ANSWER

This ECG demonstrates sinus rhythm with second-degree type II block, right-axis deviation, and ST-T wave changes in the inferior leads, suggestive of ischemia. A P-P interval of 100 beats/min meets the criteria for sinus rhythm.

Second-degree type II block is evidenced by two P waves for each QRS complex with a consistent PR interval. In this example, the PR interval is significantly prolonged at 415 ms. Normally, this would be a rather impressive first-degree AV block. However, a second P wave (integrated in the ST interval, best seen in the rhythm strip at the bottom) makes this second-degree type II block.

Right-axis deviation is defined by an R-wave axis of 90° to 180°; thus this patient qualifies at 131°. Finally, ST-T wave depressions are evident in leads II, III, and aVF, suggestive but not indicative of inferior ischemia. The patient was found to have a recurrent perivalvular abscess of his artificial aortic valve, as well as right lower lobe pneumonia.

ANSWER

This ECG demonstrates sinus rhythm with second-degree type II block, right-axis deviation, and ST-T wave changes in the inferior leads, suggestive of ischemia. A P-P interval of 100 beats/min meets the criteria for sinus rhythm.

Second-degree type II block is evidenced by two P waves for each QRS complex with a consistent PR interval. In this example, the PR interval is significantly prolonged at 415 ms. Normally, this would be a rather impressive first-degree AV block. However, a second P wave (integrated in the ST interval, best seen in the rhythm strip at the bottom) makes this second-degree type II block.

Right-axis deviation is defined by an R-wave axis of 90° to 180°; thus this patient qualifies at 131°. Finally, ST-T wave depressions are evident in leads II, III, and aVF, suggestive but not indicative of inferior ischemia. The patient was found to have a recurrent perivalvular abscess of his artificial aortic valve, as well as right lower lobe pneumonia.

ANSWER

This ECG demonstrates sinus rhythm with second-degree type II block, right-axis deviation, and ST-T wave changes in the inferior leads, suggestive of ischemia. A P-P interval of 100 beats/min meets the criteria for sinus rhythm.

Second-degree type II block is evidenced by two P waves for each QRS complex with a consistent PR interval. In this example, the PR interval is significantly prolonged at 415 ms. Normally, this would be a rather impressive first-degree AV block. However, a second P wave (integrated in the ST interval, best seen in the rhythm strip at the bottom) makes this second-degree type II block.

Right-axis deviation is defined by an R-wave axis of 90° to 180°; thus this patient qualifies at 131°. Finally, ST-T wave depressions are evident in leads II, III, and aVF, suggestive but not indicative of inferior ischemia. The patient was found to have a recurrent perivalvular abscess of his artificial aortic valve, as well as right lower lobe pneumonia.

In the largest analysis ever of cardiovascular risk associated with the initiation of nonsteroidal anti-inflammatory drugs (NSAIDs), diclofenac emerged as a clear culprit in higher risk for adverse cardiovascular outcomes.

Those beginning diclofenac had a 50% increased 30-day risk for a composite outcome of major adverse cardiovascular events (MACE) compared with individuals who didn’t initiate an NSAID or acetaminophen (95% confidence interval for incidence rate ratio, 1.4-1.7).

The risk was still significantly elevated when the study’s first author, Morten Schmidt, MD, and his colleagues compared diclofenac initiation with beginning other NSAIDs or acetaminophen. Compared with those starting ibuprofen or acetaminophen, the MACE risk was elevated 20% in diclofenac initiators (95% CI, 1.1-1.3 for both). Initiating diclofenac was associated with 30% greater risk for MACE compared with initiating naproxen (95% CI, 1.1-1.5).

“Diclofenac is the most frequently used NSAID in low-, middle-, and high-income countries and is available over the counter in most countries; therefore, its cardiovascular risk profile is of major clinical and public health importance,” wrote Dr. Schmidt and his coauthors.

In all, the study included 1,370,832 individuals who initiated diclofenac, 3,878,454 ibuprofen initiators, 291,490 naproxen initiators, and 764,781 acetaminophen initiators. Those starting diclofenac were compared with those starting other medications, and with 1,303,209 individuals who sought health care but did not start one of the medications.

The researchers used the longstanding and complete Danish health registry system to their advantage in designing a cohort trial that was modeled to resemble a clinical trial. For each month, beginning in 1996 and continuing through 2016, Dr. Schmidt and his collaborators assembled propensity-matched cohorts of individuals to compare each study group. The study design achieved many of the aims of a clinical trial while working within the ethical constraints of studying medications now known to elevate cardiovascular risk.

For each 30-day period, the investigators were then able to track and compare cardiovascular outcomes for each group. Each month, data for a new cohort were collected, beginning a new “clinical trial.” Individuals could be included in more than one month’s worth of “trial” data as long as they continued to meet inclusion criteria.

The completeness of Danish health data meant that the researchers were confident in data about comorbidities, other prescription medications, and outcomes.

Dr. Schmidt and his colleagues performed subgroup and sensitivity analyses to look at the extent to which preexisting risks for cardiovascular disease mediated MACE risk on diclofenac initiation. They found that diclofenac initiators in the highest risk group had up to 40 excess cardiovascular events per year – about half of them fatal – that were attributable to starting the medication. Although that group had the highest absolute risk, however, “the relative risks were highest in those with the lowest baseline risk,” wrote the investigators.

In addition to looking at rates of MACE, secondary outcomes for the study included evaluating the association between medication use or non-use and each individual component of the composite primary outcome. These included first-time occurrences of the nonfatal endpoints of atrial fibrillation or flutter, ischemic (but not hemorrhagic) stroke, heart failure, and myocardial infarction. Cardiac death was death from any cardiac cause.

“Supporting use of a combined endpoint, event rates consistently increased for all individual outcomes” for diclofenac initiators compared with those who did not start an NSAID, wrote Dr. Schmidt and his colleagues.

Individuals were excluded if they had known cardiovascular, kidney, liver, or ulcer disease, and if they had malignancy or serious mental health diagnoses such as dementia or schizophrenia. Participants, aged a mean 48-56 years, had to be at least 18 years of age and could not have filled a prescription for an NSAID within the previous 12 months. Men made up 36.6%-46.3% of the cohorts.

Dr. Schmidt, of Aarhus (Denmark) University, and his collaborators said that in comparison with other NSAIDs, the short half-life of diclofenac means that a supratherapeutic plasma concentration of diclofenac soon after initiation achieves not just cyclooxygenase-2 (COX-2), but also COX-1 inhibition. However, after those high levels fall, patients taking diclofenac spend a substantial period of time with unopposed COX-2 inhibition, a state that is known to be prothrombotic, and also associated with blood pressure elevation, atherogenesis, and worsening of heart failure.

Diclofenac and ibuprofen had similar gastrointestinal bleeding risks, and both medications were associated with a higher risk of bleeding than were ibuprofen, acetaminophen, or no medication.

“Comparing diclofenac initiation with no NSAID initiation, the consistency between our results and those of previous meta-analyses of both trial and observational data provides strong evidence to guide clinical decision making,” said Dr. Schmidt and his coauthors.

“Considering its cardiovascular and gastrointestinal risks, however, there is little justification to initiate diclofenac treatment before other traditional NSAIDs,” noted the investigators. “It is time to acknowledge the potential health risk of diclofenac and to reduce its use.”

The study was funded by the Department of Clinical Epidemiology Research Foundation, University of Aarhus, and by the Program for Clinical Research Infrastructure, funded by the Lundbeck Foundation, Novo Nordisk Foundation, and the Danish Research Council. The authors reported that they had no relevant conflicts of interest.
 

[email protected]

SOURCE: Schmidt M et al. BMJ 2018;362:k3426

In the largest analysis ever of cardiovascular risk associated with the initiation of nonsteroidal anti-inflammatory drugs (NSAIDs), diclofenac emerged as a clear culprit in higher risk for adverse cardiovascular outcomes.

Those beginning diclofenac had a 50% increased 30-day risk for a composite outcome of major adverse cardiovascular events (MACE) compared with individuals who didn’t initiate an NSAID or acetaminophen (95% confidence interval for incidence rate ratio, 1.4-1.7).

The risk was still significantly elevated when the study’s first author, Morten Schmidt, MD, and his colleagues compared diclofenac initiation with beginning other NSAIDs or acetaminophen. Compared with those starting ibuprofen or acetaminophen, the MACE risk was elevated 20% in diclofenac initiators (95% CI, 1.1-1.3 for both). Initiating diclofenac was associated with 30% greater risk for MACE compared with initiating naproxen (95% CI, 1.1-1.5).

“Diclofenac is the most frequently used NSAID in low-, middle-, and high-income countries and is available over the counter in most countries; therefore, its cardiovascular risk profile is of major clinical and public health importance,” wrote Dr. Schmidt and his coauthors.

In all, the study included 1,370,832 individuals who initiated diclofenac, 3,878,454 ibuprofen initiators, 291,490 naproxen initiators, and 764,781 acetaminophen initiators. Those starting diclofenac were compared with those starting other medications, and with 1,303,209 individuals who sought health care but did not start one of the medications.

The researchers used the longstanding and complete Danish health registry system to their advantage in designing a cohort trial that was modeled to resemble a clinical trial. For each month, beginning in 1996 and continuing through 2016, Dr. Schmidt and his collaborators assembled propensity-matched cohorts of individuals to compare each study group. The study design achieved many of the aims of a clinical trial while working within the ethical constraints of studying medications now known to elevate cardiovascular risk.

For each 30-day period, the investigators were then able to track and compare cardiovascular outcomes for each group. Each month, data for a new cohort were collected, beginning a new “clinical trial.” Individuals could be included in more than one month’s worth of “trial” data as long as they continued to meet inclusion criteria.

The completeness of Danish health data meant that the researchers were confident in data about comorbidities, other prescription medications, and outcomes.

Dr. Schmidt and his colleagues performed subgroup and sensitivity analyses to look at the extent to which preexisting risks for cardiovascular disease mediated MACE risk on diclofenac initiation. They found that diclofenac initiators in the highest risk group had up to 40 excess cardiovascular events per year – about half of them fatal – that were attributable to starting the medication. Although that group had the highest absolute risk, however, “the relative risks were highest in those with the lowest baseline risk,” wrote the investigators.

In addition to looking at rates of MACE, secondary outcomes for the study included evaluating the association between medication use or non-use and each individual component of the composite primary outcome. These included first-time occurrences of the nonfatal endpoints of atrial fibrillation or flutter, ischemic (but not hemorrhagic) stroke, heart failure, and myocardial infarction. Cardiac death was death from any cardiac cause.

“Supporting use of a combined endpoint, event rates consistently increased for all individual outcomes” for diclofenac initiators compared with those who did not start an NSAID, wrote Dr. Schmidt and his colleagues.

Individuals were excluded if they had known cardiovascular, kidney, liver, or ulcer disease, and if they had malignancy or serious mental health diagnoses such as dementia or schizophrenia. Participants, aged a mean 48-56 years, had to be at least 18 years of age and could not have filled a prescription for an NSAID within the previous 12 months. Men made up 36.6%-46.3% of the cohorts.

Dr. Schmidt, of Aarhus (Denmark) University, and his collaborators said that in comparison with other NSAIDs, the short half-life of diclofenac means that a supratherapeutic plasma concentration of diclofenac soon after initiation achieves not just cyclooxygenase-2 (COX-2), but also COX-1 inhibition. However, after those high levels fall, patients taking diclofenac spend a substantial period of time with unopposed COX-2 inhibition, a state that is known to be prothrombotic, and also associated with blood pressure elevation, atherogenesis, and worsening of heart failure.

Diclofenac and ibuprofen had similar gastrointestinal bleeding risks, and both medications were associated with a higher risk of bleeding than were ibuprofen, acetaminophen, or no medication.

“Comparing diclofenac initiation with no NSAID initiation, the consistency between our results and those of previous meta-analyses of both trial and observational data provides strong evidence to guide clinical decision making,” said Dr. Schmidt and his coauthors.

“Considering its cardiovascular and gastrointestinal risks, however, there is little justification to initiate diclofenac treatment before other traditional NSAIDs,” noted the investigators. “It is time to acknowledge the potential health risk of diclofenac and to reduce its use.”

The study was funded by the Department of Clinical Epidemiology Research Foundation, University of Aarhus, and by the Program for Clinical Research Infrastructure, funded by the Lundbeck Foundation, Novo Nordisk Foundation, and the Danish Research Council. The authors reported that they had no relevant conflicts of interest.
 

[email protected]

SOURCE: Schmidt M et al. BMJ 2018;362:k3426

In the largest analysis ever of cardiovascular risk associated with the initiation of nonsteroidal anti-inflammatory drugs (NSAIDs), diclofenac emerged as a clear culprit in higher risk for adverse cardiovascular outcomes.

Those beginning diclofenac had a 50% increased 30-day risk for a composite outcome of major adverse cardiovascular events (MACE) compared with individuals who didn’t initiate an NSAID or acetaminophen (95% confidence interval for incidence rate ratio, 1.4-1.7).

The risk was still significantly elevated when the study’s first author, Morten Schmidt, MD, and his colleagues compared diclofenac initiation with beginning other NSAIDs or acetaminophen. Compared with those starting ibuprofen or acetaminophen, the MACE risk was elevated 20% in diclofenac initiators (95% CI, 1.1-1.3 for both). Initiating diclofenac was associated with 30% greater risk for MACE compared with initiating naproxen (95% CI, 1.1-1.5).

“Diclofenac is the most frequently used NSAID in low-, middle-, and high-income countries and is available over the counter in most countries; therefore, its cardiovascular risk profile is of major clinical and public health importance,” wrote Dr. Schmidt and his coauthors.

In all, the study included 1,370,832 individuals who initiated diclofenac, 3,878,454 ibuprofen initiators, 291,490 naproxen initiators, and 764,781 acetaminophen initiators. Those starting diclofenac were compared with those starting other medications, and with 1,303,209 individuals who sought health care but did not start one of the medications.

