Mitchel L. Zoler, PhD

LONDON – Young and middle-age adults who survive an MI have substantially improved prospects today for having a relatively normal lifespan, compared with MI patients from the 1980s, according to data from a population-based Danish study involving more than 200,000 residents.

“Long-term mortality following an MI before age 50 years decreased remarkably over the last 3 decades and is approaching the long-term mortality of the general Danish population,” Dr. Morten Schmidt said at the annual congress of the European Society of Cardiology.

But while the absolute long-term mortality among patients who have an MI when they are less than 50 years old is now low and substantially reduced from what it was in the 1980s, the death rate among these patients is still roughly twice the rate seen in the general population and is primarily the result of ischemic heart disease and smoking-related diseases, he said.

This enduring excess risk means that young MI survivors need to continue to adhere to prescribed medical therapies and to implement lifestyle changes such as smoking cessation and increased physical activity, said Dr. Schmidt, a clinical epidemiologist at Aarhus (Denmark) University. He attributed the risk reduction that occurred from the 1980s through the 2000s to coronary intervention strategies and medical treatment for secondary prevention.

Dr. Schmidt and his associates examined mortality trends among young MI survivors using data available through the population-based registries maintained by the Danish National Health Service. As of 2009, 21,693 Danish adults younger than 50 years old had had a MI. Investigators matched them by age, gender, and year of MI on a 1:10 basis with 216,930 Danes who had no MI history. The MI patients averaged 45 years old, 84% were 40-49 years old, and 80% were men. Somewhat more than one third of the MIs occurred in 1980-1989, and slightly less than a third occurred in 1990-1999, and slightly less than a third in 2000-2009. The researchers tracked the outcomes of the MI survivors and controls through the end of 2012.

The findings showed that 10-year mortality among patients who survived for at least 1 year following their MI dropped from 24% among patients who had their MI in the 1980s to 9% among those with an MI in the 2000s.

When the researchers compared subjects’ mortality with that of the matched general population and also adjusted for comorbidities, they found that the excess 10-year mortality among MI survivors dropped from nearly fivefold above the all-cause death rate of general population during the 1980s to about a twofold increase among the MI survivors from the 2000s. During the 2000s, for every 1,000 people younger than 50 years of age who had an MI and survived for at least 1 year, six additional deaths occurred per year during each of the subsequent 9 years, compared with the general Danish population. In contrast, the MI survivors from the 1980s had an excess of 25 deaths per year, compared with the general population, for every 1,000 MI survivors who lived for at least 1 year.

Dr. Schmidt had no disclosures.

mzoler@frontlinemedcom.com

On Twitter @mitchelzoler

LONDON – Young and middle-age adults who survive an MI have substantially improved prospects today for having a relatively normal lifespan, compared with MI patients from the 1980s, according to data from a population-based Danish study involving more than 200,000 residents.

“Long-term mortality following an MI before age 50 years decreased remarkably over the last 3 decades and is approaching the long-term mortality of the general Danish population,” Dr. Morten Schmidt said at the annual congress of the European Society of Cardiology.

But while the absolute long-term mortality among patients who have an MI when they are less than 50 years old is now low and substantially reduced from what it was in the 1980s, the death rate among these patients is still roughly twice the rate seen in the general population and is primarily the result of ischemic heart disease and smoking-related diseases, he said.

This enduring excess risk means that young MI survivors need to continue to adhere to prescribed medical therapies and to implement lifestyle changes such as smoking cessation and increased physical activity, said Dr. Schmidt, a clinical epidemiologist at Aarhus (Denmark) University. He attributed the risk reduction that occurred from the 1980s through the 2000s to coronary intervention strategies and medical treatment for secondary prevention.

Dr. Schmidt and his associates examined mortality trends among young MI survivors using data available through the population-based registries maintained by the Danish National Health Service. As of 2009, 21,693 Danish adults younger than 50 years old had had a MI. Investigators matched them by age, gender, and year of MI on a 1:10 basis with 216,930 Danes who had no MI history. The MI patients averaged 45 years old, 84% were 40-49 years old, and 80% were men. Somewhat more than one third of the MIs occurred in 1980-1989, and slightly less than a third occurred in 1990-1999, and slightly less than a third in 2000-2009. The researchers tracked the outcomes of the MI survivors and controls through the end of 2012.

The findings showed that 10-year mortality among patients who survived for at least 1 year following their MI dropped from 24% among patients who had their MI in the 1980s to 9% among those with an MI in the 2000s.

When the researchers compared subjects’ mortality with that of the matched general population and also adjusted for comorbidities, they found that the excess 10-year mortality among MI survivors dropped from nearly fivefold above the all-cause death rate of general population during the 1980s to about a twofold increase among the MI survivors from the 2000s. During the 2000s, for every 1,000 people younger than 50 years of age who had an MI and survived for at least 1 year, six additional deaths occurred per year during each of the subsequent 9 years, compared with the general Danish population. In contrast, the MI survivors from the 1980s had an excess of 25 deaths per year, compared with the general population, for every 1,000 MI survivors who lived for at least 1 year.

Dr. Schmidt had no disclosures.

mzoler@frontlinemedcom.com

On Twitter @mitchelzoler

LONDON – Young and middle-age adults who survive an MI have substantially improved prospects today for having a relatively normal lifespan, compared with MI patients from the 1980s, according to data from a population-based Danish study involving more than 200,000 residents.

“Long-term mortality following an MI before age 50 years decreased remarkably over the last 3 decades and is approaching the long-term mortality of the general Danish population,” Dr. Morten Schmidt said at the annual congress of the European Society of Cardiology.

But while the absolute long-term mortality among patients who have an MI when they are less than 50 years old is now low and substantially reduced from what it was in the 1980s, the death rate among these patients is still roughly twice the rate seen in the general population and is primarily the result of ischemic heart disease and smoking-related diseases, he said.

This enduring excess risk means that young MI survivors need to continue to adhere to prescribed medical therapies and to implement lifestyle changes such as smoking cessation and increased physical activity, said Dr. Schmidt, a clinical epidemiologist at Aarhus (Denmark) University. He attributed the risk reduction that occurred from the 1980s through the 2000s to coronary intervention strategies and medical treatment for secondary prevention.

Dr. Schmidt and his associates examined mortality trends among young MI survivors using data available through the population-based registries maintained by the Danish National Health Service. As of 2009, 21,693 Danish adults younger than 50 years old had had a MI. Investigators matched them by age, gender, and year of MI on a 1:10 basis with 216,930 Danes who had no MI history. The MI patients averaged 45 years old, 84% were 40-49 years old, and 80% were men. Somewhat more than one third of the MIs occurred in 1980-1989, and slightly less than a third occurred in 1990-1999, and slightly less than a third in 2000-2009. The researchers tracked the outcomes of the MI survivors and controls through the end of 2012.

The findings showed that 10-year mortality among patients who survived for at least 1 year following their MI dropped from 24% among patients who had their MI in the 1980s to 9% among those with an MI in the 2000s.

When the researchers compared subjects’ mortality with that of the matched general population and also adjusted for comorbidities, they found that the excess 10-year mortality among MI survivors dropped from nearly fivefold above the all-cause death rate of general population during the 1980s to about a twofold increase among the MI survivors from the 2000s. During the 2000s, for every 1,000 people younger than 50 years of age who had an MI and survived for at least 1 year, six additional deaths occurred per year during each of the subsequent 9 years, compared with the general Danish population. In contrast, the MI survivors from the 1980s had an excess of 25 deaths per year, compared with the general population, for every 1,000 MI survivors who lived for at least 1 year.

Dr. Schmidt had no disclosures.

mzoler@frontlinemedcom.com

On Twitter @mitchelzoler

In an era when rehospitalization of patients with heart failure for episodes of acute decompensation has become a top target for reduction in the U.S. health care system via Medicare’s Readmissions Reduction Program CardioMEMS looks like the tool that every U.S. health care system and medical center has dreamed of having.

A wireless and battery-less implanted device, CardioMEMS guides management of stage III heart failure patients by allowing daily monitoring of patients’ pulmonary-artery pressure (PAP). Using these measures to fine-tune patient treatment with diuretics and vasodilators led to a statistically significant and clinically meaningful 37% relative reduction in heart failure rehospitalizations over an average 15-month follow-up, based on results from CardioMEMS’ pivotal U.S. trial as well as from subsequent secondary analyses. All-cause mortality was reduced and patients’ quality of life improved. And device-driven therapy yielded these benefits equally well in patients with either preserved or reduced left ventricular function as well as in a variety of other subgroups including patients with cardiac resynchronization devices or implantable cardioverter defibrillators, chronic obstructive pulmonary disease, chronic kidney disease, atrial fibrillation, pulmonary hypertension, or a history of myocardial infarction.

Yet in the first year after CardioMEMS received Food and Drug Administration approval and came onto the U.S. market, the device has taken a strikingly slow path into routine heart failure practice, according to heart failure cardiologists at several U.S. centers. A representative of St. Jude, the company that markets CardioMEMS, saidin July that sales of the device during the first half of 2015 had involved more than 200 U.S. customers and slightly surpassed earlier expectations, and the company now anticipated full 2015 sales to run roughly 25% ahead of projections made at the start of this year. Despite that, the company’s second quarter report acknowledged the challenges that CardioMEMS faced during its first year on the U.S. market.

Numbers show a slow rollout

“I belong to a consortium of academic heart failure physicians who come from many of the major U.S. academic medical centers, and a recent straw poll of the members showed that close to no one was using it [CardioMEMS] on a regular basis, and the majority said they were not yet using it at all or in the process of starting their program,” said Dr. Javed Butler, a heart failure specialist who is professor of medicine, chief of cardiology, and codirector of the Stony Brook (N.Y.) University Heart Center.

At Stony Brook, no heart failure patient had received the device as of July 2015, although Dr. Butler said that his program’s use of CardioMEMS will probably start soon. Cardiologists at a handful of other U.S. centers report similarly slow starts.

At Massachusetts General Hospital (MGH) in Boston not a single patient has received CardioMEMS, though the heart failure staff there hopes to soon launch pilot use in 10 patients, said Dr. Kimberly A. Parks, associate director of the resynchronization and advanced cardiac therapeutics program. At the University of Colorado Hospital in Aurora, three patients have received the device since their first implant in the late winter, and the program is now on track to place devices in another one or two patients each month, said Dr. Natasha L. Altman, a cardiologist who heads the center’s CardioMEMS program. At Brigham and Women’s Hospital in Boston, which participated in the CHAMPION (CardioMEMS Heart Sensor Allows Monitoring of Pressure to Improve Outcomes in NYHA Class III Heart Failure Patients) pivotal trial that led to CardioMEMS approval, so far a “handful, fewer than 10 patients” received the device since marketing began, said Dr. Akshay S. Desai, associate director of Brigham Cardiovascular Consultants. Even at Ohio State’s Wexner Medical Center in Columbus, the program run by Dr. William T. Abraham, coprincipal investigator for CHAMPION, a relatively modest number of roughly 50 patients had received CardioMEMS in routine practice since the first patient received a device there in June 2014 following the FDA’s approval, Dr. Abraham said in an interview.

Contrasting with this level of use is the substantial number of patients who meet the CHAMPION enrollment criteria of New York Heart Association class III heart failure and a heart failure hospitalization within the prior year. Experts estimate that throughout the United States this group must number at least a half-million patients, and at the level of individual medical centers that provide advanced heart failure care, the numbers likely reach several hundred patients at each site.

Several challenges slow CardioMEMS implantation

Why such a slow start for what seems to be such an attractive device that clinicians uniformly praise for having a strong evidence base in CHAMPION and a compelling medical rationale? The answer seems multifactorial, including the need to convince skeptical hospital administrators and insurance payers to provide and pay for the device and follow-up care, a requirement to ramp up the patient-monitoring and management infrastructure, and the challenge of transitioning a relatively complex therapeutic formula from a successful clinical trial model into routine care.

“If this was a pill that you could prescribe to patients at hospital discharge, people would jump on it. But CardioMEMS is not as simple as prescribing a pill. There are a lot of logistical issues that make it very difficult,” said Stony Brook’s Dr. Butler in an interview.

This sentiment was shared not only by other cardiologists but also by St. Jude itself, as a company spokesman itemized several challenges the company encountered once it began trying to sell CardioMEMS commercially. “Developing the market for CardioMEMS will continue to take time,” said the St. Jude staffer during a July webcast on the company’s second-quarter 2015 performance. CardioMEMS’ sales were affected by the need to educate multiple constituencies, satisfy new-technology review committees, address reimbursement, access capital budgets, and create consensus among disparate stakeholders, the webcast said. In addition, the early St. Jude experience selling CardioMEMS showed that once a new customer signs a contract, “we find that customers tend to introduce CardioMEMS ... [on] a pilot basis to gain experience with the technology and the reimbursement process.”

First is the challenge of selling a hospital’s administrative leadership on making an upfront capital investment in CardioMEMS equipment, giving the green light to performing procedures that just about break even relative to reimbursement, and then waiting to recoup the initial expenditure and perhaps make some money in the long term by avoiding readmissions and cutting lengths of stay. According to an analysis run by Dr. Parks of MGH, based on the CHAMPION results, for every 10 patients managed using CardioMEMS for 6 months, a center could expect to prevent nearly 15 patient-days in the hospital.

