MDedge Emergency Medicine

Emerging viruses that spread to humans from an animal host are commonplace and represent some of the deadliest diseases known. Given the details of the Wuhan coronavirus (2019-nCoV) outbreak, including the genetic profile of the disease agent, the hypothesis of a snake origin was the first raised in the peer-reviewed literature.

SISTEMA 12/Wikimedia Commons/CC BY-SA 4.0

It is a highly controversial origin story, however, given that mammals have been the sources of all other such zoonotic coronaviruses, as well as a host of other zoonotic diseases.

An animal source for emerging infections such as the 2019-nCoV is the default hypothesis, because “around 60% of all infectious diseases in humans are zoonotic, as are 75% of all emerging infectious diseases,” according to a United Nations report. The report goes on to say that, “on average, one new infectious disease emerges in humans every 4 months.”

To appreciate the emergence and nature of 2019-nCoV, it is important to examine the history of zoonotic outbreaks of other such diseases, especially with regard to the “mixing-vessel” phenomenon, which has been noted in closely related coronaviruses, including SARS and MERS, as well as the widely disparate HIV, Ebola, and influenza viruses.
 

Mutants in the mixing vessel

The mixing-vessel phenomenon is conceptually easy but molecularly complex. A single animal is coinfected with two related viruses; the virus genomes recombine together (virus “sex”) in that animal to form a new variant of virus. Such new mutant viruses can be more or less infective, more or less deadly, and more or less able to jump the species or even genus barrier. An emerging viral zoonosis can occur when a human being is exposed to one of these new viruses (either from the origin species or another species intermediate) that is capable of also infecting a human cell. Such exposure can occur from close proximity to animal waste or body fluids, as in the farm environment, or from wildlife pets or the capturing and slaughtering of wildlife for food, as is proposed in the case of the Wuhan seafood market scenario. In fact, the scientists who postulated a snake intermediary as the potential mixing vessel also stated that 2019‐nCoV appears to be a recombinant virus between a bat coronavirus and an origin‐unknown coronavirus.

Coronaviruses in particular have a history of moving from animal to human hosts (and even back again), and their detailed genetic pattern and taxonomy can reveal the animal origin of these diseases.
 

Going batty

Bats, in particular, have been shown to be a reservoir species for both alphacoronaviruses and betacoronaviruses. Given their ecology and behavior, they have been found to play a key role in transmitting coronaviruses between species. A highly pertinent example of this is the SARS coronavirus, which was shown to have likely originated in Chinese horseshoe bats. The SARS virus, which is genetically closely related to the new Wuhan coronavirus, first infected humans in the Guangdong province of southern China in 2002.

Scientists speculate that the virus was then either transmitted directly to humans from bats, or passed through an intermediate host species, with SARS-like viruses isolated from Himalayan palm civets found in a live-animal market in Guangdong. The virus infection was also detected in other animals (including a raccoon dog, Nyctereutes procyonoides) and in humans working at the market.

The MERS coronavirus is a betacoronavirus that was first reported in Saudi Arabia in 2012. It turned out to be far more deadly than either SARS or the Wuhan virus (at least as far as current estimates of the new coronavirus’s behavior). The MERS genotype was found to be closely related to MERS-like viruses in bats in Saudi Arabia, Africa, Europe, and Asia. Studies done on the cell receptor for MERS showed an apparently conserved viral receptor in both bats and humans. And an identical strain of MERS was found in bats in a nearby cave and near the workplace of the first known human patient.

Wikimedia Commons/Mickey Samuni-Blank

However, in many of the other locations of the outbreak in the Middle East, there appeared to be limited contact between bats and humans, so scientists looked for another vector species, perhaps one that was acting as an intermediate. A high seroprevalence of MERS-CoV or a closely related virus was found in camels across the Arabian Peninsula and parts of eastern and northern Africa, while tests for MERS antibodies were negative in the most-likely other species of livestock or pet animals, including chickens, cows, goats, horses, and sheep.

In addition, the MERS-related CoV carried by camels was genetically highly similar to that detected in humans, as demonstrated in one particular outbreak on a farm in Qatar where the genetic sequences of MERS-CoV in the nasal swabs from 3 of 14 seropositive camels were similar to those of 2 human cases on the same farm. Similar genomic results were found in MERS-CoV from nasal swabs from camels in Saudi Arabia.
 

Other mixing-vessel zoonoses

HIV, the viral cause of AIDS, provides an almost-textbook origin story of the rise of a zoonotic supervillain. The virus was genetically traced to have a chimpanzee-to-human origin, but it was found to be more complicated than that. The virus first emerged in the 1920s in Africa in what is now the Democratic Republic of the Congo, well before its rise to a global pandemic in the 1980s.

Researchers believe the chimpanzee virus is a hybrid of the simian immunodeficiency viruses (SIVs) naturally infecting two different monkey species: the red-capped mangabey (Cercocebus torquatus) and the greater spot-nosed monkey (Cercopithecus nictitans). Chimpanzees kill and eat monkeys, which is likely how they acquired the monkey viruses. The viruses hybridized in a chimpanzee; the hybrid virus then spread through the chimpanzee population and was later transmitted to humans who captured and slaughtered chimps for meat (becoming exposed to their blood). This was the most likely origin of HIV-1.

HIV-1 also shows one of the major risks of zoonotic infections. They can continue to mutate in its human host, increasing the risk of greater virulence, but also interfering with the production of a universally effective vaccine. Since its transmission to humans, for example, many subtypes of the HIV-1 strain have developed, with genetic differences even in the same subtypes found to be up to 20%.

CDC/Frederick A. Murphy

Ebolavirus, first detected in 1976, is another case of bats being the potential culprit. Genetic analysis has shown that African fruit bats are likely involved in the spread of the virus and may be its reservoir host. Further evidence of this was found in the most recent human-infecting Bombali variant of the virus, which was identified in samples from bats collected from Sierra Leone.

It was also found that pigs can also become infected with Zaire ebolavirus, leading to the fear that pigs could serve as a mixing vessel for it and other filoviruses. Pigs have their own forms of Ebola-like disease viruses, which are not currently transmissible to humans, but could provide a potential mixing-vessel reservoir.
 

Emergent influenzas

The Western world has been most affected by these highly mutable, multispecies zoonotic viruses. The 1957 and 1968 flu pandemics contained a mixture of gene segments from human and avian influenza viruses. “What is clear from genetic analysis of the viruses that caused these past pandemics is that reassortment (gene swapping) occurred to produce novel influenza viruses that caused the pandemics. In both of these cases, the new viruses that emerged showed major differences from the parent viruses,” according to the Centers for Disease Control and Prevention.

Influenza is, however, a good example that all zoonoses are not the result of a mixing-vessel phenomenon, with evidence showing that the origin of the catastrophic 1918 virus pandemic likely resulted from a bird influenza virus directly infecting humans and pigs at about the same time without reassortment, according to the CDC.
 

Building a protective infrastructure

The first 2 decades of the 21st century saw a huge increase in efforts to develop an infrastructure to monitor and potentially prevent the spread of new zoonoses. As part of a global effort led by the United Nations, the U.S. Agency for International AID developed the PREDICT program in 2009 “to strengthen global capacity for detection and discovery of zoonotic viruses with pandemic potential. Those include coronaviruses, the family to which SARS and MERS belong; paramyxoviruses, like Nipah virus; influenza viruses; and filoviruses, like the ebolavirus.”

PREDICT funding to the EcoHealth Alliance led to discovery of the likely bat origins of the Zaire ebolavirus during the 2013-2016 outbreak. And throughout the existence of PREDICT, more than 145,000 animals and people were surveyed in areas of likely zoonotic outbreaks, leading to the detection of more than “1,100 unique viruses, including zoonotic diseases of public health concern such as Bombali ebolavirus, Zaire ebolavirus, Marburg virus, and MERS- and SARS-like coronaviruses,” according to PREDICT partner, the University of California, Davis.

PREDICT-2 was launched in 2014 with the continuing goals of “identifying and better characterizing pathogens of known epidemic and unknown pandemic potential; recognizing animal reservoirs and amplification hosts of human-infectious viruses; and efficiently targeting intervention action at human behaviors which amplify disease transmission at critical animal-animal and animal-human interfaces in hotspots of viral evolution, spillover, amplification, and spread.”

However, in October 2019, the Trump administration cut all funding to the PREDICT program, leading to its shutdown. In a New York Times interview, Peter Daszak, president of the EcoHealth Alliance, stated: “PREDICT was an approach to heading off pandemics, instead of sitting there waiting for them to emerge and then mobilizing.”

Ultimately, in addition to its human cost, the current Wuhan coronavirus outbreak can be looked at an object lesson – a test of the pandemic surveillance and control systems currently in place, and a practice run for the next and potentially deadlier zoonotic outbreaks to come. Perhaps it is also a reminder that cutting resources to detect zoonoses at their source in their animal hosts – before they enter the human chain– is perhaps not the most prudent of ideas.

mlesney@mdedge.com

Mark Lesney is the managing editor of MDedge.com/IDPractioner. He has a PhD in plant virology and a PhD in the history of science, with a focus on the history of biotechnology and medicine. He has served as an adjunct assistant professor of the department of biochemistry and molecular & celluar biology at Georgetown University, Washington.

Emerging viruses that spread to humans from an animal host are commonplace and represent some of the deadliest diseases known. Given the details of the Wuhan coronavirus (2019-nCoV) outbreak, including the genetic profile of the disease agent, the hypothesis of a snake origin was the first raised in the peer-reviewed literature.

SISTEMA 12/Wikimedia Commons/CC BY-SA 4.0

It is a highly controversial origin story, however, given that mammals have been the sources of all other such zoonotic coronaviruses, as well as a host of other zoonotic diseases.

An animal source for emerging infections such as the 2019-nCoV is the default hypothesis, because “around 60% of all infectious diseases in humans are zoonotic, as are 75% of all emerging infectious diseases,” according to a United Nations report. The report goes on to say that, “on average, one new infectious disease emerges in humans every 4 months.”

To appreciate the emergence and nature of 2019-nCoV, it is important to examine the history of zoonotic outbreaks of other such diseases, especially with regard to the “mixing-vessel” phenomenon, which has been noted in closely related coronaviruses, including SARS and MERS, as well as the widely disparate HIV, Ebola, and influenza viruses.
 

Mutants in the mixing vessel

The mixing-vessel phenomenon is conceptually easy but molecularly complex. A single animal is coinfected with two related viruses; the virus genomes recombine together (virus “sex”) in that animal to form a new variant of virus. Such new mutant viruses can be more or less infective, more or less deadly, and more or less able to jump the species or even genus barrier. An emerging viral zoonosis can occur when a human being is exposed to one of these new viruses (either from the origin species or another species intermediate) that is capable of also infecting a human cell. Such exposure can occur from close proximity to animal waste or body fluids, as in the farm environment, or from wildlife pets or the capturing and slaughtering of wildlife for food, as is proposed in the case of the Wuhan seafood market scenario. In fact, the scientists who postulated a snake intermediary as the potential mixing vessel also stated that 2019‐nCoV appears to be a recombinant virus between a bat coronavirus and an origin‐unknown coronavirus.

Coronaviruses in particular have a history of moving from animal to human hosts (and even back again), and their detailed genetic pattern and taxonomy can reveal the animal origin of these diseases.
 

Going batty

Bats, in particular, have been shown to be a reservoir species for both alphacoronaviruses and betacoronaviruses. Given their ecology and behavior, they have been found to play a key role in transmitting coronaviruses between species. A highly pertinent example of this is the SARS coronavirus, which was shown to have likely originated in Chinese horseshoe bats. The SARS virus, which is genetically closely related to the new Wuhan coronavirus, first infected humans in the Guangdong province of southern China in 2002.

Scientists speculate that the virus was then either transmitted directly to humans from bats, or passed through an intermediate host species, with SARS-like viruses isolated from Himalayan palm civets found in a live-animal market in Guangdong. The virus infection was also detected in other animals (including a raccoon dog, Nyctereutes procyonoides) and in humans working at the market.

The MERS coronavirus is a betacoronavirus that was first reported in Saudi Arabia in 2012. It turned out to be far more deadly than either SARS or the Wuhan virus (at least as far as current estimates of the new coronavirus’s behavior). The MERS genotype was found to be closely related to MERS-like viruses in bats in Saudi Arabia, Africa, Europe, and Asia. Studies done on the cell receptor for MERS showed an apparently conserved viral receptor in both bats and humans. And an identical strain of MERS was found in bats in a nearby cave and near the workplace of the first known human patient.

Wikimedia Commons/Mickey Samuni-Blank

However, in many of the other locations of the outbreak in the Middle East, there appeared to be limited contact between bats and humans, so scientists looked for another vector species, perhaps one that was acting as an intermediate. A high seroprevalence of MERS-CoV or a closely related virus was found in camels across the Arabian Peninsula and parts of eastern and northern Africa, while tests for MERS antibodies were negative in the most-likely other species of livestock or pet animals, including chickens, cows, goats, horses, and sheep.

In addition, the MERS-related CoV carried by camels was genetically highly similar to that detected in humans, as demonstrated in one particular outbreak on a farm in Qatar where the genetic sequences of MERS-CoV in the nasal swabs from 3 of 14 seropositive camels were similar to those of 2 human cases on the same farm. Similar genomic results were found in MERS-CoV from nasal swabs from camels in Saudi Arabia.
 

Other mixing-vessel zoonoses

HIV, the viral cause of AIDS, provides an almost-textbook origin story of the rise of a zoonotic supervillain. The virus was genetically traced to have a chimpanzee-to-human origin, but it was found to be more complicated than that. The virus first emerged in the 1920s in Africa in what is now the Democratic Republic of the Congo, well before its rise to a global pandemic in the 1980s.

Researchers believe the chimpanzee virus is a hybrid of the simian immunodeficiency viruses (SIVs) naturally infecting two different monkey species: the red-capped mangabey (Cercocebus torquatus) and the greater spot-nosed monkey (Cercopithecus nictitans). Chimpanzees kill and eat monkeys, which is likely how they acquired the monkey viruses. The viruses hybridized in a chimpanzee; the hybrid virus then spread through the chimpanzee population and was later transmitted to humans who captured and slaughtered chimps for meat (becoming exposed to their blood). This was the most likely origin of HIV-1.

HIV-1 also shows one of the major risks of zoonotic infections. They can continue to mutate in its human host, increasing the risk of greater virulence, but also interfering with the production of a universally effective vaccine. Since its transmission to humans, for example, many subtypes of the HIV-1 strain have developed, with genetic differences even in the same subtypes found to be up to 20%.

CDC/Frederick A. Murphy

Ebolavirus, first detected in 1976, is another case of bats being the potential culprit. Genetic analysis has shown that African fruit bats are likely involved in the spread of the virus and may be its reservoir host. Further evidence of this was found in the most recent human-infecting Bombali variant of the virus, which was identified in samples from bats collected from Sierra Leone.

It was also found that pigs can also become infected with Zaire ebolavirus, leading to the fear that pigs could serve as a mixing vessel for it and other filoviruses. Pigs have their own forms of Ebola-like disease viruses, which are not currently transmissible to humans, but could provide a potential mixing-vessel reservoir.
 

Emergent influenzas

The Western world has been most affected by these highly mutable, multispecies zoonotic viruses. The 1957 and 1968 flu pandemics contained a mixture of gene segments from human and avian influenza viruses. “What is clear from genetic analysis of the viruses that caused these past pandemics is that reassortment (gene swapping) occurred to produce novel influenza viruses that caused the pandemics. In both of these cases, the new viruses that emerged showed major differences from the parent viruses,” according to the Centers for Disease Control and Prevention.

Influenza is, however, a good example that all zoonoses are not the result of a mixing-vessel phenomenon, with evidence showing that the origin of the catastrophic 1918 virus pandemic likely resulted from a bird influenza virus directly infecting humans and pigs at about the same time without reassortment, according to the CDC.
 