The researchers used the longstanding and complete Danish health registry system to their advantage in designing a cohort trial that was modeled to resemble a clinical trial. For each month, beginning in 1996 and continuing through 2016, Dr. Schmidt and his collaborators assembled propensity-matched cohorts of individuals to compare each study group. The study design achieved many of the aims of a clinical trial while working within the ethical constraints of studying medications now known to elevate cardiovascular risk.

For each 30-day period, the investigators were then able to track and compare cardiovascular outcomes for each group. Each month, data for a new cohort were collected, beginning a new “clinical trial.” Individuals could be included in more than one month’s worth of “trial” data as long as they continued to meet inclusion criteria.

The completeness of Danish health data meant that the researchers were confident in data about comorbidities, other prescription medications, and outcomes.

Dr. Schmidt and his colleagues performed subgroup and sensitivity analyses to look at the extent to which preexisting risks for cardiovascular disease mediated MACE risk on diclofenac initiation. They found that diclofenac initiators in the highest risk group had up to 40 excess cardiovascular events per year – about half of them fatal – that were attributable to starting the medication. Although that group had the highest absolute risk, however, “the relative risks were highest in those with the lowest baseline risk,” wrote the investigators.

In addition to looking at rates of MACE, secondary outcomes for the study included evaluating the association between medication use or non-use and each individual component of the composite primary outcome. These included first-time occurrences of the nonfatal endpoints of atrial fibrillation or flutter, ischemic (but not hemorrhagic) stroke, heart failure, and myocardial infarction. Cardiac death was death from any cardiac cause.

“Supporting use of a combined endpoint, event rates consistently increased for all individual outcomes” for diclofenac initiators compared with those who did not start an NSAID, wrote Dr. Schmidt and his colleagues.

Individuals were excluded if they had known cardiovascular, kidney, liver, or ulcer disease, and if they had malignancy or serious mental health diagnoses such as dementia or schizophrenia. Participants, aged a mean 48-56 years, had to be at least 18 years of age and could not have filled a prescription for an NSAID within the previous 12 months. Men made up 36.6%-46.3% of the cohorts.

Dr. Schmidt, of Aarhus (Denmark) University, and his collaborators said that in comparison with other NSAIDs, the short half-life of diclofenac means that a supratherapeutic plasma concentration of diclofenac soon after initiation achieves not just cyclooxygenase-2 (COX-2), but also COX-1 inhibition. However, after those high levels fall, patients taking diclofenac spend a substantial period of time with unopposed COX-2 inhibition, a state that is known to be prothrombotic, and also associated with blood pressure elevation, atherogenesis, and worsening of heart failure.

Diclofenac and ibuprofen had similar gastrointestinal bleeding risks, and both medications were associated with a higher risk of bleeding than were ibuprofen, acetaminophen, or no medication.

“Comparing diclofenac initiation with no NSAID initiation, the consistency between our results and those of previous meta-analyses of both trial and observational data provides strong evidence to guide clinical decision making,” said Dr. Schmidt and his coauthors.

“Considering its cardiovascular and gastrointestinal risks, however, there is little justification to initiate diclofenac treatment before other traditional NSAIDs,” noted the investigators. “It is time to acknowledge the potential health risk of diclofenac and to reduce its use.”

The study was funded by the Department of Clinical Epidemiology Research Foundation, University of Aarhus, and by the Program for Clinical Research Infrastructure, funded by the Lundbeck Foundation, Novo Nordisk Foundation, and the Danish Research Council. The authors reported that they had no relevant conflicts of interest.
 

[email protected]

SOURCE: Schmidt M et al. BMJ 2018;362:k3426

As cannabis continues to be legalized across many states, the reality that some users are addicts is receiving greater notice. The prospect of easier and legal availability has sparked (pun intended) public health concerns. “Cannabis is potentially a real public health problem,” says Mark A.R. Kleiman, PhD, a professor of public policy at New York University.

Scott Harms/iStockphoto

“It wasn’t obvious to me 25 years ago, when 9% of self-reported cannabis users over the last month reported daily or near-daily use. I always was prepared to say, ‘No, it’s not a very abusable drug. Nine percent of anybody will do something stupid.’ But that number is now [something like] 40%” (The Atlantic).

It’s no secret that Steve Jobs was a driven person who could be aloof and cruel to business associates. Now, with the publication of a memoir by his daughter, Lisa Brennan-Jobs, his cold path through life is revealed to have extended to the four walls of the family home. In the memoir “Small Fry,” Ms. Brennan-Jobs paints a picture of a father who, after accepting court-ordered child support, was emotionally hurtful.

Ms. Brennan-Jobs claims that he told her that she “smelled like a toilet,” when she visited Mr. Jobs on his deathbed. The remark was based on fact, as she later acknowledged (The New York Times).

A romantic relationship that stands the test of time is not a static union. There is give and take, communication, good and not-so good times, and adjustment to the changes that life brings.

But when one partner is physically present but mentally absent, the load can be crushing. Spouses of someone with Alzheimer’s disease or another progressive disorder that robs a person of their mental acuity and personality know this hell.

Less well-known, but just as devastating, is the state of “minimal consciousness” – where someone with a brain injury is left immobile and incapable of independent self-care, but who still may perceive the world and, in their own way, respond to the world and those in it.

A recent article explores the relationship of car crash victim Ian Jordon and his wife, Hilary. This past April marked the couple’s 45th wedding anniversary. For more than 30 of those years, Ian has been bedridden and unresponsive after a September 1987 car accident at the end of a shift as a police officer. He was 35 years old (Globe and Mail).

The U.S. Department of Education has announced that it is exploring the possibility that legislation governing academic enrichment grants might permit the use of the funds to purchase guns for schools.

The move has been greeted with hostility from Democrats and many educators, who decry the diversion of funds that are typically used for after school programs mental health support to a program that, they say, is fueled by the desire to appease the National Rifle Association (PBS News Hour).

As cannabis continues to be legalized across many states, the reality that some users are addicts is receiving greater notice. The prospect of easier and legal availability has sparked (pun intended) public health concerns. “Cannabis is potentially a real public health problem,” says Mark A.R. Kleiman, PhD, a professor of public policy at New York University.

Scott Harms/iStockphoto

“It wasn’t obvious to me 25 years ago, when 9% of self-reported cannabis users over the last month reported daily or near-daily use. I always was prepared to say, ‘No, it’s not a very abusable drug. Nine percent of anybody will do something stupid.’ But that number is now [something like] 40%” (The Atlantic).

It’s no secret that Steve Jobs was a driven person who could be aloof and cruel to business associates. Now, with the publication of a memoir by his daughter, Lisa Brennan-Jobs, his cold path through life is revealed to have extended to the four walls of the family home. In the memoir “Small Fry,” Ms. Brennan-Jobs paints a picture of a father who, after accepting court-ordered child support, was emotionally hurtful.

Ms. Brennan-Jobs claims that he told her that she “smelled like a toilet,” when she visited Mr. Jobs on his deathbed. The remark was based on fact, as she later acknowledged (The New York Times).

A romantic relationship that stands the test of time is not a static union. There is give and take, communication, good and not-so good times, and adjustment to the changes that life brings.

But when one partner is physically present but mentally absent, the load can be crushing. Spouses of someone with Alzheimer’s disease or another progressive disorder that robs a person of their mental acuity and personality know this hell.

Less well-known, but just as devastating, is the state of “minimal consciousness” – where someone with a brain injury is left immobile and incapable of independent self-care, but who still may perceive the world and, in their own way, respond to the world and those in it.

A recent article explores the relationship of car crash victim Ian Jordon and his wife, Hilary. This past April marked the couple’s 45th wedding anniversary. For more than 30 of those years, Ian has been bedridden and unresponsive after a September 1987 car accident at the end of a shift as a police officer. He was 35 years old (Globe and Mail).

The U.S. Department of Education has announced that it is exploring the possibility that legislation governing academic enrichment grants might permit the use of the funds to purchase guns for schools.

The move has been greeted with hostility from Democrats and many educators, who decry the diversion of funds that are typically used for after school programs mental health support to a program that, they say, is fueled by the desire to appease the National Rifle Association (PBS News Hour).

As cannabis continues to be legalized across many states, the reality that some users are addicts is receiving greater notice. The prospect of easier and legal availability has sparked (pun intended) public health concerns. “Cannabis is potentially a real public health problem,” says Mark A.R. Kleiman, PhD, a professor of public policy at New York University.

Scott Harms/iStockphoto

“It wasn’t obvious to me 25 years ago, when 9% of self-reported cannabis users over the last month reported daily or near-daily use. I always was prepared to say, ‘No, it’s not a very abusable drug. Nine percent of anybody will do something stupid.’ But that number is now [something like] 40%” (The Atlantic).

It’s no secret that Steve Jobs was a driven person who could be aloof and cruel to business associates. Now, with the publication of a memoir by his daughter, Lisa Brennan-Jobs, his cold path through life is revealed to have extended to the four walls of the family home. In the memoir “Small Fry,” Ms. Brennan-Jobs paints a picture of a father who, after accepting court-ordered child support, was emotionally hurtful.

Ms. Brennan-Jobs claims that he told her that she “smelled like a toilet,” when she visited Mr. Jobs on his deathbed. The remark was based on fact, as she later acknowledged (The New York Times).

A romantic relationship that stands the test of time is not a static union. There is give and take, communication, good and not-so good times, and adjustment to the changes that life brings.

But when one partner is physically present but mentally absent, the load can be crushing. Spouses of someone with Alzheimer’s disease or another progressive disorder that robs a person of their mental acuity and personality know this hell.

Less well-known, but just as devastating, is the state of “minimal consciousness” – where someone with a brain injury is left immobile and incapable of independent self-care, but who still may perceive the world and, in their own way, respond to the world and those in it.

A recent article explores the relationship of car crash victim Ian Jordon and his wife, Hilary. This past April marked the couple’s 45th wedding anniversary. For more than 30 of those years, Ian has been bedridden and unresponsive after a September 1987 car accident at the end of a shift as a police officer. He was 35 years old (Globe and Mail).

The U.S. Department of Education has announced that it is exploring the possibility that legislation governing academic enrichment grants might permit the use of the funds to purchase guns for schools.

The move has been greeted with hostility from Democrats and many educators, who decry the diversion of funds that are typically used for after school programs mental health support to a program that, they say, is fueled by the desire to appease the National Rifle Association (PBS News Hour).

ATLANTA – The persistence and transmission of Candida auris in health care settings appears to be dependent on environmental survival, underscoring the need for careful investigation of the environment – and, in particular, multiuse patient equipment.

That’s the key lesson from one of the largest outbreaks of the emerging, multidrug-resistant pathogen to date, David Eyre, DPhil, said at the International Conference on Emerging Infectious Diseases.

“Our experience at Oxford began with a Public Health England alert, which closely followed a similar alert from the [Centers for Disease Control and Prevention] in the summer of 2016,” Dr. Eyre of the University of Oxford (England) said during an update on the epidemiology of the outbreak and the successful, multipronged effort to control it.

[email protected]

SOURCE: Eyre D et al. ICEID 2018 Oral Abstract Presentation.

ATLANTA – The persistence and transmission of Candida auris in health care settings appears to be dependent on environmental survival, underscoring the need for careful investigation of the environment – and, in particular, multiuse patient equipment.

That’s the key lesson from one of the largest outbreaks of the emerging, multidrug-resistant pathogen to date, David Eyre, DPhil, said at the International Conference on Emerging Infectious Diseases.

“Our experience at Oxford began with a Public Health England alert, which closely followed a similar alert from the [Centers for Disease Control and Prevention] in the summer of 2016,” Dr. Eyre of the University of Oxford (England) said during an update on the epidemiology of the outbreak and the successful, multipronged effort to control it.

[email protected]

SOURCE: Eyre D et al. ICEID 2018 Oral Abstract Presentation.

ATLANTA – The persistence and transmission of Candida auris in health care settings appears to be dependent on environmental survival, underscoring the need for careful investigation of the environment – and, in particular, multiuse patient equipment.

That’s the key lesson from one of the largest outbreaks of the emerging, multidrug-resistant pathogen to date, David Eyre, DPhil, said at the International Conference on Emerging Infectious Diseases.

“Our experience at Oxford began with a Public Health England alert, which closely followed a similar alert from the [Centers for Disease Control and Prevention] in the summer of 2016,” Dr. Eyre of the University of Oxford (England) said during an update on the epidemiology of the outbreak and the successful, multipronged effort to control it.

[email protected]

SOURCE: Eyre D et al. ICEID 2018 Oral Abstract Presentation.

ORLANDO – It’s inevitable that hospitalists will soon be caring for patients who come in on insulin pumps, continuous glucose monitors, and even closed loop systems, if they haven’t done so already.

A third or more of patients with type 1 diabetes mellitus and growing numbers of patients with insulin-dependent type 2 diabetes mellitus patients are using pumps and sensor technology. The American Diabetes Association advocates allowing patients who are physically and mentally able to continue to use their pumps when hospitalized, and there’s general consensus that continuous glucose monitors (CGM) can be used in the hospital.

All in all, it’s a good thing, according to Guillermo E. Umpierrez, MD, professor of endocrinology at Emory University and chief of endocrinology at Grady Memorial Hospital, both in Atlanta.

In a talk at the annual scientific sessions of the American Diabetes Association, Dr. Umpierrez reviewed a number of studies showing that glycemic control with the new technology is no worse in the hospital – and sometimes even better – than with traditional point-of-care glucose testing and insulin administration. There is a lack of randomized, controlled trials to prove the point definitively, but what evidence does exist is promising.

“This technology is rapidly advancing, and I am very optimistic that we are going to see more and more of these devices in the hospital. If patients can manage themselves, allow them to use CGM, allow them to use their pumps,” he said.