“Our administration is in support, but skeptical; I think that’s why it’s been slow to start,” said Dr. Parks. “The biggest limitation is the upfront cost of the device, and it’s not clear that the reimbursement will allow you to break even” when putting in devices, she said in an interview. “You could justify this by saying you’ll reduce hospitalizations, but the first impression from our administrators was that we were already doing a pretty good job limiting rehospitalizations so why do we need to add this?” The MGH leadership and clinicians eventually agreed on a plan to start the program with 10 implants and then analyze the results to decide if it makes sense to continue. Dr. Parks said she and her colleagues hope to have their first 10 patients implanted with a CardioMEMS before the end of this year.

Another hurdle at MGH was setting up the infrastructure so that a nurse could monitor patients and set in motion the alerts and treatment changes designed to normalize PAP normalized when it falls out of the target range. “It’s a lot of work to put the system in place to manage the devices,” Dr. Parks noted.

Dr. Butler echoed both these challenges. “You need to convince the hospital administrators and make a case based on the cost savings [later on during ongoing management] rather than positive revenue when you do the procedure. If you can expect future cost savings it’s a viable case to make, but a more difficult case to make,” he said. “You also take on the liability of monitoring patients” long term. “If you can follow several hundred patients there may be enough [follow-up] interventions to pay the salaries of staff ” who monitor the patients, but it is very difficult if you have a nurse who is monitoring five patients,” he said. Another issue complicating the economics is that the physicians who supervise monitoring are mostly not the same ones who performed the CardioMEMS placement procedure and received the procedure’s reimbursement. “These are the system barriers that are out there,” Dr. Butler said.

Dr. Altman in Colorado faced a different challenge. “We had good buy-in from our administration. Everyone is interested in reducing rehospitalizations so the administrators were very supportive. The major roadblock has been insurers. Medicare covers it, but so far Colorado Medicaid and several private insurers do not,” Dr. Altman said in an interview. The inconsistent pattern of insurance coverage has already meant that some heart failure patients in her program who were good clinical candidates for CardioMEMS could not receive the device. “I’ve had at least six or seven good candidates, but only three received the device because of insurance reimbursement issues,” she said.

But Dr. Altman expressed optimism that the coverage situation would improve as more programs start using CarioMEMS and insurers grow more familiar with daily PAP monitoring of heart failure patients. She noted that a new CardioMEMS program will soon start at a second Denver-based medical center, and she expressed confidence that ongoing pressure from physicians and administrators at both institutions will change the mind of officials at Colorado’s Medicaid program to provide reimbursement, and once that happens she expects the private insurers will change their policies as well.

To Dr. Abraham at Ohio State, one of the developers of the concept of using an implanted PAP monitor to guide management of heart failure patients, CardioMEMS slow take off is not surprising. “It provides physicians with daily information on a patient’s hemodynamics, which is something they never had before except in the catheterization laboratory, intensive care unit or cardiac care unit. Managing patients based on hemodynamics even in the absence of worsening signs and symptoms is a paradigm shift. It takes time to adopt new things.” He noted that most hospitals and health systems already have in place case managers or nurse navigators who run systems that have relied on the insensitive parameters of signs, symptoms, and patients’ weights. The same infrastructure should be able to fairly easily switch to focusing instead on PAP, said Dr. Abraham, professor and director of cardiovascular medicine at Wexner Medical Center.

He acknowledged that the upfront capital cost required to start a CardioMEMS program can poses a financial barrier at many U.S. centers, but once that start-up price is paid the actual implantation into each patient comes close to breaking even with existing reimbursements and the system should eventually result in a return on the investment in the form of reduced readmissions and keeping patients stable, he said. Dr. Abraham suggested that the possibility also exists that maintaining better stability in patients with class III heart failure and preventing episodes of acute decompensation through better-titrated fluid-volume control could produce a long-term change in the natural history of these patients, whose disease historically has been marked by progression to class IV heart failure and the eventual need for a left ventricular assist device, heart transplant, and death. Although this potential impact of refined treatment based on daily PAP monitoring remains to be proven, a secondary analysis from CHAMPION showing a 57% relative reduction in all-cause mortality over an average of 17 months of follow-up that Dr. Abraham reported at the American College of Cardiology annual meeting in March

The hurdle of routine practice

Transitioning CardioMEMS from its successful research track record to everyday clinical practice may pose the trickiest barrier of all. The consensus among heart failure experts seems to be that the best approach to do this successfully is to start slow, focus on the most rational patients within the broad enrollment criteria used in CHAMPION, and then gradually expand from that presuming the first wave of results from routine use at a particular site look similar to those from the trial.

“The next big question for PAP monitoring is can we replicate the trial’s success in routine practice? Can this be scaled up?” said Dr. Desai from Brigham and Women’s. “We’re still learning how to identify the right patients, the ones who’ll benefit,”

“The two types of patients we are primarily implanting now are those with classic class III heart failure who were hospitalized during the past 12 months and now are hospitalized again and are right in front of us. They are the lowest-hanging fruit because they are in the hospital today,” said Dr. Abraham. “The second group are the patients who come into the clinic complaining about their symptoms. What we are not yet doing is calling in all patients” with stage III heart failure and a history of at least one hospitalization.”

Other groups are taking a much more selective approach. Dr. Altman and her colleagues in Denver are only targeting patients who have been hospitalized at least twice within the past year, and more specifically patients recently rehospitalized within 30 days of their prior hospitalization. They are also focusing on patients expected to have a high level of compliance with the daily data-collection demands of PAP monitoring and the need to regularly adjust their medication dosages after receiving call backs from their clinicians. This criteria means that they are ruling out patients with a history of substance abuse, she said.

She also noted the need to tailor the target PAP to the specific clinical status of individual patients. Patients with mitral regurgitation, for example, will have a higher “normal” diastolic PAP and hence require a somewhat different target for stability maintenance. “You need to understand each patient’s baseline pressures and adjust their medications based on that,” Dr. Altman said.

“In real life patients tend to be older and sicker, so their benefit may be even greater than what was seen in CHAMPION, but perhaps the results will also be diluted because of comorbidities like renal failure or chronic obstructive pulmonary disease,” said Dr. Butler, although post hoc subanalyses of CHAMPION data showed that these comorbidities did not blunt the positive impact of PAP-guided treatment. “I don’t know if I’ll be successful in selecting the right patients, and whether my interventions in real life will produce the same good outcomes” seen in CHAMPION. “We’ll select patients who are close to the CHAMPION criteria, but not patients on dialysis [who were excluded from CHAMPION]; we’ll select patients with a modest degree of comorbidity and reasonable expected survival,” Dr. Butler said.

“If you had a drug that reduced rehospitalization rates it would be pretty clear how to proceed, but in this case it is not the device that reduces readmissions, it just gives you data and you need to act on the data,” Dr. Butler added. He acknowledged that the CHAMPION investigators used a relatively simple, straightforward management algorithm for patients whose PAP fell out of the target range, such as a diastolic PAP greater than 20 mm Hg or less than 8 mm Hg. The first management step is to raise or reduce the patient’s diuretic dosage, and if that fails to quickly normalize PAP the next step is to adjust the vasodilator dosage.

Managing patients in CHAMPION was “not totally an art” but neither was it “totally a science,” Dr. Butler said. Managing patients based on daily data collected using a CardioMEMS device will “require a little finesse,” he said. “It’s not straight science.”

Programs that have already used PAP monitoring on a routine basis, like those in Denver and at Brigham and Women’s, consider their experience too small in size and short in duration to draw any substantive conclusions regarding their success compared with the CHAMPION results. But Dr. Abraham, whose program has now placed CardioMEMS routinely in a few dozen patients and followed them for as long as a year, said that in his center’s patients the device and management system has produced outcomes that roughly match what he saw in the pivotal trial.

“The ongoing concern is that what was achieved in the CHAMPION trial may not be what is achieved in routine practice,” said Dr. Desai. The care that patients received in the trial is “a little of a black box,” he said, and during the FDA’s approval process some reviewers raised concerns that patients in the active-treatment arm simply received more intensive surveillance, although this concern eventually resolved. “There is not a lot of skepticism” among clinicians about this treatment, but there is uncertainly about exactly whom are the best patients to treat and whether their responses be as good as in CHAMPION, Dr. Desai said in an interview.

“The proof [of efficacy] will be in each individual center’s experience” using CardioMEMS, Dr. Altman said.

CHAMPION was initially funded by CardioMEMS, which then was acquired by St. Jude which is the company marketing the CardioMEMS device and associated hardware. Dr. Butler said that he had no current relevant disclosures, although in the past he had been a consultant to CardioMEMS (prior to its acquisition by St. Jude). Dr. Parks and Dr. Altman had no disclosures. Dr. Desai has been a consultant to and has received honoraria as a speaker on behalf of CardioMEMS and St. Jude. Dr. Abraham has been a consultant to CardioMEMS and St. Jude, was co-principal investigator on the CHAMPION trial, and is the principal investigator on a new St. Jude-funded trial studying CardioMEMS.

mzoler@frontlinemedcom.com

On Twitter @mitchelzoler

In an era when rehospitalization of patients with heart failure for episodes of acute decompensation has become a top target for reduction in the U.S. health care system via Medicare’s Readmissions Reduction Program CardioMEMS looks like the tool that every U.S. health care system and medical center has dreamed of having.

A wireless and battery-less implanted device, CardioMEMS guides management of stage III heart failure patients by allowing daily monitoring of patients’ pulmonary-artery pressure (PAP). Using these measures to fine-tune patient treatment with diuretics and vasodilators led to a statistically significant and clinically meaningful 37% relative reduction in heart failure rehospitalizations over an average 15-month follow-up, based on results from CardioMEMS’ pivotal U.S. trial as well as from subsequent secondary analyses. All-cause mortality was reduced and patients’ quality of life improved. And device-driven therapy yielded these benefits equally well in patients with either preserved or reduced left ventricular function as well as in a variety of other subgroups including patients with cardiac resynchronization devices or implantable cardioverter defibrillators, chronic obstructive pulmonary disease, chronic kidney disease, atrial fibrillation, pulmonary hypertension, or a history of myocardial infarction.

Yet in the first year after CardioMEMS received Food and Drug Administration approval and came onto the U.S. market, the device has taken a strikingly slow path into routine heart failure practice, according to heart failure cardiologists at several U.S. centers. A representative of St. Jude, the company that markets CardioMEMS, saidin July that sales of the device during the first half of 2015 had involved more than 200 U.S. customers and slightly surpassed earlier expectations, and the company now anticipated full 2015 sales to run roughly 25% ahead of projections made at the start of this year. Despite that, the company’s second quarter report acknowledged the challenges that CardioMEMS faced during its first year on the U.S. market.

Numbers show a slow rollout

“I belong to a consortium of academic heart failure physicians who come from many of the major U.S. academic medical centers, and a recent straw poll of the members showed that close to no one was using it [CardioMEMS] on a regular basis, and the majority said they were not yet using it at all or in the process of starting their program,” said Dr. Javed Butler, a heart failure specialist who is professor of medicine, chief of cardiology, and codirector of the Stony Brook (N.Y.) University Heart Center.

At Stony Brook, no heart failure patient had received the device as of July 2015, although Dr. Butler said that his program’s use of CardioMEMS will probably start soon. Cardiologists at a handful of other U.S. centers report similarly slow starts.

At Massachusetts General Hospital (MGH) in Boston not a single patient has received CardioMEMS, though the heart failure staff there hopes to soon launch pilot use in 10 patients, said Dr. Kimberly A. Parks, associate director of the resynchronization and advanced cardiac therapeutics program. At the University of Colorado Hospital in Aurora, three patients have received the device since their first implant in the late winter, and the program is now on track to place devices in another one or two patients each month, said Dr. Natasha L. Altman, a cardiologist who heads the center’s CardioMEMS program. At Brigham and Women’s Hospital in Boston, which participated in the CHAMPION (CardioMEMS Heart Sensor Allows Monitoring of Pressure to Improve Outcomes in NYHA Class III Heart Failure Patients) pivotal trial that led to CardioMEMS approval, so far a “handful, fewer than 10 patients” received the device since marketing began, said Dr. Akshay S. Desai, associate director of Brigham Cardiovascular Consultants. Even at Ohio State’s Wexner Medical Center in Columbus, the program run by Dr. William T. Abraham, coprincipal investigator for CHAMPION, a relatively modest number of roughly 50 patients had received CardioMEMS in routine practice since the first patient received a device there in June 2014 following the FDA’s approval, Dr. Abraham said in an interview.

Contrasting with this level of use is the substantial number of patients who meet the CHAMPION enrollment criteria of New York Heart Association class III heart failure and a heart failure hospitalization within the prior year. Experts estimate that throughout the United States this group must number at least a half-million patients, and at the level of individual medical centers that provide advanced heart failure care, the numbers likely reach several hundred patients at each site.

Several challenges slow CardioMEMS implantation

Why such a slow start for what seems to be such an attractive device that clinicians uniformly praise for having a strong evidence base in CHAMPION and a compelling medical rationale? The answer seems multifactorial, including the need to convince skeptical hospital administrators and insurance payers to provide and pay for the device and follow-up care, a requirement to ramp up the patient-monitoring and management infrastructure, and the challenge of transitioning a relatively complex therapeutic formula from a successful clinical trial model into routine care.

“If this was a pill that you could prescribe to patients at hospital discharge, people would jump on it. But CardioMEMS is not as simple as prescribing a pill. There are a lot of logistical issues that make it very difficult,” said Stony Brook’s Dr. Butler in an interview.