Building a protective infrastructure

The first 2 decades of the 21st century saw a huge increase in efforts to develop an infrastructure to monitor and potentially prevent the spread of new zoonoses. As part of a global effort led by the United Nations, the U.S. Agency for International AID developed the PREDICT program in 2009 “to strengthen global capacity for detection and discovery of zoonotic viruses with pandemic potential. Those include coronaviruses, the family to which SARS and MERS belong; paramyxoviruses, like Nipah virus; influenza viruses; and filoviruses, like the ebolavirus.”

PREDICT funding to the EcoHealth Alliance led to discovery of the likely bat origins of the Zaire ebolavirus during the 2013-2016 outbreak. And throughout the existence of PREDICT, more than 145,000 animals and people were surveyed in areas of likely zoonotic outbreaks, leading to the detection of more than “1,100 unique viruses, including zoonotic diseases of public health concern such as Bombali ebolavirus, Zaire ebolavirus, Marburg virus, and MERS- and SARS-like coronaviruses,” according to PREDICT partner, the University of California, Davis.

PREDICT-2 was launched in 2014 with the continuing goals of “identifying and better characterizing pathogens of known epidemic and unknown pandemic potential; recognizing animal reservoirs and amplification hosts of human-infectious viruses; and efficiently targeting intervention action at human behaviors which amplify disease transmission at critical animal-animal and animal-human interfaces in hotspots of viral evolution, spillover, amplification, and spread.”

However, in October 2019, the Trump administration cut all funding to the PREDICT program, leading to its shutdown. In a New York Times interview, Peter Daszak, president of the EcoHealth Alliance, stated: “PREDICT was an approach to heading off pandemics, instead of sitting there waiting for them to emerge and then mobilizing.”

Ultimately, in addition to its human cost, the current Wuhan coronavirus outbreak can be looked at an object lesson – a test of the pandemic surveillance and control systems currently in place, and a practice run for the next and potentially deadlier zoonotic outbreaks to come. Perhaps it is also a reminder that cutting resources to detect zoonoses at their source in their animal hosts – before they enter the human chain– is perhaps not the most prudent of ideas.

mlesney@mdedge.com

Mark Lesney is the managing editor of MDedge.com/IDPractioner. He has a PhD in plant virology and a PhD in the history of science, with a focus on the history of biotechnology and medicine. He has served as an adjunct assistant professor of the department of biochemistry and molecular & celluar biology at Georgetown University, Washington.

Emerging viruses that spread to humans from an animal host are commonplace and represent some of the deadliest diseases known. Given the details of the Wuhan coronavirus (2019-nCoV) outbreak, including the genetic profile of the disease agent, the hypothesis of a snake origin was the first raised in the peer-reviewed literature.

SISTEMA 12/Wikimedia Commons/CC BY-SA 4.0

It is a highly controversial origin story, however, given that mammals have been the sources of all other such zoonotic coronaviruses, as well as a host of other zoonotic diseases.

An animal source for emerging infections such as the 2019-nCoV is the default hypothesis, because “around 60% of all infectious diseases in humans are zoonotic, as are 75% of all emerging infectious diseases,” according to a United Nations report. The report goes on to say that, “on average, one new infectious disease emerges in humans every 4 months.”

To appreciate the emergence and nature of 2019-nCoV, it is important to examine the history of zoonotic outbreaks of other such diseases, especially with regard to the “mixing-vessel” phenomenon, which has been noted in closely related coronaviruses, including SARS and MERS, as well as the widely disparate HIV, Ebola, and influenza viruses.
 

Mutants in the mixing vessel

The mixing-vessel phenomenon is conceptually easy but molecularly complex. A single animal is coinfected with two related viruses; the virus genomes recombine together (virus “sex”) in that animal to form a new variant of virus. Such new mutant viruses can be more or less infective, more or less deadly, and more or less able to jump the species or even genus barrier. An emerging viral zoonosis can occur when a human being is exposed to one of these new viruses (either from the origin species or another species intermediate) that is capable of also infecting a human cell. Such exposure can occur from close proximity to animal waste or body fluids, as in the farm environment, or from wildlife pets or the capturing and slaughtering of wildlife for food, as is proposed in the case of the Wuhan seafood market scenario. In fact, the scientists who postulated a snake intermediary as the potential mixing vessel also stated that 2019‐nCoV appears to be a recombinant virus between a bat coronavirus and an origin‐unknown coronavirus.

Coronaviruses in particular have a history of moving from animal to human hosts (and even back again), and their detailed genetic pattern and taxonomy can reveal the animal origin of these diseases.
 

Going batty

Bats, in particular, have been shown to be a reservoir species for both alphacoronaviruses and betacoronaviruses. Given their ecology and behavior, they have been found to play a key role in transmitting coronaviruses between species. A highly pertinent example of this is the SARS coronavirus, which was shown to have likely originated in Chinese horseshoe bats. The SARS virus, which is genetically closely related to the new Wuhan coronavirus, first infected humans in the Guangdong province of southern China in 2002.

Scientists speculate that the virus was then either transmitted directly to humans from bats, or passed through an intermediate host species, with SARS-like viruses isolated from Himalayan palm civets found in a live-animal market in Guangdong. The virus infection was also detected in other animals (including a raccoon dog, Nyctereutes procyonoides) and in humans working at the market.

The MERS coronavirus is a betacoronavirus that was first reported in Saudi Arabia in 2012. It turned out to be far more deadly than either SARS or the Wuhan virus (at least as far as current estimates of the new coronavirus’s behavior). The MERS genotype was found to be closely related to MERS-like viruses in bats in Saudi Arabia, Africa, Europe, and Asia. Studies done on the cell receptor for MERS showed an apparently conserved viral receptor in both bats and humans. And an identical strain of MERS was found in bats in a nearby cave and near the workplace of the first known human patient.

Wikimedia Commons/Mickey Samuni-Blank

However, in many of the other locations of the outbreak in the Middle East, there appeared to be limited contact between bats and humans, so scientists looked for another vector species, perhaps one that was acting as an intermediate. A high seroprevalence of MERS-CoV or a closely related virus was found in camels across the Arabian Peninsula and parts of eastern and northern Africa, while tests for MERS antibodies were negative in the most-likely other species of livestock or pet animals, including chickens, cows, goats, horses, and sheep.

In addition, the MERS-related CoV carried by camels was genetically highly similar to that detected in humans, as demonstrated in one particular outbreak on a farm in Qatar where the genetic sequences of MERS-CoV in the nasal swabs from 3 of 14 seropositive camels were similar to those of 2 human cases on the same farm. Similar genomic results were found in MERS-CoV from nasal swabs from camels in Saudi Arabia.
 

Other mixing-vessel zoonoses

HIV, the viral cause of AIDS, provides an almost-textbook origin story of the rise of a zoonotic supervillain. The virus was genetically traced to have a chimpanzee-to-human origin, but it was found to be more complicated than that. The virus first emerged in the 1920s in Africa in what is now the Democratic Republic of the Congo, well before its rise to a global pandemic in the 1980s.

Researchers believe the chimpanzee virus is a hybrid of the simian immunodeficiency viruses (SIVs) naturally infecting two different monkey species: the red-capped mangabey (Cercocebus torquatus) and the greater spot-nosed monkey (Cercopithecus nictitans). Chimpanzees kill and eat monkeys, which is likely how they acquired the monkey viruses. The viruses hybridized in a chimpanzee; the hybrid virus then spread through the chimpanzee population and was later transmitted to humans who captured and slaughtered chimps for meat (becoming exposed to their blood). This was the most likely origin of HIV-1.

HIV-1 also shows one of the major risks of zoonotic infections. They can continue to mutate in its human host, increasing the risk of greater virulence, but also interfering with the production of a universally effective vaccine. Since its transmission to humans, for example, many subtypes of the HIV-1 strain have developed, with genetic differences even in the same subtypes found to be up to 20%.

CDC/Frederick A. Murphy

Ebolavirus, first detected in 1976, is another case of bats being the potential culprit. Genetic analysis has shown that African fruit bats are likely involved in the spread of the virus and may be its reservoir host. Further evidence of this was found in the most recent human-infecting Bombali variant of the virus, which was identified in samples from bats collected from Sierra Leone.

It was also found that pigs can also become infected with Zaire ebolavirus, leading to the fear that pigs could serve as a mixing vessel for it and other filoviruses. Pigs have their own forms of Ebola-like disease viruses, which are not currently transmissible to humans, but could provide a potential mixing-vessel reservoir.
 

Emergent influenzas

The Western world has been most affected by these highly mutable, multispecies zoonotic viruses. The 1957 and 1968 flu pandemics contained a mixture of gene segments from human and avian influenza viruses. “What is clear from genetic analysis of the viruses that caused these past pandemics is that reassortment (gene swapping) occurred to produce novel influenza viruses that caused the pandemics. In both of these cases, the new viruses that emerged showed major differences from the parent viruses,” according to the Centers for Disease Control and Prevention.

Influenza is, however, a good example that all zoonoses are not the result of a mixing-vessel phenomenon, with evidence showing that the origin of the catastrophic 1918 virus pandemic likely resulted from a bird influenza virus directly infecting humans and pigs at about the same time without reassortment, according to the CDC.
 

Building a protective infrastructure

The first 2 decades of the 21st century saw a huge increase in efforts to develop an infrastructure to monitor and potentially prevent the spread of new zoonoses. As part of a global effort led by the United Nations, the U.S. Agency for International AID developed the PREDICT program in 2009 “to strengthen global capacity for detection and discovery of zoonotic viruses with pandemic potential. Those include coronaviruses, the family to which SARS and MERS belong; paramyxoviruses, like Nipah virus; influenza viruses; and filoviruses, like the ebolavirus.”

PREDICT funding to the EcoHealth Alliance led to discovery of the likely bat origins of the Zaire ebolavirus during the 2013-2016 outbreak. And throughout the existence of PREDICT, more than 145,000 animals and people were surveyed in areas of likely zoonotic outbreaks, leading to the detection of more than “1,100 unique viruses, including zoonotic diseases of public health concern such as Bombali ebolavirus, Zaire ebolavirus, Marburg virus, and MERS- and SARS-like coronaviruses,” according to PREDICT partner, the University of California, Davis.

PREDICT-2 was launched in 2014 with the continuing goals of “identifying and better characterizing pathogens of known epidemic and unknown pandemic potential; recognizing animal reservoirs and amplification hosts of human-infectious viruses; and efficiently targeting intervention action at human behaviors which amplify disease transmission at critical animal-animal and animal-human interfaces in hotspots of viral evolution, spillover, amplification, and spread.”

However, in October 2019, the Trump administration cut all funding to the PREDICT program, leading to its shutdown. In a New York Times interview, Peter Daszak, president of the EcoHealth Alliance, stated: “PREDICT was an approach to heading off pandemics, instead of sitting there waiting for them to emerge and then mobilizing.”

Ultimately, in addition to its human cost, the current Wuhan coronavirus outbreak can be looked at an object lesson – a test of the pandemic surveillance and control systems currently in place, and a practice run for the next and potentially deadlier zoonotic outbreaks to come. Perhaps it is also a reminder that cutting resources to detect zoonoses at their source in their animal hosts – before they enter the human chain– is perhaps not the most prudent of ideas.

mlesney@mdedge.com

Mark Lesney is the managing editor of MDedge.com/IDPractioner. He has a PhD in plant virology and a PhD in the history of science, with a focus on the history of biotechnology and medicine. He has served as an adjunct assistant professor of the department of biochemistry and molecular & celluar biology at Georgetown University, Washington.

A Chinese man became ill from a novel coronavirus (2019-nCoV) 4 days after arriving in Vietnam to visit his 27-year-old son. Three days later the healthy young man was also stricken, according to a report published online Jan. 28 in the New England Journal of Medicine.

“This family cluster of 2019-nCoV infection that occurred outside China arouses concern regarding human-to-human transmission,” the authors wrote.

The father, age 65 years and with multiple comorbidities including hypertension, type 2 diabetes, coronary heart disease with stent placement, and lung cancer, flew to Hanoi with his wife on January 13; they traveled from the Wuchang district in Wuhan, China, where outbreaks of 2019-nCoV have been occurring.

On Jan. 17, the older man and his wife met their adult son in Ho Chi Minh City, Vietnam, and shared a hotel room with him for 3 days. The father developed a fever that same day and the son developed a dry cough, fever, diarrhea, and vomiting on Jan. 20. Both men went to a hospital ED on Jan. 22.

The authors say the timing of the son’s symptoms suggests the incubation period may have been 3 days or fewer.

Upon admission to the hospital, the father reported that he had not visited a “wet market” where live and dead animals are sold while he was in Wuhan. Throat swabs were positive for 2019-nCoV on real-time reverse-transcription–polymerase-chain-reaction assays.

The man was placed in isolation and “treated empirically with antiviral agents, broad-spectrum antibiotics, and supportive therapies,” wrote Lan T. Phan, PhD, from the Pasteur Institute Ho Chi Minh City and coauthors.

On admission, chest radiographs revealed an infiltrate in the upper lobe of his left lung; he developed worsening dyspnea with hypoxemia on Jan. 25 and required supplemental oxygen at 5 L/min by nasal cannula. Chest radiographs showed a progressive infiltrate and consolidation. His fever resolved on that day and he has progressively improved.

The man’s son had a fever of 39° C (102.2° F) when the two men arrived at the hospital on Jan. 22; hospital staff isolated the son, and chest radiographs and other laboratory tests were normal with the exception of an increased C-reactive protein level.

The son’s throat swab was positive for 2019-nCoV and he is believed to have been exposed from his father; however, the strains have not been ascertained.

“This family had traveled to four cities across Vietnam using various forms of transportation, including planes, trains, and taxis,” the authors wrote. A total of 28 close contacts were identified, none of whom have developed respiratory symptoms. The older man’s wife has been healthy as well.

The authors have disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

A Chinese man became ill from a novel coronavirus (2019-nCoV) 4 days after arriving in Vietnam to visit his 27-year-old son. Three days later the healthy young man was also stricken, according to a report published online Jan. 28 in the New England Journal of Medicine.

“This family cluster of 2019-nCoV infection that occurred outside China arouses concern regarding human-to-human transmission,” the authors wrote.

The father, age 65 years and with multiple comorbidities including hypertension, type 2 diabetes, coronary heart disease with stent placement, and lung cancer, flew to Hanoi with his wife on January 13; they traveled from the Wuchang district in Wuhan, China, where outbreaks of 2019-nCoV have been occurring.

On Jan. 17, the older man and his wife met their adult son in Ho Chi Minh City, Vietnam, and shared a hotel room with him for 3 days. The father developed a fever that same day and the son developed a dry cough, fever, diarrhea, and vomiting on Jan. 20. Both men went to a hospital ED on Jan. 22.

The authors say the timing of the son’s symptoms suggests the incubation period may have been 3 days or fewer.

Upon admission to the hospital, the father reported that he had not visited a “wet market” where live and dead animals are sold while he was in Wuhan. Throat swabs were positive for 2019-nCoV on real-time reverse-transcription–polymerase-chain-reaction assays.

The man was placed in isolation and “treated empirically with antiviral agents, broad-spectrum antibiotics, and supportive therapies,” wrote Lan T. Phan, PhD, from the Pasteur Institute Ho Chi Minh City and coauthors.

On admission, chest radiographs revealed an infiltrate in the upper lobe of his left lung; he developed worsening dyspnea with hypoxemia on Jan. 25 and required supplemental oxygen at 5 L/min by nasal cannula. Chest radiographs showed a progressive infiltrate and consolidation. His fever resolved on that day and he has progressively improved.

The man’s son had a fever of 39° C (102.2° F) when the two men arrived at the hospital on Jan. 22; hospital staff isolated the son, and chest radiographs and other laboratory tests were normal with the exception of an increased C-reactive protein level.

The son’s throat swab was positive for 2019-nCoV and he is believed to have been exposed from his father; however, the strains have not been ascertained.

“This family had traveled to four cities across Vietnam using various forms of transportation, including planes, trains, and taxis,” the authors wrote. A total of 28 close contacts were identified, none of whom have developed respiratory symptoms. The older man’s wife has been healthy as well.

The authors have disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

A Chinese man became ill from a novel coronavirus (2019-nCoV) 4 days after arriving in Vietnam to visit his 27-year-old son. Three days later the healthy young man was also stricken, according to a report published online Jan. 28 in the New England Journal of Medicine.