As for closed loop systems – automated glucose sensing and insulin administration – emerging evidence suggests they “allow you to have very good glucose control and less glycemic variability,” both inside and outside of the ICU, he said. “I am very hopeful before I retire that there will be management of a significant number of patients with closed loop systems.”

To keep up, training for hospital providers on the new technology is now “mandatory at all levels,” Dr. Umpierrez said, and if they haven’t done so already, hospitals need to put policies and procedures in place for when, and when not, to allow patients to use their diabetes equipment, and how to integrate it into care.

Among many things to consider, patients must be well enough to use their pumps and monitors, be able to demonstrate their functions, and also want to participate in their own care.

Contraindications to inpatient pump use include impaired consciousness, critical illness, and hyperglycemic crises because insulin requirements change too rapidly and dramatically for pumps. Lack of trained providers and supplies is another hurdle. Pumps also need to come off for MRIs.

CGM, meanwhile, has been shown to improve glycemic control, detecting both hyperglycemia and hypoglycemia more readily than point-of-care testing. It’s good at picking up trends in glucose levels, and Dr. Umpierrez anticipates a time when readings will be transmitted to nurses’ stations automatically to track blood glucose trends. “I think that’s the future,” he said.

But, as with insulin pumps, there are caveats. Among them, it’s unclear how well CGM works during hypoxia, hypothermia, and hypotension. Thrombus formation and infections have been reported with intravascular monitors, and a number of agents can throw off some CGM devices, including acetaminophen, heparin, and dopamine.

Dr. Umpierrez disclosed relationships with AstraZeneca, Merck, Novo Nordisk, Sanofi, and other companies.

[email protected]

ORLANDO – It’s inevitable that hospitalists will soon be caring for patients who come in on insulin pumps, continuous glucose monitors, and even closed loop systems, if they haven’t done so already.

A third or more of patients with type 1 diabetes mellitus and growing numbers of patients with insulin-dependent type 2 diabetes mellitus patients are using pumps and sensor technology. The American Diabetes Association advocates allowing patients who are physically and mentally able to continue to use their pumps when hospitalized, and there’s general consensus that continuous glucose monitors (CGM) can be used in the hospital.

All in all, it’s a good thing, according to Guillermo E. Umpierrez, MD, professor of endocrinology at Emory University and chief of endocrinology at Grady Memorial Hospital, both in Atlanta.

In a talk at the annual scientific sessions of the American Diabetes Association, Dr. Umpierrez reviewed a number of studies showing that glycemic control with the new technology is no worse in the hospital – and sometimes even better – than with traditional point-of-care glucose testing and insulin administration. There is a lack of randomized, controlled trials to prove the point definitively, but what evidence does exist is promising.

“This technology is rapidly advancing, and I am very optimistic that we are going to see more and more of these devices in the hospital. If patients can manage themselves, allow them to use CGM, allow them to use their pumps,” he said.

As for closed loop systems – automated glucose sensing and insulin administration – emerging evidence suggests they “allow you to have very good glucose control and less glycemic variability,” both inside and outside of the ICU, he said. “I am very hopeful before I retire that there will be management of a significant number of patients with closed loop systems.”

To keep up, training for hospital providers on the new technology is now “mandatory at all levels,” Dr. Umpierrez said, and if they haven’t done so already, hospitals need to put policies and procedures in place for when, and when not, to allow patients to use their diabetes equipment, and how to integrate it into care.

Among many things to consider, patients must be well enough to use their pumps and monitors, be able to demonstrate their functions, and also want to participate in their own care.

Contraindications to inpatient pump use include impaired consciousness, critical illness, and hyperglycemic crises because insulin requirements change too rapidly and dramatically for pumps. Lack of trained providers and supplies is another hurdle. Pumps also need to come off for MRIs.

CGM, meanwhile, has been shown to improve glycemic control, detecting both hyperglycemia and hypoglycemia more readily than point-of-care testing. It’s good at picking up trends in glucose levels, and Dr. Umpierrez anticipates a time when readings will be transmitted to nurses’ stations automatically to track blood glucose trends. “I think that’s the future,” he said.

But, as with insulin pumps, there are caveats. Among them, it’s unclear how well CGM works during hypoxia, hypothermia, and hypotension. Thrombus formation and infections have been reported with intravascular monitors, and a number of agents can throw off some CGM devices, including acetaminophen, heparin, and dopamine.

Dr. Umpierrez disclosed relationships with AstraZeneca, Merck, Novo Nordisk, Sanofi, and other companies.

[email protected]

ORLANDO – It’s inevitable that hospitalists will soon be caring for patients who come in on insulin pumps, continuous glucose monitors, and even closed loop systems, if they haven’t done so already.

A third or more of patients with type 1 diabetes mellitus and growing numbers of patients with insulin-dependent type 2 diabetes mellitus patients are using pumps and sensor technology. The American Diabetes Association advocates allowing patients who are physically and mentally able to continue to use their pumps when hospitalized, and there’s general consensus that continuous glucose monitors (CGM) can be used in the hospital.

All in all, it’s a good thing, according to Guillermo E. Umpierrez, MD, professor of endocrinology at Emory University and chief of endocrinology at Grady Memorial Hospital, both in Atlanta.

In a talk at the annual scientific sessions of the American Diabetes Association, Dr. Umpierrez reviewed a number of studies showing that glycemic control with the new technology is no worse in the hospital – and sometimes even better – than with traditional point-of-care glucose testing and insulin administration. There is a lack of randomized, controlled trials to prove the point definitively, but what evidence does exist is promising.

“This technology is rapidly advancing, and I am very optimistic that we are going to see more and more of these devices in the hospital. If patients can manage themselves, allow them to use CGM, allow them to use their pumps,” he said.

As for closed loop systems – automated glucose sensing and insulin administration – emerging evidence suggests they “allow you to have very good glucose control and less glycemic variability,” both inside and outside of the ICU, he said. “I am very hopeful before I retire that there will be management of a significant number of patients with closed loop systems.”

To keep up, training for hospital providers on the new technology is now “mandatory at all levels,” Dr. Umpierrez said, and if they haven’t done so already, hospitals need to put policies and procedures in place for when, and when not, to allow patients to use their diabetes equipment, and how to integrate it into care.

Among many things to consider, patients must be well enough to use their pumps and monitors, be able to demonstrate their functions, and also want to participate in their own care.

Contraindications to inpatient pump use include impaired consciousness, critical illness, and hyperglycemic crises because insulin requirements change too rapidly and dramatically for pumps. Lack of trained providers and supplies is another hurdle. Pumps also need to come off for MRIs.

CGM, meanwhile, has been shown to improve glycemic control, detecting both hyperglycemia and hypoglycemia more readily than point-of-care testing. It’s good at picking up trends in glucose levels, and Dr. Umpierrez anticipates a time when readings will be transmitted to nurses’ stations automatically to track blood glucose trends. “I think that’s the future,” he said.

But, as with insulin pumps, there are caveats. Among them, it’s unclear how well CGM works during hypoxia, hypothermia, and hypotension. Thrombus formation and infections have been reported with intravascular monitors, and a number of agents can throw off some CGM devices, including acetaminophen, heparin, and dopamine.

Dr. Umpierrez disclosed relationships with AstraZeneca, Merck, Novo Nordisk, Sanofi, and other companies.

[email protected]

ABSTRACT

Meniscus allograft transplantation (MAT) has yielded excellent long-term functional outcomes when performed in properly indicated patients. When evaluating a patient for potential MAT, it is imperative to evaluate past medical history and past surgical procedures. The ideal MAT candidate is a chronologically and physiologically young patient (<50 years) with symptomatic meniscal deficiency. Existing pathology in the knee needs to be carefully considered and issues such as malalignment, cartilage defects, and/or ligamentous instability may require a staged or concomitant procedure. Once an ideal candidate is identified, graft selection and preparation are critical steps to ensure a proper fit and long-term viability of the meniscus. When selecting the graft, accurate measurements must be taken, and this is most commonly performed using plain radiographs for this. Graft fixation can be accomplished by placing vertical mattress sutures and tying those down with the knee in full extension.

Continue to: Meniscus tears are common in the young, athletic patient population...

Meniscus tears are common in the young, athletic patient population. In the United States alone, approximately 700,000 meniscectomies are performed annually.¹ Given discouraging long-term clinical results following subtotal meniscectomy in young patients, meniscal repair is preferred whenever possible.² Despite short-term symptom relief if subtotal meniscectomy is required, some patients often go on to develop localized pain in the affected compartment, effusions, and eventual development of osteoarthritis. In such patients with symptomatic meniscal deficiency, meniscal allograft transplantation (MAT) has yielded excellent long-term functional outcomes.^3-5 Three recently published systematic reviews describe the outcomes of MAT in thousands of patients, noting positive outcomes in regard to pain and function for the majority of patients.^6-8 Specifically, in a review conducted by Elattar and colleagues⁷ consisting of 44 studies comprising 1136 grafts in 1068 patients, the authors reported clinical improvement in Lysholm Knee Scoring Scale score (44 to 77), visual analog scale (48 mm to 17 mm), and International Knee Documentation Committee (84% normal/nearly normal, 89% satisfaction), among other outcomes measures. Additionally, the complication (21.3%) and failure rates (10.6%) were considered acceptable by all authors. The purpose of this article is to review indications, operative preparation, critical aspects of surgical technique, and additional concomitant procedures commonly performed alongside MAT.

1. PATIENT SELECTION

When used with the proper indications, MAT offers improved functional outcomes and reduced pain for patients with symptomatic meniscal deficiency. When evaluating a patient for potential MAT, it is imperative to evaluate past medical history and past surgical procedures. The ideal MAT candidate is a chronologically and physiologically young patient (<50 years) with symptomatic meniscal deficiency who does not have (1) evidence of diffuse osteoarthritis (Outerbridge grade <2), including the absence of significant bony flattening or osteophytes in the involved compartment; (2) inflammatory arthritis; (3) active or previous joint infection; (4) mechanical axis malalignment; or (5) morbid obesity (Table). Long-leg weight-bearing anterior-posterior alignment radiographs are important in the work-up of any patient being considered for MAT, and consideration for concomitant or staged realignment high tibial osteotomy (HTO) or distal femoral osteotomy (DFO) should be given for patients in excessive varus or valgus, respectively. Although the decision to perform a realignment osteotomy is made on a patient-specific basis, if the weight-bearing line passes medial to the medial tibial spine or lateral to the lateral tibial spine, HTO or DFO, respectively, should be considered. Importantly, MAT is not typically recommended in the asymptomatic patient.⁹ Although some recent evidence suggests MAT may have chondroprotective effects on articular cartilage following meniscectomy, there is insufficient long-term outcome data to support the use of MAT as a prophylactic measure, especially given the fact that graft deterioration inevitably occurs at 7 to 10 years, with patients having to consider avoiding meniscus-dependent activities following transplant to protect their graft from traumatic failure.^10,11

Table. Summary of Indications and Contraindications for Meniscal Allograft Transplant (MAT)

^aContraindications for MAT are controversial, as the available literature discussing contraindications is very limited. This list is based on the experience of the senior author.

Long-term prospective studies have shown high graft survival and predominantly positive functional results after MAT. Age indications have expanded, with 1 recent study reporting 6% reoperation rate and zero failures in a cohort of 37 adolescent MAT patients.¹² High survival rates hold even among an athletic population, where rates of return to play after MAT have been reported to be >75% for those competing at a high school level or higher.¹³ In an active military population, <2% of patients progressed to revision MAT or total knee arthroplasty at minimum 2-year follow-up, but 22% of patients were unable to return to military duty owing to residual knee limitations.¹⁴ In this series, tobacco use correlated with failure, whereas MAT by high-volume, fellowship-trained orthopedic surgeons decreased rates of failure.

2. GRAFT SELECTION

In preparation for MAT, accurate measurements must be taken for appropriate size matching. Several measurement techniques have been described, including using plain radiographs, 3D computed tomography (CT), and magnetic resonance imaging (MRI).^15-18 There is limited data regarding the consequences of an improperly sized donor meniscus; however, an oversized lateral meniscus has been shown to increase the contact forces across the articular cartilage.¹⁹ Additionally, an undersized allograft may result in normal forces across the articular cartilage but greater forces across the meniscus.¹⁹

When sizing the recipient knee for MAT, accurate width and length measurements are critical. The most common technique used today includes measurements using anteroposterior and lateral radiographic images as described by Pollard and colleagues.¹⁵ The width of the meniscus is determined by the distance between 2 vertical lines perpendicular to the joint line, 1 of them tangential to the margin of the tibia metaphysis and the other between the medial and lateral tibial eminence in both knees (Figures 1A,1B). The length of the meniscus is measured on a lateral radiograph. A line is drawn at the level of the articular line between the anterior surface of the tibia above the tuberosity and a parallel line that is tangential to the posterior margin of the tibial plateau. Percent corrections are performed for these dimensions as described in previous publications.

Other techniques have been described to obtain accurate measurements of the recipient knee. For example, obtaining an MRI of the contralateral knee may provide a reproducible method of measuring both the width and length of the medial and lateral menisci.²⁰ CT has been used to measure the lateral meniscus independently, and it has been shown to exhibit less error in the measure of the tibial plateau when compared with X-rays.¹⁸ Both CT and MRI are more expensive than simple radiographs, and CT exposes the patient to an increased amount of radiation. Current evidence does not support standard use of these advanced imaging modalities for meniscal sizing.

Continue to: GRAFT PREPARATION AND PLACEMENT...