This sentiment was shared not only by other cardiologists but also by St. Jude itself, as a company spokesman itemized several challenges the company encountered once it began trying to sell CardioMEMS commercially. “Developing the market for CardioMEMS will continue to take time,” said the St. Jude staffer during a July webcast on the company’s second-quarter 2015 performance. CardioMEMS’ sales were affected by the need to educate multiple constituencies, satisfy new-technology review committees, address reimbursement, access capital budgets, and create consensus among disparate stakeholders, the webcast said. In addition, the early St. Jude experience selling CardioMEMS showed that once a new customer signs a contract, “we find that customers tend to introduce CardioMEMS ... [on] a pilot basis to gain experience with the technology and the reimbursement process.”

First is the challenge of selling a hospital’s administrative leadership on making an upfront capital investment in CardioMEMS equipment, giving the green light to performing procedures that just about break even relative to reimbursement, and then waiting to recoup the initial expenditure and perhaps make some money in the long term by avoiding readmissions and cutting lengths of stay. According to an analysis run by Dr. Parks of MGH, based on the CHAMPION results, for every 10 patients managed using CardioMEMS for 6 months, a center could expect to prevent nearly 15 patient-days in the hospital.

“Our administration is in support, but skeptical; I think that’s why it’s been slow to start,” said Dr. Parks. “The biggest limitation is the upfront cost of the device, and it’s not clear that the reimbursement will allow you to break even” when putting in devices, she said in an interview. “You could justify this by saying you’ll reduce hospitalizations, but the first impression from our administrators was that we were already doing a pretty good job limiting rehospitalizations so why do we need to add this?” The MGH leadership and clinicians eventually agreed on a plan to start the program with 10 implants and then analyze the results to decide if it makes sense to continue. Dr. Parks said she and her colleagues hope to have their first 10 patients implanted with a CardioMEMS before the end of this year.

Another hurdle at MGH was setting up the infrastructure so that a nurse could monitor patients and set in motion the alerts and treatment changes designed to normalize PAP normalized when it falls out of the target range. “It’s a lot of work to put the system in place to manage the devices,” Dr. Parks noted.

Dr. Butler echoed both these challenges. “You need to convince the hospital administrators and make a case based on the cost savings [later on during ongoing management] rather than positive revenue when you do the procedure. If you can expect future cost savings it’s a viable case to make, but a more difficult case to make,” he said. “You also take on the liability of monitoring patients” long term. “If you can follow several hundred patients there may be enough [follow-up] interventions to pay the salaries of staff ” who monitor the patients, but it is very difficult if you have a nurse who is monitoring five patients,” he said. Another issue complicating the economics is that the physicians who supervise monitoring are mostly not the same ones who performed the CardioMEMS placement procedure and received the procedure’s reimbursement. “These are the system barriers that are out there,” Dr. Butler said.

Dr. Altman in Colorado faced a different challenge. “We had good buy-in from our administration. Everyone is interested in reducing rehospitalizations so the administrators were very supportive. The major roadblock has been insurers. Medicare covers it, but so far Colorado Medicaid and several private insurers do not,” Dr. Altman said in an interview. The inconsistent pattern of insurance coverage has already meant that some heart failure patients in her program who were good clinical candidates for CardioMEMS could not receive the device. “I’ve had at least six or seven good candidates, but only three received the device because of insurance reimbursement issues,” she said.

But Dr. Altman expressed optimism that the coverage situation would improve as more programs start using CarioMEMS and insurers grow more familiar with daily PAP monitoring of heart failure patients. She noted that a new CardioMEMS program will soon start at a second Denver-based medical center, and she expressed confidence that ongoing pressure from physicians and administrators at both institutions will change the mind of officials at Colorado’s Medicaid program to provide reimbursement, and once that happens she expects the private insurers will change their policies as well.

To Dr. Abraham at Ohio State, one of the developers of the concept of using an implanted PAP monitor to guide management of heart failure patients, CardioMEMS slow take off is not surprising. “It provides physicians with daily information on a patient’s hemodynamics, which is something they never had before except in the catheterization laboratory, intensive care unit or cardiac care unit. Managing patients based on hemodynamics even in the absence of worsening signs and symptoms is a paradigm shift. It takes time to adopt new things.” He noted that most hospitals and health systems already have in place case managers or nurse navigators who run systems that have relied on the insensitive parameters of signs, symptoms, and patients’ weights. The same infrastructure should be able to fairly easily switch to focusing instead on PAP, said Dr. Abraham, professor and director of cardiovascular medicine at Wexner Medical Center.

He acknowledged that the upfront capital cost required to start a CardioMEMS program can poses a financial barrier at many U.S. centers, but once that start-up price is paid the actual implantation into each patient comes close to breaking even with existing reimbursements and the system should eventually result in a return on the investment in the form of reduced readmissions and keeping patients stable, he said. Dr. Abraham suggested that the possibility also exists that maintaining better stability in patients with class III heart failure and preventing episodes of acute decompensation through better-titrated fluid-volume control could produce a long-term change in the natural history of these patients, whose disease historically has been marked by progression to class IV heart failure and the eventual need for a left ventricular assist device, heart transplant, and death. Although this potential impact of refined treatment based on daily PAP monitoring remains to be proven, a secondary analysis from CHAMPION showing a 57% relative reduction in all-cause mortality over an average of 17 months of follow-up that Dr. Abraham reported at the American College of Cardiology annual meeting in March

The hurdle of routine practice

Transitioning CardioMEMS from its successful research track record to everyday clinical practice may pose the trickiest barrier of all. The consensus among heart failure experts seems to be that the best approach to do this successfully is to start slow, focus on the most rational patients within the broad enrollment criteria used in CHAMPION, and then gradually expand from that presuming the first wave of results from routine use at a particular site look similar to those from the trial.

“The next big question for PAP monitoring is can we replicate the trial’s success in routine practice? Can this be scaled up?” said Dr. Desai from Brigham and Women’s. “We’re still learning how to identify the right patients, the ones who’ll benefit,”

“The two types of patients we are primarily implanting now are those with classic class III heart failure who were hospitalized during the past 12 months and now are hospitalized again and are right in front of us. They are the lowest-hanging fruit because they are in the hospital today,” said Dr. Abraham. “The second group are the patients who come into the clinic complaining about their symptoms. What we are not yet doing is calling in all patients” with stage III heart failure and a history of at least one hospitalization.”

Other groups are taking a much more selective approach. Dr. Altman and her colleagues in Denver are only targeting patients who have been hospitalized at least twice within the past year, and more specifically patients recently rehospitalized within 30 days of their prior hospitalization. They are also focusing on patients expected to have a high level of compliance with the daily data-collection demands of PAP monitoring and the need to regularly adjust their medication dosages after receiving call backs from their clinicians. This criteria means that they are ruling out patients with a history of substance abuse, she said.

She also noted the need to tailor the target PAP to the specific clinical status of individual patients. Patients with mitral regurgitation, for example, will have a higher “normal” diastolic PAP and hence require a somewhat different target for stability maintenance. “You need to understand each patient’s baseline pressures and adjust their medications based on that,” Dr. Altman said.

“In real life patients tend to be older and sicker, so their benefit may be even greater than what was seen in CHAMPION, but perhaps the results will also be diluted because of comorbidities like renal failure or chronic obstructive pulmonary disease,” said Dr. Butler, although post hoc subanalyses of CHAMPION data showed that these comorbidities did not blunt the positive impact of PAP-guided treatment. “I don’t know if I’ll be successful in selecting the right patients, and whether my interventions in real life will produce the same good outcomes” seen in CHAMPION. “We’ll select patients who are close to the CHAMPION criteria, but not patients on dialysis [who were excluded from CHAMPION]; we’ll select patients with a modest degree of comorbidity and reasonable expected survival,” Dr. Butler said.

“If you had a drug that reduced rehospitalization rates it would be pretty clear how to proceed, but in this case it is not the device that reduces readmissions, it just gives you data and you need to act on the data,” Dr. Butler added. He acknowledged that the CHAMPION investigators used a relatively simple, straightforward management algorithm for patients whose PAP fell out of the target range, such as a diastolic PAP greater than 20 mm Hg or less than 8 mm Hg. The first management step is to raise or reduce the patient’s diuretic dosage, and if that fails to quickly normalize PAP the next step is to adjust the vasodilator dosage.

Managing patients in CHAMPION was “not totally an art” but neither was it “totally a science,” Dr. Butler said. Managing patients based on daily data collected using a CardioMEMS device will “require a little finesse,” he said. “It’s not straight science.”

Programs that have already used PAP monitoring on a routine basis, like those in Denver and at Brigham and Women’s, consider their experience too small in size and short in duration to draw any substantive conclusions regarding their success compared with the CHAMPION results. But Dr. Abraham, whose program has now placed CardioMEMS routinely in a few dozen patients and followed them for as long as a year, said that in his center’s patients the device and management system has produced outcomes that roughly match what he saw in the pivotal trial.

“The ongoing concern is that what was achieved in the CHAMPION trial may not be what is achieved in routine practice,” said Dr. Desai. The care that patients received in the trial is “a little of a black box,” he said, and during the FDA’s approval process some reviewers raised concerns that patients in the active-treatment arm simply received more intensive surveillance, although this concern eventually resolved. “There is not a lot of skepticism” among clinicians about this treatment, but there is uncertainly about exactly whom are the best patients to treat and whether their responses be as good as in CHAMPION, Dr. Desai said in an interview.

“The proof [of efficacy] will be in each individual center’s experience” using CardioMEMS, Dr. Altman said.

CHAMPION was initially funded by CardioMEMS, which then was acquired by St. Jude which is the company marketing the CardioMEMS device and associated hardware. Dr. Butler said that he had no current relevant disclosures, although in the past he had been a consultant to CardioMEMS (prior to its acquisition by St. Jude). Dr. Parks and Dr. Altman had no disclosures. Dr. Desai has been a consultant to and has received honoraria as a speaker on behalf of CardioMEMS and St. Jude. Dr. Abraham has been a consultant to CardioMEMS and St. Jude, was co-principal investigator on the CHAMPION trial, and is the principal investigator on a new St. Jude-funded trial studying CardioMEMS.

mzoler@frontlinemedcom.com

On Twitter @mitchelzoler

In an era when rehospitalization of patients with heart failure for episodes of acute decompensation has become a top target for reduction in the U.S. health care system via Medicare’s Readmissions Reduction Program CardioMEMS looks like the tool that every U.S. health care system and medical center has dreamed of having.

A wireless and battery-less implanted device, CardioMEMS guides management of stage III heart failure patients by allowing daily monitoring of patients’ pulmonary-artery pressure (PAP). Using these measures to fine-tune patient treatment with diuretics and vasodilators led to a statistically significant and clinically meaningful 37% relative reduction in heart failure rehospitalizations over an average 15-month follow-up, based on results from CardioMEMS’ pivotal U.S. trial as well as from subsequent secondary analyses. All-cause mortality was reduced and patients’ quality of life improved. And device-driven therapy yielded these benefits equally well in patients with either preserved or reduced left ventricular function as well as in a variety of other subgroups including patients with cardiac resynchronization devices or implantable cardioverter defibrillators, chronic obstructive pulmonary disease, chronic kidney disease, atrial fibrillation, pulmonary hypertension, or a history of myocardial infarction.

Yet in the first year after CardioMEMS received Food and Drug Administration approval and came onto the U.S. market, the device has taken a strikingly slow path into routine heart failure practice, according to heart failure cardiologists at several U.S. centers. A representative of St. Jude, the company that markets CardioMEMS, saidin July that sales of the device during the first half of 2015 had involved more than 200 U.S. customers and slightly surpassed earlier expectations, and the company now anticipated full 2015 sales to run roughly 25% ahead of projections made at the start of this year. Despite that, the company’s second quarter report acknowledged the challenges that CardioMEMS faced during its first year on the U.S. market.

Numbers show a slow rollout

“I belong to a consortium of academic heart failure physicians who come from many of the major U.S. academic medical centers, and a recent straw poll of the members showed that close to no one was using it [CardioMEMS] on a regular basis, and the majority said they were not yet using it at all or in the process of starting their program,” said Dr. Javed Butler, a heart failure specialist who is professor of medicine, chief of cardiology, and codirector of the Stony Brook (N.Y.) University Heart Center.

At Stony Brook, no heart failure patient had received the device as of July 2015, although Dr. Butler said that his program’s use of CardioMEMS will probably start soon. Cardiologists at a handful of other U.S. centers report similarly slow starts.

At Massachusetts General Hospital (MGH) in Boston not a single patient has received CardioMEMS, though the heart failure staff there hopes to soon launch pilot use in 10 patients, said Dr. Kimberly A. Parks, associate director of the resynchronization and advanced cardiac therapeutics program. At the University of Colorado Hospital in Aurora, three patients have received the device since their first implant in the late winter, and the program is now on track to place devices in another one or two patients each month, said Dr. Natasha L. Altman, a cardiologist who heads the center’s CardioMEMS program. At Brigham and Women’s Hospital in Boston, which participated in the CHAMPION (CardioMEMS Heart Sensor Allows Monitoring of Pressure to Improve Outcomes in NYHA Class III Heart Failure Patients) pivotal trial that led to CardioMEMS approval, so far a “handful, fewer than 10 patients” received the device since marketing began, said Dr. Akshay S. Desai, associate director of Brigham Cardiovascular Consultants. Even at Ohio State’s Wexner Medical Center in Columbus, the program run by Dr. William T. Abraham, coprincipal investigator for CHAMPION, a relatively modest number of roughly 50 patients had received CardioMEMS in routine practice since the first patient received a device there in June 2014 following the FDA’s approval, Dr. Abraham said in an interview.