“This family cluster of 2019-nCoV infection that occurred outside China arouses concern regarding human-to-human transmission,” the authors wrote.

The father, age 65 years and with multiple comorbidities including hypertension, type 2 diabetes, coronary heart disease with stent placement, and lung cancer, flew to Hanoi with his wife on January 13; they traveled from the Wuchang district in Wuhan, China, where outbreaks of 2019-nCoV have been occurring.

On Jan. 17, the older man and his wife met their adult son in Ho Chi Minh City, Vietnam, and shared a hotel room with him for 3 days. The father developed a fever that same day and the son developed a dry cough, fever, diarrhea, and vomiting on Jan. 20. Both men went to a hospital ED on Jan. 22.

The authors say the timing of the son’s symptoms suggests the incubation period may have been 3 days or fewer.

Upon admission to the hospital, the father reported that he had not visited a “wet market” where live and dead animals are sold while he was in Wuhan. Throat swabs were positive for 2019-nCoV on real-time reverse-transcription–polymerase-chain-reaction assays.

The man was placed in isolation and “treated empirically with antiviral agents, broad-spectrum antibiotics, and supportive therapies,” wrote Lan T. Phan, PhD, from the Pasteur Institute Ho Chi Minh City and coauthors.

On admission, chest radiographs revealed an infiltrate in the upper lobe of his left lung; he developed worsening dyspnea with hypoxemia on Jan. 25 and required supplemental oxygen at 5 L/min by nasal cannula. Chest radiographs showed a progressive infiltrate and consolidation. His fever resolved on that day and he has progressively improved.

The man’s son had a fever of 39° C (102.2° F) when the two men arrived at the hospital on Jan. 22; hospital staff isolated the son, and chest radiographs and other laboratory tests were normal with the exception of an increased C-reactive protein level.

The son’s throat swab was positive for 2019-nCoV and he is believed to have been exposed from his father; however, the strains have not been ascertained.

“This family had traveled to four cities across Vietnam using various forms of transportation, including planes, trains, and taxis,” the authors wrote. A total of 28 close contacts were identified, none of whom have developed respiratory symptoms. The older man’s wife has been healthy as well.

The authors have disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

SNOWMASS, COLO. – A repeated theme threading through much of one prominent interventional cardiologist’s personal list of the top five coronary artery disease (CAD) trials of the past year is that aspirin is very often more trouble than it’s worth.

Bruce Jancin/MDedge News

“For some years I’ve been concerned that the only thing that aspirin does [in patients after percutaneous coronary intervention] is increase your risk of bleeding. It doesn’t really provide any additional ischemic protection,” Malcolm R. Bell, MBBS, said at the annual Cardiovascular Conference at Snowmass sponsored by the American College of Cardiology.

“I’ll remind you that, when we go back to the early stent days, the combination of clopidogrel and aspirin was never compared in a proper trial to clopidogrel alone. We’ve just inherited this DAPT [dual-antiplatelet therapy] philosophy,” observed Dr. Bell, professor of medicine and vice chair of the department of cardiovascular medicine at the Mayo Clinic in Rochester, Minn.

Here are the key takeaway messages from his five most important randomized trials in CAD during the last year.
 

AUGUSTUS

For years, cardiologists have grappled with how to best manage high-cardiovascular-risk patients with atrial fibrillation who seem like they might benefit from triple-antithrombotic therapy. AUGUSTUS supplied the answer: Don’t do it. Skip the aspirin and turn instead to a P2Y12 inhibitor plus a non–vitamin K antagonist oral anticoagulant (NOAC), rather than warfarin.

“I would like you to think of triple therapy as a triple threat. That’s really what triple therapy is all about”– a three-pronged threat to patient safety, Dr. Bell commented.

In AUGUSTUS, 4,614 patients with atrial fibrillation and CAD with an acute coronary syndrome (ACS) and/or percutaneous coronary intervention (PCI) in 33 countries were placed on a P2Y12 inhibitor – most often clopidogrel – and randomized double blind to either apixaban (Eliquis) or warfarin, and further to aspirin or placebo, for 6 months of antithrombotic therapy. The strategy of a P2Y12 inhibitor and apixaban without aspirin was the clear winner, resulting in significantly less major bleeding, mortality, and hospitalizations than treatment with a P2Y12 inhibitor and warfarin, with or without aspirin. Most importantly, ischemic event rates didn’t differ between the apixaban and warfarin groups. And patients randomized to aspirin had rates of ischemic events and death or hospitalization similar to placebo-treated controls, meaning aspirin accomplished nothing (N Engl J Med. 2019 Apr 18;380[16]:1509-24).

Dr. Bell noted that a meta-analysis of AUGUSTUS and three smaller randomized trials including more than 10,000 AUGUSTUS-type patients with atrial fibrillation concluded that a treatment strategy utilizing a NOAC and a P2Y12 inhibitor resulted in less bleeding than warfarin plus DAPT, and at no cost in terms of excess ischemic events. Moreover, regimens without aspirin resulted in less intracranial and other major bleeding without any difference in major adverse cardiovascular events (JAMA Cardiol. 2019 Jun 19. doi: 10.1001/jamacardio.2019.1880).

A key message of these four trials is that a NOAC is preferable to warfarin, so much so that, in high-risk patients who are already on warfarin, it’s worth considering a switch to a NOAC.

“And we should really be avoiding DAPT,” Dr. Bell added.

How soon after an ACS and/or PCI should patients with atrial fibrillation stop taking aspirin?

“In AUGUSTUS, randomization occurred at a median of 6 days, so we know that half the patients stopped their aspirin by then. In our own practice, we’re just dropping the aspirin for the most part before the patient leaves the hospital. I think if you leave them with instructions to stop the aspirin in a week’s time or a month’s time it just leads to confusion. And we should also remember that half of the major bleeding after PCI or ACS happens in the first 30 days, so it doesn’t make a lot of sense to say that we should continue it for a month and then drop it,” according to the cardiologist.
 

SMART-CHOICE and STOPDAPT-2

These two large multicenter studies demonstrate that DAPT can safely be stopped early if needed. SMART-CHOICE from South Korea and STOPDAPT-2 from Japan each randomized roughly 3,000 patients undergoing PCI to 12 months of DAPT or to DAPT for only 3 months or 1 month, respectively, at which point the aspirin was dropped and patients in the abbreviated DAPT arm continued on P2Y12 inhibitor monotherapy, mostly clopidogrel, for the remainder of the 12 months. In the Japanese STOPDAPT-2 trial, 1 month of DAPT proved superior to 12 months of DAPT for the primary composite endpoint of cardiovascular death, MI, stroke, definite stent thrombosis, or major or minor bleeding at 12 months (JAMA. 2019 Jun 25;321[24]:2414-27). In the South Korean SMART-CHOICE trial, 3 months of DAPT was noninferior to 12 months for major adverse cardiac and cerebrovascular events, and superior in terms of bleeding risk (JAMA. 2019 Jun 25;321[24]:2428-37). Of note, roughly half of patients in the two trials were lower-risk individuals undergoing PCI for stable angina.

Dr. Bell noted that, while the TWILIGHT trial (Ticagrelor With or Without Aspirin in High-Risk Patients After PCI) didn’t make his top-five list, it certainly fits well with the two East Asian studies. The TWILIGHT investigators randomized more than 7,000 patients to 12 months of DAPT or discontinuation of aspirin after 3 months. The result: a lower incidence of clinically relevant bleeding with ticagrelor monotherapy, and with no increased risk of death, MI, or stroke, compared with 12 months of DAPT (N Engl J Med. 2019 Nov 21;381[21]:2032-42).

“Again, I would just question what the added value of aspirin is here,” Dr. Bell commented. “Many interventional cardiologists are absolutely terrified of their patients having stent thrombosis, but with second-generation drug-eluting stents – the stents we’re putting in day in and day out – the risk of stent thrombosis is less than 1%. And in these two trials it was less than 0.5%. There’s more risk of having major bleeding events than there is of ischemia, so I think the balance is in favor of preventing bleeding. We know that major bleeding predicts short- and long-term mortality.”
 

COLCOT

This double-blind trial randomized 4,745 patients within 30 days post MI to low-dose colchicine or placebo on top of excellent rates of background guideline-directed medical therapy. The goal was to see if this anti-inflammatory agent could reduce cardiovascular events independent of any lipid-lowering effect, as was earlier seen with canakinumab in the CANTOS trial. It did so to a statistically significant but relatively modest degree, with a 5.5% rate of the composite cardiovascular events endpoint in the colchicine group and 7.1% in placebo-treated controls (N Engl J Med. 2019 Dec 26;381[26]:2497-505). But Dr. Bell was unimpressed.

“All-cause mortality was identical at 1.8% in both groups. So colchicine is not saving lives. In fact, the only real differences were in stroke – but the study wasn’t powered to look at stroke – and in urgent hospitalization for angina leading to revascularization, which is a soft endpoint,” he observed.

Plus, 2.5% of patients were lost to follow-up, which Dr. Bell considers “a little concerning” in a trial conducted in the current era.

“In my opinion, the evidence that colchicine is effective is weak, and I don’t think really supports the drug’s routine use post MI. We already send these patients out on numerous medications. We have to think about cost/benefit, and if a patient asks me: ‘Is this going to prevent another heart attack or make me live longer?’ I think the unequivocal answer is no,” he said.

These days colchicine is no longer an inexpensive drug, either, at an average cost of $300-$400 per month, the cardiologist added.
 

COMPLETE

This study randomized more than 4,000 patients with ST-segment elevation MI (STEMI) and multivessel disease to primary PCI of the culprit lesion only or to staged complete revascularization via PCI of all angiographically significant nonculprit lesions. Complete revascularization proved to be the superior strategy, with a 26% reduction in the risk of the composite of cardiovascular death or MI at a median of 3 years (N Engl J Med. 2019 Oct 10;381[15]:1411-21).

The optimal timing of the staged procedure remains unclear, since the study didn’t specify a protocol.

“I’m still a bit uncomfortable doing multivessel PCI at 2 o’clock in the morning in the setting of STEMI in someone I’ve never met before. I don’t think there’s a rush to do anything then. Often in this middle-of-the-night stuff, we miss things or we overinterpret things. I think it’s better to let the patient cool down, get to know them,” according to Dr. Bell.
 

EXCEL

Publication of the 5-year outcomes of the largest-ever randomized trial of PCI versus coronary artery bypass grafting (CABG) for left main coronary disease has led to furious controversy, with a few of the surgeons involved in the study opting to publically broadcast allegations of misbehavior on the part of the interventional cardiologist study leadership, charges that have been strongly denied.

The actual results are in line with findings reported from smaller randomized trials. At 5 years in EXCEL, there was no significant difference between the PCI and CABG groups in the primary composite endpoint of death, cerebrovascular accident, or MI (N Engl J Med. 2019 Nov 7;381[19]:1820-30). The all-cause mortality rate was 13% in the PCI arm and 9.9% with CABG, but this finding comes with a caveat.

“I’ll emphasize this trial was never powered to look at mortality. Neither were any of the other randomized trials. On the other hand, I don’t think you can necessarily ignore the finding of an absolute 3.1% difference,” Dr. Bell said.

PCI and CABG are both very good, mature therapies for left main disease, in his view. In the setting of more-complex coronary disease in younger patients, he often views the complete revascularization offered by surgery as the preferred option. On the other hand, in an 80-year-old with severe comorbidities, clearly PCI is attractive.

He considers the highly public nature of this interspecialty spat a regrettable black eye for the entire field of cardiovascular medicine. And he predicted that an ongoing outside neutral-party review of the study data and procedures will conclude, as he has, “there was no malfeasance at all in the trial.”

Dr. Bell reported having no financial conflicts regarding his presentation.

bjancin@mdedge.com

SNOWMASS, COLO. – A repeated theme threading through much of one prominent interventional cardiologist’s personal list of the top five coronary artery disease (CAD) trials of the past year is that aspirin is very often more trouble than it’s worth.

Bruce Jancin/MDedge News

“For some years I’ve been concerned that the only thing that aspirin does [in patients after percutaneous coronary intervention] is increase your risk of bleeding. It doesn’t really provide any additional ischemic protection,” Malcolm R. Bell, MBBS, said at the annual Cardiovascular Conference at Snowmass sponsored by the American College of Cardiology.

“I’ll remind you that, when we go back to the early stent days, the combination of clopidogrel and aspirin was never compared in a proper trial to clopidogrel alone. We’ve just inherited this DAPT [dual-antiplatelet therapy] philosophy,” observed Dr. Bell, professor of medicine and vice chair of the department of cardiovascular medicine at the Mayo Clinic in Rochester, Minn.

Here are the key takeaway messages from his five most important randomized trials in CAD during the last year.
 

AUGUSTUS

For years, cardiologists have grappled with how to best manage high-cardiovascular-risk patients with atrial fibrillation who seem like they might benefit from triple-antithrombotic therapy. AUGUSTUS supplied the answer: Don’t do it. Skip the aspirin and turn instead to a P2Y12 inhibitor plus a non–vitamin K antagonist oral anticoagulant (NOAC), rather than warfarin.

“I would like you to think of triple therapy as a triple threat. That’s really what triple therapy is all about”– a three-pronged threat to patient safety, Dr. Bell commented.

In AUGUSTUS, 4,614 patients with atrial fibrillation and CAD with an acute coronary syndrome (ACS) and/or percutaneous coronary intervention (PCI) in 33 countries were placed on a P2Y12 inhibitor – most often clopidogrel – and randomized double blind to either apixaban (Eliquis) or warfarin, and further to aspirin or placebo, for 6 months of antithrombotic therapy. The strategy of a P2Y12 inhibitor and apixaban without aspirin was the clear winner, resulting in significantly less major bleeding, mortality, and hospitalizations than treatment with a P2Y12 inhibitor and warfarin, with or without aspirin. Most importantly, ischemic event rates didn’t differ between the apixaban and warfarin groups. And patients randomized to aspirin had rates of ischemic events and death or hospitalization similar to placebo-treated controls, meaning aspirin accomplished nothing (N Engl J Med. 2019 Apr 18;380[16]:1509-24).

Dr. Bell noted that a meta-analysis of AUGUSTUS and three smaller randomized trials including more than 10,000 AUGUSTUS-type patients with atrial fibrillation concluded that a treatment strategy utilizing a NOAC and a P2Y12 inhibitor resulted in less bleeding than warfarin plus DAPT, and at no cost in terms of excess ischemic events. Moreover, regimens without aspirin resulted in less intracranial and other major bleeding without any difference in major adverse cardiovascular events (JAMA Cardiol. 2019 Jun 19. doi: 10.1001/jamacardio.2019.1880).

A key message of these four trials is that a NOAC is preferable to warfarin, so much so that, in high-risk patients who are already on warfarin, it’s worth considering a switch to a NOAC.

“And we should really be avoiding DAPT,” Dr. Bell added.

How soon after an ACS and/or PCI should patients with atrial fibrillation stop taking aspirin?

“In AUGUSTUS, randomization occurred at a median of 6 days, so we know that half the patients stopped their aspirin by then. In our own practice, we’re just dropping the aspirin for the most part before the patient leaves the hospital. I think if you leave them with instructions to stop the aspirin in a week’s time or a month’s time it just leads to confusion. And we should also remember that half of the major bleeding after PCI or ACS happens in the first 30 days, so it doesn’t make a lot of sense to say that we should continue it for a month and then drop it,” according to the cardiologist.
 

SMART-CHOICE and STOPDAPT-2

These two large multicenter studies demonstrate that DAPT can safely be stopped early if needed. SMART-CHOICE from South Korea and STOPDAPT-2 from Japan each randomized roughly 3,000 patients undergoing PCI to 12 months of DAPT or to DAPT for only 3 months or 1 month, respectively, at which point the aspirin was dropped and patients in the abbreviated DAPT arm continued on P2Y12 inhibitor monotherapy, mostly clopidogrel, for the remainder of the 12 months. In the Japanese STOPDAPT-2 trial, 1 month of DAPT proved superior to 12 months of DAPT for the primary composite endpoint of cardiovascular death, MI, stroke, definite stent thrombosis, or major or minor bleeding at 12 months (JAMA. 2019 Jun 25;321[24]:2414-27). In the South Korean SMART-CHOICE trial, 3 months of DAPT was noninferior to 12 months for major adverse cardiac and cerebrovascular events, and superior in terms of bleeding risk (JAMA. 2019 Jun 25;321[24]:2428-37). Of note, roughly half of patients in the two trials were lower-risk individuals undergoing PCI for stable angina.

