apex.

In the first 12 patients enrolled in an early feasibility trial,¹³ the average left ventricular ejection fraction was 40%, and 11 of the 12 patients had functional mitral regurgitation. The device was successfully implanted in 11 patients, while one patient developed left ventricular outflow tract obstruction and the device was uneventfully removed. All patients were still alive at 30 days, and the 11 patients who still had a prosthetic valve did not have any residual mitral regurgitation.

As of this writing, almost 80 patients have received the device, though the data have not yet been presented. Patients are being enrolled in phase 1 trials.

The NaviGate valve

Courtesy of Jose Navia.

The NaviGate valve consists of a trileaflet subassembly fabricated from bovine pericardium, mounted on a self-expanding nitinol stent, and is only implanted transatrially.

NaviGate valves were successfully implanted in two patients via a transatrial approach (Figure 2). Both patients had excellent valve performance without residual mitral regurgitation or left ventricular outflow tract obstruction. The first patient showed significant improvement in functional class and freedom from hospitalization at 6 months, but the second patient died within a week of the implant due to advanced heart failure.¹⁴ A US clinical trial is expected soon.

The Intrepid valve

Courtesy of Medtronic.

The Intrepid valve consists of an outer stent to provide fixation to the annulus and an inner stent that houses a bovine pericardial valve. The device is a self-expanding system that is delivered transapically.

In a series of 15 patients, 11 had functional mitral regurgitation (with an average left ventricular ejection fraction of 35%) and four had degenerative mitral regurgitation (with an average left ventricular ejection fraction of 57%).¹⁵ The device was successfully implanted in 14 patients, after which the average mitral valve gradient was 4 mm Hg. All patients but one were left with no regurgitation (the other patient had 1+ regurgitation).

A trial is currently under way in Europe.

The CardiAQ valve

Courtesy of Edwards Lifesciences.

The CardiAQ is constructed of bovine pericardium and can be delivered by the transseptal or transapical route.

Of 12 patients treated under compassionate use,¹⁶ two-thirds (eight patients) had functional mitral regurgitation. Two patients died during the procedure, three died of noncardiac complications within 30 days, and one more died of sepsis shortly after 30 days. This early experience demonstrates the importance of careful patient selection and postprocedural management in the feasibility assessment of these new technologies.

Patients are being enrolled in phase 1 trials.

The Tiara valve

Reprinted from EuroIntervention (Cheung A, et al. Transcatheter mitral valve implantation with Tiara bioprosthesis. EuroIntervention 2014; 10:U115-U119.) © 2014 with permission from Europa Digital & Publishing.

The Tiara valve, a self-expanding prosthesis with bovine pericardial leaflets, is delivered by the transapical route.

Eleven patients underwent Tiara implantation as part of either a Canadian special access registry or an international feasibility trial. Their average Society of Thoracic Surgeons score (ie, their calculated risk of major morbidity or operative mortality) was 15.6%, and their average left ventricular ejection fraction was 29%. Only two patients had degenerative mitral regurgitation. Nine patients had uneventful procedures and demonstrated no residual mitral regurgitation and no left ventricular outflow tract obstruction. The procedure was converted to open surgery in two patients owing to valve malpositioning, and both of them died within 30 days. One patient in whom the procedure was successful suffered erosion of the septum and died on day 4.¹⁷

Patients are being enrolled in phase 1 trials.

DEGENERATIVE MITRAL STENOSIS

Reprinted with permission from Wolters Kluwer Health, Inc. (Sud K, et al. Degenerated mitral stenosis: unmet need for percutaneous interventions. Circulation 2016; 133:1594–1604).

In patients with degenerative mitral stenosis, extensive mitral annular calcification may provide an adequate “frame” to hold a transcatheter valve prosthesis (Figure 3). Exploiting this feature, numerous investigators have successfully deployed prosthetic valves designed for TAVR in the calcified mitral annulus via the retrograde transapical and antegrade transseptal routes.

Guerrero and colleagues presented results from the first global registry of TMVR in mitral annular calcification at the 2016 EuroPCR Congress.¹⁸ Of 104 patients analyzed, almost all received an Edwards’ Sapien balloon-expandable valve (first-generation, Sapien XT, or Sapien 3); the others received Boston Scientific’s Lotus or Direct Flow Medical (Direct Flow Medical, Santa Clara, CA) valves. With an average age of 73 years and a high prevalence of comorbidities such as diabetes, chronic obstructive pulmonary disease, atrial fibrillation, chronic kidney disease, and prior cardiac surgery, the group presented extreme surgical risk, with an average Society of Thoracic Surgeons risk score of 14.4%. Slightly more than 40% of the patients underwent transapical implantation, slightly less than 40% underwent transfemoral or transseptal implantation, and just under 20% had a direct atrial approach.

The implantation was technically successful in 78 of 104 patients (75%); 13 patients (12.5%) required a second mitral valve to be placed, 11 patients (10.5%) had left ventricular outflow tract obstruction, four patients (4%) had valve embolization, and two patients (2%) had left ventricular perforation. At 30 days, 11 of 104 patients (10.6%) had died of cardiac causes and 15 patients (14.4%) had died of noncardiac causes. When divided roughly into three equal groups by chronological order, the last third of patients, compared with the first third of patients, enjoyed greater technical success (80%, n = 32/40 vs 62.5%, n = 20/32), better 30-day survival (85%, n = 34/40 vs 62.5%, n = 20/32), and no conversion to open surgery (0 vs 12.5%, n = 4/32), likely demonstrating both improved patient selection and lessons learned from shared experience. At 1 year, almost 90% of patients had New York Heart Association class I or II symptoms. Prior to the procedure, 91.5% had New York Heart Association class III or IV symptoms.

At present, TMVR in mitral annular calcification is not approved in the United States or elsewhere. However, multiple registries are currently enrolling patients or are in formative stages to push the frontier of the currently available technologies until better, dedicated devices are available for this group of patients.

BIOPROSTHETIC VALVE OR VALVE RING FAILURE

Implantation of a TAVR prosthetic inside a degenerated bioprosthetic mitral valve (valve-in-valve) and mitral valve ring (valve-in-ring) is generally limited to case series with short-term results using the Edwards Sapien series, Boston Scientific Lotus, Medtronic Melody (Medtronic, Minneapolis, MN), and Direct Flow Medical valves (Figure 4).^19–23

The largest collective experience was presented in the Valve-in-Valve International Data (VIVID) registry, which included 349 patients who had mitral valve-in-valve placement and 88 patients who had mitral valve-in-ring procedures. Their average age was 74 and the mean Society of Thoracic Surgeons score was 12.9% in both groups.24 Of the 437 patients, 345 patients (78.9%) underwent transapical implantation, and 391 patients (89.5%) received  a Sapien XT or Sapien 3 valve. In the valve-in-valve group, 41% of the patients had regurgitation, 25% had stenosis, and 34% had both. In the valve-in-ring group, 60% of the patients had regurgitation, 17% had stenosis, and 23% had both.

Valve placement was successful in most patients. The rate of stroke was low (2.9% with valve-in-valve placement, 1.1% with valve-in-ring placement), though the rate of moderate or greater residual mitral regurgitation was significantly higher in patients undergoing valve-in-ring procedures (14.8% vs 2.6%, P < .001), as was the rate of left ventricular outflow tract obstruction (8% vs 2.6%, P = .03). There was also a trend toward worse 30-day mortality in the valve-in-ring group (11.4% vs 7.7%, P = .15). As with aortic valve-in-valve procedures, small surgical mitral valves (≤ 25 mm) were associated with higher postprocedural gradients.

Eleid and colleagues²⁵ published their experience with antegrade transseptal TMVR in 48 patients with an average Society of Thoracic Surgeons score of 13.2%, 33 of whom underwent valve-in-valve procedures and nine of whom underwent valve-in-ring procedures. (The other six patients underwent mitral valve implantation for severe mitral annular calcification.) In the valve-in-valve group, 31 patients successfully underwent implant procedures, but two patients died during the procedure from left ventricular perforation. Of the nine valve-in-ring patients, two had acute embolization of the valve and were converted to open surgery. Among the seven patients in whom implantation was successful, two developed significant left ventricular outflow tract obstruction; one was treated with surgical resection of the anterior mitral valve leaflet and the other was medically managed.

CONCLUSION

Transcatheter mitral valve replacement in regurgitant mitral valves, failing mitral valve bioprosthetics and rings, and calcified mitral annuli has been effectively conducted in a number of patients who had no surgical options due to prohibitive surgical risk. International registries and our experience have demonstrated that the valve-in-valve procedure using a TAVR prosthesis carries the greatest likelihood of success, given the rigid frame of the surgical bioprosthetic that allows stable valve deployment. While approved in Europe for this indication, use of these devices for this application in the United States is considered “off label” and is performed only in clinically extenuating circumstances. Implantation of TAVR prosthetics in patients with prior mitral ring repair or for native mitral stenosis also has been performed successfully, although left ventricular outflow tract obstruction is a significant risk in this early experience.