Contrasting with this level of use is the substantial number of patients who meet the CHAMPION enrollment criteria of New York Heart Association class III heart failure and a heart failure hospitalization within the prior year. Experts estimate that throughout the United States this group must number at least a half-million patients, and at the level of individual medical centers that provide advanced heart failure care, the numbers likely reach several hundred patients at each site.

Several challenges slow CardioMEMS implantation

Why such a slow start for what seems to be such an attractive device that clinicians uniformly praise for having a strong evidence base in CHAMPION and a compelling medical rationale? The answer seems multifactorial, including the need to convince skeptical hospital administrators and insurance payers to provide and pay for the device and follow-up care, a requirement to ramp up the patient-monitoring and management infrastructure, and the challenge of transitioning a relatively complex therapeutic formula from a successful clinical trial model into routine care.

“If this was a pill that you could prescribe to patients at hospital discharge, people would jump on it. But CardioMEMS is not as simple as prescribing a pill. There are a lot of logistical issues that make it very difficult,” said Stony Brook’s Dr. Butler in an interview.

This sentiment was shared not only by other cardiologists but also by St. Jude itself, as a company spokesman itemized several challenges the company encountered once it began trying to sell CardioMEMS commercially. “Developing the market for CardioMEMS will continue to take time,” said the St. Jude staffer during a July webcast on the company’s second-quarter 2015 performance. CardioMEMS’ sales were affected by the need to educate multiple constituencies, satisfy new-technology review committees, address reimbursement, access capital budgets, and create consensus among disparate stakeholders, the webcast said. In addition, the early St. Jude experience selling CardioMEMS showed that once a new customer signs a contract, “we find that customers tend to introduce CardioMEMS ... [on] a pilot basis to gain experience with the technology and the reimbursement process.”

First is the challenge of selling a hospital’s administrative leadership on making an upfront capital investment in CardioMEMS equipment, giving the green light to performing procedures that just about break even relative to reimbursement, and then waiting to recoup the initial expenditure and perhaps make some money in the long term by avoiding readmissions and cutting lengths of stay. According to an analysis run by Dr. Parks of MGH, based on the CHAMPION results, for every 10 patients managed using CardioMEMS for 6 months, a center could expect to prevent nearly 15 patient-days in the hospital.

“Our administration is in support, but skeptical; I think that’s why it’s been slow to start,” said Dr. Parks. “The biggest limitation is the upfront cost of the device, and it’s not clear that the reimbursement will allow you to break even” when putting in devices, she said in an interview. “You could justify this by saying you’ll reduce hospitalizations, but the first impression from our administrators was that we were already doing a pretty good job limiting rehospitalizations so why do we need to add this?” The MGH leadership and clinicians eventually agreed on a plan to start the program with 10 implants and then analyze the results to decide if it makes sense to continue. Dr. Parks said she and her colleagues hope to have their first 10 patients implanted with a CardioMEMS before the end of this year.

Another hurdle at MGH was setting up the infrastructure so that a nurse could monitor patients and set in motion the alerts and treatment changes designed to normalize PAP normalized when it falls out of the target range. “It’s a lot of work to put the system in place to manage the devices,” Dr. Parks noted.

Dr. Butler echoed both these challenges. “You need to convince the hospital administrators and make a case based on the cost savings [later on during ongoing management] rather than positive revenue when you do the procedure. If you can expect future cost savings it’s a viable case to make, but a more difficult case to make,” he said. “You also take on the liability of monitoring patients” long term. “If you can follow several hundred patients there may be enough [follow-up] interventions to pay the salaries of staff ” who monitor the patients, but it is very difficult if you have a nurse who is monitoring five patients,” he said. Another issue complicating the economics is that the physicians who supervise monitoring are mostly not the same ones who performed the CardioMEMS placement procedure and received the procedure’s reimbursement. “These are the system barriers that are out there,” Dr. Butler said.

Dr. Altman in Colorado faced a different challenge. “We had good buy-in from our administration. Everyone is interested in reducing rehospitalizations so the administrators were very supportive. The major roadblock has been insurers. Medicare covers it, but so far Colorado Medicaid and several private insurers do not,” Dr. Altman said in an interview. The inconsistent pattern of insurance coverage has already meant that some heart failure patients in her program who were good clinical candidates for CardioMEMS could not receive the device. “I’ve had at least six or seven good candidates, but only three received the device because of insurance reimbursement issues,” she said.

But Dr. Altman expressed optimism that the coverage situation would improve as more programs start using CarioMEMS and insurers grow more familiar with daily PAP monitoring of heart failure patients. She noted that a new CardioMEMS program will soon start at a second Denver-based medical center, and she expressed confidence that ongoing pressure from physicians and administrators at both institutions will change the mind of officials at Colorado’s Medicaid program to provide reimbursement, and once that happens she expects the private insurers will change their policies as well.

To Dr. Abraham at Ohio State, one of the developers of the concept of using an implanted PAP monitor to guide management of heart failure patients, CardioMEMS slow take off is not surprising. “It provides physicians with daily information on a patient’s hemodynamics, which is something they never had before except in the catheterization laboratory, intensive care unit or cardiac care unit. Managing patients based on hemodynamics even in the absence of worsening signs and symptoms is a paradigm shift. It takes time to adopt new things.” He noted that most hospitals and health systems already have in place case managers or nurse navigators who run systems that have relied on the insensitive parameters of signs, symptoms, and patients’ weights. The same infrastructure should be able to fairly easily switch to focusing instead on PAP, said Dr. Abraham, professor and director of cardiovascular medicine at Wexner Medical Center.

He acknowledged that the upfront capital cost required to start a CardioMEMS program can poses a financial barrier at many U.S. centers, but once that start-up price is paid the actual implantation into each patient comes close to breaking even with existing reimbursements and the system should eventually result in a return on the investment in the form of reduced readmissions and keeping patients stable, he said. Dr. Abraham suggested that the possibility also exists that maintaining better stability in patients with class III heart failure and preventing episodes of acute decompensation through better-titrated fluid-volume control could produce a long-term change in the natural history of these patients, whose disease historically has been marked by progression to class IV heart failure and the eventual need for a left ventricular assist device, heart transplant, and death. Although this potential impact of refined treatment based on daily PAP monitoring remains to be proven, a secondary analysis from CHAMPION showing a 57% relative reduction in all-cause mortality over an average of 17 months of follow-up that Dr. Abraham reported at the American College of Cardiology annual meeting in March

The hurdle of routine practice

Transitioning CardioMEMS from its successful research track record to everyday clinical practice may pose the trickiest barrier of all. The consensus among heart failure experts seems to be that the best approach to do this successfully is to start slow, focus on the most rational patients within the broad enrollment criteria used in CHAMPION, and then gradually expand from that presuming the first wave of results from routine use at a particular site look similar to those from the trial.

“The next big question for PAP monitoring is can we replicate the trial’s success in routine practice? Can this be scaled up?” said Dr. Desai from Brigham and Women’s. “We’re still learning how to identify the right patients, the ones who’ll benefit,”

“The two types of patients we are primarily implanting now are those with classic class III heart failure who were hospitalized during the past 12 months and now are hospitalized again and are right in front of us. They are the lowest-hanging fruit because they are in the hospital today,” said Dr. Abraham. “The second group are the patients who come into the clinic complaining about their symptoms. What we are not yet doing is calling in all patients” with stage III heart failure and a history of at least one hospitalization.”

Other groups are taking a much more selective approach. Dr. Altman and her colleagues in Denver are only targeting patients who have been hospitalized at least twice within the past year, and more specifically patients recently rehospitalized within 30 days of their prior hospitalization. They are also focusing on patients expected to have a high level of compliance with the daily data-collection demands of PAP monitoring and the need to regularly adjust their medication dosages after receiving call backs from their clinicians. This criteria means that they are ruling out patients with a history of substance abuse, she said.

She also noted the need to tailor the target PAP to the specific clinical status of individual patients. Patients with mitral regurgitation, for example, will have a higher “normal” diastolic PAP and hence require a somewhat different target for stability maintenance. “You need to understand each patient’s baseline pressures and adjust their medications based on that,” Dr. Altman said.

“In real life patients tend to be older and sicker, so their benefit may be even greater than what was seen in CHAMPION, but perhaps the results will also be diluted because of comorbidities like renal failure or chronic obstructive pulmonary disease,” said Dr. Butler, although post hoc subanalyses of CHAMPION data showed that these comorbidities did not blunt the positive impact of PAP-guided treatment. “I don’t know if I’ll be successful in selecting the right patients, and whether my interventions in real life will produce the same good outcomes” seen in CHAMPION. “We’ll select patients who are close to the CHAMPION criteria, but not patients on dialysis [who were excluded from CHAMPION]; we’ll select patients with a modest degree of comorbidity and reasonable expected survival,” Dr. Butler said.

“If you had a drug that reduced rehospitalization rates it would be pretty clear how to proceed, but in this case it is not the device that reduces readmissions, it just gives you data and you need to act on the data,” Dr. Butler added. He acknowledged that the CHAMPION investigators used a relatively simple, straightforward management algorithm for patients whose PAP fell out of the target range, such as a diastolic PAP greater than 20 mm Hg or less than 8 mm Hg. The first management step is to raise or reduce the patient’s diuretic dosage, and if that fails to quickly normalize PAP the next step is to adjust the vasodilator dosage.

Managing patients in CHAMPION was “not totally an art” but neither was it “totally a science,” Dr. Butler said. Managing patients based on daily data collected using a CardioMEMS device will “require a little finesse,” he said. “It’s not straight science.”

Programs that have already used PAP monitoring on a routine basis, like those in Denver and at Brigham and Women’s, consider their experience too small in size and short in duration to draw any substantive conclusions regarding their success compared with the CHAMPION results. But Dr. Abraham, whose program has now placed CardioMEMS routinely in a few dozen patients and followed them for as long as a year, said that in his center’s patients the device and management system has produced outcomes that roughly match what he saw in the pivotal trial.

“The ongoing concern is that what was achieved in the CHAMPION trial may not be what is achieved in routine practice,” said Dr. Desai. The care that patients received in the trial is “a little of a black box,” he said, and during the FDA’s approval process some reviewers raised concerns that patients in the active-treatment arm simply received more intensive surveillance, although this concern eventually resolved. “There is not a lot of skepticism” among clinicians about this treatment, but there is uncertainly about exactly whom are the best patients to treat and whether their responses be as good as in CHAMPION, Dr. Desai said in an interview.

“The proof [of efficacy] will be in each individual center’s experience” using CardioMEMS, Dr. Altman said.

CHAMPION was initially funded by CardioMEMS, which then was acquired by St. Jude which is the company marketing the CardioMEMS device and associated hardware. Dr. Butler said that he had no current relevant disclosures, although in the past he had been a consultant to CardioMEMS (prior to its acquisition by St. Jude). Dr. Parks and Dr. Altman had no disclosures. Dr. Desai has been a consultant to and has received honoraria as a speaker on behalf of CardioMEMS and St. Jude. Dr. Abraham has been a consultant to CardioMEMS and St. Jude, was co-principal investigator on the CHAMPION trial, and is the principal investigator on a new St. Jude-funded trial studying CardioMEMS.

mzoler@frontlinemedcom.com

On Twitter @mitchelzoler

LONDON – U.S. patients hospitalized for heart failure and treated with antibiotics during their hospital stay had an increased rate both for developing Clostridium difficile infection and dying from it, based on nationwide data collected from nearly six million patients.

“Heart failure was an independent risk factor” in multivariate analyses that controlled for demographic factors as well as for several comorbidities of heart failure, Dr. Petra Mamic said in a video interview at the annual congress of the European Society of Cardiology.

She and her associates used data collected by the National Inpatient Sample during 2012 in more than 5.8 million U.S. hospitalized patients who received antibiotic treatment for a urinary tract infection, pneumonia, or sepsis. They compared the rate of subsequent infection with C. difficile in the roughly 1.4 million of these patients who had heart failure and the nearly 4.5 million without heart failure. In a multivariate analysis heart failure patients were 13% more likely to develop C. difficile infection compared with patients without heart failure. In a second multivariate analysis that focused just on patients with heart failure those who had become infected by C. difficile were 81% more likely to die in hospital compared with heart failure patients without this type of infection.

“Heart failure patients are frequently hospitalized and have a lot of bacterial infections, and so receive treatment with a lot of antibiotics,” said Dr. Mamic, an internal medicine physician at Stanford (Calif.) University. “What is important is that C. difficile infection is preventable. Our ultimate goal is to prevent C. difficile in these patients who have such high morbidity and mortality,”

Dr. Mamic had no disclosures.

mzoler@frontlinemedcom.com

On Twitter @mitchelzoler

LONDON – U.S. patients hospitalized for heart failure and treated with antibiotics during their hospital stay had an increased rate both for developing Clostridium difficile infection and dying from it, based on nationwide data collected from nearly six million patients.

“Heart failure was an independent risk factor” in multivariate analyses that controlled for demographic factors as well as for several comorbidities of heart failure, Dr. Petra Mamic said in a video interview at the annual congress of the European Society of Cardiology.

She and her associates used data collected by the National Inpatient Sample during 2012 in more than 5.8 million U.S. hospitalized patients who received antibiotic treatment for a urinary tract infection, pneumonia, or sepsis. They compared the rate of subsequent infection with C. difficile in the roughly 1.4 million of these patients who had heart failure and the nearly 4.5 million without heart failure. In a multivariate analysis heart failure patients were 13% more likely to develop C. difficile infection compared with patients without heart failure. In a second multivariate analysis that focused just on patients with heart failure those who had become infected by C. difficile were 81% more likely to die in hospital compared with heart failure patients without this type of infection.