Dr. Bell noted that, while the TWILIGHT trial (Ticagrelor With or Without Aspirin in High-Risk Patients After PCI) didn’t make his top-five list, it certainly fits well with the two East Asian studies. The TWILIGHT investigators randomized more than 7,000 patients to 12 months of DAPT or discontinuation of aspirin after 3 months. The result: a lower incidence of clinically relevant bleeding with ticagrelor monotherapy, and with no increased risk of death, MI, or stroke, compared with 12 months of DAPT (N Engl J Med. 2019 Nov 21;381[21]:2032-42).

“Again, I would just question what the added value of aspirin is here,” Dr. Bell commented. “Many interventional cardiologists are absolutely terrified of their patients having stent thrombosis, but with second-generation drug-eluting stents – the stents we’re putting in day in and day out – the risk of stent thrombosis is less than 1%. And in these two trials it was less than 0.5%. There’s more risk of having major bleeding events than there is of ischemia, so I think the balance is in favor of preventing bleeding. We know that major bleeding predicts short- and long-term mortality.”
 

COLCOT

This double-blind trial randomized 4,745 patients within 30 days post MI to low-dose colchicine or placebo on top of excellent rates of background guideline-directed medical therapy. The goal was to see if this anti-inflammatory agent could reduce cardiovascular events independent of any lipid-lowering effect, as was earlier seen with canakinumab in the CANTOS trial. It did so to a statistically significant but relatively modest degree, with a 5.5% rate of the composite cardiovascular events endpoint in the colchicine group and 7.1% in placebo-treated controls (N Engl J Med. 2019 Dec 26;381[26]:2497-505). But Dr. Bell was unimpressed.

“All-cause mortality was identical at 1.8% in both groups. So colchicine is not saving lives. In fact, the only real differences were in stroke – but the study wasn’t powered to look at stroke – and in urgent hospitalization for angina leading to revascularization, which is a soft endpoint,” he observed.

Plus, 2.5% of patients were lost to follow-up, which Dr. Bell considers “a little concerning” in a trial conducted in the current era.

“In my opinion, the evidence that colchicine is effective is weak, and I don’t think really supports the drug’s routine use post MI. We already send these patients out on numerous medications. We have to think about cost/benefit, and if a patient asks me: ‘Is this going to prevent another heart attack or make me live longer?’ I think the unequivocal answer is no,” he said.

These days colchicine is no longer an inexpensive drug, either, at an average cost of $300-$400 per month, the cardiologist added.
 

COMPLETE

This study randomized more than 4,000 patients with ST-segment elevation MI (STEMI) and multivessel disease to primary PCI of the culprit lesion only or to staged complete revascularization via PCI of all angiographically significant nonculprit lesions. Complete revascularization proved to be the superior strategy, with a 26% reduction in the risk of the composite of cardiovascular death or MI at a median of 3 years (N Engl J Med. 2019 Oct 10;381[15]:1411-21).

The optimal timing of the staged procedure remains unclear, since the study didn’t specify a protocol.

“I’m still a bit uncomfortable doing multivessel PCI at 2 o’clock in the morning in the setting of STEMI in someone I’ve never met before. I don’t think there’s a rush to do anything then. Often in this middle-of-the-night stuff, we miss things or we overinterpret things. I think it’s better to let the patient cool down, get to know them,” according to Dr. Bell.
 

EXCEL

Publication of the 5-year outcomes of the largest-ever randomized trial of PCI versus coronary artery bypass grafting (CABG) for left main coronary disease has led to furious controversy, with a few of the surgeons involved in the study opting to publically broadcast allegations of misbehavior on the part of the interventional cardiologist study leadership, charges that have been strongly denied.

The actual results are in line with findings reported from smaller randomized trials. At 5 years in EXCEL, there was no significant difference between the PCI and CABG groups in the primary composite endpoint of death, cerebrovascular accident, or MI (N Engl J Med. 2019 Nov 7;381[19]:1820-30). The all-cause mortality rate was 13% in the PCI arm and 9.9% with CABG, but this finding comes with a caveat.

“I’ll emphasize this trial was never powered to look at mortality. Neither were any of the other randomized trials. On the other hand, I don’t think you can necessarily ignore the finding of an absolute 3.1% difference,” Dr. Bell said.

PCI and CABG are both very good, mature therapies for left main disease, in his view. In the setting of more-complex coronary disease in younger patients, he often views the complete revascularization offered by surgery as the preferred option. On the other hand, in an 80-year-old with severe comorbidities, clearly PCI is attractive.

He considers the highly public nature of this interspecialty spat a regrettable black eye for the entire field of cardiovascular medicine. And he predicted that an ongoing outside neutral-party review of the study data and procedures will conclude, as he has, “there was no malfeasance at all in the trial.”

Dr. Bell reported having no financial conflicts regarding his presentation.

bjancin@mdedge.com

SNOWMASS, COLO. – A repeated theme threading through much of one prominent interventional cardiologist’s personal list of the top five coronary artery disease (CAD) trials of the past year is that aspirin is very often more trouble than it’s worth.

Bruce Jancin/MDedge News

“For some years I’ve been concerned that the only thing that aspirin does [in patients after percutaneous coronary intervention] is increase your risk of bleeding. It doesn’t really provide any additional ischemic protection,” Malcolm R. Bell, MBBS, said at the annual Cardiovascular Conference at Snowmass sponsored by the American College of Cardiology.

“I’ll remind you that, when we go back to the early stent days, the combination of clopidogrel and aspirin was never compared in a proper trial to clopidogrel alone. We’ve just inherited this DAPT [dual-antiplatelet therapy] philosophy,” observed Dr. Bell, professor of medicine and vice chair of the department of cardiovascular medicine at the Mayo Clinic in Rochester, Minn.

Here are the key takeaway messages from his five most important randomized trials in CAD during the last year.
 

AUGUSTUS

For years, cardiologists have grappled with how to best manage high-cardiovascular-risk patients with atrial fibrillation who seem like they might benefit from triple-antithrombotic therapy. AUGUSTUS supplied the answer: Don’t do it. Skip the aspirin and turn instead to a P2Y12 inhibitor plus a non–vitamin K antagonist oral anticoagulant (NOAC), rather than warfarin.

“I would like you to think of triple therapy as a triple threat. That’s really what triple therapy is all about”– a three-pronged threat to patient safety, Dr. Bell commented.

In AUGUSTUS, 4,614 patients with atrial fibrillation and CAD with an acute coronary syndrome (ACS) and/or percutaneous coronary intervention (PCI) in 33 countries were placed on a P2Y12 inhibitor – most often clopidogrel – and randomized double blind to either apixaban (Eliquis) or warfarin, and further to aspirin or placebo, for 6 months of antithrombotic therapy. The strategy of a P2Y12 inhibitor and apixaban without aspirin was the clear winner, resulting in significantly less major bleeding, mortality, and hospitalizations than treatment with a P2Y12 inhibitor and warfarin, with or without aspirin. Most importantly, ischemic event rates didn’t differ between the apixaban and warfarin groups. And patients randomized to aspirin had rates of ischemic events and death or hospitalization similar to placebo-treated controls, meaning aspirin accomplished nothing (N Engl J Med. 2019 Apr 18;380[16]:1509-24).

Dr. Bell noted that a meta-analysis of AUGUSTUS and three smaller randomized trials including more than 10,000 AUGUSTUS-type patients with atrial fibrillation concluded that a treatment strategy utilizing a NOAC and a P2Y12 inhibitor resulted in less bleeding than warfarin plus DAPT, and at no cost in terms of excess ischemic events. Moreover, regimens without aspirin resulted in less intracranial and other major bleeding without any difference in major adverse cardiovascular events (JAMA Cardiol. 2019 Jun 19. doi: 10.1001/jamacardio.2019.1880).

A key message of these four trials is that a NOAC is preferable to warfarin, so much so that, in high-risk patients who are already on warfarin, it’s worth considering a switch to a NOAC.

“And we should really be avoiding DAPT,” Dr. Bell added.

How soon after an ACS and/or PCI should patients with atrial fibrillation stop taking aspirin?

“In AUGUSTUS, randomization occurred at a median of 6 days, so we know that half the patients stopped their aspirin by then. In our own practice, we’re just dropping the aspirin for the most part before the patient leaves the hospital. I think if you leave them with instructions to stop the aspirin in a week’s time or a month’s time it just leads to confusion. And we should also remember that half of the major bleeding after PCI or ACS happens in the first 30 days, so it doesn’t make a lot of sense to say that we should continue it for a month and then drop it,” according to the cardiologist.
 

SMART-CHOICE and STOPDAPT-2

These two large multicenter studies demonstrate that DAPT can safely be stopped early if needed. SMART-CHOICE from South Korea and STOPDAPT-2 from Japan each randomized roughly 3,000 patients undergoing PCI to 12 months of DAPT or to DAPT for only 3 months or 1 month, respectively, at which point the aspirin was dropped and patients in the abbreviated DAPT arm continued on P2Y12 inhibitor monotherapy, mostly clopidogrel, for the remainder of the 12 months. In the Japanese STOPDAPT-2 trial, 1 month of DAPT proved superior to 12 months of DAPT for the primary composite endpoint of cardiovascular death, MI, stroke, definite stent thrombosis, or major or minor bleeding at 12 months (JAMA. 2019 Jun 25;321[24]:2414-27). In the South Korean SMART-CHOICE trial, 3 months of DAPT was noninferior to 12 months for major adverse cardiac and cerebrovascular events, and superior in terms of bleeding risk (JAMA. 2019 Jun 25;321[24]:2428-37). Of note, roughly half of patients in the two trials were lower-risk individuals undergoing PCI for stable angina.

Dr. Bell noted that, while the TWILIGHT trial (Ticagrelor With or Without Aspirin in High-Risk Patients After PCI) didn’t make his top-five list, it certainly fits well with the two East Asian studies. The TWILIGHT investigators randomized more than 7,000 patients to 12 months of DAPT or discontinuation of aspirin after 3 months. The result: a lower incidence of clinically relevant bleeding with ticagrelor monotherapy, and with no increased risk of death, MI, or stroke, compared with 12 months of DAPT (N Engl J Med. 2019 Nov 21;381[21]:2032-42).

“Again, I would just question what the added value of aspirin is here,” Dr. Bell commented. “Many interventional cardiologists are absolutely terrified of their patients having stent thrombosis, but with second-generation drug-eluting stents – the stents we’re putting in day in and day out – the risk of stent thrombosis is less than 1%. And in these two trials it was less than 0.5%. There’s more risk of having major bleeding events than there is of ischemia, so I think the balance is in favor of preventing bleeding. We know that major bleeding predicts short- and long-term mortality.”
 

COLCOT

This double-blind trial randomized 4,745 patients within 30 days post MI to low-dose colchicine or placebo on top of excellent rates of background guideline-directed medical therapy. The goal was to see if this anti-inflammatory agent could reduce cardiovascular events independent of any lipid-lowering effect, as was earlier seen with canakinumab in the CANTOS trial. It did so to a statistically significant but relatively modest degree, with a 5.5% rate of the composite cardiovascular events endpoint in the colchicine group and 7.1% in placebo-treated controls (N Engl J Med. 2019 Dec 26;381[26]:2497-505). But Dr. Bell was unimpressed.

“All-cause mortality was identical at 1.8% in both groups. So colchicine is not saving lives. In fact, the only real differences were in stroke – but the study wasn’t powered to look at stroke – and in urgent hospitalization for angina leading to revascularization, which is a soft endpoint,” he observed.

Plus, 2.5% of patients were lost to follow-up, which Dr. Bell considers “a little concerning” in a trial conducted in the current era.

“In my opinion, the evidence that colchicine is effective is weak, and I don’t think really supports the drug’s routine use post MI. We already send these patients out on numerous medications. We have to think about cost/benefit, and if a patient asks me: ‘Is this going to prevent another heart attack or make me live longer?’ I think the unequivocal answer is no,” he said.

These days colchicine is no longer an inexpensive drug, either, at an average cost of $300-$400 per month, the cardiologist added.
 

COMPLETE

This study randomized more than 4,000 patients with ST-segment elevation MI (STEMI) and multivessel disease to primary PCI of the culprit lesion only or to staged complete revascularization via PCI of all angiographically significant nonculprit lesions. Complete revascularization proved to be the superior strategy, with a 26% reduction in the risk of the composite of cardiovascular death or MI at a median of 3 years (N Engl J Med. 2019 Oct 10;381[15]:1411-21).

The optimal timing of the staged procedure remains unclear, since the study didn’t specify a protocol.

“I’m still a bit uncomfortable doing multivessel PCI at 2 o’clock in the morning in the setting of STEMI in someone I’ve never met before. I don’t think there’s a rush to do anything then. Often in this middle-of-the-night stuff, we miss things or we overinterpret things. I think it’s better to let the patient cool down, get to know them,” according to Dr. Bell.
 

EXCEL

Publication of the 5-year outcomes of the largest-ever randomized trial of PCI versus coronary artery bypass grafting (CABG) for left main coronary disease has led to furious controversy, with a few of the surgeons involved in the study opting to publically broadcast allegations of misbehavior on the part of the interventional cardiologist study leadership, charges that have been strongly denied.

The actual results are in line with findings reported from smaller randomized trials. At 5 years in EXCEL, there was no significant difference between the PCI and CABG groups in the primary composite endpoint of death, cerebrovascular accident, or MI (N Engl J Med. 2019 Nov 7;381[19]:1820-30). The all-cause mortality rate was 13% in the PCI arm and 9.9% with CABG, but this finding comes with a caveat.

“I’ll emphasize this trial was never powered to look at mortality. Neither were any of the other randomized trials. On the other hand, I don’t think you can necessarily ignore the finding of an absolute 3.1% difference,” Dr. Bell said.

PCI and CABG are both very good, mature therapies for left main disease, in his view. In the setting of more-complex coronary disease in younger patients, he often views the complete revascularization offered by surgery as the preferred option. On the other hand, in an 80-year-old with severe comorbidities, clearly PCI is attractive.

He considers the highly public nature of this interspecialty spat a regrettable black eye for the entire field of cardiovascular medicine. And he predicted that an ongoing outside neutral-party review of the study data and procedures will conclude, as he has, “there was no malfeasance at all in the trial.”

Dr. Bell reported having no financial conflicts regarding his presentation.

bjancin@mdedge.com

U.S. public health officials attempted to stymie concerns about the coronavirus during a press conference on Tuesday, emphasizing that most Americans are not in danger of contracting the illness and urging citizens not to take extreme measures in response to the low-risk virus.

“Right now, there is no spread of this virus in our communities here at home,” Centers for Disease Control and Prevention director Robert Redfield, MD, said during the Jan. 28 press conference. “This is why our current assessment is that the immediate health risk of this new virus to the general public is low in our nation. The coming days and weeks are likely to bring more confirmed cases here and around the world, including the possibility of some person-to-person spreading, but our goal of the ongoing U.S. public health response is to contain this outbreak and prevent sustained spread of the virus in our country.”

During the press conference, Department Health & Human Services Secretary Alex M. Azar II, reiterated there have been only five confirmed U.S. cases of the coronavirus thus far and all were associated with travel to Wuhan, China, where the virus first appeared. The number of confirmed cases in China, meanwhile, has risen to more than 4,500 with about 100 associated deaths.

U.S. health providers should be on the lookout for any patient who has traveled to China recently, particularly to Hubei province, and they should pay close attention to any relevant symptoms, Secretary Azar said during the press conference.

He defended the decision not to declare a public health emergency at this time, stressing that such a move is based on standards and requirements not yet met by the coronavirus.