Devices designed specifically for TMVR are in their clinical infancy and have been implanted successfully in only small numbers of patients, most of whom had functional mitral regurgitation. Despite reasonable technical success, most of these trials have been plagued by high mortality rates at 30 days in large part due to the extreme risk of the patients in whom these procedures have been conducted. At present, enrollment in TMVR trials for patients with degenerative or functional mitral regurgitation is limited to those without a surgical option and who conform to very specific anatomic criteria.

In the last 10 years, we have seen a revolution in transcatheter therapies for structural heart disease. The most widely embraced, transcatheter aortic valve replacement (TAVR) was originally intended for patients in whom surgery was considered impossible, but it has now been established as an excellent alternative to surgical aortic valve replacement in patients at high or intermediate risk.^1–3 As TAVR has become established, with well-designed devices and acceptable safety and efficacy, it has inspired operators and inventors to push the envelope of innovation to transcatheter mitral valve replacement (TMVR).

This review summarizes the newest data available for the TMVR devices currently being tested in patients with native mitral regurgitation, bioprosthetic degeneration, and degenerative mitral stenosis.

THE MITRAL VALVE: THE NEW FRONTIER

Whereas the pathologic mechanisms of aortic stenosis generally all result in the same anatomic consequence (ie, calcification of the valve leaflets and commissures resulting in reduced mobility), mitral valve regurgitation is much more heterogeneous. Primary (degenerative) mitral regurgitation is caused by intrinsic valve pathology such as myxomatous degeneration, chordal detachment, fibroelastic deficiency, endocarditis, and other conditions that prevent the leaflets from coapting properly. In contrast, in secondary or functional mitral regurgitation, the leaflets are normal but do not coapt properly because of apical tethering to a dilated left ventricle, reduced closing forces with left ventricular dysfunction, or annular dilation as the result of either left ventricular or left atrial dilation.

Surgical mitral valve repair is safe and effective in patients with degenerative mitral regurgitation caused by leaflet prolapse and flail. However, some patients cannot undergo surgery because they have comorbid conditions that place them at extreme risk.⁴ For example, most patients with functional mitral regurgitation due to ischemic or dilated cardiomyopathy have significant surgical risk and multiple comorbidities, and in this group surgical repair has limited efficacy.⁵ A sizeable proportion of patients with mitral regurgitation may not be offered surgery because their risk is too high.⁶ Therefore, alternatives to the current surgical treatments have the potential to benefit a large number of patients.

Similarly, many patients with degenerative mitral stenosis caused by calcification of the mitral annulus also cannot undergo cardiac surgery because of prohibitively high risk. While rheumatic disease is the most common cause of mitral stenosis worldwide, degenerative mitral stenosis may be the cause in up to one-fourth of patients overall and up to 60% of patients older than 80 years.⁷ In the latter group, not only do old age and comorbidities such as diabetes mellitus and chronic kidney disease pose surgical risks, the technical challenge of surgically implanting a prosthetic mitral valve in the setting of a calcified annulus may be significant.⁸

The mitral valve is, therefore, the perfect new frontier for percutaneous valve replacement therapies, and TMVR is emerging as a potential option for patients with mitral regurgitation and degenerative mitral stenosis. The currently available percutaneous treatment options for mitral regurgitation include edge-to-edge leaflet repair, direct and indirect annuloplasty, spacers, and left ventricular remodeling devices (Table 1).^9,10 As surgical mitral valve repair is strongly preferred over mitral valve replacement, the percutaneous procedures and the devices that are used are engineered to approximate the current standard surgical techniques. However, given the complex pathologies involved, surgical repair often requires the use of multiple repair techniques in the same patient. Therefore, percutaneous repair may also require more than one type of device in the same patient and may not be anatomically feasible in many patients. Replacing the entire valve may obviate some of these challenges.

Reprinted with permission from Wolters Kluwer Health, Inc. (Sud K, et al. Degenerated mitral stenosis: unmet need for percutaneous interventions. Circulation 2016; 133:1594–1604).

Compared with the aortic valve, the mitral valve poses a greater challenge to percutaneous treatment due to its structure and dynamic relationship with the left ventricle. Some specific challenges facing the development of TMVR are that the mitral valve is large, it is difficult to access, it is asymmetrical, it lacks an anatomically well-defined annulus to which to anchor the replacement valve, its geometry changes throughout the cardiac cycle, and placing a replacement valve in it entails the risk of left ventricular outflow tract obstruction. Despite these challenges, a number of devices are undergoing preclinical testing, a few are in phase 1 clinical trials, and registries are being kept. Depending on the specific device, an antegrade transseptal approach to the mitral valve (via the femoral vein) or a retrograde transapical approach (via direct left ventricular access) may be used (Figure 1).

NATIVE MITRAL VALVE REGURGITATION

For degenerative mitral regurgitation, the standard of care is cardiac surgery at a hospital experienced with mitral valve repair, and with very low rates of mortality and morbidity. For patients in whom the surgical risk is prohibitive, percutaneous edge-to-edge leaflet repair using the MitraClip (Abbott Vascular, Minneapolis, MN) is the best option if the anatomy permits. If the mitral valve pathology is not amenable to MitraClip repair, the patient may be evaluated for TMVR under a clinical trial protocol.

For functional mitral regurgitation, the decisions are more complex. If the patient has chronic atrial fibrillation, electrical cardioversion and antiarrhythmic drug therapy may restore and maintain sinus rhythm, though if the left atrium is large, sinus rhythm may not be possible. If the patient has left ventricular dysfunction, guideline-directed medical therapy should be optimized; this reduces the risk of exacerbations, hospitalizations, and death and may also reduce the degree of regurgitation. If the patient has severe left ventricular dysfunction and a wide QRS duration, cardiac resynchronization therapy (biventricular pacing) may also be beneficial and reduce functional mitral regurgitation. If symptoms and severe functional mitral regurgitation persist despite these measures and the patient’s surgical risk is deemed to be extreme, options include MitraClip placement as part of the randomized Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy (COAPT) trial, which compares guideline-directed medical therapy with guideline-directed therapy plus MitraClip. Another option is enrollment in a clinical trial or registry of TMVR.

At this writing, six TMVR devices have been implanted in humans:

• Fortis (Edwards Lifesciences, Irvine, CA)
• Tendyne (Tendyne Holding Inc, Roseville, MN)
• NaviGate (NaviGate Cardiac Structures, Inc, Lake Forest, CA)
• Intrepid (Medtronic, Minneapolis, MN)
• CardiAQ (Edwards Lifesciences, Irvine, CA)
• Tiara (Neovasc Inc, Richmond, BC).

Most of the early experience with these valves has not yet been published, but some data have been presented at national and international meetings.

The Fortis valve

Courtesy of Edwards Lifesciences.

The Fortis valve consists of a self-expanding nitinol frame and leaflets made of bovine pericardium and is implanted via a transapical approach.

The device was successfully implanted in three patients in Quebec City, Canada, and at 6 months, all had improved significantly in functional class and none had needed to be hospitalized.¹¹ Echocardiographic assessment demonstrated trace or less mitral regurgitation and a mean transvalvular gradient less than 4 mm Hg in all.

Bapat and colleagues¹² attempted to implant the device in 13 patients in Europe and Canada. The average left ventricular ejection fraction was 34%, and 12 of 13 patients (92%) had functional mitral regurgitation. Procedural success was achieved in 10 patients, but five patients died within 30 days. While the deaths were due to nonvalvular issues (multi­organ failure, septic shock, intestinal ischemia after failed valve implantation and conversion to open surgery, malnutrition leading to respiratory failure, and valve thrombosis), the trial is currently on hold as more data are collected and reviewed. Among the eight patients who survived the first month, all were still alive at 6 months, and echocardiography demonstrated no or trivial mitral regurgitation in six patients (80%) and mild regurgitation in two patients (20%); the average mitral gradient was 4 mm Hg, and there was no change in mean left ventricular ejection fraction.

The Tendyne valve

Reprinted from EuroIntervention (Perpetua EM, et al. The Tendyne transcatheter mitral valve implantation system. EuroIntervention 2015; 11:W78-W79.) © 2015 with permission from Europa Digital Publishing.

The Tendyne valve is a self-expanding prosthesis with porcine pericardial leaflets. It is delivered transapically and is held in place by a tether from the valve to the left ventricular apex.

In the first 12 patients enrolled in an early feasibility trial,¹³ the average left ventricular ejection fraction was 40%, and 11 of the 12 patients had functional mitral regurgitation. The device was successfully implanted in 11 patients, while one patient developed left ventricular outflow tract obstruction and the device was uneventfully removed. All patients were still alive at 30 days, and the 11 patients who still had a prosthetic valve did not have any residual mitral regurgitation.

As of this writing, almost 80 patients have received the device, though the data have not yet been presented. Patients are being enrolled in phase 1 trials.

The NaviGate valve

Courtesy of Jose Navia.

The NaviGate valve consists of a trileaflet subassembly fabricated from bovine pericardium, mounted on a self-expanding nitinol stent, and is only implanted transatrially.

NaviGate valves were successfully implanted in two patients via a transatrial approach (Figure 2). Both patients had excellent valve performance without residual mitral regurgitation or left ventricular outflow tract obstruction. The first patient showed significant improvement in functional class and freedom from hospitalization at 6 months, but the second patient died within a week of the implant due to advanced heart failure.¹⁴ A US clinical trial is expected soon.