3. GRAFT PREPARATION AND PLACEMENT

At the time of surgery, the meniscus allograft is thawed in sterile saline and prepared on the back table. This can be done before or after the diagnostic arthroscopy and bone-slot preparation. Excess soft tissue surrounding the meniscal rim and/or anterior and posterior horns should be removed. Several techniques for MAT have been described, but we generally prefer a bridge-in-slot technique for both medial and lateral MAT.²¹ To prepare the meniscus allograft for a bridge-in-slot technique, the graft is cut with an oscillating saw to a width of 7 mm, with care taken to ensure that the bony insertions of both meniscal horns are preserved. Next, a transverse cut is made 10 mm below the meniscal horns to set the depth of the bone bridge. To assist with the sizing of the bone bridge, a rectangular sizing block and cutting jig is used (Figures 2A-2C). After marking the middle and posterior thirds of the meniscus, a No. 2 non-absorbable suture is placed at the junction of the posterior and middle thirds of the meniscus. This completes preparation of the allograft prior to implantation.

Attention is then turned to back the arthroscopy. A standard posteromedial (medial meniscus) or posterolateral (lateral meniscus) accessory incision is made, and a Henning retractor is carefully placed in order to receive the sutures that will be placed through the meniscus allograft via a standard inside-out repair technique. First, a zone-specific cannula is used to place a nitinol wire out the accessory incision. The looped end of the wire is pulled out of the anterior arthrotomy incision that will be used to shuttle the meniscus allograft into the joint. In order to pass the meniscal allograft into the joint, the passing suture previously placed through the meniscus is shuttled through the nitinol wire, and the wire is then pulled out the accessory incision, advancing the meniscus through the anteiror arthrotomy. As the meniscus is introduced, the traction suture is then gently tensioned to get the allograft completely into the joint. Next, the bone bridge is seated into the previously created bone slot, as the soft tissue component is manually pushed beneath the ipsilateral femoral condyle. Under direct visualization, the soft tissue component is reduced with a probe using firm, constant traction. To aid in reduction, it may be useful to apply compartment-specific varus or valgus stress and to cycle the knee once the meniscal complex is reduced.

4. GRAFT FIXATION

Once the graft has been passed completely into the joint, with the bone bridge seated into the bone slot, the long end of an Army-Navy retractor is placed firmly through the arthrotomy on the meniscal bone bridge, maintaining a downward force to allow the bridge to remain slotted. To lever down on the posterior aspect of the graft, a freer elevator is used from anterosuperior to posteroinferior. The bone bridge is then secured using a bioabsorbable interference screw, placed central to the bone bridge opposing the block to the ipsilateral compartment. The remainder of the meniscus is secured with an inside-out repair technique, working from posterior to anterior through a standard medial or lateral meniscal repair approach. In total, approximately 6 to 10 vertical mattress sutures are placed, and these can be placed both superiorly and inferiorly on the meniscus. Posteriorly, an all-inside suture repair device may be helpful. Finally, the anterior aspect of the meniscus is repaired to the capsule in an open fashion prior to closing the arthrotomy. Sutures are tied with the leg in extension. The meniscal repair incision is closed in a standard fashion using layers.

5. CONCOMITANT PATHOLOGY AND MAT

The presence of concomitant knee pathology in the context of meniscus deficiency is a challenging problem that requires careful attention to all aspects of the underlying condition of the knee. In cases where MAT is indicated, issues of malalignment, cartilage defects, and/or ligamentous instability may also need to be addressed either concomitantly or in staged fashion. For example, medial meniscal deficiency in the setting of varus alignment can be addressed with a concomitant HTO, whereas lateral meniscal deficiency in the setting of valgus malalignment can be addressed with a concomitant DFO. In both cases, the osteotomy corrects an abnormal mechanical axis, offloading the diseased compartment. This accomplishes 2 goals, namely to preserve the new MAT graft and to protect underlying articular cartilage.^22-24 The osteotomy is an important contributor to additional pain relief by offloading the compartment, and clinical studies have demonstrated that failure to address malalignment in the setting of surgical intervention for cartilage and meniscal insufficiency leads to inferior clinical outcomes and poor survival of transplanted tissue.^25-28

Continue to: In a meniscus-deficient patient with chondral lesions...

In a meniscus-deficient patient with chondral lesions (Outerbridge grade 3 or 4), concomitant MAT and cartilage restoration should be considered. Depending on the size and location of the chondral lesion, options include marrow stimulation, autologous chondrocyte implantation, osteochondral autograft transfer, as well as chondral and/or osteochondral allograft transplantation. In a systematic review of concomitant MAT and cartilage restoration procedures, Harris and colleagues²⁵ found that failure rates of the combined surgery were similar to those of either surgery in isolation.

Young athletes sustaining anterior cruciate ligament (ACL) tears commonly also have meniscal pathology that must be addressed. Most cases are treated with meniscal repair or partial meniscectomy, but occasionally patients present with ACL tear and symptomatic meniscal deficiency. Specifically, MAT survival relies largely on a knee with ligamentous stability, whereas outcomes of ACL reconstruction are improved with intact and functional menisci.²⁹ The surgical technique for MAT is modified slightly in the setting of performing a concomitant ACL reconstruction, with the ACL tibial tunnel drilled to avoid the meniscal bone slot if possible, followed by femoral tunnel creation. Femoral fixation of the ACL graft is accomplished after preparation of the meniscal slot. The meniscal graft is set into place (sutures are not yet tied), and tibial fixation of the ACL graft is performed next. We typically use an Achilles allograft for the ACL reconstruction, with the bone block used for femoral fixation to avoid bony impingement between the MAT bone bridge/block and the ACL graft. With the knee in full extension, the MAT sutures are tied at the conclusion of the surgical procedure. Concomitant MAT and ACL reconstruction has yielded positive long-term clinical outcomes, improved joint stability, and findings similar to historical results of ACL reconstruction or MAT performed in isolation.^30,31

CONCLUSION

When used with the proper indications, MAT has demonstrated the ability to restore function and reduce pain. Successful meniscal transplant requires attention to the patient’s past medical and surgical history. Similarly, care must be taken to address any concomitant knee pathology, such as coronal realignment, ligament reconstruction, or cartilage restoration.

ABSTRACT

Meniscus allograft transplantation (MAT) has yielded excellent long-term functional outcomes when performed in properly indicated patients. When evaluating a patient for potential MAT, it is imperative to evaluate past medical history and past surgical procedures. The ideal MAT candidate is a chronologically and physiologically young patient (<50 years) with symptomatic meniscal deficiency. Existing pathology in the knee needs to be carefully considered and issues such as malalignment, cartilage defects, and/or ligamentous instability may require a staged or concomitant procedure. Once an ideal candidate is identified, graft selection and preparation are critical steps to ensure a proper fit and long-term viability of the meniscus. When selecting the graft, accurate measurements must be taken, and this is most commonly performed using plain radiographs for this. Graft fixation can be accomplished by placing vertical mattress sutures and tying those down with the knee in full extension.

Continue to: Meniscus tears are common in the young, athletic patient population...

Meniscus tears are common in the young, athletic patient population. In the United States alone, approximately 700,000 meniscectomies are performed annually.¹ Given discouraging long-term clinical results following subtotal meniscectomy in young patients, meniscal repair is preferred whenever possible.² Despite short-term symptom relief if subtotal meniscectomy is required, some patients often go on to develop localized pain in the affected compartment, effusions, and eventual development of osteoarthritis. In such patients with symptomatic meniscal deficiency, meniscal allograft transplantation (MAT) has yielded excellent long-term functional outcomes.^3-5 Three recently published systematic reviews describe the outcomes of MAT in thousands of patients, noting positive outcomes in regard to pain and function for the majority of patients.^6-8 Specifically, in a review conducted by Elattar and colleagues⁷ consisting of 44 studies comprising 1136 grafts in 1068 patients, the authors reported clinical improvement in Lysholm Knee Scoring Scale score (44 to 77), visual analog scale (48 mm to 17 mm), and International Knee Documentation Committee (84% normal/nearly normal, 89% satisfaction), among other outcomes measures. Additionally, the complication (21.3%) and failure rates (10.6%) were considered acceptable by all authors. The purpose of this article is to review indications, operative preparation, critical aspects of surgical technique, and additional concomitant procedures commonly performed alongside MAT.

1. PATIENT SELECTION

When used with the proper indications, MAT offers improved functional outcomes and reduced pain for patients with symptomatic meniscal deficiency. When evaluating a patient for potential MAT, it is imperative to evaluate past medical history and past surgical procedures. The ideal MAT candidate is a chronologically and physiologically young patient (<50 years) with symptomatic meniscal deficiency who does not have (1) evidence of diffuse osteoarthritis (Outerbridge grade <2), including the absence of significant bony flattening or osteophytes in the involved compartment; (2) inflammatory arthritis; (3) active or previous joint infection; (4) mechanical axis malalignment; or (5) morbid obesity (Table). Long-leg weight-bearing anterior-posterior alignment radiographs are important in the work-up of any patient being considered for MAT, and consideration for concomitant or staged realignment high tibial osteotomy (HTO) or distal femoral osteotomy (DFO) should be given for patients in excessive varus or valgus, respectively. Although the decision to perform a realignment osteotomy is made on a patient-specific basis, if the weight-bearing line passes medial to the medial tibial spine or lateral to the lateral tibial spine, HTO or DFO, respectively, should be considered. Importantly, MAT is not typically recommended in the asymptomatic patient.⁹ Although some recent evidence suggests MAT may have chondroprotective effects on articular cartilage following meniscectomy, there is insufficient long-term outcome data to support the use of MAT as a prophylactic measure, especially given the fact that graft deterioration inevitably occurs at 7 to 10 years, with patients having to consider avoiding meniscus-dependent activities following transplant to protect their graft from traumatic failure.^10,11

Table. Summary of Indications and Contraindications for Meniscal Allograft Transplant (MAT)

^aContraindications for MAT are controversial, as the available literature discussing contraindications is very limited. This list is based on the experience of the senior author.

Long-term prospective studies have shown high graft survival and predominantly positive functional results after MAT. Age indications have expanded, with 1 recent study reporting 6% reoperation rate and zero failures in a cohort of 37 adolescent MAT patients.¹² High survival rates hold even among an athletic population, where rates of return to play after MAT have been reported to be >75% for those competing at a high school level or higher.¹³ In an active military population, <2% of patients progressed to revision MAT or total knee arthroplasty at minimum 2-year follow-up, but 22% of patients were unable to return to military duty owing to residual knee limitations.¹⁴ In this series, tobacco use correlated with failure, whereas MAT by high-volume, fellowship-trained orthopedic surgeons decreased rates of failure.

2. GRAFT SELECTION

In preparation for MAT, accurate measurements must be taken for appropriate size matching. Several measurement techniques have been described, including using plain radiographs, 3D computed tomography (CT), and magnetic resonance imaging (MRI).^15-18 There is limited data regarding the consequences of an improperly sized donor meniscus; however, an oversized lateral meniscus has been shown to increase the contact forces across the articular cartilage.¹⁹ Additionally, an undersized allograft may result in normal forces across the articular cartilage but greater forces across the meniscus.¹⁹

When sizing the recipient knee for MAT, accurate width and length measurements are critical. The most common technique used today includes measurements using anteroposterior and lateral radiographic images as described by Pollard and colleagues.¹⁵ The width of the meniscus is determined by the distance between 2 vertical lines perpendicular to the joint line, 1 of them tangential to the margin of the tibia metaphysis and the other between the medial and lateral tibial eminence in both knees (Figures 1A,1B). The length of the meniscus is measured on a lateral radiograph. A line is drawn at the level of the articular line between the anterior surface of the tibia above the tuberosity and a parallel line that is tangential to the posterior margin of the tibial plateau. Percent corrections are performed for these dimensions as described in previous publications.

Other techniques have been described to obtain accurate measurements of the recipient knee. For example, obtaining an MRI of the contralateral knee may provide a reproducible method of measuring both the width and length of the medial and lateral menisci.²⁰ CT has been used to measure the lateral meniscus independently, and it has been shown to exhibit less error in the measure of the tibial plateau when compared with X-rays.¹⁸ Both CT and MRI are more expensive than simple radiographs, and CT exposes the patient to an increased amount of radiation. Current evidence does not support standard use of these advanced imaging modalities for meniscal sizing.

Continue to: GRAFT PREPARATION AND PLACEMENT...

3. GRAFT PREPARATION AND PLACEMENT

At the time of surgery, the meniscus allograft is thawed in sterile saline and prepared on the back table. This can be done before or after the diagnostic arthroscopy and bone-slot preparation. Excess soft tissue surrounding the meniscal rim and/or anterior and posterior horns should be removed. Several techniques for MAT have been described, but we generally prefer a bridge-in-slot technique for both medial and lateral MAT.²¹ To prepare the meniscus allograft for a bridge-in-slot technique, the graft is cut with an oscillating saw to a width of 7 mm, with care taken to ensure that the bony insertions of both meniscal horns are preserved. Next, a transverse cut is made 10 mm below the meniscal horns to set the depth of the bone bridge. To assist with the sizing of the bone bridge, a rectangular sizing block and cutting jig is used (Figures 2A-2C). After marking the middle and posterior thirds of the meniscus, a No. 2 non-absorbable suture is placed at the junction of the posterior and middle thirds of the meniscus. This completes preparation of the allograft prior to implantation.

Attention is then turned to back the arthroscopy. A standard posteromedial (medial meniscus) or posterolateral (lateral meniscus) accessory incision is made, and a Henning retractor is carefully placed in order to receive the sutures that will be placed through the meniscus allograft via a standard inside-out repair technique. First, a zone-specific cannula is used to place a nitinol wire out the accessory incision. The looped end of the wire is pulled out of the anterior arthrotomy incision that will be used to shuttle the meniscus allograft into the joint. In order to pass the meniscal allograft into the joint, the passing suture previously placed through the meniscus is shuttled through the nitinol wire, and the wire is then pulled out the accessory incision, advancing the meniscus through the anteiror arthrotomy. As the meniscus is introduced, the traction suture is then gently tensioned to get the allograft completely into the joint. Next, the bone bridge is seated into the previously created bone slot, as the soft tissue component is manually pushed beneath the ipsilateral femoral condyle. Under direct visualization, the soft tissue component is reduced with a probe using firm, constant traction. To aid in reduction, it may be useful to apply compartment-specific varus or valgus stress and to cycle the knee once the meniscal complex is reduced.