“It’s important to remember where we are right now; we have five cases in the United States, each of those individuals with direct contact to Wuhan and no person-to-person transmission in the United States,” Secretary Azar said. “I won’t hesitate at all to invoke any authorities that I need to ensure that we’re taking all the steps to protect the American people, but I’ll do it when it’s appropriate under the standards that we have and the authorities that I need.”

In the meantime, a number of efforts are underway by U.S. agencies to assess the nation’s emergency preparedness stockpile, to assist American families in China with evacuation, and to pursue research into diagnostics and a potential vaccine for the virus, Secretary Azar said.

HHS.gov

U.S. public health officials attempted to stymie concerns about the coronavirus during a press conference on Tuesday, emphasizing that most Americans are not in danger of contracting the illness and urging citizens not to take extreme measures in response to the low-risk virus.

“Right now, there is no spread of this virus in our communities here at home,” Centers for Disease Control and Prevention director Robert Redfield, MD, said during the Jan. 28 press conference. “This is why our current assessment is that the immediate health risk of this new virus to the general public is low in our nation. The coming days and weeks are likely to bring more confirmed cases here and around the world, including the possibility of some person-to-person spreading, but our goal of the ongoing U.S. public health response is to contain this outbreak and prevent sustained spread of the virus in our country.”

During the press conference, Department Health & Human Services Secretary Alex M. Azar II, reiterated there have been only five confirmed U.S. cases of the coronavirus thus far and all were associated with travel to Wuhan, China, where the virus first appeared. The number of confirmed cases in China, meanwhile, has risen to more than 4,500 with about 100 associated deaths.

U.S. health providers should be on the lookout for any patient who has traveled to China recently, particularly to Hubei province, and they should pay close attention to any relevant symptoms, Secretary Azar said during the press conference.

He defended the decision not to declare a public health emergency at this time, stressing that such a move is based on standards and requirements not yet met by the coronavirus.

“It’s important to remember where we are right now; we have five cases in the United States, each of those individuals with direct contact to Wuhan and no person-to-person transmission in the United States,” Secretary Azar said. “I won’t hesitate at all to invoke any authorities that I need to ensure that we’re taking all the steps to protect the American people, but I’ll do it when it’s appropriate under the standards that we have and the authorities that I need.”

In the meantime, a number of efforts are underway by U.S. agencies to assess the nation’s emergency preparedness stockpile, to assist American families in China with evacuation, and to pursue research into diagnostics and a potential vaccine for the virus, Secretary Azar said.

HHS.gov

U.S. public health officials attempted to stymie concerns about the coronavirus during a press conference on Tuesday, emphasizing that most Americans are not in danger of contracting the illness and urging citizens not to take extreme measures in response to the low-risk virus.

“Right now, there is no spread of this virus in our communities here at home,” Centers for Disease Control and Prevention director Robert Redfield, MD, said during the Jan. 28 press conference. “This is why our current assessment is that the immediate health risk of this new virus to the general public is low in our nation. The coming days and weeks are likely to bring more confirmed cases here and around the world, including the possibility of some person-to-person spreading, but our goal of the ongoing U.S. public health response is to contain this outbreak and prevent sustained spread of the virus in our country.”

During the press conference, Department Health & Human Services Secretary Alex M. Azar II, reiterated there have been only five confirmed U.S. cases of the coronavirus thus far and all were associated with travel to Wuhan, China, where the virus first appeared. The number of confirmed cases in China, meanwhile, has risen to more than 4,500 with about 100 associated deaths.

U.S. health providers should be on the lookout for any patient who has traveled to China recently, particularly to Hubei province, and they should pay close attention to any relevant symptoms, Secretary Azar said during the press conference.

He defended the decision not to declare a public health emergency at this time, stressing that such a move is based on standards and requirements not yet met by the coronavirus.

“It’s important to remember where we are right now; we have five cases in the United States, each of those individuals with direct contact to Wuhan and no person-to-person transmission in the United States,” Secretary Azar said. “I won’t hesitate at all to invoke any authorities that I need to ensure that we’re taking all the steps to protect the American people, but I’ll do it when it’s appropriate under the standards that we have and the authorities that I need.”

In the meantime, a number of efforts are underway by U.S. agencies to assess the nation’s emergency preparedness stockpile, to assist American families in China with evacuation, and to pursue research into diagnostics and a potential vaccine for the virus, Secretary Azar said.

HHS.gov

The Food and Drug Administration is strengthening a previous warning regarding the uncommon risk of serious bowel complications associated with the schizophrenia medication clozapine (Clozaril, FazaClo ODT, Versacloz).

Wikimedia Commons/FitzColinGerald/ Creative Commons License

According to the FDA press release, dated Jan. 28, clozapine affects bowel function in a majority of patients, and constipation is a common adverse event associated with clozapine use. This can uncommonly progress to serious bowel complications, including complete bowel blockage, and can result in hospitalization or even death if the constipation is not diagnosed and treated quickly.

Patients should contact their health care clinician if their bowel movements are less frequent, they have a bowel movement less than three times a week, they have hard or dry stool, or they have difficulty passing gas. Urgent care is needed if patients are experiencing nausea, vomiting, belly pain, or bloating, according to the FDA.

In addition, health care clinicians should evaluate bowel function before beginning clozapine treatment, avoid coprescribing with other anticholinergic medicines, advise and question patients about the risks of clozapine and their bowel movements, monitor patients for complications, and consider prophylactic laxative treatment in patients with a history of constipation or bowel obstruction, the FDA added.

lfranki@mdedge.com

The Food and Drug Administration is strengthening a previous warning regarding the uncommon risk of serious bowel complications associated with the schizophrenia medication clozapine (Clozaril, FazaClo ODT, Versacloz).

Wikimedia Commons/FitzColinGerald/ Creative Commons License

According to the FDA press release, dated Jan. 28, clozapine affects bowel function in a majority of patients, and constipation is a common adverse event associated with clozapine use. This can uncommonly progress to serious bowel complications, including complete bowel blockage, and can result in hospitalization or even death if the constipation is not diagnosed and treated quickly.

Patients should contact their health care clinician if their bowel movements are less frequent, they have a bowel movement less than three times a week, they have hard or dry stool, or they have difficulty passing gas. Urgent care is needed if patients are experiencing nausea, vomiting, belly pain, or bloating, according to the FDA.

In addition, health care clinicians should evaluate bowel function before beginning clozapine treatment, avoid coprescribing with other anticholinergic medicines, advise and question patients about the risks of clozapine and their bowel movements, monitor patients for complications, and consider prophylactic laxative treatment in patients with a history of constipation or bowel obstruction, the FDA added.

lfranki@mdedge.com

The Food and Drug Administration is strengthening a previous warning regarding the uncommon risk of serious bowel complications associated with the schizophrenia medication clozapine (Clozaril, FazaClo ODT, Versacloz).

Wikimedia Commons/FitzColinGerald/ Creative Commons License

According to the FDA press release, dated Jan. 28, clozapine affects bowel function in a majority of patients, and constipation is a common adverse event associated with clozapine use. This can uncommonly progress to serious bowel complications, including complete bowel blockage, and can result in hospitalization or even death if the constipation is not diagnosed and treated quickly.

Patients should contact their health care clinician if their bowel movements are less frequent, they have a bowel movement less than three times a week, they have hard or dry stool, or they have difficulty passing gas. Urgent care is needed if patients are experiencing nausea, vomiting, belly pain, or bloating, according to the FDA.

In addition, health care clinicians should evaluate bowel function before beginning clozapine treatment, avoid coprescribing with other anticholinergic medicines, advise and question patients about the risks of clozapine and their bowel movements, monitor patients for complications, and consider prophylactic laxative treatment in patients with a history of constipation or bowel obstruction, the FDA added.

lfranki@mdedge.com

The Food and Drug Administration has approved a triple-combination tablet (Trijardy XR), comprising empagliflozin (Jardiance), linagliptin (Tradjenta), and extended-release metformin hydrochloride, for the treatment of adults with type 2 diabetes.

Trijardy XR will be available in four different dosages and is indicated as a once-daily treatment, together with diet and exercise, for adults who are already on treatment for type 2 disease but require additional agents to attain healthy hemoglobin A_1c targets, according to a statement released by Eli Lilly, which will market the newly approved treatment together with Boehringer Ingelheim.

“Type 2 diabetes is a complex disease that often requires the use of multiple antidiabetic medications to improve glycemic control. Having three different diabetes medications in a single tablet is an important advance in diabetes treatment,” Ralph DeFronzo, MD, professor and diabetes division chief at the University of Texas Health San Antonio, said in the release.

All three drugs are separately well-established therapies for type 2 diabetes. Metformin is the most commonly prescribed treatment for type 2. Empagliflozin, a sodium-glucose transporter 2 inhibitor, and linagliptin, a single-dose dipeptidyl peptidase–4 inhibitor, are approved for the reduction of blood sugar in patients with type 2 disease, and empagliflozin is also approved for lowering the risk of cardiovascular death in adults with type 2 and established cardiovascular disease, according to the statement. (In 2015, the FDA approved a combination of empagliflozin and linagliptin, Glyxambi, as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes.)

The approval of the triple-combination treatment was based on findings from two randomized, open-label trials that assessed the bioequivalence of empagliflozin, linagliptin, and extended-release metformin hydrochloride fixed-dose combination tablets, as well as their individual components. In addition, the trials established that the safety profile of the combination therapy was similar to the safety profiles of the components, the statement said.

Lactic acidosis, pancreatitis, and heart failure are among the side effects associated with the combination therapy, with upper respiratory tract infection and gastroenteritis among the most common. Serious side effects include dehydration, ketoacidosis, kidney problems, urinary tract and vaginal yeast infections, and hypoglycemia.

As with empagliflozin and linagliptin alone, the combination therapy is not recommended for individuals with type 1 diabetes or diabetic ketoacidosis, and it has not been tested in patients with a history of pancreatitis. The combination also has a warning for lactic acidosis, a rare, but serious, condition that can arise with metformin accumulation.

The combination product is contraindicated for people with kidney problems and end-stage renal disease or who are on dialysis; have metabolic acidosis or diabetic ketoacidosis; or are allergic to empagliflozin, linagliptin, or metformin.

The Food and Drug Administration has approved a triple-combination tablet (Trijardy XR), comprising empagliflozin (Jardiance), linagliptin (Tradjenta), and extended-release metformin hydrochloride, for the treatment of adults with type 2 diabetes.

Trijardy XR will be available in four different dosages and is indicated as a once-daily treatment, together with diet and exercise, for adults who are already on treatment for type 2 disease but require additional agents to attain healthy hemoglobin A_1c targets, according to a statement released by Eli Lilly, which will market the newly approved treatment together with Boehringer Ingelheim.

“Type 2 diabetes is a complex disease that often requires the use of multiple antidiabetic medications to improve glycemic control. Having three different diabetes medications in a single tablet is an important advance in diabetes treatment,” Ralph DeFronzo, MD, professor and diabetes division chief at the University of Texas Health San Antonio, said in the release.

All three drugs are separately well-established therapies for type 2 diabetes. Metformin is the most commonly prescribed treatment for type 2. Empagliflozin, a sodium-glucose transporter 2 inhibitor, and linagliptin, a single-dose dipeptidyl peptidase–4 inhibitor, are approved for the reduction of blood sugar in patients with type 2 disease, and empagliflozin is also approved for lowering the risk of cardiovascular death in adults with type 2 and established cardiovascular disease, according to the statement. (In 2015, the FDA approved a combination of empagliflozin and linagliptin, Glyxambi, as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes.)

The approval of the triple-combination treatment was based on findings from two randomized, open-label trials that assessed the bioequivalence of empagliflozin, linagliptin, and extended-release metformin hydrochloride fixed-dose combination tablets, as well as their individual components. In addition, the trials established that the safety profile of the combination therapy was similar to the safety profiles of the components, the statement said.

Lactic acidosis, pancreatitis, and heart failure are among the side effects associated with the combination therapy, with upper respiratory tract infection and gastroenteritis among the most common. Serious side effects include dehydration, ketoacidosis, kidney problems, urinary tract and vaginal yeast infections, and hypoglycemia.

As with empagliflozin and linagliptin alone, the combination therapy is not recommended for individuals with type 1 diabetes or diabetic ketoacidosis, and it has not been tested in patients with a history of pancreatitis. The combination also has a warning for lactic acidosis, a rare, but serious, condition that can arise with metformin accumulation.

The combination product is contraindicated for people with kidney problems and end-stage renal disease or who are on dialysis; have metabolic acidosis or diabetic ketoacidosis; or are allergic to empagliflozin, linagliptin, or metformin.

The Food and Drug Administration has approved a triple-combination tablet (Trijardy XR), comprising empagliflozin (Jardiance), linagliptin (Tradjenta), and extended-release metformin hydrochloride, for the treatment of adults with type 2 diabetes.

Trijardy XR will be available in four different dosages and is indicated as a once-daily treatment, together with diet and exercise, for adults who are already on treatment for type 2 disease but require additional agents to attain healthy hemoglobin A_1c targets, according to a statement released by Eli Lilly, which will market the newly approved treatment together with Boehringer Ingelheim.

“Type 2 diabetes is a complex disease that often requires the use of multiple antidiabetic medications to improve glycemic control. Having three different diabetes medications in a single tablet is an important advance in diabetes treatment,” Ralph DeFronzo, MD, professor and diabetes division chief at the University of Texas Health San Antonio, said in the release.

All three drugs are separately well-established therapies for type 2 diabetes. Metformin is the most commonly prescribed treatment for type 2. Empagliflozin, a sodium-glucose transporter 2 inhibitor, and linagliptin, a single-dose dipeptidyl peptidase–4 inhibitor, are approved for the reduction of blood sugar in patients with type 2 disease, and empagliflozin is also approved for lowering the risk of cardiovascular death in adults with type 2 and established cardiovascular disease, according to the statement. (In 2015, the FDA approved a combination of empagliflozin and linagliptin, Glyxambi, as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes.)

The approval of the triple-combination treatment was based on findings from two randomized, open-label trials that assessed the bioequivalence of empagliflozin, linagliptin, and extended-release metformin hydrochloride fixed-dose combination tablets, as well as their individual components. In addition, the trials established that the safety profile of the combination therapy was similar to the safety profiles of the components, the statement said.

Lactic acidosis, pancreatitis, and heart failure are among the side effects associated with the combination therapy, with upper respiratory tract infection and gastroenteritis among the most common. Serious side effects include dehydration, ketoacidosis, kidney problems, urinary tract and vaginal yeast infections, and hypoglycemia.

As with empagliflozin and linagliptin alone, the combination therapy is not recommended for individuals with type 1 diabetes or diabetic ketoacidosis, and it has not been tested in patients with a history of pancreatitis. The combination also has a warning for lactic acidosis, a rare, but serious, condition that can arise with metformin accumulation.

The combination product is contraindicated for people with kidney problems and end-stage renal disease or who are on dialysis; have metabolic acidosis or diabetic ketoacidosis; or are allergic to empagliflozin, linagliptin, or metformin.

SNOWMASS, COLO. – The tragic opioid epidemic has “one small bright spot”: an expanding pool of eligible donor hearts for transplantation, Akshay S. Desai, MD, said at the annual Cardiovascular Conference at Snowmass sponsored by the American College of Cardiology.

Bruce Jancin/MDedge News

For decades, the annual volume of heart transplantations performed in the U.S. was static because of the huge mismatch between donor organ supply and demand. But heart transplant volume has increased steadily in the last few years – a result of the opioid epidemic.

Data from the U.S. Organ Procurement and Transplantation Network show that the proportion of donor hearts obtained from individuals who died from drug intoxication climbed from a mere 1.5% in 1999 to 17.6% in 2017, the most recent year for which data are available. Meanwhile, the size of the heart transplant waiting list, which rose year after year in 2009-2015, has since declined (N Engl J Med. 2019 Feb 7;380[6]:597-9).

“What’s amazing is that, even though these patients might have historically been considered high risk in general, the organs recovered from these patients – and particularly the hearts – don’t seem to be any worse in terms of allograft survival than the organs recovered from patients who died from other causes, which are the traditional sources, like blunt head trauma, gunshot wounds, or stroke, that lead to brain death. In general, these organs are useful and do quite well,” according to Dr. Desai, medical director of the cardiomyopathy and heart failure program at Brigham and Women’s Hospital, Boston.