The Intrepid valve

Courtesy of Medtronic.

The Intrepid valve consists of an outer stent to provide fixation to the annulus and an inner stent that houses a bovine pericardial valve. The device is a self-expanding system that is delivered transapically.

In a series of 15 patients, 11 had functional mitral regurgitation (with an average left ventricular ejection fraction of 35%) and four had degenerative mitral regurgitation (with an average left ventricular ejection fraction of 57%).¹⁵ The device was successfully implanted in 14 patients, after which the average mitral valve gradient was 4 mm Hg. All patients but one were left with no regurgitation (the other patient had 1+ regurgitation).

A trial is currently under way in Europe.

The CardiAQ valve

Courtesy of Edwards Lifesciences.

The CardiAQ is constructed of bovine pericardium and can be delivered by the transseptal or transapical route.

Of 12 patients treated under compassionate use,¹⁶ two-thirds (eight patients) had functional mitral regurgitation. Two patients died during the procedure, three died of noncardiac complications within 30 days, and one more died of sepsis shortly after 30 days. This early experience demonstrates the importance of careful patient selection and postprocedural management in the feasibility assessment of these new technologies.

Patients are being enrolled in phase 1 trials.

The Tiara valve

Reprinted from EuroIntervention (Cheung A, et al. Transcatheter mitral valve implantation with Tiara bioprosthesis. EuroIntervention 2014; 10:U115-U119.) © 2014 with permission from Europa Digital &amp; Publishing.

The Tiara valve, a self-expanding prosthesis with bovine pericardial leaflets, is delivered by the transapical route.

Eleven patients underwent Tiara implantation as part of either a Canadian special access registry or an international feasibility trial. Their average Society of Thoracic Surgeons score (ie, their calculated risk of major morbidity or operative mortality) was 15.6%, and their average left ventricular ejection fraction was 29%. Only two patients had degenerative mitral regurgitation. Nine patients had uneventful procedures and demonstrated no residual mitral regurgitation and no left ventricular outflow tract obstruction. The procedure was converted to open surgery in two patients owing to valve malpositioning, and both of them died within 30 days. One patient in whom the procedure was successful suffered erosion of the septum and died on day 4.¹⁷

Patients are being enrolled in phase 1 trials.

DEGENERATIVE MITRAL STENOSIS

Reprinted with permission from Wolters Kluwer Health, Inc. (Sud K, et al. Degenerated mitral stenosis: unmet need for percutaneous interventions. Circulation 2016; 133:1594–1604).

In patients with degenerative mitral stenosis, extensive mitral annular calcification may provide an adequate “frame” to hold a transcatheter valve prosthesis (Figure 3). Exploiting this feature, numerous investigators have successfully deployed prosthetic valves designed for TAVR in the calcified mitral annulus via the retrograde transapical and antegrade transseptal routes.

Guerrero and colleagues presented results from the first global registry of TMVR in mitral annular calcification at the 2016 EuroPCR Congress.¹⁸ Of 104 patients analyzed, almost all received an Edwards’ Sapien balloon-expandable valve (first-generation, Sapien XT, or Sapien 3); the others received Boston Scientific’s Lotus or Direct Flow Medical (Direct Flow Medical, Santa Clara, CA) valves. With an average age of 73 years and a high prevalence of comorbidities such as diabetes, chronic obstructive pulmonary disease, atrial fibrillation, chronic kidney disease, and prior cardiac surgery, the group presented extreme surgical risk, with an average Society of Thoracic Surgeons risk score of 14.4%. Slightly more than 40% of the patients underwent transapical implantation, slightly less than 40% underwent transfemoral or transseptal implantation, and just under 20% had a direct atrial approach.

The implantation was technically successful in 78 of 104 patients (75%); 13 patients (12.5%) required a second mitral valve to be placed, 11 patients (10.5%) had left ventricular outflow tract obstruction, four patients (4%) had valve embolization, and two patients (2%) had left ventricular perforation. At 30 days, 11 of 104 patients (10.6%) had died of cardiac causes and 15 patients (14.4%) had died of noncardiac causes. When divided roughly into three equal groups by chronological order, the last third of patients, compared with the first third of patients, enjoyed greater technical success (80%, n = 32/40 vs 62.5%, n = 20/32), better 30-day survival (85%, n = 34/40 vs 62.5%, n = 20/32), and no conversion to open surgery (0 vs 12.5%, n = 4/32), likely demonstrating both improved patient selection and lessons learned from shared experience. At 1 year, almost 90% of patients had New York Heart Association class I or II symptoms. Prior to the procedure, 91.5% had New York Heart Association class III or IV symptoms.

At present, TMVR in mitral annular calcification is not approved in the United States or elsewhere. However, multiple registries are currently enrolling patients or are in formative stages to push the frontier of the currently available technologies until better, dedicated devices are available for this group of patients.

BIOPROSTHETIC VALVE OR VALVE RING FAILURE

Implantation of a TAVR prosthetic inside a degenerated bioprosthetic mitral valve (valve-in-valve) and mitral valve ring (valve-in-ring) is generally limited to case series with short-term results using the Edwards Sapien series, Boston Scientific Lotus, Medtronic Melody (Medtronic, Minneapolis, MN), and Direct Flow Medical valves (Figure 4).^19–23

The largest collective experience was presented in the Valve-in-Valve International Data (VIVID) registry, which included 349 patients who had mitral valve-in-valve placement and 88 patients who had mitral valve-in-ring procedures. Their average age was 74 and the mean Society of Thoracic Surgeons score was 12.9% in both groups.24 Of the 437 patients, 345 patients (78.9%) underwent transapical implantation, and 391 patients (89.5%) received  a Sapien XT or Sapien 3 valve. In the valve-in-valve group, 41% of the patients had regurgitation, 25% had stenosis, and 34% had both. In the valve-in-ring group, 60% of the patients had regurgitation, 17% had stenosis, and 23% had both.

Valve placement was successful in most patients. The rate of stroke was low (2.9% with valve-in-valve placement, 1.1% with valve-in-ring placement), though the rate of moderate or greater residual mitral regurgitation was significantly higher in patients undergoing valve-in-ring procedures (14.8% vs 2.6%, P < .001), as was the rate of left ventricular outflow tract obstruction (8% vs 2.6%, P = .03). There was also a trend toward worse 30-day mortality in the valve-in-ring group (11.4% vs 7.7%, P = .15). As with aortic valve-in-valve procedures, small surgical mitral valves (≤ 25 mm) were associated with higher postprocedural gradients.

Eleid and colleagues²⁵ published their experience with antegrade transseptal TMVR in 48 patients with an average Society of Thoracic Surgeons score of 13.2%, 33 of whom underwent valve-in-valve procedures and nine of whom underwent valve-in-ring procedures. (The other six patients underwent mitral valve implantation for severe mitral annular calcification.) In the valve-in-valve group, 31 patients successfully underwent implant procedures, but two patients died during the procedure from left ventricular perforation. Of the nine valve-in-ring patients, two had acute embolization of the valve and were converted to open surgery. Among the seven patients in whom implantation was successful, two developed significant left ventricular outflow tract obstruction; one was treated with surgical resection of the anterior mitral valve leaflet and the other was medically managed.

CONCLUSION

Transcatheter mitral valve replacement in regurgitant mitral valves, failing mitral valve bioprosthetics and rings, and calcified mitral annuli has been effectively conducted in a number of patients who had no surgical options due to prohibitive surgical risk. International registries and our experience have demonstrated that the valve-in-valve procedure using a TAVR prosthesis carries the greatest likelihood of success, given the rigid frame of the surgical bioprosthetic that allows stable valve deployment. While approved in Europe for this indication, use of these devices for this application in the United States is considered “off label” and is performed only in clinically extenuating circumstances. Implantation of TAVR prosthetics in patients with prior mitral ring repair or for native mitral stenosis also has been performed successfully, although left ventricular outflow tract obstruction is a significant risk in this early experience.

Devices designed specifically for TMVR are in their clinical infancy and have been implanted successfully in only small numbers of patients, most of whom had functional mitral regurgitation. Despite reasonable technical success, most of these trials have been plagued by high mortality rates at 30 days in large part due to the extreme risk of the patients in whom these procedures have been conducted. At present, enrollment in TMVR trials for patients with degenerative or functional mitral regurgitation is limited to those without a surgical option and who conform to very specific anatomic criteria.

In the last 10 years, we have seen a revolution in transcatheter therapies for structural heart disease. The most widely embraced, transcatheter aortic valve replacement (TAVR) was originally intended for patients in whom surgery was considered impossible, but it has now been established as an excellent alternative to surgical aortic valve replacement in patients at high or intermediate risk.^1–3 As TAVR has become established, with well-designed devices and acceptable safety and efficacy, it has inspired operators and inventors to push the envelope of innovation to transcatheter mitral valve replacement (TMVR).

This review summarizes the newest data available for the TMVR devices currently being tested in patients with native mitral regurgitation, bioprosthetic degeneration, and degenerative mitral stenosis.