“Heart failure patients are frequently hospitalized and have a lot of bacterial infections, and so receive treatment with a lot of antibiotics,” said Dr. Mamic, an internal medicine physician at Stanford (Calif.) University. “What is important is that C. difficile infection is preventable. Our ultimate goal is to prevent C. difficile in these patients who have such high morbidity and mortality,”

Dr. Mamic had no disclosures.

mzoler@frontlinemedcom.com

On Twitter @mitchelzoler

LONDON – U.S. patients hospitalized for heart failure and treated with antibiotics during their hospital stay had an increased rate both for developing Clostridium difficile infection and dying from it, based on nationwide data collected from nearly six million patients.

“Heart failure was an independent risk factor” in multivariate analyses that controlled for demographic factors as well as for several comorbidities of heart failure, Dr. Petra Mamic said in a video interview at the annual congress of the European Society of Cardiology.

She and her associates used data collected by the National Inpatient Sample during 2012 in more than 5.8 million U.S. hospitalized patients who received antibiotic treatment for a urinary tract infection, pneumonia, or sepsis. They compared the rate of subsequent infection with C. difficile in the roughly 1.4 million of these patients who had heart failure and the nearly 4.5 million without heart failure. In a multivariate analysis heart failure patients were 13% more likely to develop C. difficile infection compared with patients without heart failure. In a second multivariate analysis that focused just on patients with heart failure those who had become infected by C. difficile were 81% more likely to die in hospital compared with heart failure patients without this type of infection.

“Heart failure patients are frequently hospitalized and have a lot of bacterial infections, and so receive treatment with a lot of antibiotics,” said Dr. Mamic, an internal medicine physician at Stanford (Calif.) University. “What is important is that C. difficile infection is preventable. Our ultimate goal is to prevent C. difficile in these patients who have such high morbidity and mortality,”

Dr. Mamic had no disclosures.

mzoler@frontlinemedcom.com

On Twitter @mitchelzoler

WASHINGTON – Proving disease modification of Alzheimer’s disease in a clinical drug trial may not be easy.

Some researchers developing drugs for treating Alzheimer’s disease hope to find a way to tweak the classic, double-blind, phase III trial design to gather data that can prove a drug has disease-modifying effects in addition to the standard goal of showing symptomatic treatment effects. But the complex statistical analyses they have developed to accomplish this faced some skepticism from Food and Drug Administration staff members during a panel discussion at a special session on the topic at the Alzheimer’s Association International Conference 2015.

Mitchel L. Zoler/Frontline Medical News

“Everyone agrees that No. 1, we need to have drugs that are proven effective, but both clinicians and families want to know whether it’s important to start treatment of Alzheimer’s disease as early as possible or wait, and they want to know whether the benefits of treatment will persist or increase with time,” explained Dr. Paul Aisen, professor of neurology and director of the Alzheimer’s Therapeutic Research Institute at the University of Southern California, Los Angeles. Both properties – added value to patients from early initiation of treatment and persistent or accruing benefit from prolonged treatment – are hallmarks of a disease-modifying effect. “This is what we are trying to get at” with novel trial designs and analysis, he said in an interview. “It’s secondary to talking about efficacy, but it’s still clinically important.”

“Disease modification is an important concept because it indicates that the drug is affecting the underlying biology of the disease. What we have now [for treating Alzheimer’s disease] are drugs that only affect symptoms or are palliative,” commented Dr. David S. Knopman, professor of neurology at the Mayo Clinic in Rochester, Minn. and a participant in the session on disease modification at the meeting. “In principal a drug with a disease-modifying effect would have a bigger and more enduring effect and could be started earlier in the disease and would ultimately be of greater benefit to patients and society by reducing disease burden. The problem is that showing disease modification turns out to be very challenging,” Dr. Knopman said in an interview.

Mitchel L. Zoler/Frontline Medical News

Solanezumab tested in delayed-start studies

During the session at the meeting, Dr. Aisen, the session organizer, presented results from post-hoc analysis of data collected in two phase III trials that tested the efficacy of the antiamyloid antibody solanezumab in patients with mild or moderate Alzheimer’s disease. Results from the placebo-controlled, double-blind phases of the two trials, EXPEDITION 1 and EXPEDITION 2, failed to show a statistically significant benefit from solanezumab treatment for the studies’ primary endpoint. Those findings appeared in a paper published last year (N Engl J Med. 2014 Jan 23;370:311-21).

The new analyses that Dr. Aisen reported came from the open-label extension phase of the two trials, which enabled patients originally enrolled in the placebo arms to start treatment on solanezumab, while patients from the active-treatment arms could remain on longer-term treatment with the drug. The new analyses also focused exclusively on patients who entered the study with “mild” Alzheimer’s disease, defined as a score on the Mini Mental State Examination of 20-26.

Post-hoc analysis of the combined trial results indicated that at the end of the 18-month, placebo-controlled phase patients who entered with mild Alzheimer’s disease had a statistically significant benefit from solanezumab treatment, compared with the placebo group. This observation led to the launch of a new trial, EXPEDITION 3, that exclusively enrolled patients with mild Alzheimer’s disease but in other ways resembled the first two failed trials. Results from EXPEDITION 3 are expected sometime in early 2017, Dr. Aisen said.

The analysis of extended treatment, which produced a trial design known as “delayed start,” aimed to test whether solanezumab produced disease modification of Alzheimer’s disease. The concept was that if the initial 18 months of drug treatment of patients in the active arm produced true disease modification then the difference in efficacy between the active and placebo arms in patients with mild disease seen at 18 months should remain roughly constant over subsequent months of solanezumab treatment of all patients, with no catchup by the patients first randomized to placebo and no hence no convergence of the outcome curves of the two treatment subgroups: patients on continuous solanezumab treatment and patients who first received placebo and then had a delayed start on solanezumab.

At the end of the EXPEDITION 1 and EXPEDITION 2 trials, 654 patients from the active-treatment arms remained enrolled and continued solanezumab treatment and 660 patients from the placebo arms remained enrolled and started solanezumab treatment for the first time. All patients continued on active treatment for up to 24 additional months, although many eventually dropped out of treatment and follow-up. After 2 years of extended treatment, 323 patients remained in the group that had initially been in the active treatment arms and 303 patients remained from those initially enrolled in the placebo arms.

Dr. Aisen presented results that compared the early-start and delayed-start subgroups by four different measures of efficacy, and each of the four analyses showed that the separation between the outcomes of the two treatment subgroups remained fairly constant during follow-up of as long as 2 years, findings consistent with the hypothesis of disease modification according to the statistical tests developed by researchers at Lilly, the company that sponsored the EXPEDITION studies and is developing solanezumab. “The curves are consistent across measures and over time. The late-start group did not appear to catch up. The shape of the curves supports disease modification,” Dr. Aisen said.

“This is the first time that a delayed start methodology has been analyzed in an Alzheimer’s disease clinical trial,” he noted.

The FDA’s view

Several staffers from the FDA who formed a panel at the session to discuss the results and the delayed-start trial design as a way to try to prove disease modification expressed skepticism about the validity and relevance of this analysis.

Mitchel L. Zoler/Frontline Medical News

“The delayed-start design is a clever idea, but it is tough to establish disease modification,” said Lisa LaVange, Ph.D., director of biostatistics in the FDA’s Center for Drug Evaluation and Research. “The new methods [for analyzing delayed-start outcomes] are intriguing, but you want to show that the difference doesn’t deteriorate with time, and that requires the first difference [at the end of the placebo-controlled phase] to be significant and meaningful. You need to show first one thing, and then another, and that’s complicated.”

Dr. LaVange also highlighted the issue of many patients dropping out from the extended-treatment phase. “One of the biggest problems with delayed start is the missing-data problem. We need to be very careful when imputing missing data for dropouts. The missing data aspect of delayed start needs more attention.”

Another concern voiced by the FDA staffers who commented on delayed-start trials and trying to prove disease modification was the paramount importance of showing efficacy during the placebo-controlled phase of the trial.

Mitchel L. Zoler/Frontline Medical News

“We want to modify the disease, but the prize is clearly a large treatment effect. Disease modification is absolutely not required for drug approval,” said Dr. William Dunn, director of the division of neurology products for the FDA’s Center for Drug Evaluation and Research. “What we are after is a treatment effect.”

The EXPEDITION trials and the delayed-start analysis for disease modification effects were funded by Lilly, the company developing solanezumab. Dr. Aisen has received research support from Lilly. Dr. Knopman received an honorarium from Lilly for chairing the data and safety-monitoring committee for two of their trials through 2012, but since then he has not had a financial relationship with the company. He currently is an investigator in a trial sponsored by Lilly. Dr. Knopman said he has no other disclosures. Dr. LaVange and Dr. Dunn had no disclosures.

mzoler@frontlinemedcom.com

On Twitter @mitchelzoler

WASHINGTON – Proving disease modification of Alzheimer’s disease in a clinical drug trial may not be easy.

Some researchers developing drugs for treating Alzheimer’s disease hope to find a way to tweak the classic, double-blind, phase III trial design to gather data that can prove a drug has disease-modifying effects in addition to the standard goal of showing symptomatic treatment effects. But the complex statistical analyses they have developed to accomplish this faced some skepticism from Food and Drug Administration staff members during a panel discussion at a special session on the topic at the Alzheimer’s Association International Conference 2015.

Mitchel L. Zoler/Frontline Medical News

“Everyone agrees that No. 1, we need to have drugs that are proven effective, but both clinicians and families want to know whether it’s important to start treatment of Alzheimer’s disease as early as possible or wait, and they want to know whether the benefits of treatment will persist or increase with time,” explained Dr. Paul Aisen, professor of neurology and director of the Alzheimer’s Therapeutic Research Institute at the University of Southern California, Los Angeles. Both properties – added value to patients from early initiation of treatment and persistent or accruing benefit from prolonged treatment – are hallmarks of a disease-modifying effect. “This is what we are trying to get at” with novel trial designs and analysis, he said in an interview. “It’s secondary to talking about efficacy, but it’s still clinically important.”

“Disease modification is an important concept because it indicates that the drug is affecting the underlying biology of the disease. What we have now [for treating Alzheimer’s disease] are drugs that only affect symptoms or are palliative,” commented Dr. David S. Knopman, professor of neurology at the Mayo Clinic in Rochester, Minn. and a participant in the session on disease modification at the meeting. “In principal a drug with a disease-modifying effect would have a bigger and more enduring effect and could be started earlier in the disease and would ultimately be of greater benefit to patients and society by reducing disease burden. The problem is that showing disease modification turns out to be very challenging,” Dr. Knopman said in an interview.

Mitchel L. Zoler/Frontline Medical News

Solanezumab tested in delayed-start studies

During the session at the meeting, Dr. Aisen, the session organizer, presented results from post-hoc analysis of data collected in two phase III trials that tested the efficacy of the antiamyloid antibody solanezumab in patients with mild or moderate Alzheimer’s disease. Results from the placebo-controlled, double-blind phases of the two trials, EXPEDITION 1 and EXPEDITION 2, failed to show a statistically significant benefit from solanezumab treatment for the studies’ primary endpoint. Those findings appeared in a paper published last year (N Engl J Med. 2014 Jan 23;370:311-21).

The new analyses that Dr. Aisen reported came from the open-label extension phase of the two trials, which enabled patients originally enrolled in the placebo arms to start treatment on solanezumab, while patients from the active-treatment arms could remain on longer-term treatment with the drug. The new analyses also focused exclusively on patients who entered the study with “mild” Alzheimer’s disease, defined as a score on the Mini Mental State Examination of 20-26.

Post-hoc analysis of the combined trial results indicated that at the end of the 18-month, placebo-controlled phase patients who entered with mild Alzheimer’s disease had a statistically significant benefit from solanezumab treatment, compared with the placebo group. This observation led to the launch of a new trial, EXPEDITION 3, that exclusively enrolled patients with mild Alzheimer’s disease but in other ways resembled the first two failed trials. Results from EXPEDITION 3 are expected sometime in early 2017, Dr. Aisen said.

The analysis of extended treatment, which produced a trial design known as “delayed start,” aimed to test whether solanezumab produced disease modification of Alzheimer’s disease. The concept was that if the initial 18 months of drug treatment of patients in the active arm produced true disease modification then the difference in efficacy between the active and placebo arms in patients with mild disease seen at 18 months should remain roughly constant over subsequent months of solanezumab treatment of all patients, with no catchup by the patients first randomized to placebo and no hence no convergence of the outcome curves of the two treatment subgroups: patients on continuous solanezumab treatment and patients who first received placebo and then had a delayed start on solanezumab.

At the end of the EXPEDITION 1 and EXPEDITION 2 trials, 654 patients from the active-treatment arms remained enrolled and continued solanezumab treatment and 660 patients from the placebo arms remained enrolled and started solanezumab treatment for the first time. All patients continued on active treatment for up to 24 additional months, although many eventually dropped out of treatment and follow-up. After 2 years of extended treatment, 323 patients remained in the group that had initially been in the active treatment arms and 303 patients remained from those initially enrolled in the placebo arms.

Dr. Aisen presented results that compared the early-start and delayed-start subgroups by four different measures of efficacy, and each of the four analyses showed that the separation between the outcomes of the two treatment subgroups remained fairly constant during follow-up of as long as 2 years, findings consistent with the hypothesis of disease modification according to the statistical tests developed by researchers at Lilly, the company that sponsored the EXPEDITION studies and is developing solanezumab. “The curves are consistent across measures and over time. The late-start group did not appear to catch up. The shape of the curves supports disease modification,” Dr. Aisen said.