He highlighted several other recent developments in the field of cardiac transplantation that promise to further expand the donor heart pool, including acceptance of hepatitis C–infected donors and organ donation after circulatory rather than brain death. Dr. Desai also drew attention to the unintended perverse consequences of a recent redesign of the U.S. donor heart allocation system and discussed the impressive improvement in clinical outcomes with mechanical circulatory support. He noted that, while relatively few cardiologists practice in the highly specialized centers where heart transplants take place, virtually all cardiologists are affected by advances in heart transplantation since hundreds of thousands of the estimated 7 million Americans with heart failure have advanced disease.

Heart transplantation, he emphasized, is becoming increasingly complex. Recipients are on average older, sicker, and have more comorbidities than in times past. As a result, there is greater need for dual organ transplants: heart/lung, heart/liver, or heart/kidney. Plus, more patients come to transplantation after prior cardiac surgery for implantation of a ventricular assist device, so sensitization to blood products is a growing issue. And, of course, the pool of transplant candidates has expanded.

“We’re now forced to take patients previously considered to have contraindications to transplant; for example, diabetes was a contraindication to transplant in the early years, but now it’s the rule in 35%-40% of our patients who present with advanced heart failure,” the cardiologist noted.
 

Transplants from HCV-infected donors to uninfected recipients

Hearts and lungs from donors with hepatitis C viremia were traditionally deemed unsuitable for transplant. That’s all changed in the current era of highly effective direct-acting antiviral agents for the treatment of HCV infection.

In the DONATE HCV trial, Dr. Desai’s colleagues at Brigham and Women’s Hospital showed that giving HCV-uninfected recipients of hearts or lungs from HCV-viremic donors a shortened 4-week course of treatment with sofosbuvir-velpatasvir (Epclusa) beginning within a few hours after transplantation uniformly blocked viral replication. Six months after transplantation, none of the study participants had a detectable HCV viral load, and all had excellent graft function (N Engl J Med. 2019 Apr 25;380[17]:1606-17).

“This is effective prevention of HCV infection by aggressive upfront therapy,” Dr. Desai explained. “We can now take organs from HCV-viremic patients and use them in solid organ transplantation. This has led to a skyrocketing increase in donors with HCV infection, and those donations have helped us clear the waiting list.”
 

Donation after circulatory death

Australian transplant physicians have pioneered the use of donor hearts obtained after circulatory death in individuals with devastating neurologic injury who didn’t quite meet the criteria for brain death, which is the traditional prerequisite. In the new scenario, withdrawal of life-supporting therapy is followed by circulatory death, then the donor heart is procured and preserved via extracorporeal perfusion until transplantation.

The Australians report excellent outcomes, with rates of overall survival and rejection episodes similar to outcomes from brain-dead donors (J Am Coll Cardiol. 2019 Apr 2;73[12]:1447-59). The first U.S. heart transplant involving donation after circulatory death took place at Duke University in Durham, North Carolina. A multicenter U.S. clinical trial of this practice is underway.

If the results are positive and the practice of donation after circulatory death becomes widely implemented, the U.S. heart donor pool could increase by 30%.
 

Recent overhaul of donor heart allocation system may have backfired

The U.S. donor heart allocation system was redesigned in the fall of 2018 in an effort to reduce waiting times. One of the biggest changes involved breaking down the category with the highest urgency status into three new subcategories based upon sickness. Now, the highest-urgency category is for patients in cardiogenic shock who are supported by extracorporeal membrane oxygenation (ECMO) or other temporary mechanical circulatory support devices.

But an analysis of United Network for Organ Sharing (UNOS) data suggests this change has unintended adverse consequences for clinical outcomes.

Indeed, the investigators reported that the use of ECMO support is fourfold greater in the new system, the use of durable left ventricular assist devices (LVADs) as a bridge to transplant is down, and outcomes are worse. The 180-day rate of freedom from death or retransplantation was 77.9%, down significantly from 93.4% in the former system. In a multivariate analysis, patients transplanted in the new system had an adjusted 2.1-fold increased risk of death or retransplantation (J Heart Lung Transplant. 2020 Jan;39[1]:1-4).

“When you create a new listing system, you create new incentives, and people start to manage patients differently,” Dr. Desai observed. “Increasingly now, the path direct to transplant is through temporary mechanical circulatory support rather than durable mechanical circulatory support. Is that a good idea? We don’t know, but if you look at the best data, those on ECMO or percutaneous VADs have the worst outcomes. So the question of whether we should take the sickest of sick patients directly to transplant as a standard strategy has come under scrutiny.”
 

Improved durable LVAD technology brings impressive clinical outcomes

Results of the landmark MOMENTUM 3 randomized trial showed that 2-year clinical outcomes with the magnetically levitated centrifugal-flow HeartMate 3 LVAD now rival those of percutaneous mitral valve repair using the MitraClip device. Two-year all-cause mortality in the LVAD recipients was 22% versus 29.1% with the MitraClip in the COAPT trial and 34.9% in the MITRA-FR trial. The HeartMate 3 reduces the hemocompatibility issues that plagued earlier-generation durable LVADs, with resultant lower rates of pump thrombosis, stroke, and GI bleeding. Indeed, the outcomes in MOMENTUM 3 were so good – and so similar – with the HeartMate 3, regardless of whether the intended treatment goal was as a bridge to transplant or as lifelong destination therapy, that the investigators have recently proposed doing away with those distinctions.

“It is possible that use of arbitrary categorizations based on current or future transplant eligibility should be clinically abandoned in favor of a single preimplant strategy: to extend the survival and improve the quality of life of patients with medically refractory heart failure,” according to the investigators (JAMA Cardiol. 2020 Jan 15. doi: 10.1001/jamacardio.2019.5323).

The next step forward in LVAD technology is already on the horizon: a fully implantable device that eliminates the transcutaneous drive-line for the power supply, which is prone to infection and diminishes overall quality of life. This investigational device utilizes wireless coplanar energy transfer, with a coil ring placed around the lung and fixed to the chest wall. The implanted battery provides more than 6 hours of power without a recharge (J Heart Lung Transplant. 2019 Apr;38[4]:339-43).

“The first LVAD patient has gone swimming in Kazakhstan,” according to Dr. Desai.

Myocardial recovery in LVAD recipients remains elusive

The initial hope for LVADs was that they would not only be able to serve as a bridge to transplantation or as lifetime therapy, but that the prolonged unloading of the ventricle would enable potent medical therapy to rescue myocardial function so that the device could eventually be explanted. That does happen, but only rarely. In a large registry study, myocardial recovery occurred in only about 1% of patients on mechanical circulatory support. Attempts to enhance the process by add-on stem cell therapy have thus far been ineffective.

“For the moment, recovery is still a hope, not a reality,” the cardiologist said.

He reported serving as a consultant to more than a dozen pharmaceutical or medical device companies and receiving research grants from Alnylam, AstraZeneca, Bayer Healthcare, MyoKardia, and Novartis.

bjancin@mdedge.com
 

SNOWMASS, COLO. – The tragic opioid epidemic has “one small bright spot”: an expanding pool of eligible donor hearts for transplantation, Akshay S. Desai, MD, said at the annual Cardiovascular Conference at Snowmass sponsored by the American College of Cardiology.

Bruce Jancin/MDedge News

For decades, the annual volume of heart transplantations performed in the U.S. was static because of the huge mismatch between donor organ supply and demand. But heart transplant volume has increased steadily in the last few years – a result of the opioid epidemic.

Data from the U.S. Organ Procurement and Transplantation Network show that the proportion of donor hearts obtained from individuals who died from drug intoxication climbed from a mere 1.5% in 1999 to 17.6% in 2017, the most recent year for which data are available. Meanwhile, the size of the heart transplant waiting list, which rose year after year in 2009-2015, has since declined (N Engl J Med. 2019 Feb 7;380[6]:597-9).

“What’s amazing is that, even though these patients might have historically been considered high risk in general, the organs recovered from these patients – and particularly the hearts – don’t seem to be any worse in terms of allograft survival than the organs recovered from patients who died from other causes, which are the traditional sources, like blunt head trauma, gunshot wounds, or stroke, that lead to brain death. In general, these organs are useful and do quite well,” according to Dr. Desai, medical director of the cardiomyopathy and heart failure program at Brigham and Women’s Hospital, Boston.

He highlighted several other recent developments in the field of cardiac transplantation that promise to further expand the donor heart pool, including acceptance of hepatitis C–infected donors and organ donation after circulatory rather than brain death. Dr. Desai also drew attention to the unintended perverse consequences of a recent redesign of the U.S. donor heart allocation system and discussed the impressive improvement in clinical outcomes with mechanical circulatory support. He noted that, while relatively few cardiologists practice in the highly specialized centers where heart transplants take place, virtually all cardiologists are affected by advances in heart transplantation since hundreds of thousands of the estimated 7 million Americans with heart failure have advanced disease.

Heart transplantation, he emphasized, is becoming increasingly complex. Recipients are on average older, sicker, and have more comorbidities than in times past. As a result, there is greater need for dual organ transplants: heart/lung, heart/liver, or heart/kidney. Plus, more patients come to transplantation after prior cardiac surgery for implantation of a ventricular assist device, so sensitization to blood products is a growing issue. And, of course, the pool of transplant candidates has expanded.

“We’re now forced to take patients previously considered to have contraindications to transplant; for example, diabetes was a contraindication to transplant in the early years, but now it’s the rule in 35%-40% of our patients who present with advanced heart failure,” the cardiologist noted.
 

Transplants from HCV-infected donors to uninfected recipients

Hearts and lungs from donors with hepatitis C viremia were traditionally deemed unsuitable for transplant. That’s all changed in the current era of highly effective direct-acting antiviral agents for the treatment of HCV infection.

In the DONATE HCV trial, Dr. Desai’s colleagues at Brigham and Women’s Hospital showed that giving HCV-uninfected recipients of hearts or lungs from HCV-viremic donors a shortened 4-week course of treatment with sofosbuvir-velpatasvir (Epclusa) beginning within a few hours after transplantation uniformly blocked viral replication. Six months after transplantation, none of the study participants had a detectable HCV viral load, and all had excellent graft function (N Engl J Med. 2019 Apr 25;380[17]:1606-17).

“This is effective prevention of HCV infection by aggressive upfront therapy,” Dr. Desai explained. “We can now take organs from HCV-viremic patients and use them in solid organ transplantation. This has led to a skyrocketing increase in donors with HCV infection, and those donations have helped us clear the waiting list.”
 

Donation after circulatory death

Australian transplant physicians have pioneered the use of donor hearts obtained after circulatory death in individuals with devastating neurologic injury who didn’t quite meet the criteria for brain death, which is the traditional prerequisite. In the new scenario, withdrawal of life-supporting therapy is followed by circulatory death, then the donor heart is procured and preserved via extracorporeal perfusion until transplantation.

The Australians report excellent outcomes, with rates of overall survival and rejection episodes similar to outcomes from brain-dead donors (J Am Coll Cardiol. 2019 Apr 2;73[12]:1447-59). The first U.S. heart transplant involving donation after circulatory death took place at Duke University in Durham, North Carolina. A multicenter U.S. clinical trial of this practice is underway.

If the results are positive and the practice of donation after circulatory death becomes widely implemented, the U.S. heart donor pool could increase by 30%.
 

Recent overhaul of donor heart allocation system may have backfired

The U.S. donor heart allocation system was redesigned in the fall of 2018 in an effort to reduce waiting times. One of the biggest changes involved breaking down the category with the highest urgency status into three new subcategories based upon sickness. Now, the highest-urgency category is for patients in cardiogenic shock who are supported by extracorporeal membrane oxygenation (ECMO) or other temporary mechanical circulatory support devices.

But an analysis of United Network for Organ Sharing (UNOS) data suggests this change has unintended adverse consequences for clinical outcomes.

Indeed, the investigators reported that the use of ECMO support is fourfold greater in the new system, the use of durable left ventricular assist devices (LVADs) as a bridge to transplant is down, and outcomes are worse. The 180-day rate of freedom from death or retransplantation was 77.9%, down significantly from 93.4% in the former system. In a multivariate analysis, patients transplanted in the new system had an adjusted 2.1-fold increased risk of death or retransplantation (J Heart Lung Transplant. 2020 Jan;39[1]:1-4).

“When you create a new listing system, you create new incentives, and people start to manage patients differently,” Dr. Desai observed. “Increasingly now, the path direct to transplant is through temporary mechanical circulatory support rather than durable mechanical circulatory support. Is that a good idea? We don’t know, but if you look at the best data, those on ECMO or percutaneous VADs have the worst outcomes. So the question of whether we should take the sickest of sick patients directly to transplant as a standard strategy has come under scrutiny.”
 

Improved durable LVAD technology brings impressive clinical outcomes

Results of the landmark MOMENTUM 3 randomized trial showed that 2-year clinical outcomes with the magnetically levitated centrifugal-flow HeartMate 3 LVAD now rival those of percutaneous mitral valve repair using the MitraClip device. Two-year all-cause mortality in the LVAD recipients was 22% versus 29.1% with the MitraClip in the COAPT trial and 34.9% in the MITRA-FR trial. The HeartMate 3 reduces the hemocompatibility issues that plagued earlier-generation durable LVADs, with resultant lower rates of pump thrombosis, stroke, and GI bleeding. Indeed, the outcomes in MOMENTUM 3 were so good – and so similar – with the HeartMate 3, regardless of whether the intended treatment goal was as a bridge to transplant or as lifelong destination therapy, that the investigators have recently proposed doing away with those distinctions.

“It is possible that use of arbitrary categorizations based on current or future transplant eligibility should be clinically abandoned in favor of a single preimplant strategy: to extend the survival and improve the quality of life of patients with medically refractory heart failure,” according to the investigators (JAMA Cardiol. 2020 Jan 15. doi: 10.1001/jamacardio.2019.5323).

The next step forward in LVAD technology is already on the horizon: a fully implantable device that eliminates the transcutaneous drive-line for the power supply, which is prone to infection and diminishes overall quality of life. This investigational device utilizes wireless coplanar energy transfer, with a coil ring placed around the lung and fixed to the chest wall. The implanted battery provides more than 6 hours of power without a recharge (J Heart Lung Transplant. 2019 Apr;38[4]:339-43).

“The first LVAD patient has gone swimming in Kazakhstan,” according to Dr. Desai.

Myocardial recovery in LVAD recipients remains elusive

The initial hope for LVADs was that they would not only be able to serve as a bridge to transplantation or as lifetime therapy, but that the prolonged unloading of the ventricle would enable potent medical therapy to rescue myocardial function so that the device could eventually be explanted. That does happen, but only rarely. In a large registry study, myocardial recovery occurred in only about 1% of patients on mechanical circulatory support. Attempts to enhance the process by add-on stem cell therapy have thus far been ineffective.

“For the moment, recovery is still a hope, not a reality,” the cardiologist said.

He reported serving as a consultant to more than a dozen pharmaceutical or medical device companies and receiving research grants from Alnylam, AstraZeneca, Bayer Healthcare, MyoKardia, and Novartis.

bjancin@mdedge.com
 

SNOWMASS, COLO. – The tragic opioid epidemic has “one small bright spot”: an expanding pool of eligible donor hearts for transplantation, Akshay S. Desai, MD, said at the annual Cardiovascular Conference at Snowmass sponsored by the American College of Cardiology.

Bruce Jancin/MDedge News

For decades, the annual volume of heart transplantations performed in the U.S. was static because of the huge mismatch between donor organ supply and demand. But heart transplant volume has increased steadily in the last few years – a result of the opioid epidemic.

Data from the U.S. Organ Procurement and Transplantation Network show that the proportion of donor hearts obtained from individuals who died from drug intoxication climbed from a mere 1.5% in 1999 to 17.6% in 2017, the most recent year for which data are available. Meanwhile, the size of the heart transplant waiting list, which rose year after year in 2009-2015, has since declined (N Engl J Med. 2019 Feb 7;380[6]:597-9).