THE MITRAL VALVE: THE NEW FRONTIER

Whereas the pathologic mechanisms of aortic stenosis generally all result in the same anatomic consequence (ie, calcification of the valve leaflets and commissures resulting in reduced mobility), mitral valve regurgitation is much more heterogeneous. Primary (degenerative) mitral regurgitation is caused by intrinsic valve pathology such as myxomatous degeneration, chordal detachment, fibroelastic deficiency, endocarditis, and other conditions that prevent the leaflets from coapting properly. In contrast, in secondary or functional mitral regurgitation, the leaflets are normal but do not coapt properly because of apical tethering to a dilated left ventricle, reduced closing forces with left ventricular dysfunction, or annular dilation as the result of either left ventricular or left atrial dilation.

Surgical mitral valve repair is safe and effective in patients with degenerative mitral regurgitation caused by leaflet prolapse and flail. However, some patients cannot undergo surgery because they have comorbid conditions that place them at extreme risk.⁴ For example, most patients with functional mitral regurgitation due to ischemic or dilated cardiomyopathy have significant surgical risk and multiple comorbidities, and in this group surgical repair has limited efficacy.⁵ A sizeable proportion of patients with mitral regurgitation may not be offered surgery because their risk is too high.⁶ Therefore, alternatives to the current surgical treatments have the potential to benefit a large number of patients.

Similarly, many patients with degenerative mitral stenosis caused by calcification of the mitral annulus also cannot undergo cardiac surgery because of prohibitively high risk. While rheumatic disease is the most common cause of mitral stenosis worldwide, degenerative mitral stenosis may be the cause in up to one-fourth of patients overall and up to 60% of patients older than 80 years.⁷ In the latter group, not only do old age and comorbidities such as diabetes mellitus and chronic kidney disease pose surgical risks, the technical challenge of surgically implanting a prosthetic mitral valve in the setting of a calcified annulus may be significant.⁸

The mitral valve is, therefore, the perfect new frontier for percutaneous valve replacement therapies, and TMVR is emerging as a potential option for patients with mitral regurgitation and degenerative mitral stenosis. The currently available percutaneous treatment options for mitral regurgitation include edge-to-edge leaflet repair, direct and indirect annuloplasty, spacers, and left ventricular remodeling devices (Table 1).^9,10 As surgical mitral valve repair is strongly preferred over mitral valve replacement, the percutaneous procedures and the devices that are used are engineered to approximate the current standard surgical techniques. However, given the complex pathologies involved, surgical repair often requires the use of multiple repair techniques in the same patient. Therefore, percutaneous repair may also require more than one type of device in the same patient and may not be anatomically feasible in many patients. Replacing the entire valve may obviate some of these challenges.

Reprinted with permission from Wolters Kluwer Health, Inc. (Sud K, et al. Degenerated mitral stenosis: unmet need for percutaneous interventions. Circulation 2016; 133:1594–1604).

Compared with the aortic valve, the mitral valve poses a greater challenge to percutaneous treatment due to its structure and dynamic relationship with the left ventricle. Some specific challenges facing the development of TMVR are that the mitral valve is large, it is difficult to access, it is asymmetrical, it lacks an anatomically well-defined annulus to which to anchor the replacement valve, its geometry changes throughout the cardiac cycle, and placing a replacement valve in it entails the risk of left ventricular outflow tract obstruction. Despite these challenges, a number of devices are undergoing preclinical testing, a few are in phase 1 clinical trials, and registries are being kept. Depending on the specific device, an antegrade transseptal approach to the mitral valve (via the femoral vein) or a retrograde transapical approach (via direct left ventricular access) may be used (Figure 1).

NATIVE MITRAL VALVE REGURGITATION

For degenerative mitral regurgitation, the standard of care is cardiac surgery at a hospital experienced with mitral valve repair, and with very low rates of mortality and morbidity. For patients in whom the surgical risk is prohibitive, percutaneous edge-to-edge leaflet repair using the MitraClip (Abbott Vascular, Minneapolis, MN) is the best option if the anatomy permits. If the mitral valve pathology is not amenable to MitraClip repair, the patient may be evaluated for TMVR under a clinical trial protocol.

For functional mitral regurgitation, the decisions are more complex. If the patient has chronic atrial fibrillation, electrical cardioversion and antiarrhythmic drug therapy may restore and maintain sinus rhythm, though if the left atrium is large, sinus rhythm may not be possible. If the patient has left ventricular dysfunction, guideline-directed medical therapy should be optimized; this reduces the risk of exacerbations, hospitalizations, and death and may also reduce the degree of regurgitation. If the patient has severe left ventricular dysfunction and a wide QRS duration, cardiac resynchronization therapy (biventricular pacing) may also be beneficial and reduce functional mitral regurgitation. If symptoms and severe functional mitral regurgitation persist despite these measures and the patient’s surgical risk is deemed to be extreme, options include MitraClip placement as part of the randomized Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy (COAPT) trial, which compares guideline-directed medical therapy with guideline-directed therapy plus MitraClip. Another option is enrollment in a clinical trial or registry of TMVR.

At this writing, six TMVR devices have been implanted in humans:

• Fortis (Edwards Lifesciences, Irvine, CA)
• Tendyne (Tendyne Holding Inc, Roseville, MN)
• NaviGate (NaviGate Cardiac Structures, Inc, Lake Forest, CA)
• Intrepid (Medtronic, Minneapolis, MN)
• CardiAQ (Edwards Lifesciences, Irvine, CA)
• Tiara (Neovasc Inc, Richmond, BC).

Most of the early experience with these valves has not yet been published, but some data have been presented at national and international meetings.

The Fortis valve

Courtesy of Edwards Lifesciences.

The Fortis valve consists of a self-expanding nitinol frame and leaflets made of bovine pericardium and is implanted via a transapical approach.

The device was successfully implanted in three patients in Quebec City, Canada, and at 6 months, all had improved significantly in functional class and none had needed to be hospitalized.¹¹ Echocardiographic assessment demonstrated trace or less mitral regurgitation and a mean transvalvular gradient less than 4 mm Hg in all.

Bapat and colleagues¹² attempted to implant the device in 13 patients in Europe and Canada. The average left ventricular ejection fraction was 34%, and 12 of 13 patients (92%) had functional mitral regurgitation. Procedural success was achieved in 10 patients, but five patients died within 30 days. While the deaths were due to nonvalvular issues (multi­organ failure, septic shock, intestinal ischemia after failed valve implantation and conversion to open surgery, malnutrition leading to respiratory failure, and valve thrombosis), the trial is currently on hold as more data are collected and reviewed. Among the eight patients who survived the first month, all were still alive at 6 months, and echocardiography demonstrated no or trivial mitral regurgitation in six patients (80%) and mild regurgitation in two patients (20%); the average mitral gradient was 4 mm Hg, and there was no change in mean left ventricular ejection fraction.

The Tendyne valve

Reprinted from EuroIntervention (Perpetua EM, et al. The Tendyne transcatheter mitral valve implantation system. EuroIntervention 2015; 11:W78-W79.) © 2015 with permission from Europa Digital Publishing.

The Tendyne valve is a self-expanding prosthesis with porcine pericardial leaflets. It is delivered transapically and is held in place by a tether from the valve to the left ventricular apex.

In the first 12 patients enrolled in an early feasibility trial,¹³ the average left ventricular ejection fraction was 40%, and 11 of the 12 patients had functional mitral regurgitation. The device was successfully implanted in 11 patients, while one patient developed left ventricular outflow tract obstruction and the device was uneventfully removed. All patients were still alive at 30 days, and the 11 patients who still had a prosthetic valve did not have any residual mitral regurgitation.

As of this writing, almost 80 patients have received the device, though the data have not yet been presented. Patients are being enrolled in phase 1 trials.

The NaviGate valve

Courtesy of Jose Navia.

The NaviGate valve consists of a trileaflet subassembly fabricated from bovine pericardium, mounted on a self-expanding nitinol stent, and is only implanted transatrially.

NaviGate valves were successfully implanted in two patients via a transatrial approach (Figure 2). Both patients had excellent valve performance without residual mitral regurgitation or left ventricular outflow tract obstruction. The first patient showed significant improvement in functional class and freedom from hospitalization at 6 months, but the second patient died within a week of the implant due to advanced heart failure.¹⁴ A US clinical trial is expected soon.

The Intrepid valve

Courtesy of Medtronic.

The Intrepid valve consists of an outer stent to provide fixation to the annulus and an inner stent that houses a bovine pericardial valve. The device is a self-expanding system that is delivered transapically.

In a series of 15 patients, 11 had functional mitral regurgitation (with an average left ventricular ejection fraction of 35%) and four had degenerative mitral regurgitation (with an average left ventricular ejection fraction of 57%).¹⁵ The device was successfully implanted in 14 patients, after which the average mitral valve gradient was 4 mm Hg. All patients but one were left with no regurgitation (the other patient had 1+ regurgitation).

A trial is currently under way in Europe.

The CardiAQ valve

Courtesy of Edwards Lifesciences.

The CardiAQ is constructed of bovine pericardium and can be delivered by the transseptal or transapical route.

Of 12 patients treated under compassionate use,¹⁶ two-thirds (eight patients) had functional mitral regurgitation. Two patients died during the procedure, three died of noncardiac complications within 30 days, and one more died of sepsis shortly after 30 days. This early experience demonstrates the importance of careful patient selection and postprocedural management in the feasibility assessment of these new technologies.