4. GRAFT FIXATION

Once the graft has been passed completely into the joint, with the bone bridge seated into the bone slot, the long end of an Army-Navy retractor is placed firmly through the arthrotomy on the meniscal bone bridge, maintaining a downward force to allow the bridge to remain slotted. To lever down on the posterior aspect of the graft, a freer elevator is used from anterosuperior to posteroinferior. The bone bridge is then secured using a bioabsorbable interference screw, placed central to the bone bridge opposing the block to the ipsilateral compartment. The remainder of the meniscus is secured with an inside-out repair technique, working from posterior to anterior through a standard medial or lateral meniscal repair approach. In total, approximately 6 to 10 vertical mattress sutures are placed, and these can be placed both superiorly and inferiorly on the meniscus. Posteriorly, an all-inside suture repair device may be helpful. Finally, the anterior aspect of the meniscus is repaired to the capsule in an open fashion prior to closing the arthrotomy. Sutures are tied with the leg in extension. The meniscal repair incision is closed in a standard fashion using layers.

5. CONCOMITANT PATHOLOGY AND MAT

The presence of concomitant knee pathology in the context of meniscus deficiency is a challenging problem that requires careful attention to all aspects of the underlying condition of the knee. In cases where MAT is indicated, issues of malalignment, cartilage defects, and/or ligamentous instability may also need to be addressed either concomitantly or in staged fashion. For example, medial meniscal deficiency in the setting of varus alignment can be addressed with a concomitant HTO, whereas lateral meniscal deficiency in the setting of valgus malalignment can be addressed with a concomitant DFO. In both cases, the osteotomy corrects an abnormal mechanical axis, offloading the diseased compartment. This accomplishes 2 goals, namely to preserve the new MAT graft and to protect underlying articular cartilage.^22-24 The osteotomy is an important contributor to additional pain relief by offloading the compartment, and clinical studies have demonstrated that failure to address malalignment in the setting of surgical intervention for cartilage and meniscal insufficiency leads to inferior clinical outcomes and poor survival of transplanted tissue.^25-28

Continue to: In a meniscus-deficient patient with chondral lesions...

In a meniscus-deficient patient with chondral lesions (Outerbridge grade 3 or 4), concomitant MAT and cartilage restoration should be considered. Depending on the size and location of the chondral lesion, options include marrow stimulation, autologous chondrocyte implantation, osteochondral autograft transfer, as well as chondral and/or osteochondral allograft transplantation. In a systematic review of concomitant MAT and cartilage restoration procedures, Harris and colleagues²⁵ found that failure rates of the combined surgery were similar to those of either surgery in isolation.

Young athletes sustaining anterior cruciate ligament (ACL) tears commonly also have meniscal pathology that must be addressed. Most cases are treated with meniscal repair or partial meniscectomy, but occasionally patients present with ACL tear and symptomatic meniscal deficiency. Specifically, MAT survival relies largely on a knee with ligamentous stability, whereas outcomes of ACL reconstruction are improved with intact and functional menisci.²⁹ The surgical technique for MAT is modified slightly in the setting of performing a concomitant ACL reconstruction, with the ACL tibial tunnel drilled to avoid the meniscal bone slot if possible, followed by femoral tunnel creation. Femoral fixation of the ACL graft is accomplished after preparation of the meniscal slot. The meniscal graft is set into place (sutures are not yet tied), and tibial fixation of the ACL graft is performed next. We typically use an Achilles allograft for the ACL reconstruction, with the bone block used for femoral fixation to avoid bony impingement between the MAT bone bridge/block and the ACL graft. With the knee in full extension, the MAT sutures are tied at the conclusion of the surgical procedure. Concomitant MAT and ACL reconstruction has yielded positive long-term clinical outcomes, improved joint stability, and findings similar to historical results of ACL reconstruction or MAT performed in isolation.^30,31

CONCLUSION

When used with the proper indications, MAT has demonstrated the ability to restore function and reduce pain. Successful meniscal transplant requires attention to the patient’s past medical and surgical history. Similarly, care must be taken to address any concomitant knee pathology, such as coronal realignment, ligament reconstruction, or cartilage restoration.

ABSTRACT

Meniscus allograft transplantation (MAT) has yielded excellent long-term functional outcomes when performed in properly indicated patients. When evaluating a patient for potential MAT, it is imperative to evaluate past medical history and past surgical procedures. The ideal MAT candidate is a chronologically and physiologically young patient (<50 years) with symptomatic meniscal deficiency. Existing pathology in the knee needs to be carefully considered and issues such as malalignment, cartilage defects, and/or ligamentous instability may require a staged or concomitant procedure. Once an ideal candidate is identified, graft selection and preparation are critical steps to ensure a proper fit and long-term viability of the meniscus. When selecting the graft, accurate measurements must be taken, and this is most commonly performed using plain radiographs for this. Graft fixation can be accomplished by placing vertical mattress sutures and tying those down with the knee in full extension.

Continue to: Meniscus tears are common in the young, athletic patient population...

Meniscus tears are common in the young, athletic patient population. In the United States alone, approximately 700,000 meniscectomies are performed annually.¹ Given discouraging long-term clinical results following subtotal meniscectomy in young patients, meniscal repair is preferred whenever possible.² Despite short-term symptom relief if subtotal meniscectomy is required, some patients often go on to develop localized pain in the affected compartment, effusions, and eventual development of osteoarthritis. In such patients with symptomatic meniscal deficiency, meniscal allograft transplantation (MAT) has yielded excellent long-term functional outcomes.^3-5 Three recently published systematic reviews describe the outcomes of MAT in thousands of patients, noting positive outcomes in regard to pain and function for the majority of patients.^6-8 Specifically, in a review conducted by Elattar and colleagues⁷ consisting of 44 studies comprising 1136 grafts in 1068 patients, the authors reported clinical improvement in Lysholm Knee Scoring Scale score (44 to 77), visual analog scale (48 mm to 17 mm), and International Knee Documentation Committee (84% normal/nearly normal, 89% satisfaction), among other outcomes measures. Additionally, the complication (21.3%) and failure rates (10.6%) were considered acceptable by all authors. The purpose of this article is to review indications, operative preparation, critical aspects of surgical technique, and additional concomitant procedures commonly performed alongside MAT.

1. PATIENT SELECTION

When used with the proper indications, MAT offers improved functional outcomes and reduced pain for patients with symptomatic meniscal deficiency. When evaluating a patient for potential MAT, it is imperative to evaluate past medical history and past surgical procedures. The ideal MAT candidate is a chronologically and physiologically young patient (<50 years) with symptomatic meniscal deficiency who does not have (1) evidence of diffuse osteoarthritis (Outerbridge grade <2), including the absence of significant bony flattening or osteophytes in the involved compartment; (2) inflammatory arthritis; (3) active or previous joint infection; (4) mechanical axis malalignment; or (5) morbid obesity (Table). Long-leg weight-bearing anterior-posterior alignment radiographs are important in the work-up of any patient being considered for MAT, and consideration for concomitant or staged realignment high tibial osteotomy (HTO) or distal femoral osteotomy (DFO) should be given for patients in excessive varus or valgus, respectively. Although the decision to perform a realignment osteotomy is made on a patient-specific basis, if the weight-bearing line passes medial to the medial tibial spine or lateral to the lateral tibial spine, HTO or DFO, respectively, should be considered. Importantly, MAT is not typically recommended in the asymptomatic patient.⁹ Although some recent evidence suggests MAT may have chondroprotective effects on articular cartilage following meniscectomy, there is insufficient long-term outcome data to support the use of MAT as a prophylactic measure, especially given the fact that graft deterioration inevitably occurs at 7 to 10 years, with patients having to consider avoiding meniscus-dependent activities following transplant to protect their graft from traumatic failure.^10,11

Table. Summary of Indications and Contraindications for Meniscal Allograft Transplant (MAT)

^aContraindications for MAT are controversial, as the available literature discussing contraindications is very limited. This list is based on the experience of the senior author.

Long-term prospective studies have shown high graft survival and predominantly positive functional results after MAT. Age indications have expanded, with 1 recent study reporting 6% reoperation rate and zero failures in a cohort of 37 adolescent MAT patients.¹² High survival rates hold even among an athletic population, where rates of return to play after MAT have been reported to be >75% for those competing at a high school level or higher.¹³ In an active military population, <2% of patients progressed to revision MAT or total knee arthroplasty at minimum 2-year follow-up, but 22% of patients were unable to return to military duty owing to residual knee limitations.¹⁴ In this series, tobacco use correlated with failure, whereas MAT by high-volume, fellowship-trained orthopedic surgeons decreased rates of failure.

2. GRAFT SELECTION

In preparation for MAT, accurate measurements must be taken for appropriate size matching. Several measurement techniques have been described, including using plain radiographs, 3D computed tomography (CT), and magnetic resonance imaging (MRI).^15-18 There is limited data regarding the consequences of an improperly sized donor meniscus; however, an oversized lateral meniscus has been shown to increase the contact forces across the articular cartilage.¹⁹ Additionally, an undersized allograft may result in normal forces across the articular cartilage but greater forces across the meniscus.¹⁹

When sizing the recipient knee for MAT, accurate width and length measurements are critical. The most common technique used today includes measurements using anteroposterior and lateral radiographic images as described by Pollard and colleagues.¹⁵ The width of the meniscus is determined by the distance between 2 vertical lines perpendicular to the joint line, 1 of them tangential to the margin of the tibia metaphysis and the other between the medial and lateral tibial eminence in both knees (Figures 1A,1B). The length of the meniscus is measured on a lateral radiograph. A line is drawn at the level of the articular line between the anterior surface of the tibia above the tuberosity and a parallel line that is tangential to the posterior margin of the tibial plateau. Percent corrections are performed for these dimensions as described in previous publications.

Other techniques have been described to obtain accurate measurements of the recipient knee. For example, obtaining an MRI of the contralateral knee may provide a reproducible method of measuring both the width and length of the medial and lateral menisci.²⁰ CT has been used to measure the lateral meniscus independently, and it has been shown to exhibit less error in the measure of the tibial plateau when compared with X-rays.¹⁸ Both CT and MRI are more expensive than simple radiographs, and CT exposes the patient to an increased amount of radiation. Current evidence does not support standard use of these advanced imaging modalities for meniscal sizing.

Continue to: GRAFT PREPARATION AND PLACEMENT...

3. GRAFT PREPARATION AND PLACEMENT

At the time of surgery, the meniscus allograft is thawed in sterile saline and prepared on the back table. This can be done before or after the diagnostic arthroscopy and bone-slot preparation. Excess soft tissue surrounding the meniscal rim and/or anterior and posterior horns should be removed. Several techniques for MAT have been described, but we generally prefer a bridge-in-slot technique for both medial and lateral MAT.²¹ To prepare the meniscus allograft for a bridge-in-slot technique, the graft is cut with an oscillating saw to a width of 7 mm, with care taken to ensure that the bony insertions of both meniscal horns are preserved. Next, a transverse cut is made 10 mm below the meniscal horns to set the depth of the bone bridge. To assist with the sizing of the bone bridge, a rectangular sizing block and cutting jig is used (Figures 2A-2C). After marking the middle and posterior thirds of the meniscus, a No. 2 non-absorbable suture is placed at the junction of the posterior and middle thirds of the meniscus. This completes preparation of the allograft prior to implantation.

Attention is then turned to back the arthroscopy. A standard posteromedial (medial meniscus) or posterolateral (lateral meniscus) accessory incision is made, and a Henning retractor is carefully placed in order to receive the sutures that will be placed through the meniscus allograft via a standard inside-out repair technique. First, a zone-specific cannula is used to place a nitinol wire out the accessory incision. The looped end of the wire is pulled out of the anterior arthrotomy incision that will be used to shuttle the meniscus allograft into the joint. In order to pass the meniscal allograft into the joint, the passing suture previously placed through the meniscus is shuttled through the nitinol wire, and the wire is then pulled out the accessory incision, advancing the meniscus through the anteiror arthrotomy. As the meniscus is introduced, the traction suture is then gently tensioned to get the allograft completely into the joint. Next, the bone bridge is seated into the previously created bone slot, as the soft tissue component is manually pushed beneath the ipsilateral femoral condyle. Under direct visualization, the soft tissue component is reduced with a probe using firm, constant traction. To aid in reduction, it may be useful to apply compartment-specific varus or valgus stress and to cycle the knee once the meniscal complex is reduced.

4. GRAFT FIXATION

Once the graft has been passed completely into the joint, with the bone bridge seated into the bone slot, the long end of an Army-Navy retractor is placed firmly through the arthrotomy on the meniscal bone bridge, maintaining a downward force to allow the bridge to remain slotted. To lever down on the posterior aspect of the graft, a freer elevator is used from anterosuperior to posteroinferior. The bone bridge is then secured using a bioabsorbable interference screw, placed central to the bone bridge opposing the block to the ipsilateral compartment. The remainder of the meniscus is secured with an inside-out repair technique, working from posterior to anterior through a standard medial or lateral meniscal repair approach. In total, approximately 6 to 10 vertical mattress sutures are placed, and these can be placed both superiorly and inferiorly on the meniscus. Posteriorly, an all-inside suture repair device may be helpful. Finally, the anterior aspect of the meniscus is repaired to the capsule in an open fashion prior to closing the arthrotomy. Sutures are tied with the leg in extension. The meniscal repair incision is closed in a standard fashion using layers.