“What’s amazing is that, even though these patients might have historically been considered high risk in general, the organs recovered from these patients – and particularly the hearts – don’t seem to be any worse in terms of allograft survival than the organs recovered from patients who died from other causes, which are the traditional sources, like blunt head trauma, gunshot wounds, or stroke, that lead to brain death. In general, these organs are useful and do quite well,” according to Dr. Desai, medical director of the cardiomyopathy and heart failure program at Brigham and Women’s Hospital, Boston.

He highlighted several other recent developments in the field of cardiac transplantation that promise to further expand the donor heart pool, including acceptance of hepatitis C–infected donors and organ donation after circulatory rather than brain death. Dr. Desai also drew attention to the unintended perverse consequences of a recent redesign of the U.S. donor heart allocation system and discussed the impressive improvement in clinical outcomes with mechanical circulatory support. He noted that, while relatively few cardiologists practice in the highly specialized centers where heart transplants take place, virtually all cardiologists are affected by advances in heart transplantation since hundreds of thousands of the estimated 7 million Americans with heart failure have advanced disease.

Heart transplantation, he emphasized, is becoming increasingly complex. Recipients are on average older, sicker, and have more comorbidities than in times past. As a result, there is greater need for dual organ transplants: heart/lung, heart/liver, or heart/kidney. Plus, more patients come to transplantation after prior cardiac surgery for implantation of a ventricular assist device, so sensitization to blood products is a growing issue. And, of course, the pool of transplant candidates has expanded.

“We’re now forced to take patients previously considered to have contraindications to transplant; for example, diabetes was a contraindication to transplant in the early years, but now it’s the rule in 35%-40% of our patients who present with advanced heart failure,” the cardiologist noted.
 

Transplants from HCV-infected donors to uninfected recipients

Hearts and lungs from donors with hepatitis C viremia were traditionally deemed unsuitable for transplant. That’s all changed in the current era of highly effective direct-acting antiviral agents for the treatment of HCV infection.

In the DONATE HCV trial, Dr. Desai’s colleagues at Brigham and Women’s Hospital showed that giving HCV-uninfected recipients of hearts or lungs from HCV-viremic donors a shortened 4-week course of treatment with sofosbuvir-velpatasvir (Epclusa) beginning within a few hours after transplantation uniformly blocked viral replication. Six months after transplantation, none of the study participants had a detectable HCV viral load, and all had excellent graft function (N Engl J Med. 2019 Apr 25;380[17]:1606-17).

“This is effective prevention of HCV infection by aggressive upfront therapy,” Dr. Desai explained. “We can now take organs from HCV-viremic patients and use them in solid organ transplantation. This has led to a skyrocketing increase in donors with HCV infection, and those donations have helped us clear the waiting list.”
 

Donation after circulatory death

Australian transplant physicians have pioneered the use of donor hearts obtained after circulatory death in individuals with devastating neurologic injury who didn’t quite meet the criteria for brain death, which is the traditional prerequisite. In the new scenario, withdrawal of life-supporting therapy is followed by circulatory death, then the donor heart is procured and preserved via extracorporeal perfusion until transplantation.

The Australians report excellent outcomes, with rates of overall survival and rejection episodes similar to outcomes from brain-dead donors (J Am Coll Cardiol. 2019 Apr 2;73[12]:1447-59). The first U.S. heart transplant involving donation after circulatory death took place at Duke University in Durham, North Carolina. A multicenter U.S. clinical trial of this practice is underway.

If the results are positive and the practice of donation after circulatory death becomes widely implemented, the U.S. heart donor pool could increase by 30%.
 

Recent overhaul of donor heart allocation system may have backfired

The U.S. donor heart allocation system was redesigned in the fall of 2018 in an effort to reduce waiting times. One of the biggest changes involved breaking down the category with the highest urgency status into three new subcategories based upon sickness. Now, the highest-urgency category is for patients in cardiogenic shock who are supported by extracorporeal membrane oxygenation (ECMO) or other temporary mechanical circulatory support devices.

But an analysis of United Network for Organ Sharing (UNOS) data suggests this change has unintended adverse consequences for clinical outcomes.

Indeed, the investigators reported that the use of ECMO support is fourfold greater in the new system, the use of durable left ventricular assist devices (LVADs) as a bridge to transplant is down, and outcomes are worse. The 180-day rate of freedom from death or retransplantation was 77.9%, down significantly from 93.4% in the former system. In a multivariate analysis, patients transplanted in the new system had an adjusted 2.1-fold increased risk of death or retransplantation (J Heart Lung Transplant. 2020 Jan;39[1]:1-4).

“When you create a new listing system, you create new incentives, and people start to manage patients differently,” Dr. Desai observed. “Increasingly now, the path direct to transplant is through temporary mechanical circulatory support rather than durable mechanical circulatory support. Is that a good idea? We don’t know, but if you look at the best data, those on ECMO or percutaneous VADs have the worst outcomes. So the question of whether we should take the sickest of sick patients directly to transplant as a standard strategy has come under scrutiny.”
 

Improved durable LVAD technology brings impressive clinical outcomes

Results of the landmark MOMENTUM 3 randomized trial showed that 2-year clinical outcomes with the magnetically levitated centrifugal-flow HeartMate 3 LVAD now rival those of percutaneous mitral valve repair using the MitraClip device. Two-year all-cause mortality in the LVAD recipients was 22% versus 29.1% with the MitraClip in the COAPT trial and 34.9% in the MITRA-FR trial. The HeartMate 3 reduces the hemocompatibility issues that plagued earlier-generation durable LVADs, with resultant lower rates of pump thrombosis, stroke, and GI bleeding. Indeed, the outcomes in MOMENTUM 3 were so good – and so similar – with the HeartMate 3, regardless of whether the intended treatment goal was as a bridge to transplant or as lifelong destination therapy, that the investigators have recently proposed doing away with those distinctions.

“It is possible that use of arbitrary categorizations based on current or future transplant eligibility should be clinically abandoned in favor of a single preimplant strategy: to extend the survival and improve the quality of life of patients with medically refractory heart failure,” according to the investigators (JAMA Cardiol. 2020 Jan 15. doi: 10.1001/jamacardio.2019.5323).

The next step forward in LVAD technology is already on the horizon: a fully implantable device that eliminates the transcutaneous drive-line for the power supply, which is prone to infection and diminishes overall quality of life. This investigational device utilizes wireless coplanar energy transfer, with a coil ring placed around the lung and fixed to the chest wall. The implanted battery provides more than 6 hours of power without a recharge (J Heart Lung Transplant. 2019 Apr;38[4]:339-43).

“The first LVAD patient has gone swimming in Kazakhstan,” according to Dr. Desai.

Myocardial recovery in LVAD recipients remains elusive

The initial hope for LVADs was that they would not only be able to serve as a bridge to transplantation or as lifetime therapy, but that the prolonged unloading of the ventricle would enable potent medical therapy to rescue myocardial function so that the device could eventually be explanted. That does happen, but only rarely. In a large registry study, myocardial recovery occurred in only about 1% of patients on mechanical circulatory support. Attempts to enhance the process by add-on stem cell therapy have thus far been ineffective.

“For the moment, recovery is still a hope, not a reality,” the cardiologist said.

He reported serving as a consultant to more than a dozen pharmaceutical or medical device companies and receiving research grants from Alnylam, AstraZeneca, Bayer Healthcare, MyoKardia, and Novartis.

bjancin@mdedge.com
 

Five cases of the new infectious coronavirus, 2019-nCoV, have been confirmed in the United States, Nancy Messonnier, MD, director of the National Center for Immunization and Respiratory Diseases at the Centers for Disease Control and Prevention, said during a Jan. 27 press briefing.

A total of 110 individuals are under investigation in 26 states, she said. While five cases have been confirmed positive for the virus, 32 cases were confirmed negative. There have been no new cases overnight.

Last week, CDC scientists developed a real-time polymerase chain reaction (PCR) test that can diagnose the virus in respiratory and serum samples from clinical specimens. On Jan. 24, the protocol for this test was publicly posted. “This is essentially a blueprint to make the test,” Dr. Messonnier explained. “Currently, we are refining the use of the test so that it can provide optimal guidance to states and labs on how to use it. We are working on a plan so that priority states get these test kits as soon as possible. In the coming weeks, we will share these tests with domestic and international partners so they can test for this virus themselves.”

The CDC uploaded the entire genome of the virus from the first two cases in the United States to GenBank. It was similar to the one that China had previously posted. “Right now, based on CDC’s analysis of the available data, it doesn’t look like the virus has mutated,” she said. “And we are growing the virus in cell culture, which is necessary for further studies, including the additional genetic characterization.”

As of today, 16 international locations, including the United States, have identified cases of the virus. CDC officials are continuing to screen passengers from Wuhan, China, at five designated airports. “This serves two purposes: first to detect the illness and rapidly respond to [affected] people entering the country,” Dr. Messonnier said. “The second purpose is to educate travelers about the symptoms of this new virus, and what to do if they develop symptoms. I expect that in the coming days, our travel recommendations will change. Risk depends on exposure. Right now, we have an handful of new patients with this new virus here in the U.S. However, at this time in the U.S., this virus is not spreading in the community. For that reason, we believe that the immediate health risk of the new virus to the general American public is low.”

The CDC is asking its clinical lab partners to send virus samples to the CDC to ensure that results are analyzed as accurately as possible.

dbrunk@mdedge.com

Five cases of the new infectious coronavirus, 2019-nCoV, have been confirmed in the United States, Nancy Messonnier, MD, director of the National Center for Immunization and Respiratory Diseases at the Centers for Disease Control and Prevention, said during a Jan. 27 press briefing.

A total of 110 individuals are under investigation in 26 states, she said. While five cases have been confirmed positive for the virus, 32 cases were confirmed negative. There have been no new cases overnight.

Last week, CDC scientists developed a real-time polymerase chain reaction (PCR) test that can diagnose the virus in respiratory and serum samples from clinical specimens. On Jan. 24, the protocol for this test was publicly posted. “This is essentially a blueprint to make the test,” Dr. Messonnier explained. “Currently, we are refining the use of the test so that it can provide optimal guidance to states and labs on how to use it. We are working on a plan so that priority states get these test kits as soon as possible. In the coming weeks, we will share these tests with domestic and international partners so they can test for this virus themselves.”

The CDC uploaded the entire genome of the virus from the first two cases in the United States to GenBank. It was similar to the one that China had previously posted. “Right now, based on CDC’s analysis of the available data, it doesn’t look like the virus has mutated,” she said. “And we are growing the virus in cell culture, which is necessary for further studies, including the additional genetic characterization.”

As of today, 16 international locations, including the United States, have identified cases of the virus. CDC officials are continuing to screen passengers from Wuhan, China, at five designated airports. “This serves two purposes: first to detect the illness and rapidly respond to [affected] people entering the country,” Dr. Messonnier said. “The second purpose is to educate travelers about the symptoms of this new virus, and what to do if they develop symptoms. I expect that in the coming days, our travel recommendations will change. Risk depends on exposure. Right now, we have an handful of new patients with this new virus here in the U.S. However, at this time in the U.S., this virus is not spreading in the community. For that reason, we believe that the immediate health risk of the new virus to the general American public is low.”

The CDC is asking its clinical lab partners to send virus samples to the CDC to ensure that results are analyzed as accurately as possible.

dbrunk@mdedge.com

Five cases of the new infectious coronavirus, 2019-nCoV, have been confirmed in the United States, Nancy Messonnier, MD, director of the National Center for Immunization and Respiratory Diseases at the Centers for Disease Control and Prevention, said during a Jan. 27 press briefing.

A total of 110 individuals are under investigation in 26 states, she said. While five cases have been confirmed positive for the virus, 32 cases were confirmed negative. There have been no new cases overnight.

Last week, CDC scientists developed a real-time polymerase chain reaction (PCR) test that can diagnose the virus in respiratory and serum samples from clinical specimens. On Jan. 24, the protocol for this test was publicly posted. “This is essentially a blueprint to make the test,” Dr. Messonnier explained. “Currently, we are refining the use of the test so that it can provide optimal guidance to states and labs on how to use it. We are working on a plan so that priority states get these test kits as soon as possible. In the coming weeks, we will share these tests with domestic and international partners so they can test for this virus themselves.”

The CDC uploaded the entire genome of the virus from the first two cases in the United States to GenBank. It was similar to the one that China had previously posted. “Right now, based on CDC’s analysis of the available data, it doesn’t look like the virus has mutated,” she said. “And we are growing the virus in cell culture, which is necessary for further studies, including the additional genetic characterization.”

As of today, 16 international locations, including the United States, have identified cases of the virus. CDC officials are continuing to screen passengers from Wuhan, China, at five designated airports. “This serves two purposes: first to detect the illness and rapidly respond to [affected] people entering the country,” Dr. Messonnier said. “The second purpose is to educate travelers about the symptoms of this new virus, and what to do if they develop symptoms. I expect that in the coming days, our travel recommendations will change. Risk depends on exposure. Right now, we have an handful of new patients with this new virus here in the U.S. However, at this time in the U.S., this virus is not spreading in the community. For that reason, we believe that the immediate health risk of the new virus to the general American public is low.”

The CDC is asking its clinical lab partners to send virus samples to the CDC to ensure that results are analyzed as accurately as possible.

dbrunk@mdedge.com

NATIONAL HARBOR, MD. – A pilot program of daily arrhythmia self-vigilance has allowed selected patients with no atrial fibrillation following a catheter ablation procedure to safely come off a regimen of daily oral anticoagulation despite having residual risk factors for ischemic stroke.

Mitchel L. Zoler/MDedge News

This program, which started several years ago at the University of Pennsylvania in Philadelphia, has now managed 190 patients and followed them for a median of just over 3 years, and during 576 patient-years of follow-up, just a single patient had an ischemic cerebrovascular event that occurred with no atrial fibrillation (AFib) recurrence and appeared to be caused by an atherosclerotic embolism, Francis E. Marchlinski, MD, said at the annual International AF Symposium.

Although this strategy has not yet been tested in a prospective, randomized trial, this anecdotal, single-center experience suggests that the approach is “safe and effective” for selected patients who are eager to come off of their anticoagulation regimen when they remain arrhythmia free following catheter ablation of their AFib, said Dr. Marchlinski, professor of medicine and director of electrophysiology at the University of Pennsylvania. He and his associates developed this strategy as a way to more safely allow these patients to stop taking a daily oral anticoagulant because he found that many patients were stopping on their own, with no safety strategy in place.

“Patients tell me they don’t want to be on an oral anticoagulant because a parent had a hemorrhagic stroke, and they say they’re willing to accept the risk” of having an ischemic stroke by coming off anticoagulation. “This is a way for them to do it safely,” Dr. Marchlinski said in an interview. He stressed that he only allows his patients to go this route if they understand the risk and accept their shared responsibility for vigilant, twice-daily pulse monitoring to detect resumption of an irregular heart beat.

Since 2011, Dr. Marchlinski’s program ablated 1,216 patients with AFib who then remained arrhythmia free during 3 weeks of continuous ECG monitoring following their procedure. Among these patients, 443 had a CHA2DS2-VAScscore of either 0 (men) or 1 (women) that indicated no ongoing need for oral anticoagulation according to current guidelines. Of the remaining 773 patients with a CHA2DS2-VASc score of at least 1 in men and 2 in women, the clinicians determined 583 to be ineligible for the program because of their unwillingness to accept the risk, unwillingness to comply with daily pulse checks, a history of asymptomatic AFib, a CHA2DS2-VASc score greater than 4, or a resting pulse above 90 beats per minute, leaving 190 patients eligible to participate. Among these patients, 105 (55%) had a CHA2DS2-VASc score of 2-4, which should prompt anticoagulation according to current guidelines.Participating patients committed to check their resting pulse by palpation at least twice daily and to contacting the program immediately if their resting rate spiked by more than 20 beats per minutes or in another way seemed irregular. Patients were also instructed to restart their oral anticoagulation immediately if they experienced AFib symptoms that persisted for more than 5 minutes. Many patients in the program also use a wearable device (usually a watch) to monitor their resting pulse and to generate a 30-second ECG recording that they can send as an electronic file to the University of Pennsylvania staff. “We embrace wearables,” Dr. Marchlinski said. Those without a wearable can undergo transtelephonic EEG monitoring to document a suspected arrhythmia recurrence, and all patients undergo annual monitoring by continuous ECG for at least 2 weeks.During follow-up, in addition to the 1 patient free from recurrent AFib who had an atherosclerotic embolism, 34 patients resumed anticoagulant treatment because of AFib recurrence; 12 withdrew from the program because of noncompliance or preference, or because an exclusion appeared; 29 resumed oral anticoagulation transiently but then discontinued the drug a second time when their AFib recurrence resolved; and 114 patients (60% of the starting cohort of 190) remained completely off anticoagulation during a median of 37 months. These data updated a published report from Dr. Marchlinski and his associates on their first 99 patients followed for a median of 30 months (J Cardiovasc Electrophysiol. 2019 May;30[5]:631-8).