Patients are being enrolled in phase 1 trials.

The Tiara valve

Reprinted from EuroIntervention (Cheung A, et al. Transcatheter mitral valve implantation with Tiara bioprosthesis. EuroIntervention 2014; 10:U115-U119.) © 2014 with permission from Europa Digital &amp; Publishing.

The Tiara valve, a self-expanding prosthesis with bovine pericardial leaflets, is delivered by the transapical route.

Eleven patients underwent Tiara implantation as part of either a Canadian special access registry or an international feasibility trial. Their average Society of Thoracic Surgeons score (ie, their calculated risk of major morbidity or operative mortality) was 15.6%, and their average left ventricular ejection fraction was 29%. Only two patients had degenerative mitral regurgitation. Nine patients had uneventful procedures and demonstrated no residual mitral regurgitation and no left ventricular outflow tract obstruction. The procedure was converted to open surgery in two patients owing to valve malpositioning, and both of them died within 30 days. One patient in whom the procedure was successful suffered erosion of the septum and died on day 4.¹⁷

Patients are being enrolled in phase 1 trials.

DEGENERATIVE MITRAL STENOSIS

Reprinted with permission from Wolters Kluwer Health, Inc. (Sud K, et al. Degenerated mitral stenosis: unmet need for percutaneous interventions. Circulation 2016; 133:1594–1604).

In patients with degenerative mitral stenosis, extensive mitral annular calcification may provide an adequate “frame” to hold a transcatheter valve prosthesis (Figure 3). Exploiting this feature, numerous investigators have successfully deployed prosthetic valves designed for TAVR in the calcified mitral annulus via the retrograde transapical and antegrade transseptal routes.

Guerrero and colleagues presented results from the first global registry of TMVR in mitral annular calcification at the 2016 EuroPCR Congress.¹⁸ Of 104 patients analyzed, almost all received an Edwards’ Sapien balloon-expandable valve (first-generation, Sapien XT, or Sapien 3); the others received Boston Scientific’s Lotus or Direct Flow Medical (Direct Flow Medical, Santa Clara, CA) valves. With an average age of 73 years and a high prevalence of comorbidities such as diabetes, chronic obstructive pulmonary disease, atrial fibrillation, chronic kidney disease, and prior cardiac surgery, the group presented extreme surgical risk, with an average Society of Thoracic Surgeons risk score of 14.4%. Slightly more than 40% of the patients underwent transapical implantation, slightly less than 40% underwent transfemoral or transseptal implantation, and just under 20% had a direct atrial approach.

The implantation was technically successful in 78 of 104 patients (75%); 13 patients (12.5%) required a second mitral valve to be placed, 11 patients (10.5%) had left ventricular outflow tract obstruction, four patients (4%) had valve embolization, and two patients (2%) had left ventricular perforation. At 30 days, 11 of 104 patients (10.6%) had died of cardiac causes and 15 patients (14.4%) had died of noncardiac causes. When divided roughly into three equal groups by chronological order, the last third of patients, compared with the first third of patients, enjoyed greater technical success (80%, n = 32/40 vs 62.5%, n = 20/32), better 30-day survival (85%, n = 34/40 vs 62.5%, n = 20/32), and no conversion to open surgery (0 vs 12.5%, n = 4/32), likely demonstrating both improved patient selection and lessons learned from shared experience. At 1 year, almost 90% of patients had New York Heart Association class I or II symptoms. Prior to the procedure, 91.5% had New York Heart Association class III or IV symptoms.

At present, TMVR in mitral annular calcification is not approved in the United States or elsewhere. However, multiple registries are currently enrolling patients or are in formative stages to push the frontier of the currently available technologies until better, dedicated devices are available for this group of patients.

BIOPROSTHETIC VALVE OR VALVE RING FAILURE

Implantation of a TAVR prosthetic inside a degenerated bioprosthetic mitral valve (valve-in-valve) and mitral valve ring (valve-in-ring) is generally limited to case series with short-term results using the Edwards Sapien series, Boston Scientific Lotus, Medtronic Melody (Medtronic, Minneapolis, MN), and Direct Flow Medical valves (Figure 4).^19–23

The largest collective experience was presented in the Valve-in-Valve International Data (VIVID) registry, which included 349 patients who had mitral valve-in-valve placement and 88 patients who had mitral valve-in-ring procedures. Their average age was 74 and the mean Society of Thoracic Surgeons score was 12.9% in both groups.24 Of the 437 patients, 345 patients (78.9%) underwent transapical implantation, and 391 patients (89.5%) received  a Sapien XT or Sapien 3 valve. In the valve-in-valve group, 41% of the patients had regurgitation, 25% had stenosis, and 34% had both. In the valve-in-ring group, 60% of the patients had regurgitation, 17% had stenosis, and 23% had both.

Valve placement was successful in most patients. The rate of stroke was low (2.9% with valve-in-valve placement, 1.1% with valve-in-ring placement), though the rate of moderate or greater residual mitral regurgitation was significantly higher in patients undergoing valve-in-ring procedures (14.8% vs 2.6%, P < .001), as was the rate of left ventricular outflow tract obstruction (8% vs 2.6%, P = .03). There was also a trend toward worse 30-day mortality in the valve-in-ring group (11.4% vs 7.7%, P = .15). As with aortic valve-in-valve procedures, small surgical mitral valves (≤ 25 mm) were associated with higher postprocedural gradients.

Eleid and colleagues²⁵ published their experience with antegrade transseptal TMVR in 48 patients with an average Society of Thoracic Surgeons score of 13.2%, 33 of whom underwent valve-in-valve procedures and nine of whom underwent valve-in-ring procedures. (The other six patients underwent mitral valve implantation for severe mitral annular calcification.) In the valve-in-valve group, 31 patients successfully underwent implant procedures, but two patients died during the procedure from left ventricular perforation. Of the nine valve-in-ring patients, two had acute embolization of the valve and were converted to open surgery. Among the seven patients in whom implantation was successful, two developed significant left ventricular outflow tract obstruction; one was treated with surgical resection of the anterior mitral valve leaflet and the other was medically managed.

CONCLUSION

Transcatheter mitral valve replacement in regurgitant mitral valves, failing mitral valve bioprosthetics and rings, and calcified mitral annuli has been effectively conducted in a number of patients who had no surgical options due to prohibitive surgical risk. International registries and our experience have demonstrated that the valve-in-valve procedure using a TAVR prosthesis carries the greatest likelihood of success, given the rigid frame of the surgical bioprosthetic that allows stable valve deployment. While approved in Europe for this indication, use of these devices for this application in the United States is considered “off label” and is performed only in clinically extenuating circumstances. Implantation of TAVR prosthetics in patients with prior mitral ring repair or for native mitral stenosis also has been performed successfully, although left ventricular outflow tract obstruction is a significant risk in this early experience.

Devices designed specifically for TMVR are in their clinical infancy and have been implanted successfully in only small numbers of patients, most of whom had functional mitral regurgitation. Despite reasonable technical success, most of these trials have been plagued by high mortality rates at 30 days in large part due to the extreme risk of the patients in whom these procedures have been conducted. At present, enrollment in TMVR trials for patients with degenerative or functional mitral regurgitation is limited to those without a surgical option and who conform to very specific anatomic criteria.

Interventional cardiology has made great strides in the last few decades. Percutaneous coronary intervention (PCI) is among the most commonly performed medical procedures globally.¹ At the time of inception, PCI was plagued by high complication rates—balloon catheters had a 50% target-lesion restenosis rate at 6 months and required emergency bypass surgery in up to 6% patients.² With passage of time, the complication rate of PCI has markedly decreased.

The introduction of stents had a dramatic impact on lowering the complication rates. Initially, the bare-metal stents (BMS) reduced the stent restenosis rate to 10% to 15%. Drug-eluting stents (DES) have further revolutionized the field (Figure 1), significantly lowering rates of stent thrombosis (less than 0.5% in 1 year) and risk of restenosis (less than 5% in 1 year).^3–6 The second-generation DES widely used in contemporary practice have made even more reductions owing to their improved designs and metallic and polymer composition; and concurrent advancements in the medical management, including use of antithrombotic and antiproliferative drugs, have further contributed to improved rates.

What, then, is to be hoped for? Unfortunately, with the advent of stents, complications such as stent thrombosis and stent restenosis also emerged. These complications can be life-threatening in the form of post-procedural or late myocardial infarction and cardiac death. Thus, although the US Food and Drug Administration (FDA) assesses target-lesion failure (defined as a composite of cardiac death, target vessel myocardial infarction, or ischemia-driven target vessel revascularization) at 1 year, patients can have complications for the remainder of their lives. Despite the advancements attained by the second-generation DES over their predecessors, the issue of stent thrombosis and restenosis continues to plague second-generation DES with a 2% to 2.5% increased rate of target-lesion failure each year, seemingly forever (Figure 2).^7,8

This article will briefly discuss the stent design and pathophysiology driving stent thrombosis and restenosis along with potential strategies to mitigate the problem. It pays special emphasis to bioresorbable stents, given their increasing interest among interventional cardiologists and patients, and given their potential to transform the practice of PCI.