“This is the first time that a delayed start methodology has been analyzed in an Alzheimer’s disease clinical trial,” he noted.

The FDA’s view

Several staffers from the FDA who formed a panel at the session to discuss the results and the delayed-start trial design as a way to try to prove disease modification expressed skepticism about the validity and relevance of this analysis.

Mitchel L. Zoler/Frontline Medical News

“The delayed-start design is a clever idea, but it is tough to establish disease modification,” said Lisa LaVange, Ph.D., director of biostatistics in the FDA’s Center for Drug Evaluation and Research. “The new methods [for analyzing delayed-start outcomes] are intriguing, but you want to show that the difference doesn’t deteriorate with time, and that requires the first difference [at the end of the placebo-controlled phase] to be significant and meaningful. You need to show first one thing, and then another, and that’s complicated.”

Dr. LaVange also highlighted the issue of many patients dropping out from the extended-treatment phase. “One of the biggest problems with delayed start is the missing-data problem. We need to be very careful when imputing missing data for dropouts. The missing data aspect of delayed start needs more attention.”

Another concern voiced by the FDA staffers who commented on delayed-start trials and trying to prove disease modification was the paramount importance of showing efficacy during the placebo-controlled phase of the trial.

Mitchel L. Zoler/Frontline Medical News

“We want to modify the disease, but the prize is clearly a large treatment effect. Disease modification is absolutely not required for drug approval,” said Dr. William Dunn, director of the division of neurology products for the FDA’s Center for Drug Evaluation and Research. “What we are after is a treatment effect.”

The EXPEDITION trials and the delayed-start analysis for disease modification effects were funded by Lilly, the company developing solanezumab. Dr. Aisen has received research support from Lilly. Dr. Knopman received an honorarium from Lilly for chairing the data and safety-monitoring committee for two of their trials through 2012, but since then he has not had a financial relationship with the company. He currently is an investigator in a trial sponsored by Lilly. Dr. Knopman said he has no other disclosures. Dr. LaVange and Dr. Dunn had no disclosures.

mzoler@frontlinemedcom.com

On Twitter @mitchelzoler

WASHINGTON – Proving disease modification of Alzheimer’s disease in a clinical drug trial may not be easy.

Some researchers developing drugs for treating Alzheimer’s disease hope to find a way to tweak the classic, double-blind, phase III trial design to gather data that can prove a drug has disease-modifying effects in addition to the standard goal of showing symptomatic treatment effects. But the complex statistical analyses they have developed to accomplish this faced some skepticism from Food and Drug Administration staff members during a panel discussion at a special session on the topic at the Alzheimer’s Association International Conference 2015.

Mitchel L. Zoler/Frontline Medical News

“Everyone agrees that No. 1, we need to have drugs that are proven effective, but both clinicians and families want to know whether it’s important to start treatment of Alzheimer’s disease as early as possible or wait, and they want to know whether the benefits of treatment will persist or increase with time,” explained Dr. Paul Aisen, professor of neurology and director of the Alzheimer’s Therapeutic Research Institute at the University of Southern California, Los Angeles. Both properties – added value to patients from early initiation of treatment and persistent or accruing benefit from prolonged treatment – are hallmarks of a disease-modifying effect. “This is what we are trying to get at” with novel trial designs and analysis, he said in an interview. “It’s secondary to talking about efficacy, but it’s still clinically important.”

“Disease modification is an important concept because it indicates that the drug is affecting the underlying biology of the disease. What we have now [for treating Alzheimer’s disease] are drugs that only affect symptoms or are palliative,” commented Dr. David S. Knopman, professor of neurology at the Mayo Clinic in Rochester, Minn. and a participant in the session on disease modification at the meeting. “In principal a drug with a disease-modifying effect would have a bigger and more enduring effect and could be started earlier in the disease and would ultimately be of greater benefit to patients and society by reducing disease burden. The problem is that showing disease modification turns out to be very challenging,” Dr. Knopman said in an interview.

Mitchel L. Zoler/Frontline Medical News

Solanezumab tested in delayed-start studies

During the session at the meeting, Dr. Aisen, the session organizer, presented results from post-hoc analysis of data collected in two phase III trials that tested the efficacy of the antiamyloid antibody solanezumab in patients with mild or moderate Alzheimer’s disease. Results from the placebo-controlled, double-blind phases of the two trials, EXPEDITION 1 and EXPEDITION 2, failed to show a statistically significant benefit from solanezumab treatment for the studies’ primary endpoint. Those findings appeared in a paper published last year (N Engl J Med. 2014 Jan 23;370:311-21).

The new analyses that Dr. Aisen reported came from the open-label extension phase of the two trials, which enabled patients originally enrolled in the placebo arms to start treatment on solanezumab, while patients from the active-treatment arms could remain on longer-term treatment with the drug. The new analyses also focused exclusively on patients who entered the study with “mild” Alzheimer’s disease, defined as a score on the Mini Mental State Examination of 20-26.

Post-hoc analysis of the combined trial results indicated that at the end of the 18-month, placebo-controlled phase patients who entered with mild Alzheimer’s disease had a statistically significant benefit from solanezumab treatment, compared with the placebo group. This observation led to the launch of a new trial, EXPEDITION 3, that exclusively enrolled patients with mild Alzheimer’s disease but in other ways resembled the first two failed trials. Results from EXPEDITION 3 are expected sometime in early 2017, Dr. Aisen said.

The analysis of extended treatment, which produced a trial design known as “delayed start,” aimed to test whether solanezumab produced disease modification of Alzheimer’s disease. The concept was that if the initial 18 months of drug treatment of patients in the active arm produced true disease modification then the difference in efficacy between the active and placebo arms in patients with mild disease seen at 18 months should remain roughly constant over subsequent months of solanezumab treatment of all patients, with no catchup by the patients first randomized to placebo and no hence no convergence of the outcome curves of the two treatment subgroups: patients on continuous solanezumab treatment and patients who first received placebo and then had a delayed start on solanezumab.

At the end of the EXPEDITION 1 and EXPEDITION 2 trials, 654 patients from the active-treatment arms remained enrolled and continued solanezumab treatment and 660 patients from the placebo arms remained enrolled and started solanezumab treatment for the first time. All patients continued on active treatment for up to 24 additional months, although many eventually dropped out of treatment and follow-up. After 2 years of extended treatment, 323 patients remained in the group that had initially been in the active treatment arms and 303 patients remained from those initially enrolled in the placebo arms.

Dr. Aisen presented results that compared the early-start and delayed-start subgroups by four different measures of efficacy, and each of the four analyses showed that the separation between the outcomes of the two treatment subgroups remained fairly constant during follow-up of as long as 2 years, findings consistent with the hypothesis of disease modification according to the statistical tests developed by researchers at Lilly, the company that sponsored the EXPEDITION studies and is developing solanezumab. “The curves are consistent across measures and over time. The late-start group did not appear to catch up. The shape of the curves supports disease modification,” Dr. Aisen said.

“This is the first time that a delayed start methodology has been analyzed in an Alzheimer’s disease clinical trial,” he noted.

The FDA’s view

Several staffers from the FDA who formed a panel at the session to discuss the results and the delayed-start trial design as a way to try to prove disease modification expressed skepticism about the validity and relevance of this analysis.

Mitchel L. Zoler/Frontline Medical News

“The delayed-start design is a clever idea, but it is tough to establish disease modification,” said Lisa LaVange, Ph.D., director of biostatistics in the FDA’s Center for Drug Evaluation and Research. “The new methods [for analyzing delayed-start outcomes] are intriguing, but you want to show that the difference doesn’t deteriorate with time, and that requires the first difference [at the end of the placebo-controlled phase] to be significant and meaningful. You need to show first one thing, and then another, and that’s complicated.”

Dr. LaVange also highlighted the issue of many patients dropping out from the extended-treatment phase. “One of the biggest problems with delayed start is the missing-data problem. We need to be very careful when imputing missing data for dropouts. The missing data aspect of delayed start needs more attention.”

Another concern voiced by the FDA staffers who commented on delayed-start trials and trying to prove disease modification was the paramount importance of showing efficacy during the placebo-controlled phase of the trial.

Mitchel L. Zoler/Frontline Medical News

“We want to modify the disease, but the prize is clearly a large treatment effect. Disease modification is absolutely not required for drug approval,” said Dr. William Dunn, director of the division of neurology products for the FDA’s Center for Drug Evaluation and Research. “What we are after is a treatment effect.”

The EXPEDITION trials and the delayed-start analysis for disease modification effects were funded by Lilly, the company developing solanezumab. Dr. Aisen has received research support from Lilly. Dr. Knopman received an honorarium from Lilly for chairing the data and safety-monitoring committee for two of their trials through 2012, but since then he has not had a financial relationship with the company. He currently is an investigator in a trial sponsored by Lilly. Dr. Knopman said he has no other disclosures. Dr. LaVange and Dr. Dunn had no disclosures.

mzoler@frontlinemedcom.com

On Twitter @mitchelzoler

The coincidence of two recent news items highlighted the tension between a more unfettered approach to pharmaceutical drug marketing and the need for caution when promoting and prescribing drugs.

A federal court judge issued a decision August 7 that ruled the drug company Amarin was not subject to Food and Drug Administration penalty for truthful but off-label promotion of the FDA-approved drug Vascepa, a triglyceride-lowering agent. Also on August 7, Dr. Frances Oldham Kelsey died at 101 years old. She was the FDA staffer singled out for recognition in 1962 as the primary firewall who prevented the agency from approving thalidomide for U.S. marketing as a treatment for morning sickness in pregnant woman, thereby sparing America from the epidemic of thalidomide-induced birth defects seen in Europe.

National LIbrary of Medicine http://www.nlm.nih.gov/changingthefaceofmedicine/physicians/biography_182.html

Despite the interesting juxtaposition of these two events, talking about them in the same breath requires a couple of important caveats: Vascepa has received FDA acceptance as safe for its approved indication, and circumstances would need to be unusual and severe for physicians to consider prescribing it to pregnant women. Society has dramatically changed the way it thinks about dosing pregnant women with drugs, compared with 60 years ago. It’s an attitudinal change driven at least in part by the thalidomide tragedy.

But the careful line that regulatory agencies and physicians must navigate that can mean denying patients potentially useful or even life-saving drugs because of insufficient evidence of safety and the need for caution against unsuspected consequences remains an enduring fact of medical practice.

Underappreciated threats exist even from drugs widely perceived as commonplace and benign. Consider NSAIDs. In July, the FDA strengthened and broadened its label warning for drugs in this class to say that treatment with NSAIDs of all types, including those sold OTC, can increase a person’s risk for MI, stroke, and heart failure, and that the elevated risk occurs even after just a few weeks of NSAID use.

Also in July, I covered a report at the Alzheimer’s Association International Conference 2015 on the off-label use for treating agitation in Alzheimer’s disease patients with the combination of dextromethorphan and quinidine, a formulation branded as Nuedexta with FDA approval for treating pseudobulbar affect. Although this combination is already on the U.S. market, and the main active agent dextromethorphan is also widely marketed in several OTC cough-medicine products, the principal investigator of the Alzheimer’s disease study, Dr. Jeffrey L. Cummings, told me that he cautions physicians against prescribing the dextromethorphan plus quinidine combination to patients with Alzheimer’s disease agitation, even though controlling Alzheimer’s agitation is a major unmet need for patients and their families. Dr. Cummings stressed that the 93 patients he studied during 10 weeks of treatment were too few people followed for too short a period to draw any conclusions on safety in this new patient population.

Once a drug receives FDA approval, and so presumably has an adequate evidence base proving clinical safety, extrapolation of its safety to different patient types can be tricky. As clinical experience with a drug or a drug class accumulates and as use expands to different sorts of patients, appreciation often grows for subtle or uncommon adverse effects not signaled during initial testing. How many physicians or patients suspected a potential risk from all prescription NSAIDs before the FDA issued its first warning about the class 10 year ago, and how many remained oblivious to the danger from OTC NSAIDs until the FDA strengthened its warning a few weeks ago? And nearly 60 years ago, few physicians aside from Dr. Kelsey and her associates at the FDA focused on the unanticipated danger posed by thalidomide treatment during pregnancy.

Truthful free speech about possible benefits of FDA-approved drugs for additional indications is a interesting concept, but physicians and patients must remain mindful of the need for caution and the danger of extrapolating too much and being too aggressive with drug use when an agent’s safety is uncertain.

mzoler@frontlinemedcom.com

On Twitter @mitchelzoler

The coincidence of two recent news items highlighted the tension between a more unfettered approach to pharmaceutical drug marketing and the need for caution when promoting and prescribing drugs.

A federal court judge issued a decision August 7 that ruled the drug company Amarin was not subject to Food and Drug Administration penalty for truthful but off-label promotion of the FDA-approved drug Vascepa, a triglyceride-lowering agent. Also on August 7, Dr. Frances Oldham Kelsey died at 101 years old. She was the FDA staffer singled out for recognition in 1962 as the primary firewall who prevented the agency from approving thalidomide for U.S. marketing as a treatment for morning sickness in pregnant woman, thereby sparing America from the epidemic of thalidomide-induced birth defects seen in Europe.