5. CONCOMITANT PATHOLOGY AND MAT

The presence of concomitant knee pathology in the context of meniscus deficiency is a challenging problem that requires careful attention to all aspects of the underlying condition of the knee. In cases where MAT is indicated, issues of malalignment, cartilage defects, and/or ligamentous instability may also need to be addressed either concomitantly or in staged fashion. For example, medial meniscal deficiency in the setting of varus alignment can be addressed with a concomitant HTO, whereas lateral meniscal deficiency in the setting of valgus malalignment can be addressed with a concomitant DFO. In both cases, the osteotomy corrects an abnormal mechanical axis, offloading the diseased compartment. This accomplishes 2 goals, namely to preserve the new MAT graft and to protect underlying articular cartilage.^22-24 The osteotomy is an important contributor to additional pain relief by offloading the compartment, and clinical studies have demonstrated that failure to address malalignment in the setting of surgical intervention for cartilage and meniscal insufficiency leads to inferior clinical outcomes and poor survival of transplanted tissue.^25-28

Continue to: In a meniscus-deficient patient with chondral lesions...

In a meniscus-deficient patient with chondral lesions (Outerbridge grade 3 or 4), concomitant MAT and cartilage restoration should be considered. Depending on the size and location of the chondral lesion, options include marrow stimulation, autologous chondrocyte implantation, osteochondral autograft transfer, as well as chondral and/or osteochondral allograft transplantation. In a systematic review of concomitant MAT and cartilage restoration procedures, Harris and colleagues²⁵ found that failure rates of the combined surgery were similar to those of either surgery in isolation.

Young athletes sustaining anterior cruciate ligament (ACL) tears commonly also have meniscal pathology that must be addressed. Most cases are treated with meniscal repair or partial meniscectomy, but occasionally patients present with ACL tear and symptomatic meniscal deficiency. Specifically, MAT survival relies largely on a knee with ligamentous stability, whereas outcomes of ACL reconstruction are improved with intact and functional menisci.²⁹ The surgical technique for MAT is modified slightly in the setting of performing a concomitant ACL reconstruction, with the ACL tibial tunnel drilled to avoid the meniscal bone slot if possible, followed by femoral tunnel creation. Femoral fixation of the ACL graft is accomplished after preparation of the meniscal slot. The meniscal graft is set into place (sutures are not yet tied), and tibial fixation of the ACL graft is performed next. We typically use an Achilles allograft for the ACL reconstruction, with the bone block used for femoral fixation to avoid bony impingement between the MAT bone bridge/block and the ACL graft. With the knee in full extension, the MAT sutures are tied at the conclusion of the surgical procedure. Concomitant MAT and ACL reconstruction has yielded positive long-term clinical outcomes, improved joint stability, and findings similar to historical results of ACL reconstruction or MAT performed in isolation.^30,31

CONCLUSION

When used with the proper indications, MAT has demonstrated the ability to restore function and reduce pain. Successful meniscal transplant requires attention to the patient’s past medical and surgical history. Similarly, care must be taken to address any concomitant knee pathology, such as coronal realignment, ligament reconstruction, or cartilage restoration.

Some policy responses to the opioid epidemic have immediate, beneficial effects, while others lead to short-term harms that might be offset by long-term health benefits, according to researchers who have mathematically modeled the impact of 11 interventions.

Policies that expand addiction treatment or curb harmful effects of addiction such as overdose and infection were immediately beneficial in the model, with no negative effects on life years (LYs), quality-adjusted life years (QALYs), or addiction deaths, the researchers reported.

In contrast, policies that constrain prescription opioid supply resulted in some benefits, but also short-term harms because of inadequate pain control and users switching to heroin.

However, the modeling study also suggests those harms might be mitigated over the long term as new addictions are averted, according to Allison L. Pitt, a PhD candidate in the department of management science and engineering at Stanford (Calif.) University, and her coauthors.

Combining different interventions had additive benefits in the model, prompting Ms. Pitt and her coauthors to recommend a multifaceted policy approach to curb opioid abuse and reduce addiction deaths.

“No epidemic has ever been averted solely by treating single affected cases,” they wrote in the American Journal of Public Health. “Instead, portfolios of policies will likely be required, including those that prevent addiction, treat addiction, and mitigate its effects.”

In their study, Ms. Pitt and her colleagues projected the impact of 11 policies aimed at curbing opioid addiction and reducing addiction deaths. They used dynamic compartmental modeling, a technique commonly used for evaluating the spread of contagious disease.

This technique is appropriate for studying the opioid epidemic, because it allows for dynamic modeling of addiction incidence that reflects a changing number of prescription holders, the authors said in their report, which focused on projected outcomes of various interventions at 5 and 10 years.

None of the policies substantially reduced opioid-related deaths in 5-year outcomes projections, they found. Increasing availability of naloxone averted 4% of addiction deaths, the highest reduction of any intervention over that time period.

However, interventions focused on providing services for people with addictions did generally provide uniform benefits over the 5-year horizon: “Naloxone availability, needle exchange, medication-assisted treatment, and psychosocial treatment policies generate gains in LYs and QALYs and reduce deaths, without harming any group,” Ms. Pitt and her coauthors said.

Interventions that reduced opioid supply, such as excess opioid disposal and reduced prescribing for transitioning pain, increased LYs and QALYs while decreasing total addiction deaths over 5 years. However, the investigators said, those benefits were partly offset by increases in heroin-related deaths.

Drug rescheduling was associated with a 45.6% increase in heroin-related deaths over 5 years in the model, the highest percentage increase of any intervention in the published data.

Over the 10-year horizon, addiction deaths continued to decrease proportionally for naloxone availability and needle-exchange policies, authors said. By comparison, policies focused on opioid supply, such as excess opioid disposal and reduced prescribing for transitioning pain, averted substantially more deaths over 10 years than would be expected, compared with the 5-year results, investigators said.

Acute pain prescribing, which increased opioid-related deaths over 5 years in the model, was associated with a decrease in opioid-related deaths over 10 years, they added.

The report coauthors were Keith Humphreys, PhD, of Stanford’s department of psychiatry and behavioral sciences, and Margaret L. Brandeau, PhD, of the university’s department of management science and engineering.

The coauthors cited several limitations. One is that the opioid epidemic is changing in unpredictable ways. Therefore, numerous assumptions about the epidemic were made based on the opinions of clinicians and scientists.

The study was supported by a grant from the National Institute on Drug Abuse. Dr. Humphreys reported support through a Senior Career Research Scientist award from the VA Health Services Research and Development Service.

SOURCE: Pitt AL et al. Am J Public Health. 2018 Aug 23. doi: 10.2105/AJPH.2018.304590.

Some policy responses to the opioid epidemic have immediate, beneficial effects, while others lead to short-term harms that might be offset by long-term health benefits, according to researchers who have mathematically modeled the impact of 11 interventions.

Policies that expand addiction treatment or curb harmful effects of addiction such as overdose and infection were immediately beneficial in the model, with no negative effects on life years (LYs), quality-adjusted life years (QALYs), or addiction deaths, the researchers reported.

In contrast, policies that constrain prescription opioid supply resulted in some benefits, but also short-term harms because of inadequate pain control and users switching to heroin.

However, the modeling study also suggests those harms might be mitigated over the long term as new addictions are averted, according to Allison L. Pitt, a PhD candidate in the department of management science and engineering at Stanford (Calif.) University, and her coauthors.

Combining different interventions had additive benefits in the model, prompting Ms. Pitt and her coauthors to recommend a multifaceted policy approach to curb opioid abuse and reduce addiction deaths.

“No epidemic has ever been averted solely by treating single affected cases,” they wrote in the American Journal of Public Health. “Instead, portfolios of policies will likely be required, including those that prevent addiction, treat addiction, and mitigate its effects.”

In their study, Ms. Pitt and her colleagues projected the impact of 11 policies aimed at curbing opioid addiction and reducing addiction deaths. They used dynamic compartmental modeling, a technique commonly used for evaluating the spread of contagious disease.

This technique is appropriate for studying the opioid epidemic, because it allows for dynamic modeling of addiction incidence that reflects a changing number of prescription holders, the authors said in their report, which focused on projected outcomes of various interventions at 5 and 10 years.

None of the policies substantially reduced opioid-related deaths in 5-year outcomes projections, they found. Increasing availability of naloxone averted 4% of addiction deaths, the highest reduction of any intervention over that time period.

However, interventions focused on providing services for people with addictions did generally provide uniform benefits over the 5-year horizon: “Naloxone availability, needle exchange, medication-assisted treatment, and psychosocial treatment policies generate gains in LYs and QALYs and reduce deaths, without harming any group,” Ms. Pitt and her coauthors said.

Interventions that reduced opioid supply, such as excess opioid disposal and reduced prescribing for transitioning pain, increased LYs and QALYs while decreasing total addiction deaths over 5 years. However, the investigators said, those benefits were partly offset by increases in heroin-related deaths.

Drug rescheduling was associated with a 45.6% increase in heroin-related deaths over 5 years in the model, the highest percentage increase of any intervention in the published data.

Over the 10-year horizon, addiction deaths continued to decrease proportionally for naloxone availability and needle-exchange policies, authors said. By comparison, policies focused on opioid supply, such as excess opioid disposal and reduced prescribing for transitioning pain, averted substantially more deaths over 10 years than would be expected, compared with the 5-year results, investigators said.

Acute pain prescribing, which increased opioid-related deaths over 5 years in the model, was associated with a decrease in opioid-related deaths over 10 years, they added.

The report coauthors were Keith Humphreys, PhD, of Stanford’s department of psychiatry and behavioral sciences, and Margaret L. Brandeau, PhD, of the university’s department of management science and engineering.

The coauthors cited several limitations. One is that the opioid epidemic is changing in unpredictable ways. Therefore, numerous assumptions about the epidemic were made based on the opinions of clinicians and scientists.

The study was supported by a grant from the National Institute on Drug Abuse. Dr. Humphreys reported support through a Senior Career Research Scientist award from the VA Health Services Research and Development Service.

SOURCE: Pitt AL et al. Am J Public Health. 2018 Aug 23. doi: 10.2105/AJPH.2018.304590.

Some policy responses to the opioid epidemic have immediate, beneficial effects, while others lead to short-term harms that might be offset by long-term health benefits, according to researchers who have mathematically modeled the impact of 11 interventions.

Policies that expand addiction treatment or curb harmful effects of addiction such as overdose and infection were immediately beneficial in the model, with no negative effects on life years (LYs), quality-adjusted life years (QALYs), or addiction deaths, the researchers reported.

In contrast, policies that constrain prescription opioid supply resulted in some benefits, but also short-term harms because of inadequate pain control and users switching to heroin.

However, the modeling study also suggests those harms might be mitigated over the long term as new addictions are averted, according to Allison L. Pitt, a PhD candidate in the department of management science and engineering at Stanford (Calif.) University, and her coauthors.

Combining different interventions had additive benefits in the model, prompting Ms. Pitt and her coauthors to recommend a multifaceted policy approach to curb opioid abuse and reduce addiction deaths.

“No epidemic has ever been averted solely by treating single affected cases,” they wrote in the American Journal of Public Health. “Instead, portfolios of policies will likely be required, including those that prevent addiction, treat addiction, and mitigate its effects.”

In their study, Ms. Pitt and her colleagues projected the impact of 11 policies aimed at curbing opioid addiction and reducing addiction deaths. They used dynamic compartmental modeling, a technique commonly used for evaluating the spread of contagious disease.

This technique is appropriate for studying the opioid epidemic, because it allows for dynamic modeling of addiction incidence that reflects a changing number of prescription holders, the authors said in their report, which focused on projected outcomes of various interventions at 5 and 10 years.

None of the policies substantially reduced opioid-related deaths in 5-year outcomes projections, they found. Increasing availability of naloxone averted 4% of addiction deaths, the highest reduction of any intervention over that time period.

However, interventions focused on providing services for people with addictions did generally provide uniform benefits over the 5-year horizon: “Naloxone availability, needle exchange, medication-assisted treatment, and psychosocial treatment policies generate gains in LYs and QALYs and reduce deaths, without harming any group,” Ms. Pitt and her coauthors said.

Interventions that reduced opioid supply, such as excess opioid disposal and reduced prescribing for transitioning pain, increased LYs and QALYs while decreasing total addiction deaths over 5 years. However, the investigators said, those benefits were partly offset by increases in heroin-related deaths.

Drug rescheduling was associated with a 45.6% increase in heroin-related deaths over 5 years in the model, the highest percentage increase of any intervention in the published data.

Over the 10-year horizon, addiction deaths continued to decrease proportionally for naloxone availability and needle-exchange policies, authors said. By comparison, policies focused on opioid supply, such as excess opioid disposal and reduced prescribing for transitioning pain, averted substantially more deaths over 10 years than would be expected, compared with the 5-year results, investigators said.

Acute pain prescribing, which increased opioid-related deaths over 5 years in the model, was associated with a decrease in opioid-related deaths over 10 years, they added.

The report coauthors were Keith Humphreys, PhD, of Stanford’s department of psychiatry and behavioral sciences, and Margaret L. Brandeau, PhD, of the university’s department of management science and engineering.

The coauthors cited several limitations. One is that the opioid epidemic is changing in unpredictable ways. Therefore, numerous assumptions about the epidemic were made based on the opinions of clinicians and scientists.

The study was supported by a grant from the National Institute on Drug Abuse. Dr. Humphreys reported support through a Senior Career Research Scientist award from the VA Health Services Research and Development Service.

SOURCE: Pitt AL et al. Am J Public Health. 2018 Aug 23. doi: 10.2105/AJPH.2018.304590.

The Roman Catholic Church continues to be rocked by the burgeoning reality of priests as sexual predators. Some Catholics, including the Pope, have stepped up and acknowledged the blame for the decades of abuse, but others have been less inclined to do so. The latter attitude was and still is crushing to some the victims.

“Being raised Catholic, I remember – you don’t speak out against your own church,” Jim VanSickle says in an interview with National Catholic Reporter. “Nobody’s going to listen to you.”

Many of the survivors, Mr. VanSickle included, belonged to very conservative parishes. Parishioners often showed no compassion. After being sexually assaulted at age 16, he suffered in silence for almost 4 decades before speaking out during the recent release of Grand Jury report on the church abuses by the Pennsylvania attorney general.