STENT DESIGN

Contemporary DES essentially consist of three components:

• A metallic alloy with a mesh-like design serves as the platform for the stent.
• This framework is coated with a multi-layered polymer that holds and releases the active drug in a controlled manner so that its effects can be extended.

• 

  An antiproliferative drug (absent in the bioresorbable stents) that inhibits the smooth muscle proliferation and neointimal hyperplastic response: sirolimus or paclitaxel in first-generation DES; everolimus or zotarolimus in second-generation DES (Figure 3).

WHAT CAUSES STENT THROMBOSIS AND RESTENOSIS?

Several theories and pathophysiological mechanisms have been proposed to explain these late adverse events (Table 1). However, our overall understanding of the cause remains modest at best. The major factor seems to be persistent presence of polymer on the stent and the ensuing inflammation. The second issue appears to be related to neoathero­sclerosis that is generally defined as lipid or calcified neointima. Neoathero­sclerosis is especially problematic for the second-generation DES. Neoatherosclerosis eventually predisposes to the development of thin cap fibroadenoma, and the rupture of thin cap leads to stent thrombosis and restenosis.

Autopsy studies suggest that approxi­mately 50% of first- and second-generation DES start developing neoatherosclerosis within 1 to 3 years of implantation.⁹ Turbulence created by thick strutted stents or incomplete impaction of stents to the vessel wall predisposes the stents to platelet aggregation and fibrinogen deposition, thereby increasing the risk of neoatherosclerosis. Despite these pathologic insights, no treatment strategy has been shown to attenuate the problem, with the exception of high-dose statins.

CAN WE SOLVE THE PROBLEM?

Three technological approaches have been proposed to overcome stent thrombosis and restenosis:

• Stents coated with bioresorbable polymers that quickly degrade
• Stents without polymers
• Stents that are completely resorbed.

STENTS WITH BIORESORBABLE POLYMERS

As described above, the presence of a polymer on the stent predisposes it to inflammation. Therefore, it would be logical to hypothesize that a bioresorbable polymer would reduce the inflammation. This approach is typified by the second-generation paclitaxel-eluting stent (Synergy, Boston Scientific). It has a biodegradable coating that resorbs within 4 months and releases everolimus in a dose intensity similar to that seen with the contemporary second-generation DES.

The largest trial of this device to date, the Evolve II study, randomly assigned 1,684 patients to the biostable-polymer, everolimus-eluting chromium stent (Promus, Boston Scientific) or the paclitaxel-eluting stent (Synergy, Boston Scientific).¹⁰ Two-year follow-up data suggest that the rate of target-lesion failure was 9.4% in the paclitaxel-eluting stent patients vs 8.5% in the everolimus-eluting stent patients. Notably, no definite stent thrombosis was seen in the Synergy-­treated patients 24 hours after the initial device implantation.

STENTS WITHOUT POLYMERS

If polymers predispose to inflammation, stents without polymers should mitigate the risk. Such stent types are exemplified by the BioFreedom (Biosensors International) stainless steel stent, a polymer-free umirolimus (also known as biolimus A9)-eluting stent. These stents have a microstructured surface that holds the drug without a polymer and releases the active drug over a few months.

The LEADERS FREE clinical trial studied this stent in 2,466 patients at high risk of bleeding.¹¹ The patients were randomized to receive either a BMS or the polymer-free stent.  All patients were required to receive dual antiplatelet therapy for only 1 month. At 1 year, the composite risk of cardiac death, myocardial infarction, and stent thrombois was 9.4% in patients with BioFreedom stents vs 12.9% in BMS patients. Of note, the primary end point did not include stent restenosis, thereby not disadvantaging the BMS.

Medtronic’s polymer-free, sirolimus-eluting stent is currently under investigation in the RevElution clinical trial.¹² It has a cylindrical structure with the core replaced by the active drug sirolimus. Abluminal holes in the stent allow controlled release of the drug. A pharmacokinetic analysis show that 90% of the medication is released within the first 90 days and that tissue concentrations are maintained in the therapeutic range until at least that time.¹³ This actually exceeds that of the second-generation everolimus-eluting DES.

BIORESORBABLE STENTS

Bioresorbable scaffolds or stents disappear entirely over time and have drawn considerable attention in the interventional cardiology community. The FDA recently approved Abbott’s Poly-L-Lactic Acid (PLLA) everolimus-eluting stent (Absorb). The rate of bioresorption of this device can be controlled by modulating the respective contribution of amorphous and crystalline PLLA backbone. The advantage of bioresorbable stents appears to stem from the fact that with bioresorbable devices, the vessel may actually expand and the purported nidus for inflammation goes away. This has been demonstrated by serial intravascular ultrasound-based studies.¹⁴

The return of pulsatility also appears to modulate the transition of smooth muscles from proliferative back to their contractile phenotype. This has been hypothesized to reduce the risk of neoatherosclerosis and, consequently, stent restenosis. The limitation of this device is the large strut size (157 micron for Absorb vs 81 microns for Xience). Dissolving metallic scaffolds also tend to have thicker struts than the current DES (120 vs approximately 80 microns).

The Absorb III trial was a pivotal noninferiority US trial that led to the device approval.15 In this trial, 2,008 patients were randomized to receive the Absorb bioresorbable, everolimus-eluting stent or the DES Xience. The primary study end point was target-lesion failure at 1 year. As is often the case with US landmark studies, patient and lesion complexities were limited. Patients with acute coronary syndrome, elevated cardiac enzymes, high-risk anatomic lesions such as bifurcation lesions, and chronic total occlusion were excluded. Patients with diabetes comprised less than one-third of the patients, and lesions were relatively short at 13 ± 6 mm.

Device success per lesion was lower with Absorb than with Xience (94.3% vs 99.3%; P < .0001). This is likely due to the larger strut size. Absorb III did meet the prespecified primary end point for noninferiority (P = .007), although the rate of adverse events was somewhat higher (7.8% vs 6.1%). A subgroup analysis reveals that 19% of all lesions were smaller than what was originally intended, and in these patients, the Absorb device performed poorly with a 4.6% risk of device thrombosis. When limited to patients with the intended reference vessel sizes, the results of target-lesion failure and stent thrombosis were similar (6.6% vs 5.5% and 0.8% vs 0.5%, respectively).¹⁵

The implantation technique also seems to have influenced the results, with increased use of post-dilation as the study evolved. Recent observations from the MICAT group have shown that the use of high pressure post-dilation and other procedural advancements may considerably reduce adverse outcomes associated with Absorb (Figure 4).¹⁶ Thus, while the pooled analysis in the form of a meta-analysis has suggested an increased risk of device thrombosis,¹⁷ the difference is attenuated by selecting lesions of appropriate size, high-pressure post-dilation, and procedural advancements (Table 2).

CONCLUSION AND THE WAY FORWARD

Current first-generation bioresorbable stents can achieve results similar to those of second-generation DES, provided that they are used in patients with noncomplicated coronary lesions and the implant techniques are optimized. We do not know the outcomes of bioresorbable stents in patients with complex lesions. Current experience suggests that other changes in technique would be needed. For example, minimizing scaffold overlap in long and bifurcating lesions. Whether that would translate into diminishing the rate of late adverse events remains to be determined. As of now, we only have data on approxi­mately 100 highly selected patients beyond 3 years (no adverse events 2.5 to 5 years after implantation).

Several investigational second-generation bioresorbable stents, including Elixir’s Dissolve PLLA, Boston Scientific’s FAST, and a newer version of Absorb, are in early clinical trials. Smaller strut thickness holds the promise of attenuating the risk of stent thrombosis. Since the polymer persists, no reduction in dual antiplatelet therapy duration is likely to be achieved.

Results from long-term follow-up of Absorb III and on-going trials are eagerly awaited to ascertain whether the rate of late complications of DES can be mitigated. It would not be surprising if the second-generation bioresorbable stents make DES a thing of the past within the next decade.

Interventional cardiology has made great strides in the last few decades. Percutaneous coronary intervention (PCI) is among the most commonly performed medical procedures globally.¹ At the time of inception, PCI was plagued by high complication rates—balloon catheters had a 50% target-lesion restenosis rate at 6 months and required emergency bypass surgery in up to 6% patients.² With passage of time, the complication rate of PCI has markedly decreased.

The introduction of stents had a dramatic impact on lowering the complication rates. Initially, the bare-metal stents (BMS) reduced the stent restenosis rate to 10% to 15%. Drug-eluting stents (DES) have further revolutionized the field (Figure 1), significantly lowering rates of stent thrombosis (less than 0.5% in 1 year) and risk of restenosis (less than 5% in 1 year).^3–6 The second-generation DES widely used in contemporary practice have made even more reductions owing to their improved designs and metallic and polymer composition; and concurrent advancements in the medical management, including use of antithrombotic and antiproliferative drugs, have further contributed to improved rates.