This experience underscored the need for ongoing rhythm monitoring even in the absence of AFib symptoms, as six patients developed asymptomatic AFib detected by monitoring, including one patient whose recurrence occurred 30 months after the ablation procedure.

Dr. Marchlinski stressed the stringent selection process he applies to limit this approach to patients who are willing to faithfully monitor their pulse and symptoms daily, and who accept the risk that this approach may pose and their responsibility to stay in contact with the clinical team. The program calls patients at the 6-month mark between annual monitoring to remind them of their need for daily attention.

“Being off anticoagulants is very important to these patients,” he explained, and he highlighted the added workload this strategy places on his staff. “I think this has legs” for adoption by other cardiac arrhythmia programs, “but it depends on the time the staff is willing to spend” monitoring and following these patients, some of whom regularly send in ECG traces from their wearable devices for assessment. “It takes a village” to make this program work, he said.

Dr. Marchlinski has been a consultant to or has received honoraria from Abbott EP/St. Jude, Biosense Webster, Biotronik, Boston Scientific, and Medtronic.

mzoler@mdedge.com

NATIONAL HARBOR, MD. – A pilot program of daily arrhythmia self-vigilance has allowed selected patients with no atrial fibrillation following a catheter ablation procedure to safely come off a regimen of daily oral anticoagulation despite having residual risk factors for ischemic stroke.

Mitchel L. Zoler/MDedge News

This program, which started several years ago at the University of Pennsylvania in Philadelphia, has now managed 190 patients and followed them for a median of just over 3 years, and during 576 patient-years of follow-up, just a single patient had an ischemic cerebrovascular event that occurred with no atrial fibrillation (AFib) recurrence and appeared to be caused by an atherosclerotic embolism, Francis E. Marchlinski, MD, said at the annual International AF Symposium.

Although this strategy has not yet been tested in a prospective, randomized trial, this anecdotal, single-center experience suggests that the approach is “safe and effective” for selected patients who are eager to come off of their anticoagulation regimen when they remain arrhythmia free following catheter ablation of their AFib, said Dr. Marchlinski, professor of medicine and director of electrophysiology at the University of Pennsylvania. He and his associates developed this strategy as a way to more safely allow these patients to stop taking a daily oral anticoagulant because he found that many patients were stopping on their own, with no safety strategy in place.

“Patients tell me they don’t want to be on an oral anticoagulant because a parent had a hemorrhagic stroke, and they say they’re willing to accept the risk” of having an ischemic stroke by coming off anticoagulation. “This is a way for them to do it safely,” Dr. Marchlinski said in an interview. He stressed that he only allows his patients to go this route if they understand the risk and accept their shared responsibility for vigilant, twice-daily pulse monitoring to detect resumption of an irregular heart beat.

Since 2011, Dr. Marchlinski’s program ablated 1,216 patients with AFib who then remained arrhythmia free during 3 weeks of continuous ECG monitoring following their procedure. Among these patients, 443 had a CHA2DS2-VAScscore of either 0 (men) or 1 (women) that indicated no ongoing need for oral anticoagulation according to current guidelines. Of the remaining 773 patients with a CHA2DS2-VASc score of at least 1 in men and 2 in women, the clinicians determined 583 to be ineligible for the program because of their unwillingness to accept the risk, unwillingness to comply with daily pulse checks, a history of asymptomatic AFib, a CHA2DS2-VASc score greater than 4, or a resting pulse above 90 beats per minute, leaving 190 patients eligible to participate. Among these patients, 105 (55%) had a CHA2DS2-VASc score of 2-4, which should prompt anticoagulation according to current guidelines.Participating patients committed to check their resting pulse by palpation at least twice daily and to contacting the program immediately if their resting rate spiked by more than 20 beats per minutes or in another way seemed irregular. Patients were also instructed to restart their oral anticoagulation immediately if they experienced AFib symptoms that persisted for more than 5 minutes. Many patients in the program also use a wearable device (usually a watch) to monitor their resting pulse and to generate a 30-second ECG recording that they can send as an electronic file to the University of Pennsylvania staff. “We embrace wearables,” Dr. Marchlinski said. Those without a wearable can undergo transtelephonic EEG monitoring to document a suspected arrhythmia recurrence, and all patients undergo annual monitoring by continuous ECG for at least 2 weeks.During follow-up, in addition to the 1 patient free from recurrent AFib who had an atherosclerotic embolism, 34 patients resumed anticoagulant treatment because of AFib recurrence; 12 withdrew from the program because of noncompliance or preference, or because an exclusion appeared; 29 resumed oral anticoagulation transiently but then discontinued the drug a second time when their AFib recurrence resolved; and 114 patients (60% of the starting cohort of 190) remained completely off anticoagulation during a median of 37 months. These data updated a published report from Dr. Marchlinski and his associates on their first 99 patients followed for a median of 30 months (J Cardiovasc Electrophysiol. 2019 May;30[5]:631-8).

This experience underscored the need for ongoing rhythm monitoring even in the absence of AFib symptoms, as six patients developed asymptomatic AFib detected by monitoring, including one patient whose recurrence occurred 30 months after the ablation procedure.

Dr. Marchlinski stressed the stringent selection process he applies to limit this approach to patients who are willing to faithfully monitor their pulse and symptoms daily, and who accept the risk that this approach may pose and their responsibility to stay in contact with the clinical team. The program calls patients at the 6-month mark between annual monitoring to remind them of their need for daily attention.

“Being off anticoagulants is very important to these patients,” he explained, and he highlighted the added workload this strategy places on his staff. “I think this has legs” for adoption by other cardiac arrhythmia programs, “but it depends on the time the staff is willing to spend” monitoring and following these patients, some of whom regularly send in ECG traces from their wearable devices for assessment. “It takes a village” to make this program work, he said.

Dr. Marchlinski has been a consultant to or has received honoraria from Abbott EP/St. Jude, Biosense Webster, Biotronik, Boston Scientific, and Medtronic.

mzoler@mdedge.com

NATIONAL HARBOR, MD. – A pilot program of daily arrhythmia self-vigilance has allowed selected patients with no atrial fibrillation following a catheter ablation procedure to safely come off a regimen of daily oral anticoagulation despite having residual risk factors for ischemic stroke.

Mitchel L. Zoler/MDedge News

This program, which started several years ago at the University of Pennsylvania in Philadelphia, has now managed 190 patients and followed them for a median of just over 3 years, and during 576 patient-years of follow-up, just a single patient had an ischemic cerebrovascular event that occurred with no atrial fibrillation (AFib) recurrence and appeared to be caused by an atherosclerotic embolism, Francis E. Marchlinski, MD, said at the annual International AF Symposium.

Although this strategy has not yet been tested in a prospective, randomized trial, this anecdotal, single-center experience suggests that the approach is “safe and effective” for selected patients who are eager to come off of their anticoagulation regimen when they remain arrhythmia free following catheter ablation of their AFib, said Dr. Marchlinski, professor of medicine and director of electrophysiology at the University of Pennsylvania. He and his associates developed this strategy as a way to more safely allow these patients to stop taking a daily oral anticoagulant because he found that many patients were stopping on their own, with no safety strategy in place.

“Patients tell me they don’t want to be on an oral anticoagulant because a parent had a hemorrhagic stroke, and they say they’re willing to accept the risk” of having an ischemic stroke by coming off anticoagulation. “This is a way for them to do it safely,” Dr. Marchlinski said in an interview. He stressed that he only allows his patients to go this route if they understand the risk and accept their shared responsibility for vigilant, twice-daily pulse monitoring to detect resumption of an irregular heart beat.

Since 2011, Dr. Marchlinski’s program ablated 1,216 patients with AFib who then remained arrhythmia free during 3 weeks of continuous ECG monitoring following their procedure. Among these patients, 443 had a CHA2DS2-VAScscore of either 0 (men) or 1 (women) that indicated no ongoing need for oral anticoagulation according to current guidelines. Of the remaining 773 patients with a CHA2DS2-VASc score of at least 1 in men and 2 in women, the clinicians determined 583 to be ineligible for the program because of their unwillingness to accept the risk, unwillingness to comply with daily pulse checks, a history of asymptomatic AFib, a CHA2DS2-VASc score greater than 4, or a resting pulse above 90 beats per minute, leaving 190 patients eligible to participate. Among these patients, 105 (55%) had a CHA2DS2-VASc score of 2-4, which should prompt anticoagulation according to current guidelines.Participating patients committed to check their resting pulse by palpation at least twice daily and to contacting the program immediately if their resting rate spiked by more than 20 beats per minutes or in another way seemed irregular. Patients were also instructed to restart their oral anticoagulation immediately if they experienced AFib symptoms that persisted for more than 5 minutes. Many patients in the program also use a wearable device (usually a watch) to monitor their resting pulse and to generate a 30-second ECG recording that they can send as an electronic file to the University of Pennsylvania staff. “We embrace wearables,” Dr. Marchlinski said. Those without a wearable can undergo transtelephonic EEG monitoring to document a suspected arrhythmia recurrence, and all patients undergo annual monitoring by continuous ECG for at least 2 weeks.During follow-up, in addition to the 1 patient free from recurrent AFib who had an atherosclerotic embolism, 34 patients resumed anticoagulant treatment because of AFib recurrence; 12 withdrew from the program because of noncompliance or preference, or because an exclusion appeared; 29 resumed oral anticoagulation transiently but then discontinued the drug a second time when their AFib recurrence resolved; and 114 patients (60% of the starting cohort of 190) remained completely off anticoagulation during a median of 37 months. These data updated a published report from Dr. Marchlinski and his associates on their first 99 patients followed for a median of 30 months (J Cardiovasc Electrophysiol. 2019 May;30[5]:631-8).

This experience underscored the need for ongoing rhythm monitoring even in the absence of AFib symptoms, as six patients developed asymptomatic AFib detected by monitoring, including one patient whose recurrence occurred 30 months after the ablation procedure.

Dr. Marchlinski stressed the stringent selection process he applies to limit this approach to patients who are willing to faithfully monitor their pulse and symptoms daily, and who accept the risk that this approach may pose and their responsibility to stay in contact with the clinical team. The program calls patients at the 6-month mark between annual monitoring to remind them of their need for daily attention.

“Being off anticoagulants is very important to these patients,” he explained, and he highlighted the added workload this strategy places on his staff. “I think this has legs” for adoption by other cardiac arrhythmia programs, “but it depends on the time the staff is willing to spend” monitoring and following these patients, some of whom regularly send in ECG traces from their wearable devices for assessment. “It takes a village” to make this program work, he said.

Dr. Marchlinski has been a consultant to or has received honoraria from Abbott EP/St. Jude, Biosense Webster, Biotronik, Boston Scientific, and Medtronic.

mzoler@mdedge.com

The Food and Drug Administration has approved fidaxomicin (Dificid) for the treatment of Clostridioides difficile–associated diarrhea in children aged 6 months and older.

Approval was based on results from SUNSHINE, a phase 3, multicenter, investigator-blind, randomized, parallel-group study in 142 pediatric patients aged between 6 months and 18 years with confirmed C. difficile infection who received either fidaxomicin or vancomycin for 10 days. Clinical response 2 days after the conclusion of treatment was similar in both groups (77.6% for fidaxomicin vs. 70.5% for vancomycin), and fidaxomicin had a superior sustained response 30 days after the conclusion of treatment (68.4% vs. 50.0%).

The safety of fidaxomicin was assessed in a pair of clinical trials involving 136 patients; the most common adverse events were pyrexia, abdominal pain, vomiting, diarrhea, constipation, increased aminotransferases, and rash. Four patients discontinued fidaxomicin treatment because of adverse events, and four patients died during the trials, though all deaths were in patients aged younger than 2 years and seemed to be related to other comorbidities.

“C. difficile is an important cause of health care– and community-associated diarrheal illness in children, and sustained cure is difficult to achieve in some patients. The fidaxomicin pediatric trial was the first randomized, controlled trial of C. difficile infection treatment in children,” Larry K. Kociolek, MD, associate medical director of infection prevention and control at Ann & Robert H. Lurie Children’s Hospital of Chicago, said in the press release from Merck, manufacturer of fidaxomicin.

*This story was updated on 1/27/2020. 

lfranki@mdedge.com

The Food and Drug Administration has approved fidaxomicin (Dificid) for the treatment of Clostridioides difficile–associated diarrhea in children aged 6 months and older.

Approval was based on results from SUNSHINE, a phase 3, multicenter, investigator-blind, randomized, parallel-group study in 142 pediatric patients aged between 6 months and 18 years with confirmed C. difficile infection who received either fidaxomicin or vancomycin for 10 days. Clinical response 2 days after the conclusion of treatment was similar in both groups (77.6% for fidaxomicin vs. 70.5% for vancomycin), and fidaxomicin had a superior sustained response 30 days after the conclusion of treatment (68.4% vs. 50.0%).

The safety of fidaxomicin was assessed in a pair of clinical trials involving 136 patients; the most common adverse events were pyrexia, abdominal pain, vomiting, diarrhea, constipation, increased aminotransferases, and rash. Four patients discontinued fidaxomicin treatment because of adverse events, and four patients died during the trials, though all deaths were in patients aged younger than 2 years and seemed to be related to other comorbidities.

“C. difficile is an important cause of health care– and community-associated diarrheal illness in children, and sustained cure is difficult to achieve in some patients. The fidaxomicin pediatric trial was the first randomized, controlled trial of C. difficile infection treatment in children,” Larry K. Kociolek, MD, associate medical director of infection prevention and control at Ann & Robert H. Lurie Children’s Hospital of Chicago, said in the press release from Merck, manufacturer of fidaxomicin.

*This story was updated on 1/27/2020. 

lfranki@mdedge.com

The Food and Drug Administration has approved fidaxomicin (Dificid) for the treatment of Clostridioides difficile–associated diarrhea in children aged 6 months and older.

Approval was based on results from SUNSHINE, a phase 3, multicenter, investigator-blind, randomized, parallel-group study in 142 pediatric patients aged between 6 months and 18 years with confirmed C. difficile infection who received either fidaxomicin or vancomycin for 10 days. Clinical response 2 days after the conclusion of treatment was similar in both groups (77.6% for fidaxomicin vs. 70.5% for vancomycin), and fidaxomicin had a superior sustained response 30 days after the conclusion of treatment (68.4% vs. 50.0%).

The safety of fidaxomicin was assessed in a pair of clinical trials involving 136 patients; the most common adverse events were pyrexia, abdominal pain, vomiting, diarrhea, constipation, increased aminotransferases, and rash. Four patients discontinued fidaxomicin treatment because of adverse events, and four patients died during the trials, though all deaths were in patients aged younger than 2 years and seemed to be related to other comorbidities.

“C. difficile is an important cause of health care– and community-associated diarrheal illness in children, and sustained cure is difficult to achieve in some patients. The fidaxomicin pediatric trial was the first randomized, controlled trial of C. difficile infection treatment in children,” Larry K. Kociolek, MD, associate medical director of infection prevention and control at Ann & Robert H. Lurie Children’s Hospital of Chicago, said in the press release from Merck, manufacturer of fidaxomicin.

*This story was updated on 1/27/2020. 

lfranki@mdedge.com