“I’ve known others [who] came forward. They were ridiculed and ostracized – even by their own family members,” Mr. VanSickle says.

“We lived in a neighborhood where most of the people in the subdivision were Catholic. Everything in our lives revolved around the church,” said another victim, Utah resident Judy Larson. To be in that kind of environment and try to say something horrible happened to you, by a person everybody thinks is a god on earth, you’re all alone.”

As reported by Zita Ballinger Fletcher of the Catholic News Service, “survivors also faced a stigma caused by sexual assault. The victims were molested at an age when they did not know about sex. Confused, they realized what happened when they grew up. Feeling disgust, anger, and shame, they feared hostile reactions from their traditional communities.”

The childhood horror has left many of the victims angry and disillusioned with the Catholic Church.

“People say, ‘You’re a bad person,’ ” Mr. VanSickle says. “It’s amazing that they attack their own people. They attack their own faithful.”

Click here to read about the challenges faced by these survivors.

The Roman Catholic Church continues to be rocked by the burgeoning reality of priests as sexual predators. Some Catholics, including the Pope, have stepped up and acknowledged the blame for the decades of abuse, but others have been less inclined to do so. The latter attitude was and still is crushing to some the victims.

“Being raised Catholic, I remember – you don’t speak out against your own church,” Jim VanSickle says in an interview with National Catholic Reporter. “Nobody’s going to listen to you.”

Many of the survivors, Mr. VanSickle included, belonged to very conservative parishes. Parishioners often showed no compassion. After being sexually assaulted at age 16, he suffered in silence for almost 4 decades before speaking out during the recent release of Grand Jury report on the church abuses by the Pennsylvania attorney general.

“I’ve known others [who] came forward. They were ridiculed and ostracized – even by their own family members,” Mr. VanSickle says.

“We lived in a neighborhood where most of the people in the subdivision were Catholic. Everything in our lives revolved around the church,” said another victim, Utah resident Judy Larson. To be in that kind of environment and try to say something horrible happened to you, by a person everybody thinks is a god on earth, you’re all alone.”

As reported by Zita Ballinger Fletcher of the Catholic News Service, “survivors also faced a stigma caused by sexual assault. The victims were molested at an age when they did not know about sex. Confused, they realized what happened when they grew up. Feeling disgust, anger, and shame, they feared hostile reactions from their traditional communities.”

The childhood horror has left many of the victims angry and disillusioned with the Catholic Church.

“People say, ‘You’re a bad person,’ ” Mr. VanSickle says. “It’s amazing that they attack their own people. They attack their own faithful.”

Click here to read about the challenges faced by these survivors.

The Roman Catholic Church continues to be rocked by the burgeoning reality of priests as sexual predators. Some Catholics, including the Pope, have stepped up and acknowledged the blame for the decades of abuse, but others have been less inclined to do so. The latter attitude was and still is crushing to some the victims.

“Being raised Catholic, I remember – you don’t speak out against your own church,” Jim VanSickle says in an interview with National Catholic Reporter. “Nobody’s going to listen to you.”

Many of the survivors, Mr. VanSickle included, belonged to very conservative parishes. Parishioners often showed no compassion. After being sexually assaulted at age 16, he suffered in silence for almost 4 decades before speaking out during the recent release of Grand Jury report on the church abuses by the Pennsylvania attorney general.

“I’ve known others [who] came forward. They were ridiculed and ostracized – even by their own family members,” Mr. VanSickle says.

“We lived in a neighborhood where most of the people in the subdivision were Catholic. Everything in our lives revolved around the church,” said another victim, Utah resident Judy Larson. To be in that kind of environment and try to say something horrible happened to you, by a person everybody thinks is a god on earth, you’re all alone.”

As reported by Zita Ballinger Fletcher of the Catholic News Service, “survivors also faced a stigma caused by sexual assault. The victims were molested at an age when they did not know about sex. Confused, they realized what happened when they grew up. Feeling disgust, anger, and shame, they feared hostile reactions from their traditional communities.”

The childhood horror has left many of the victims angry and disillusioned with the Catholic Church.

“People say, ‘You’re a bad person,’ ” Mr. VanSickle says. “It’s amazing that they attack their own people. They attack their own faithful.”

Click here to read about the challenges faced by these survivors.

MUNICH – The big news in the field of heart failure at the annual congress of the European Society of Cardiology concerned an obscure form of the disease traditionally considered rare: transthyretin amyloid cardiomyopathy (TAC).

Bruce Jancin/MDedge News

It turns out that TAC is far more common than previously recognized; it can now be diagnosed and staged noninvasively; and – most important of all – there is for the first time an effective disease-modifying treatment in the form of a novel oral drug called tafamidis, as demonstrated in the Transthyretin Amyloidosis Cardiomyopathy Clinical Trial (ATTR-ACT) presented at the meeting.

“This is the first phase 3 trial that can offer a chance for people with a terrible, severe disease. And within the last year, while the trial was being conducted, it became clear that this disease is much more underdiagnosed than rare,” said Claudio Rapezzi, MD, ATTR-ACT principal investigator and director of the school of cardiovascular diseases at the University of Bologna, Italy.

ATTR-ACT participants randomized to tafamidis showed significant reductions in all-cause mortality and cardiovascular hospitalizations, compared with placebo-treated controls at 30 months follow-up. They also experienced significantly lesser declines in both quality of life as reflected in Kansas City Cardiomyopathy Questionnaire scores and in physical function as captured in 6-minute walk distance.

Bruce Jancin/MDedge News

Designated discussant Jacob George, MD, was over the moon regarding the results.

“This is a pioneering, game-changing trial that is likely to transform the way we diagnose and treat patients with cardiac amyloidosis,” said Dr. George of Kaplan Medical Center in Rehovot, Israel.

“We’re now in an era that, to my opinion, any patient with nonischemic unexplained heart failure should be screened for the presence of amyloidosis because, first, we now know how to prognosticate these patients, and second, we can offer them a real disease-modifying agent,” he added.
 

An underdiagnosed disease

Transthyretin amyloid cardiomyopathy occurs when transthyretin, a transport protein, becomes destabilized and misfolds, promoting deposition of amyloid fibrils in the myocardium. This results in progressive ventricular wall thickening and stiffness, manifest as restrictive cardiomyopathy and progressive heart failure. The cause of transthyretin destabilization can be either autosomal dominant inheritance of any of more than 100 pathogenic mutations in the transthyretin gene identified to date or a spontaneous wild type protein.

Think of TAC as a sort of dementia of the heart. As Dr. George noted, the cardiac disease bears “remarkable similarities” to Alzheimer’s disease, with both conditions entailing extracellular deposition of amyloid.

In the heritable form of TAC, patients typically present with heart failure symptoms at about age 50-55, while the wild type form becomes symptomatic much later at a mean age of about 75. Average survival from time of diagnosis is only about 3 years.

Recent studies from multiple centers have reported that the prevalence of TAC was 16% in patients undergoing transcatheter aortic valve replacement for severe aortic stenosis, 13% among patients with heart failure with preserved ejection fraction, and 5% in patients who had been presumed to have hypertrophic cardiomyopathy: So, not a rare condition.

“In our clinic, vast and surprising numbers of patients with unexplained nonischemic heart failure are scan positive [for TAC],” according to Dr. George.
 

Breakthroughs in diagnosis and staging

The echocardiographic red flag for TAC in a patient with heart failure symptoms is symmetric hypertrophy with a normal end-diastolic volume and thickened ventricles. The end-diastolic interventricular septal wall thickness is typically about 15 mm. The left ventricular ejection fraction is typically in the normal range, “but the clue is not the preservation of the ejection fraction, it’s the [normal] quality of the volume,” Dr. Rapezzi said.

A clinical clue suggestive of TAC upon physical examination, even in the absence of heart failure symptoms, is development of bilateral carpal tunnel syndrome in an older man. That’s because the same disease process that results in TAC can involve deposition of amyloid fibrils in peripheral nerves. Indeed, tafamidis is already approved in Europe and Japan under the trade name Vyndaqel as a treatment for familial amyloid polyneuropathy. For TAC, however, tafamidis remains investigational with fast-track status provided by both the Food and Drug Administration and the European Medicines Agency.

When TAC is suspected, it’s no longer necessary to subject patients to an onerous myocardial biopsy. Total body scintigraphy with bone tracers has been shown to be nearly as sensitive and specific as biopsy for the diagnosis.

Staging can now be done noninvasively as well. Investigators at the U.K. National Amyloidosis Centre recently reported that patients with TAC can be accurately staged using two biomarkers: N-terminal pro-B-type natriuretic peptide (NT-proBNP) and estimated glomerular filtration rate (eGFR). In their series of 869 patients with TAC, median survival for those with stage I disease as defined by their protocol was 69 months, compared with 47 months for stage II disease and 24 months for those with stage III disease. This simple U.K. staging system was then validated in a separate French cohort of TAC patients (Eur Heart J. 2018 Aug 7;39[30]:2799-806).
 

The ATTR-ACT trial

Dr. Rapezzi reported on 441 patients with TAC who were randomized to oral tafamidis at either 20 mg or 80 mg per day or placebo and followed prospectively for 30 months in the 13-country, double-blind, phase 3 trial. At 30 months, all-cause mortality was 29.5% in patients who received tafamidis, compared with 42.9% in controls, for a 30% relative risk reduction. The rate of cardiovascular hospitalizations was 0.48 per year with tafamidis, compared with 0.70 per year with placebo, for a 38% relative risk reduction. The mortality benefit didn’t achieve significance until 15-18 months into the trial, as to be expected given tafamidis’ mechanism of action, which involves binding to transthyretin, gradually stabilizing it, and curbing amyloid fibril deposition.

Of note, the benefit was similar regardless of the dose used and whether patients had hereditary or wild type TAC.

Tafamidis proved safe and well tolerated, with a side-effect profile similar to placebo. While diarrhea and urinary tract infections have been an issue in tafamidis-treated patients with familial amyloid polyneuropathy, these adverse events were actually less common in TAC patients who received tafamidis than with placebo, according to Dr. Rapezzi.

A key point, the cardiologist emphasized, is that the benefits of active treatment were greatest in patients with earlier-stage disease. Therefore it’s vital that the diagnosis of TAC be made early, with prompt initiation of treatment to follow, in order to catch the disease at a more reversible stage. That could mean there will be a whole lot more bone scintigraphy being done in patients with unexplained nonischemic heart failure.

Dr. Rapezzi reported receiving research grants, speaker honoraria, and consulting fees from Pfizer, which sponsored the ATTR-ACT trial. Simultaneous with his presentation in Munich, the study results were published online at NEJM.org (doi: 10.1056/NEJMoa1805689). Dr. George reported no financial conflicts.

[email protected]

MUNICH – The big news in the field of heart failure at the annual congress of the European Society of Cardiology concerned an obscure form of the disease traditionally considered rare: transthyretin amyloid cardiomyopathy (TAC).

Bruce Jancin/MDedge News

It turns out that TAC is far more common than previously recognized; it can now be diagnosed and staged noninvasively; and – most important of all – there is for the first time an effective disease-modifying treatment in the form of a novel oral drug called tafamidis, as demonstrated in the Transthyretin Amyloidosis Cardiomyopathy Clinical Trial (ATTR-ACT) presented at the meeting.

“This is the first phase 3 trial that can offer a chance for people with a terrible, severe disease. And within the last year, while the trial was being conducted, it became clear that this disease is much more underdiagnosed than rare,” said Claudio Rapezzi, MD, ATTR-ACT principal investigator and director of the school of cardiovascular diseases at the University of Bologna, Italy.

ATTR-ACT participants randomized to tafamidis showed significant reductions in all-cause mortality and cardiovascular hospitalizations, compared with placebo-treated controls at 30 months follow-up. They also experienced significantly lesser declines in both quality of life as reflected in Kansas City Cardiomyopathy Questionnaire scores and in physical function as captured in 6-minute walk distance.

Bruce Jancin/MDedge News

Designated discussant Jacob George, MD, was over the moon regarding the results.

“This is a pioneering, game-changing trial that is likely to transform the way we diagnose and treat patients with cardiac amyloidosis,” said Dr. George of Kaplan Medical Center in Rehovot, Israel.

“We’re now in an era that, to my opinion, any patient with nonischemic unexplained heart failure should be screened for the presence of amyloidosis because, first, we now know how to prognosticate these patients, and second, we can offer them a real disease-modifying agent,” he added.
 

An underdiagnosed disease

Transthyretin amyloid cardiomyopathy occurs when transthyretin, a transport protein, becomes destabilized and misfolds, promoting deposition of amyloid fibrils in the myocardium. This results in progressive ventricular wall thickening and stiffness, manifest as restrictive cardiomyopathy and progressive heart failure. The cause of transthyretin destabilization can be either autosomal dominant inheritance of any of more than 100 pathogenic mutations in the transthyretin gene identified to date or a spontaneous wild type protein.

Think of TAC as a sort of dementia of the heart. As Dr. George noted, the cardiac disease bears “remarkable similarities” to Alzheimer’s disease, with both conditions entailing extracellular deposition of amyloid.

In the heritable form of TAC, patients typically present with heart failure symptoms at about age 50-55, while the wild type form becomes symptomatic much later at a mean age of about 75. Average survival from time of diagnosis is only about 3 years.

Recent studies from multiple centers have reported that the prevalence of TAC was 16% in patients undergoing transcatheter aortic valve replacement for severe aortic stenosis, 13% among patients with heart failure with preserved ejection fraction, and 5% in patients who had been presumed to have hypertrophic cardiomyopathy: So, not a rare condition.

“In our clinic, vast and surprising numbers of patients with unexplained nonischemic heart failure are scan positive [for TAC],” according to Dr. George.
 