What, then, is to be hoped for? Unfortunately, with the advent of stents, complications such as stent thrombosis and stent restenosis also emerged. These complications can be life-threatening in the form of post-procedural or late myocardial infarction and cardiac death. Thus, although the US Food and Drug Administration (FDA) assesses target-lesion failure (defined as a composite of cardiac death, target vessel myocardial infarction, or ischemia-driven target vessel revascularization) at 1 year, patients can have complications for the remainder of their lives. Despite the advancements attained by the second-generation DES over their predecessors, the issue of stent thrombosis and restenosis continues to plague second-generation DES with a 2% to 2.5% increased rate of target-lesion failure each year, seemingly forever (Figure 2).^7,8

This article will briefly discuss the stent design and pathophysiology driving stent thrombosis and restenosis along with potential strategies to mitigate the problem. It pays special emphasis to bioresorbable stents, given their increasing interest among interventional cardiologists and patients, and given their potential to transform the practice of PCI.

STENT DESIGN

Contemporary DES essentially consist of three components:

• A metallic alloy with a mesh-like design serves as the platform for the stent.
• This framework is coated with a multi-layered polymer that holds and releases the active drug in a controlled manner so that its effects can be extended.

• 

  An antiproliferative drug (absent in the bioresorbable stents) that inhibits the smooth muscle proliferation and neointimal hyperplastic response: sirolimus or paclitaxel in first-generation DES; everolimus or zotarolimus in second-generation DES (Figure 3).

WHAT CAUSES STENT THROMBOSIS AND RESTENOSIS?

Several theories and pathophysiological mechanisms have been proposed to explain these late adverse events (Table 1). However, our overall understanding of the cause remains modest at best. The major factor seems to be persistent presence of polymer on the stent and the ensuing inflammation. The second issue appears to be related to neoathero­sclerosis that is generally defined as lipid or calcified neointima. Neoathero­sclerosis is especially problematic for the second-generation DES. Neoatherosclerosis eventually predisposes to the development of thin cap fibroadenoma, and the rupture of thin cap leads to stent thrombosis and restenosis.

Autopsy studies suggest that approxi­mately 50% of first- and second-generation DES start developing neoatherosclerosis within 1 to 3 years of implantation.⁹ Turbulence created by thick strutted stents or incomplete impaction of stents to the vessel wall predisposes the stents to platelet aggregation and fibrinogen deposition, thereby increasing the risk of neoatherosclerosis. Despite these pathologic insights, no treatment strategy has been shown to attenuate the problem, with the exception of high-dose statins.

CAN WE SOLVE THE PROBLEM?

Three technological approaches have been proposed to overcome stent thrombosis and restenosis:

• Stents coated with bioresorbable polymers that quickly degrade
• Stents without polymers
• Stents that are completely resorbed.

STENTS WITH BIORESORBABLE POLYMERS

As described above, the presence of a polymer on the stent predisposes it to inflammation. Therefore, it would be logical to hypothesize that a bioresorbable polymer would reduce the inflammation. This approach is typified by the second-generation paclitaxel-eluting stent (Synergy, Boston Scientific). It has a biodegradable coating that resorbs within 4 months and releases everolimus in a dose intensity similar to that seen with the contemporary second-generation DES.

The largest trial of this device to date, the Evolve II study, randomly assigned 1,684 patients to the biostable-polymer, everolimus-eluting chromium stent (Promus, Boston Scientific) or the paclitaxel-eluting stent (Synergy, Boston Scientific).¹⁰ Two-year follow-up data suggest that the rate of target-lesion failure was 9.4% in the paclitaxel-eluting stent patients vs 8.5% in the everolimus-eluting stent patients. Notably, no definite stent thrombosis was seen in the Synergy-­treated patients 24 hours after the initial device implantation.

STENTS WITHOUT POLYMERS

If polymers predispose to inflammation, stents without polymers should mitigate the risk. Such stent types are exemplified by the BioFreedom (Biosensors International) stainless steel stent, a polymer-free umirolimus (also known as biolimus A9)-eluting stent. These stents have a microstructured surface that holds the drug without a polymer and releases the active drug over a few months.

The LEADERS FREE clinical trial studied this stent in 2,466 patients at high risk of bleeding.¹¹ The patients were randomized to receive either a BMS or the polymer-free stent.  All patients were required to receive dual antiplatelet therapy for only 1 month. At 1 year, the composite risk of cardiac death, myocardial infarction, and stent thrombois was 9.4% in patients with BioFreedom stents vs 12.9% in BMS patients. Of note, the primary end point did not include stent restenosis, thereby not disadvantaging the BMS.

Medtronic’s polymer-free, sirolimus-eluting stent is currently under investigation in the RevElution clinical trial.¹² It has a cylindrical structure with the core replaced by the active drug sirolimus. Abluminal holes in the stent allow controlled release of the drug. A pharmacokinetic analysis show that 90% of the medication is released within the first 90 days and that tissue concentrations are maintained in the therapeutic range until at least that time.¹³ This actually exceeds that of the second-generation everolimus-eluting DES.

BIORESORBABLE STENTS

Bioresorbable scaffolds or stents disappear entirely over time and have drawn considerable attention in the interventional cardiology community. The FDA recently approved Abbott’s Poly-L-Lactic Acid (PLLA) everolimus-eluting stent (Absorb). The rate of bioresorption of this device can be controlled by modulating the respective contribution of amorphous and crystalline PLLA backbone. The advantage of bioresorbable stents appears to stem from the fact that with bioresorbable devices, the vessel may actually expand and the purported nidus for inflammation goes away. This has been demonstrated by serial intravascular ultrasound-based studies.¹⁴

The return of pulsatility also appears to modulate the transition of smooth muscles from proliferative back to their contractile phenotype. This has been hypothesized to reduce the risk of neoatherosclerosis and, consequently, stent restenosis. The limitation of this device is the large strut size (157 micron for Absorb vs 81 microns for Xience). Dissolving metallic scaffolds also tend to have thicker struts than the current DES (120 vs approximately 80 microns).

The Absorb III trial was a pivotal noninferiority US trial that led to the device approval.15 In this trial, 2,008 patients were randomized to receive the Absorb bioresorbable, everolimus-eluting stent or the DES Xience. The primary study end point was target-lesion failure at 1 year. As is often the case with US landmark studies, patient and lesion complexities were limited. Patients with acute coronary syndrome, elevated cardiac enzymes, high-risk anatomic lesions such as bifurcation lesions, and chronic total occlusion were excluded. Patients with diabetes comprised less than one-third of the patients, and lesions were relatively short at 13 ± 6 mm.

Device success per lesion was lower with Absorb than with Xience (94.3% vs 99.3%; P < .0001). This is likely due to the larger strut size. Absorb III did meet the prespecified primary end point for noninferiority (P = .007), although the rate of adverse events was somewhat higher (7.8% vs 6.1%). A subgroup analysis reveals that 19% of all lesions were smaller than what was originally intended, and in these patients, the Absorb device performed poorly with a 4.6% risk of device thrombosis. When limited to patients with the intended reference vessel sizes, the results of target-lesion failure and stent thrombosis were similar (6.6% vs 5.5% and 0.8% vs 0.5%, respectively).¹⁵

The implantation technique also seems to have influenced the results, with increased use of post-dilation as the study evolved. Recent observations from the MICAT group have shown that the use of high pressure post-dilation and other procedural advancements may considerably reduce adverse outcomes associated with Absorb (Figure 4).¹⁶ Thus, while the pooled analysis in the form of a meta-analysis has suggested an increased risk of device thrombosis,¹⁷ the difference is attenuated by selecting lesions of appropriate size, high-pressure post-dilation, and procedural advancements (Table 2).

CONCLUSION AND THE WAY FORWARD

Current first-generation bioresorbable stents can achieve results similar to those of second-generation DES, provided that they are used in patients with noncomplicated coronary lesions and the implant techniques are optimized. We do not know the outcomes of bioresorbable stents in patients with complex lesions. Current experience suggests that other changes in technique would be needed. For example, minimizing scaffold overlap in long and bifurcating lesions. Whether that would translate into diminishing the rate of late adverse events remains to be determined. As of now, we only have data on approxi­mately 100 highly selected patients beyond 3 years (no adverse events 2.5 to 5 years after implantation).

Several investigational second-generation bioresorbable stents, including Elixir’s Dissolve PLLA, Boston Scientific’s FAST, and a newer version of Absorb, are in early clinical trials. Smaller strut thickness holds the promise of attenuating the risk of stent thrombosis. Since the polymer persists, no reduction in dual antiplatelet therapy duration is likely to be achieved.

Results from long-term follow-up of Absorb III and on-going trials are eagerly awaited to ascertain whether the rate of late complications of DES can be mitigated. It would not be surprising if the second-generation bioresorbable stents make DES a thing of the past within the next decade.

Interventional cardiology has made great strides in the last few decades. Percutaneous coronary intervention (PCI) is among the most commonly performed medical procedures globally.¹ At the time of inception, PCI was plagued by high complication rates—balloon catheters had a 50% target-lesion restenosis rate at 6 months and required emergency bypass surgery in up to 6% patients.² With passage of time, the complication rate of PCI has markedly decreased.