National LIbrary of Medicine http://www.nlm.nih.gov/changingthefaceofmedicine/physicians/biography_182.html

Despite the interesting juxtaposition of these two events, talking about them in the same breath requires a couple of important caveats: Vascepa has received FDA acceptance as safe for its approved indication, and circumstances would need to be unusual and severe for physicians to consider prescribing it to pregnant women. Society has dramatically changed the way it thinks about dosing pregnant women with drugs, compared with 60 years ago. It’s an attitudinal change driven at least in part by the thalidomide tragedy.

But the careful line that regulatory agencies and physicians must navigate that can mean denying patients potentially useful or even life-saving drugs because of insufficient evidence of safety and the need for caution against unsuspected consequences remains an enduring fact of medical practice.

Underappreciated threats exist even from drugs widely perceived as commonplace and benign. Consider NSAIDs. In July, the FDA strengthened and broadened its label warning for drugs in this class to say that treatment with NSAIDs of all types, including those sold OTC, can increase a person’s risk for MI, stroke, and heart failure, and that the elevated risk occurs even after just a few weeks of NSAID use.

Also in July, I covered a report at the Alzheimer’s Association International Conference 2015 on the off-label use for treating agitation in Alzheimer’s disease patients with the combination of dextromethorphan and quinidine, a formulation branded as Nuedexta with FDA approval for treating pseudobulbar affect. Although this combination is already on the U.S. market, and the main active agent dextromethorphan is also widely marketed in several OTC cough-medicine products, the principal investigator of the Alzheimer’s disease study, Dr. Jeffrey L. Cummings, told me that he cautions physicians against prescribing the dextromethorphan plus quinidine combination to patients with Alzheimer’s disease agitation, even though controlling Alzheimer’s agitation is a major unmet need for patients and their families. Dr. Cummings stressed that the 93 patients he studied during 10 weeks of treatment were too few people followed for too short a period to draw any conclusions on safety in this new patient population.

Once a drug receives FDA approval, and so presumably has an adequate evidence base proving clinical safety, extrapolation of its safety to different patient types can be tricky. As clinical experience with a drug or a drug class accumulates and as use expands to different sorts of patients, appreciation often grows for subtle or uncommon adverse effects not signaled during initial testing. How many physicians or patients suspected a potential risk from all prescription NSAIDs before the FDA issued its first warning about the class 10 year ago, and how many remained oblivious to the danger from OTC NSAIDs until the FDA strengthened its warning a few weeks ago? And nearly 60 years ago, few physicians aside from Dr. Kelsey and her associates at the FDA focused on the unanticipated danger posed by thalidomide treatment during pregnancy.

Truthful free speech about possible benefits of FDA-approved drugs for additional indications is a interesting concept, but physicians and patients must remain mindful of the need for caution and the danger of extrapolating too much and being too aggressive with drug use when an agent’s safety is uncertain.

mzoler@frontlinemedcom.com

On Twitter @mitchelzoler

The coincidence of two recent news items highlighted the tension between a more unfettered approach to pharmaceutical drug marketing and the need for caution when promoting and prescribing drugs.

A federal court judge issued a decision August 7 that ruled the drug company Amarin was not subject to Food and Drug Administration penalty for truthful but off-label promotion of the FDA-approved drug Vascepa, a triglyceride-lowering agent. Also on August 7, Dr. Frances Oldham Kelsey died at 101 years old. She was the FDA staffer singled out for recognition in 1962 as the primary firewall who prevented the agency from approving thalidomide for U.S. marketing as a treatment for morning sickness in pregnant woman, thereby sparing America from the epidemic of thalidomide-induced birth defects seen in Europe.

National LIbrary of Medicine http://www.nlm.nih.gov/changingthefaceofmedicine/physicians/biography_182.html

Despite the interesting juxtaposition of these two events, talking about them in the same breath requires a couple of important caveats: Vascepa has received FDA acceptance as safe for its approved indication, and circumstances would need to be unusual and severe for physicians to consider prescribing it to pregnant women. Society has dramatically changed the way it thinks about dosing pregnant women with drugs, compared with 60 years ago. It’s an attitudinal change driven at least in part by the thalidomide tragedy.

But the careful line that regulatory agencies and physicians must navigate that can mean denying patients potentially useful or even life-saving drugs because of insufficient evidence of safety and the need for caution against unsuspected consequences remains an enduring fact of medical practice.

Underappreciated threats exist even from drugs widely perceived as commonplace and benign. Consider NSAIDs. In July, the FDA strengthened and broadened its label warning for drugs in this class to say that treatment with NSAIDs of all types, including those sold OTC, can increase a person’s risk for MI, stroke, and heart failure, and that the elevated risk occurs even after just a few weeks of NSAID use.

Also in July, I covered a report at the Alzheimer’s Association International Conference 2015 on the off-label use for treating agitation in Alzheimer’s disease patients with the combination of dextromethorphan and quinidine, a formulation branded as Nuedexta with FDA approval for treating pseudobulbar affect. Although this combination is already on the U.S. market, and the main active agent dextromethorphan is also widely marketed in several OTC cough-medicine products, the principal investigator of the Alzheimer’s disease study, Dr. Jeffrey L. Cummings, told me that he cautions physicians against prescribing the dextromethorphan plus quinidine combination to patients with Alzheimer’s disease agitation, even though controlling Alzheimer’s agitation is a major unmet need for patients and their families. Dr. Cummings stressed that the 93 patients he studied during 10 weeks of treatment were too few people followed for too short a period to draw any conclusions on safety in this new patient population.

Once a drug receives FDA approval, and so presumably has an adequate evidence base proving clinical safety, extrapolation of its safety to different patient types can be tricky. As clinical experience with a drug or a drug class accumulates and as use expands to different sorts of patients, appreciation often grows for subtle or uncommon adverse effects not signaled during initial testing. How many physicians or patients suspected a potential risk from all prescription NSAIDs before the FDA issued its first warning about the class 10 year ago, and how many remained oblivious to the danger from OTC NSAIDs until the FDA strengthened its warning a few weeks ago? And nearly 60 years ago, few physicians aside from Dr. Kelsey and her associates at the FDA focused on the unanticipated danger posed by thalidomide treatment during pregnancy.

Truthful free speech about possible benefits of FDA-approved drugs for additional indications is a interesting concept, but physicians and patients must remain mindful of the need for caution and the danger of extrapolating too much and being too aggressive with drug use when an agent’s safety is uncertain.

mzoler@frontlinemedcom.com

On Twitter @mitchelzoler

WASHINGTON – Age-related cognitive declines have a different presentation in women and in men.

As men age they show a steeper decline, compared with women, in their ability to name words from a list, to name words that start with a specific letter, and in trail-making tests, according to initial, baseline results from 587 people enrolled in an online program designed to assess and intervene against age-related declines in cognitive function.

Mitchel L. Zoler/Frontline Medical News

In contrast, age-related declines among women, compared with men, showed up more commonly for reading comprehension, three-dimensional rotation, and clock rotation tests, Thomas Beaudry said at the Alzheimer’s Association International Conference 2015. Scores on reaction time and on the Wisconsin Card Sorting Test declined with age at roughly similar rates regardless of sex.

These sex differences in rates of age-related cognitive declines in various mental function tests “suggest that careful thought needs to be put into the selection of tests used for diagnosis” of early-onset Alzheimer’s disease and other forms of age-related dementia, said Mr. Beaudry, a researcher at the McGill University Research Centre for Studies in Aging in Montreal.

Mr. Beaudry and his associates developed a website that allows registered participants to undergo assessments of their cognitive function at baseline. Participants are also encouraged to regularly play a variety of “brain games” online designed to improve or at least help maintain their cognitive function. Known as the Prevention of Neurodegenerative Diseases in Everyone at Risk (P.O.N.D.E.R.) program, it had enrolled 1,536 participants aged 16-97 years old as of July, Mr. Beaudry said. The enrollees averaged 57 years old, and 79% were women. About 60% of people who initially enrolled in the program have remained active participants, he said.

At the time of enrollment, participants complete a panel of eight cognitive function tests that cover memory, attention, executive function, orientation, constructive abilities, problem solving, language, and perceptual skills. In addition to completing these assessments at baseline, participants receive follow-up requests to undergo reassessment every 6 months. The baseline data that Mr. Beaudry and his associates analyzed and presented at the meeting came from the first 587 people who completed their enrollment assessments.

“What makes P.O.N.D.E.R. unique is the training approach” in which participants are asked to play brain games on the website, he said. The games are designed to challenge and develop the same cognitive skills addressed by the assessments. “The presymptomatic phase of Alzheimer’s disease presents a window for intervention through cognitive training to delay the onset and progression of the disease,” Mr. Beaudry said.

mzoler@frontlinemedcom.com

WASHINGTON – Age-related cognitive declines have a different presentation in women and in men.

As men age they show a steeper decline, compared with women, in their ability to name words from a list, to name words that start with a specific letter, and in trail-making tests, according to initial, baseline results from 587 people enrolled in an online program designed to assess and intervene against age-related declines in cognitive function.

Mitchel L. Zoler/Frontline Medical News

In contrast, age-related declines among women, compared with men, showed up more commonly for reading comprehension, three-dimensional rotation, and clock rotation tests, Thomas Beaudry said at the Alzheimer’s Association International Conference 2015. Scores on reaction time and on the Wisconsin Card Sorting Test declined with age at roughly similar rates regardless of sex.

These sex differences in rates of age-related cognitive declines in various mental function tests “suggest that careful thought needs to be put into the selection of tests used for diagnosis” of early-onset Alzheimer’s disease and other forms of age-related dementia, said Mr. Beaudry, a researcher at the McGill University Research Centre for Studies in Aging in Montreal.

Mr. Beaudry and his associates developed a website that allows registered participants to undergo assessments of their cognitive function at baseline. Participants are also encouraged to regularly play a variety of “brain games” online designed to improve or at least help maintain their cognitive function. Known as the Prevention of Neurodegenerative Diseases in Everyone at Risk (P.O.N.D.E.R.) program, it had enrolled 1,536 participants aged 16-97 years old as of July, Mr. Beaudry said. The enrollees averaged 57 years old, and 79% were women. About 60% of people who initially enrolled in the program have remained active participants, he said.

At the time of enrollment, participants complete a panel of eight cognitive function tests that cover memory, attention, executive function, orientation, constructive abilities, problem solving, language, and perceptual skills. In addition to completing these assessments at baseline, participants receive follow-up requests to undergo reassessment every 6 months. The baseline data that Mr. Beaudry and his associates analyzed and presented at the meeting came from the first 587 people who completed their enrollment assessments.

“What makes P.O.N.D.E.R. unique is the training approach” in which participants are asked to play brain games on the website, he said. The games are designed to challenge and develop the same cognitive skills addressed by the assessments. “The presymptomatic phase of Alzheimer’s disease presents a window for intervention through cognitive training to delay the onset and progression of the disease,” Mr. Beaudry said.

mzoler@frontlinemedcom.com

WASHINGTON – Age-related cognitive declines have a different presentation in women and in men.

As men age they show a steeper decline, compared with women, in their ability to name words from a list, to name words that start with a specific letter, and in trail-making tests, according to initial, baseline results from 587 people enrolled in an online program designed to assess and intervene against age-related declines in cognitive function.

Mitchel L. Zoler/Frontline Medical News

In contrast, age-related declines among women, compared with men, showed up more commonly for reading comprehension, three-dimensional rotation, and clock rotation tests, Thomas Beaudry said at the Alzheimer’s Association International Conference 2015. Scores on reaction time and on the Wisconsin Card Sorting Test declined with age at roughly similar rates regardless of sex.

These sex differences in rates of age-related cognitive declines in various mental function tests “suggest that careful thought needs to be put into the selection of tests used for diagnosis” of early-onset Alzheimer’s disease and other forms of age-related dementia, said Mr. Beaudry, a researcher at the McGill University Research Centre for Studies in Aging in Montreal.

Mr. Beaudry and his associates developed a website that allows registered participants to undergo assessments of their cognitive function at baseline. Participants are also encouraged to regularly play a variety of “brain games” online designed to improve or at least help maintain their cognitive function. Known as the Prevention of Neurodegenerative Diseases in Everyone at Risk (P.O.N.D.E.R.) program, it had enrolled 1,536 participants aged 16-97 years old as of July, Mr. Beaudry said. The enrollees averaged 57 years old, and 79% were women. About 60% of people who initially enrolled in the program have remained active participants, he said.

At the time of enrollment, participants complete a panel of eight cognitive function tests that cover memory, attention, executive function, orientation, constructive abilities, problem solving, language, and perceptual skills. In addition to completing these assessments at baseline, participants receive follow-up requests to undergo reassessment every 6 months. The baseline data that Mr. Beaudry and his associates analyzed and presented at the meeting came from the first 587 people who completed their enrollment assessments.

“What makes P.O.N.D.E.R. unique is the training approach” in which participants are asked to play brain games on the website, he said. The games are designed to challenge and develop the same cognitive skills addressed by the assessments. “The presymptomatic phase of Alzheimer’s disease presents a window for intervention through cognitive training to delay the onset and progression of the disease,” Mr. Beaudry said.

mzoler@frontlinemedcom.com

WASHINGTON – A 3-month program of supervised aerobic exercise and strength training led to modest but statistically significant improvement in cognition in a pilot, single-center study that enrolled 15 patients with mild cognitive impairment.

“Aerobic strength training is an effective strategy capable of slowing down or even reversing early phases of cognitive decline,” Dr. Barbara Ukropcova said at the Alzheimer’s Association International Conference 2015. The impact of training on improved cognition might be mediated through increased physical fitness, muscle mass, and strength and motor performance, as well as by improvements in specific metabolic parameters that the study results documented, said Dr. Ukropcova, a researcher at the Institute of Experimental Endocrinology of the Slovak Academy of Sciences in Bratislava, Slovakia.