Breakthroughs in diagnosis and staging

The echocardiographic red flag for TAC in a patient with heart failure symptoms is symmetric hypertrophy with a normal end-diastolic volume and thickened ventricles. The end-diastolic interventricular septal wall thickness is typically about 15 mm. The left ventricular ejection fraction is typically in the normal range, “but the clue is not the preservation of the ejection fraction, it’s the [normal] quality of the volume,” Dr. Rapezzi said.

A clinical clue suggestive of TAC upon physical examination, even in the absence of heart failure symptoms, is development of bilateral carpal tunnel syndrome in an older man. That’s because the same disease process that results in TAC can involve deposition of amyloid fibrils in peripheral nerves. Indeed, tafamidis is already approved in Europe and Japan under the trade name Vyndaqel as a treatment for familial amyloid polyneuropathy. For TAC, however, tafamidis remains investigational with fast-track status provided by both the Food and Drug Administration and the European Medicines Agency.

When TAC is suspected, it’s no longer necessary to subject patients to an onerous myocardial biopsy. Total body scintigraphy with bone tracers has been shown to be nearly as sensitive and specific as biopsy for the diagnosis.

Staging can now be done noninvasively as well. Investigators at the U.K. National Amyloidosis Centre recently reported that patients with TAC can be accurately staged using two biomarkers: N-terminal pro-B-type natriuretic peptide (NT-proBNP) and estimated glomerular filtration rate (eGFR). In their series of 869 patients with TAC, median survival for those with stage I disease as defined by their protocol was 69 months, compared with 47 months for stage II disease and 24 months for those with stage III disease. This simple U.K. staging system was then validated in a separate French cohort of TAC patients (Eur Heart J. 2018 Aug 7;39[30]:2799-806).
 

The ATTR-ACT trial

Dr. Rapezzi reported on 441 patients with TAC who were randomized to oral tafamidis at either 20 mg or 80 mg per day or placebo and followed prospectively for 30 months in the 13-country, double-blind, phase 3 trial. At 30 months, all-cause mortality was 29.5% in patients who received tafamidis, compared with 42.9% in controls, for a 30% relative risk reduction. The rate of cardiovascular hospitalizations was 0.48 per year with tafamidis, compared with 0.70 per year with placebo, for a 38% relative risk reduction. The mortality benefit didn’t achieve significance until 15-18 months into the trial, as to be expected given tafamidis’ mechanism of action, which involves binding to transthyretin, gradually stabilizing it, and curbing amyloid fibril deposition.

Of note, the benefit was similar regardless of the dose used and whether patients had hereditary or wild type TAC.

Tafamidis proved safe and well tolerated, with a side-effect profile similar to placebo. While diarrhea and urinary tract infections have been an issue in tafamidis-treated patients with familial amyloid polyneuropathy, these adverse events were actually less common in TAC patients who received tafamidis than with placebo, according to Dr. Rapezzi.

A key point, the cardiologist emphasized, is that the benefits of active treatment were greatest in patients with earlier-stage disease. Therefore it’s vital that the diagnosis of TAC be made early, with prompt initiation of treatment to follow, in order to catch the disease at a more reversible stage. That could mean there will be a whole lot more bone scintigraphy being done in patients with unexplained nonischemic heart failure.

Dr. Rapezzi reported receiving research grants, speaker honoraria, and consulting fees from Pfizer, which sponsored the ATTR-ACT trial. Simultaneous with his presentation in Munich, the study results were published online at NEJM.org (doi: 10.1056/NEJMoa1805689). Dr. George reported no financial conflicts.

[email protected]

MUNICH – The big news in the field of heart failure at the annual congress of the European Society of Cardiology concerned an obscure form of the disease traditionally considered rare: transthyretin amyloid cardiomyopathy (TAC).

Bruce Jancin/MDedge News

It turns out that TAC is far more common than previously recognized; it can now be diagnosed and staged noninvasively; and – most important of all – there is for the first time an effective disease-modifying treatment in the form of a novel oral drug called tafamidis, as demonstrated in the Transthyretin Amyloidosis Cardiomyopathy Clinical Trial (ATTR-ACT) presented at the meeting.

“This is the first phase 3 trial that can offer a chance for people with a terrible, severe disease. And within the last year, while the trial was being conducted, it became clear that this disease is much more underdiagnosed than rare,” said Claudio Rapezzi, MD, ATTR-ACT principal investigator and director of the school of cardiovascular diseases at the University of Bologna, Italy.

ATTR-ACT participants randomized to tafamidis showed significant reductions in all-cause mortality and cardiovascular hospitalizations, compared with placebo-treated controls at 30 months follow-up. They also experienced significantly lesser declines in both quality of life as reflected in Kansas City Cardiomyopathy Questionnaire scores and in physical function as captured in 6-minute walk distance.

Bruce Jancin/MDedge News

Designated discussant Jacob George, MD, was over the moon regarding the results.

“This is a pioneering, game-changing trial that is likely to transform the way we diagnose and treat patients with cardiac amyloidosis,” said Dr. George of Kaplan Medical Center in Rehovot, Israel.

“We’re now in an era that, to my opinion, any patient with nonischemic unexplained heart failure should be screened for the presence of amyloidosis because, first, we now know how to prognosticate these patients, and second, we can offer them a real disease-modifying agent,” he added.
 

An underdiagnosed disease

Transthyretin amyloid cardiomyopathy occurs when transthyretin, a transport protein, becomes destabilized and misfolds, promoting deposition of amyloid fibrils in the myocardium. This results in progressive ventricular wall thickening and stiffness, manifest as restrictive cardiomyopathy and progressive heart failure. The cause of transthyretin destabilization can be either autosomal dominant inheritance of any of more than 100 pathogenic mutations in the transthyretin gene identified to date or a spontaneous wild type protein.

Think of TAC as a sort of dementia of the heart. As Dr. George noted, the cardiac disease bears “remarkable similarities” to Alzheimer’s disease, with both conditions entailing extracellular deposition of amyloid.

In the heritable form of TAC, patients typically present with heart failure symptoms at about age 50-55, while the wild type form becomes symptomatic much later at a mean age of about 75. Average survival from time of diagnosis is only about 3 years.

Recent studies from multiple centers have reported that the prevalence of TAC was 16% in patients undergoing transcatheter aortic valve replacement for severe aortic stenosis, 13% among patients with heart failure with preserved ejection fraction, and 5% in patients who had been presumed to have hypertrophic cardiomyopathy: So, not a rare condition.

“In our clinic, vast and surprising numbers of patients with unexplained nonischemic heart failure are scan positive [for TAC],” according to Dr. George.
 

Breakthroughs in diagnosis and staging

The echocardiographic red flag for TAC in a patient with heart failure symptoms is symmetric hypertrophy with a normal end-diastolic volume and thickened ventricles. The end-diastolic interventricular septal wall thickness is typically about 15 mm. The left ventricular ejection fraction is typically in the normal range, “but the clue is not the preservation of the ejection fraction, it’s the [normal] quality of the volume,” Dr. Rapezzi said.

A clinical clue suggestive of TAC upon physical examination, even in the absence of heart failure symptoms, is development of bilateral carpal tunnel syndrome in an older man. That’s because the same disease process that results in TAC can involve deposition of amyloid fibrils in peripheral nerves. Indeed, tafamidis is already approved in Europe and Japan under the trade name Vyndaqel as a treatment for familial amyloid polyneuropathy. For TAC, however, tafamidis remains investigational with fast-track status provided by both the Food and Drug Administration and the European Medicines Agency.

When TAC is suspected, it’s no longer necessary to subject patients to an onerous myocardial biopsy. Total body scintigraphy with bone tracers has been shown to be nearly as sensitive and specific as biopsy for the diagnosis.

Staging can now be done noninvasively as well. Investigators at the U.K. National Amyloidosis Centre recently reported that patients with TAC can be accurately staged using two biomarkers: N-terminal pro-B-type natriuretic peptide (NT-proBNP) and estimated glomerular filtration rate (eGFR). In their series of 869 patients with TAC, median survival for those with stage I disease as defined by their protocol was 69 months, compared with 47 months for stage II disease and 24 months for those with stage III disease. This simple U.K. staging system was then validated in a separate French cohort of TAC patients (Eur Heart J. 2018 Aug 7;39[30]:2799-806).
 

The ATTR-ACT trial

Dr. Rapezzi reported on 441 patients with TAC who were randomized to oral tafamidis at either 20 mg or 80 mg per day or placebo and followed prospectively for 30 months in the 13-country, double-blind, phase 3 trial. At 30 months, all-cause mortality was 29.5% in patients who received tafamidis, compared with 42.9% in controls, for a 30% relative risk reduction. The rate of cardiovascular hospitalizations was 0.48 per year with tafamidis, compared with 0.70 per year with placebo, for a 38% relative risk reduction. The mortality benefit didn’t achieve significance until 15-18 months into the trial, as to be expected given tafamidis’ mechanism of action, which involves binding to transthyretin, gradually stabilizing it, and curbing amyloid fibril deposition.

Of note, the benefit was similar regardless of the dose used and whether patients had hereditary or wild type TAC.

Tafamidis proved safe and well tolerated, with a side-effect profile similar to placebo. While diarrhea and urinary tract infections have been an issue in tafamidis-treated patients with familial amyloid polyneuropathy, these adverse events were actually less common in TAC patients who received tafamidis than with placebo, according to Dr. Rapezzi.

A key point, the cardiologist emphasized, is that the benefits of active treatment were greatest in patients with earlier-stage disease. Therefore it’s vital that the diagnosis of TAC be made early, with prompt initiation of treatment to follow, in order to catch the disease at a more reversible stage. That could mean there will be a whole lot more bone scintigraphy being done in patients with unexplained nonischemic heart failure.

Dr. Rapezzi reported receiving research grants, speaker honoraria, and consulting fees from Pfizer, which sponsored the ATTR-ACT trial. Simultaneous with his presentation in Munich, the study results were published online at NEJM.org (doi: 10.1056/NEJMoa1805689). Dr. George reported no financial conflicts.

[email protected]

A suicide attempt can be devastating for family members. For a son or daughter, the fallout can include feelings of guilt at missing the warning signs and the knowledge that they may have contributed to the despair that might have driven their loved one to trying to end their own lives.

PhotoDisk

There also can be the feeling that the attempt to deliberately exit this life is an indication that those left behind are not valued.

As related in a StoryCorps episode, which described the attempted suicide of Linda Kwong and the toll on her daughter Emily, Linda’s longstanding suicidal depression was separate from her love for her family.

The news of the suicide attempt rocked Emily. “I described our family as a table, and you were the most important leg. So you disappearing just knocked the whole thing over,” she says.

Yet, the past had seen Emily distancing herself from Linda, with the reality of her mother’s ongoing darkness. “I thought if I spent too much time with you, I would become like you,” Emily says to Linda during their StoryCorps interview.

In the aftermath of Linda’s suicide attempt, the mother-daughter bond could have been shattered. Instead, in the intervening 5 years, it has been stripped down and rebuilt, with both individuals coming to a better understanding of one another and the pain in their lives.

“I mean, I know it’s not over yet, but seeing you come back from this, I couldn’t be more proud of you,” Emily says to Linda.

“I can’t believe that you can use the word ‘proud,’ but it makes me feel like that bond between us will always be there,” Linda says. “And that means the world to me.”

Click here to listen to their StoryCorps episode, broadcast on NPR.

A suicide attempt can be devastating for family members. For a son or daughter, the fallout can include feelings of guilt at missing the warning signs and the knowledge that they may have contributed to the despair that might have driven their loved one to trying to end their own lives.

PhotoDisk

There also can be the feeling that the attempt to deliberately exit this life is an indication that those left behind are not valued.

As related in a StoryCorps episode, which described the attempted suicide of Linda Kwong and the toll on her daughter Emily, Linda’s longstanding suicidal depression was separate from her love for her family.

The news of the suicide attempt rocked Emily. “I described our family as a table, and you were the most important leg. So you disappearing just knocked the whole thing over,” she says.

Yet, the past had seen Emily distancing herself from Linda, with the reality of her mother’s ongoing darkness. “I thought if I spent too much time with you, I would become like you,” Emily says to Linda during their StoryCorps interview.

In the aftermath of Linda’s suicide attempt, the mother-daughter bond could have been shattered. Instead, in the intervening 5 years, it has been stripped down and rebuilt, with both individuals coming to a better understanding of one another and the pain in their lives.

“I mean, I know it’s not over yet, but seeing you come back from this, I couldn’t be more proud of you,” Emily says to Linda.

“I can’t believe that you can use the word ‘proud,’ but it makes me feel like that bond between us will always be there,” Linda says. “And that means the world to me.”

Click here to listen to their StoryCorps episode, broadcast on NPR.

A suicide attempt can be devastating for family members. For a son or daughter, the fallout can include feelings of guilt at missing the warning signs and the knowledge that they may have contributed to the despair that might have driven their loved one to trying to end their own lives.

PhotoDisk

There also can be the feeling that the attempt to deliberately exit this life is an indication that those left behind are not valued.

As related in a StoryCorps episode, which described the attempted suicide of Linda Kwong and the toll on her daughter Emily, Linda’s longstanding suicidal depression was separate from her love for her family.

The news of the suicide attempt rocked Emily. “I described our family as a table, and you were the most important leg. So you disappearing just knocked the whole thing over,” she says.

Yet, the past had seen Emily distancing herself from Linda, with the reality of her mother’s ongoing darkness. “I thought if I spent too much time with you, I would become like you,” Emily says to Linda during their StoryCorps interview.

In the aftermath of Linda’s suicide attempt, the mother-daughter bond could have been shattered. Instead, in the intervening 5 years, it has been stripped down and rebuilt, with both individuals coming to a better understanding of one another and the pain in their lives.

“I mean, I know it’s not over yet, but seeing you come back from this, I couldn’t be more proud of you,” Emily says to Linda.

“I can’t believe that you can use the word ‘proud,’ but it makes me feel like that bond between us will always be there,” Linda says. “And that means the world to me.”

Click here to listen to their StoryCorps episode, broadcast on NPR.