The introduction of stents had a dramatic impact on lowering the complication rates. Initially, the bare-metal stents (BMS) reduced the stent restenosis rate to 10% to 15%. Drug-eluting stents (DES) have further revolutionized the field (Figure 1), significantly lowering rates of stent thrombosis (less than 0.5% in 1 year) and risk of restenosis (less than 5% in 1 year).^3–6 The second-generation DES widely used in contemporary practice have made even more reductions owing to their improved designs and metallic and polymer composition; and concurrent advancements in the medical management, including use of antithrombotic and antiproliferative drugs, have further contributed to improved rates.

What, then, is to be hoped for? Unfortunately, with the advent of stents, complications such as stent thrombosis and stent restenosis also emerged. These complications can be life-threatening in the form of post-procedural or late myocardial infarction and cardiac death. Thus, although the US Food and Drug Administration (FDA) assesses target-lesion failure (defined as a composite of cardiac death, target vessel myocardial infarction, or ischemia-driven target vessel revascularization) at 1 year, patients can have complications for the remainder of their lives. Despite the advancements attained by the second-generation DES over their predecessors, the issue of stent thrombosis and restenosis continues to plague second-generation DES with a 2% to 2.5% increased rate of target-lesion failure each year, seemingly forever (Figure 2).^7,8

This article will briefly discuss the stent design and pathophysiology driving stent thrombosis and restenosis along with potential strategies to mitigate the problem. It pays special emphasis to bioresorbable stents, given their increasing interest among interventional cardiologists and patients, and given their potential to transform the practice of PCI.

STENT DESIGN

Contemporary DES essentially consist of three components:

• A metallic alloy with a mesh-like design serves as the platform for the stent.
• This framework is coated with a multi-layered polymer that holds and releases the active drug in a controlled manner so that its effects can be extended.

• 

  An antiproliferative drug (absent in the bioresorbable stents) that inhibits the smooth muscle proliferation and neointimal hyperplastic response: sirolimus or paclitaxel in first-generation DES; everolimus or zotarolimus in second-generation DES (Figure 3).

WHAT CAUSES STENT THROMBOSIS AND RESTENOSIS?

Several theories and pathophysiological mechanisms have been proposed to explain these late adverse events (Table 1). However, our overall understanding of the cause remains modest at best. The major factor seems to be persistent presence of polymer on the stent and the ensuing inflammation. The second issue appears to be related to neoathero­sclerosis that is generally defined as lipid or calcified neointima. Neoathero­sclerosis is especially problematic for the second-generation DES. Neoatherosclerosis eventually predisposes to the development of thin cap fibroadenoma, and the rupture of thin cap leads to stent thrombosis and restenosis.

Autopsy studies suggest that approxi­mately 50% of first- and second-generation DES start developing neoatherosclerosis within 1 to 3 years of implantation.⁹ Turbulence created by thick strutted stents or incomplete impaction of stents to the vessel wall predisposes the stents to platelet aggregation and fibrinogen deposition, thereby increasing the risk of neoatherosclerosis. Despite these pathologic insights, no treatment strategy has been shown to attenuate the problem, with the exception of high-dose statins.

CAN WE SOLVE THE PROBLEM?

Three technological approaches have been proposed to overcome stent thrombosis and restenosis:

• Stents coated with bioresorbable polymers that quickly degrade
• Stents without polymers
• Stents that are completely resorbed.

STENTS WITH BIORESORBABLE POLYMERS

As described above, the presence of a polymer on the stent predisposes it to inflammation. Therefore, it would be logical to hypothesize that a bioresorbable polymer would reduce the inflammation. This approach is typified by the second-generation paclitaxel-eluting stent (Synergy, Boston Scientific). It has a biodegradable coating that resorbs within 4 months and releases everolimus in a dose intensity similar to that seen with the contemporary second-generation DES.

The largest trial of this device to date, the Evolve II study, randomly assigned 1,684 patients to the biostable-polymer, everolimus-eluting chromium stent (Promus, Boston Scientific) or the paclitaxel-eluting stent (Synergy, Boston Scientific).¹⁰ Two-year follow-up data suggest that the rate of target-lesion failure was 9.4% in the paclitaxel-eluting stent patients vs 8.5% in the everolimus-eluting stent patients. Notably, no definite stent thrombosis was seen in the Synergy-­treated patients 24 hours after the initial device implantation.

STENTS WITHOUT POLYMERS

If polymers predispose to inflammation, stents without polymers should mitigate the risk. Such stent types are exemplified by the BioFreedom (Biosensors International) stainless steel stent, a polymer-free umirolimus (also known as biolimus A9)-eluting stent. These stents have a microstructured surface that holds the drug without a polymer and releases the active drug over a few months.

The LEADERS FREE clinical trial studied this stent in 2,466 patients at high risk of bleeding.¹¹ The patients were randomized to receive either a BMS or the polymer-free stent.  All patients were required to receive dual antiplatelet therapy for only 1 month. At 1 year, the composite risk of cardiac death, myocardial infarction, and stent thrombois was 9.4% in patients with BioFreedom stents vs 12.9% in BMS patients. Of note, the primary end point did not include stent restenosis, thereby not disadvantaging the BMS.

Medtronic’s polymer-free, sirolimus-eluting stent is currently under investigation in the RevElution clinical trial.¹² It has a cylindrical structure with the core replaced by the active drug sirolimus. Abluminal holes in the stent allow controlled release of the drug. A pharmacokinetic analysis show that 90% of the medication is released within the first 90 days and that tissue concentrations are maintained in the therapeutic range until at least that time.¹³ This actually exceeds that of the second-generation everolimus-eluting DES.

BIORESORBABLE STENTS

Bioresorbable scaffolds or stents disappear entirely over time and have drawn considerable attention in the interventional cardiology community. The FDA recently approved Abbott’s Poly-L-Lactic Acid (PLLA) everolimus-eluting stent (Absorb). The rate of bioresorption of this device can be controlled by modulating the respective contribution of amorphous and crystalline PLLA backbone. The advantage of bioresorbable stents appears to stem from the fact that with bioresorbable devices, the vessel may actually expand and the purported nidus for inflammation goes away. This has been demonstrated by serial intravascular ultrasound-based studies.¹⁴

The return of pulsatility also appears to modulate the transition of smooth muscles from proliferative back to their contractile phenotype. This has been hypothesized to reduce the risk of neoatherosclerosis and, consequently, stent restenosis. The limitation of this device is the large strut size (157 micron for Absorb vs 81 microns for Xience). Dissolving metallic scaffolds also tend to have thicker struts than the current DES (120 vs approximately 80 microns).

The Absorb III trial was a pivotal noninferiority US trial that led to the device approval.15 In this trial, 2,008 patients were randomized to receive the Absorb bioresorbable, everolimus-eluting stent or the DES Xience. The primary study end point was target-lesion failure at 1 year. As is often the case with US landmark studies, patient and lesion complexities were limited. Patients with acute coronary syndrome, elevated cardiac enzymes, high-risk anatomic lesions such as bifurcation lesions, and chronic total occlusion were excluded. Patients with diabetes comprised less than one-third of the patients, and lesions were relatively short at 13 ± 6 mm.

Device success per lesion was lower with Absorb than with Xience (94.3% vs 99.3%; P < .0001). This is likely due to the larger strut size. Absorb III did meet the prespecified primary end point for noninferiority (P = .007), although the rate of adverse events was somewhat higher (7.8% vs 6.1%). A subgroup analysis reveals that 19% of all lesions were smaller than what was originally intended, and in these patients, the Absorb device performed poorly with a 4.6% risk of device thrombosis. When limited to patients with the intended reference vessel sizes, the results of target-lesion failure and stent thrombosis were similar (6.6% vs 5.5% and 0.8% vs 0.5%, respectively).¹⁵

The implantation technique also seems to have influenced the results, with increased use of post-dilation as the study evolved. Recent observations from the MICAT group have shown that the use of high pressure post-dilation and other procedural advancements may considerably reduce adverse outcomes associated with Absorb (Figure 4).¹⁶ Thus, while the pooled analysis in the form of a meta-analysis has suggested an increased risk of device thrombosis,¹⁷ the difference is attenuated by selecting lesions of appropriate size, high-pressure post-dilation, and procedural advancements (Table 2).

CONCLUSION AND THE WAY FORWARD

Current first-generation bioresorbable stents can achieve results similar to those of second-generation DES, provided that they are used in patients with noncomplicated coronary lesions and the implant techniques are optimized. We do not know the outcomes of bioresorbable stents in patients with complex lesions. Current experience suggests that other changes in technique would be needed. For example, minimizing scaffold overlap in long and bifurcating lesions. Whether that would translate into diminishing the rate of late adverse events remains to be determined. As of now, we only have data on approxi­mately 100 highly selected patients beyond 3 years (no adverse events 2.5 to 5 years after implantation).

Several investigational second-generation bioresorbable stents, including Elixir’s Dissolve PLLA, Boston Scientific’s FAST, and a newer version of Absorb, are in early clinical trials. Smaller strut thickness holds the promise of attenuating the risk of stent thrombosis. Since the polymer persists, no reduction in dual antiplatelet therapy duration is likely to be achieved.

Results from long-term follow-up of Absorb III and on-going trials are eagerly awaited to ascertain whether the rate of late complications of DES can be mitigated. It would not be surprising if the second-generation bioresorbable stents make DES a thing of the past within the next decade.