Mitchel L. Zoler/Frontline Medical News

Although the study involved just 15 patients with mild cognitive impairment, as well as 11 control participants with normal cognitive scores, Dr. Ukropcova said that she believes the impact of regular exercise on cognition is real, in part because the results showed a multifold change in some of the metabolic parameters that linked with improved cognitive function.

“We plan to enroll increased numbers of patients that will hopefully prove” the ability of exercise to improve impaired cognition, she said in an interview. Future studies also will look at metabolic parameters in greater detail with the aim of finding biomarkers that can better define the relationship between exercise and cognition.

Dr. Ukropcova stressed the importance of starting regular exercise during childhood and maintaining it throughout life to help preserve cognitive function instead of waiting to start to exercise once impairment has been diagnosed.

Her study had participants engage in one 45-minute session of aerobic-coordination training each week and two 60-minute sessions of supervised strength and aerobic exercise each week for 12 weeks. The researchers performed a detailed set of physical assessments, metabolic measures, and cognitive tests on each participant before they began the program and at the end of the 12-week training program.

The average age of the 15 people with mild cognitive impairment was 72 years, and the average body mass index was 27 kg/m². Twelve were women. The average age of the 11 people in the control group was 65 years, and the average body mass index also was 27 kg/m^2. Six were women.

During the 12 weeks of the study, the dropout rate was 10%, and participants completed an average of 80% of their scheduled training and exercise sessions, Dr. Ukropcova said.

At the end of the 12-week program, all participants showed statistically significant increases in aerobic fitness, measured by their maximal oxygen uptake (V0₂ max), muscle strength, speed during a 10-meter walk test, and speed during a chair-stand test. Metabolic measures showed a significantly decreased average serum level of lactate, “indicating improved metabolic capacity,” Dr. Ukropcova said, and a “substantial” increase in circulating levels of brain-derived neurotrophic factor, specifically in the participants with mild cognitive impairment.

Following the training period, the participants with mild cognitive impairment showed statistically significant improvements in their average scores on the Mini Mental State Examination, the Montreal Cognitive Assessment, and the Addenbrooke’s Cognitive Examination-Revised. For example, their average score on the Mini Mental State Examination rose from 26.5 before the exercise program began to 28 after 12 weeks. Control participants showed no statistically significant changes in any of these measures.

Analysis of data from all participants showed significant positive correlations between higher levels of physical activity, walking speed, and aerobic fitness and cognitive measures, as well as positive correlations between improved metabolic parameters and cognitive measures, Dr. Ukropcova reported.

mzoler@frontlinemedcom.com

On Twitter @mitchelzoler

WASHINGTON – A 3-month program of supervised aerobic exercise and strength training led to modest but statistically significant improvement in cognition in a pilot, single-center study that enrolled 15 patients with mild cognitive impairment.

“Aerobic strength training is an effective strategy capable of slowing down or even reversing early phases of cognitive decline,” Dr. Barbara Ukropcova said at the Alzheimer’s Association International Conference 2015. The impact of training on improved cognition might be mediated through increased physical fitness, muscle mass, and strength and motor performance, as well as by improvements in specific metabolic parameters that the study results documented, said Dr. Ukropcova, a researcher at the Institute of Experimental Endocrinology of the Slovak Academy of Sciences in Bratislava, Slovakia.

Mitchel L. Zoler/Frontline Medical News

Although the study involved just 15 patients with mild cognitive impairment, as well as 11 control participants with normal cognitive scores, Dr. Ukropcova said that she believes the impact of regular exercise on cognition is real, in part because the results showed a multifold change in some of the metabolic parameters that linked with improved cognitive function.

“We plan to enroll increased numbers of patients that will hopefully prove” the ability of exercise to improve impaired cognition, she said in an interview. Future studies also will look at metabolic parameters in greater detail with the aim of finding biomarkers that can better define the relationship between exercise and cognition.

Dr. Ukropcova stressed the importance of starting regular exercise during childhood and maintaining it throughout life to help preserve cognitive function instead of waiting to start to exercise once impairment has been diagnosed.

Her study had participants engage in one 45-minute session of aerobic-coordination training each week and two 60-minute sessions of supervised strength and aerobic exercise each week for 12 weeks. The researchers performed a detailed set of physical assessments, metabolic measures, and cognitive tests on each participant before they began the program and at the end of the 12-week training program.

The average age of the 15 people with mild cognitive impairment was 72 years, and the average body mass index was 27 kg/m². Twelve were women. The average age of the 11 people in the control group was 65 years, and the average body mass index also was 27 kg/m^2. Six were women.

During the 12 weeks of the study, the dropout rate was 10%, and participants completed an average of 80% of their scheduled training and exercise sessions, Dr. Ukropcova said.

At the end of the 12-week program, all participants showed statistically significant increases in aerobic fitness, measured by their maximal oxygen uptake (V0₂ max), muscle strength, speed during a 10-meter walk test, and speed during a chair-stand test. Metabolic measures showed a significantly decreased average serum level of lactate, “indicating improved metabolic capacity,” Dr. Ukropcova said, and a “substantial” increase in circulating levels of brain-derived neurotrophic factor, specifically in the participants with mild cognitive impairment.

Following the training period, the participants with mild cognitive impairment showed statistically significant improvements in their average scores on the Mini Mental State Examination, the Montreal Cognitive Assessment, and the Addenbrooke’s Cognitive Examination-Revised. For example, their average score on the Mini Mental State Examination rose from 26.5 before the exercise program began to 28 after 12 weeks. Control participants showed no statistically significant changes in any of these measures.

Analysis of data from all participants showed significant positive correlations between higher levels of physical activity, walking speed, and aerobic fitness and cognitive measures, as well as positive correlations between improved metabolic parameters and cognitive measures, Dr. Ukropcova reported.

mzoler@frontlinemedcom.com

On Twitter @mitchelzoler

WASHINGTON – A 3-month program of supervised aerobic exercise and strength training led to modest but statistically significant improvement in cognition in a pilot, single-center study that enrolled 15 patients with mild cognitive impairment.

“Aerobic strength training is an effective strategy capable of slowing down or even reversing early phases of cognitive decline,” Dr. Barbara Ukropcova said at the Alzheimer’s Association International Conference 2015. The impact of training on improved cognition might be mediated through increased physical fitness, muscle mass, and strength and motor performance, as well as by improvements in specific metabolic parameters that the study results documented, said Dr. Ukropcova, a researcher at the Institute of Experimental Endocrinology of the Slovak Academy of Sciences in Bratislava, Slovakia.

Mitchel L. Zoler/Frontline Medical News

Although the study involved just 15 patients with mild cognitive impairment, as well as 11 control participants with normal cognitive scores, Dr. Ukropcova said that she believes the impact of regular exercise on cognition is real, in part because the results showed a multifold change in some of the metabolic parameters that linked with improved cognitive function.

“We plan to enroll increased numbers of patients that will hopefully prove” the ability of exercise to improve impaired cognition, she said in an interview. Future studies also will look at metabolic parameters in greater detail with the aim of finding biomarkers that can better define the relationship between exercise and cognition.

Dr. Ukropcova stressed the importance of starting regular exercise during childhood and maintaining it throughout life to help preserve cognitive function instead of waiting to start to exercise once impairment has been diagnosed.

Her study had participants engage in one 45-minute session of aerobic-coordination training each week and two 60-minute sessions of supervised strength and aerobic exercise each week for 12 weeks. The researchers performed a detailed set of physical assessments, metabolic measures, and cognitive tests on each participant before they began the program and at the end of the 12-week training program.

The average age of the 15 people with mild cognitive impairment was 72 years, and the average body mass index was 27 kg/m². Twelve were women. The average age of the 11 people in the control group was 65 years, and the average body mass index also was 27 kg/m^2. Six were women.

During the 12 weeks of the study, the dropout rate was 10%, and participants completed an average of 80% of their scheduled training and exercise sessions, Dr. Ukropcova said.

At the end of the 12-week program, all participants showed statistically significant increases in aerobic fitness, measured by their maximal oxygen uptake (V0₂ max), muscle strength, speed during a 10-meter walk test, and speed during a chair-stand test. Metabolic measures showed a significantly decreased average serum level of lactate, “indicating improved metabolic capacity,” Dr. Ukropcova said, and a “substantial” increase in circulating levels of brain-derived neurotrophic factor, specifically in the participants with mild cognitive impairment.

Following the training period, the participants with mild cognitive impairment showed statistically significant improvements in their average scores on the Mini Mental State Examination, the Montreal Cognitive Assessment, and the Addenbrooke’s Cognitive Examination-Revised. For example, their average score on the Mini Mental State Examination rose from 26.5 before the exercise program began to 28 after 12 weeks. Control participants showed no statistically significant changes in any of these measures.

Analysis of data from all participants showed significant positive correlations between higher levels of physical activity, walking speed, and aerobic fitness and cognitive measures, as well as positive correlations between improved metabolic parameters and cognitive measures, Dr. Ukropcova reported.

mzoler@frontlinemedcom.com

On Twitter @mitchelzoler

WASHINGTON – A 7-minute screening tool nearly doubled the rate at which primary care physicians could identify elderly patients in their practices with dementia in a German study involving more than 6,800 community-dwelling people.

“Screening can considerably improve the recognition of dementia in primary care,” Dr. Tilly Eichler said at the Alzheimer’s Association International Conference 2015. But she cautioned that further research needs to be done to determine the best ways to identify the specific type of dementia a patient has, and must also follow patients long term to assess the benefits and risks from a more aggressive approach to dementia diagnosis in community-dwelling primary care patients.

Mitchel L. Zoler/Frontline Medical News

The majority of patients identified with dementia in primary care practices had an unspecified cause for their dementia, noted Dr. Eichler, a researcher with the German Center for Neurodegenerative Diseases in Greifswald, Germany.

Dr. Eichler and her associates arranged for 136 German primary care physicians to administer the DemTect screening tool (Int J Geriatr Psychiatry. 2004 Feb;19(2):136-43), a five-part test that takes about 7 minutes to administer, to screen 6,838 community dwellers aged 70 years or older as part of the DelpHi-MV (Dementia: Life- and Person-Centered Help in Mecklenburg–Western Pomerania) study. The DemTect test identified 1,166 people (17%) with potential dementia based on scoring 8 or less on the screening tool. After obtaining informed consent, the researchers performed a detailed assessment of 468 of that population. The 468 people flagged by screening as possibly having dementia were all 70-79 years old, 60% were women, and half of them lived alone.

Medical records for this subgroup showed that 179 (38%) had already been diagnosed with dementia prior to screening based on their scores on the Mini-Mental State Examination (MMSE). Among the remaining 289 people identified by their DemTect score as potentially having dementia, MMSE testing identified another 171 people with dementia, increasing the total of this subgroup diagnosed with dementia by a relative 96%, compared with the 179 patients who had been identified with dementia prior to screening.

Two-thirds of the patients with newly diagnosed dementia had an unspecified form while 18% had Alzheimer’s disease, 14% had vascular dementia, and the remainder had other forms of dementia, Dr. Eichler said. Combining the newly identified 171 people with dementia and the 179 people previously diagnosed resulted in a total of 350 people diagnosed with definite dementia by the MMSE, 75% of the 468 identified as potentially having dementia based on their scores with the DemTect screening tool.

Dr. Eichler had no relevant financial disclosures.

mzoler@frontlinemedcom.com


On Twitter@mitchelzoler

WASHINGTON – A 7-minute screening tool nearly doubled the rate at which primary care physicians could identify elderly patients in their practices with dementia in a German study involving more than 6,800 community-dwelling people.

“Screening can considerably improve the recognition of dementia in primary care,” Dr. Tilly Eichler said at the Alzheimer’s Association International Conference 2015. But she cautioned that further research needs to be done to determine the best ways to identify the specific type of dementia a patient has, and must also follow patients long term to assess the benefits and risks from a more aggressive approach to dementia diagnosis in community-dwelling primary care patients.

Mitchel L. Zoler/Frontline Medical News

The majority of patients identified with dementia in primary care practices had an unspecified cause for their dementia, noted Dr. Eichler, a researcher with the German Center for Neurodegenerative Diseases in Greifswald, Germany.

Dr. Eichler and her associates arranged for 136 German primary care physicians to administer the DemTect screening tool (Int J Geriatr Psychiatry. 2004 Feb;19(2):136-43), a five-part test that takes about 7 minutes to administer, to screen 6,838 community dwellers aged 70 years or older as part of the DelpHi-MV (Dementia: Life- and Person-Centered Help in Mecklenburg–Western Pomerania) study. The DemTect test identified 1,166 people (17%) with potential dementia based on scoring 8 or less on the screening tool. After obtaining informed consent, the researchers performed a detailed assessment of 468 of that population. The 468 people flagged by screening as possibly having dementia were all 70-79 years old, 60% were women, and half of them lived alone.

Medical records for this subgroup showed that 179 (38%) had already been diagnosed with dementia prior to screening based on their scores on the Mini-Mental State Examination (MMSE). Among the remaining 289 people identified by their DemTect score as potentially having dementia, MMSE testing identified another 171 people with dementia, increasing the total of this subgroup diagnosed with dementia by a relative 96%, compared with the 179 patients who had been identified with dementia prior to screening.

Two-thirds of the patients with newly diagnosed dementia had an unspecified form while 18% had Alzheimer’s disease, 14% had vascular dementia, and the remainder had other forms of dementia, Dr. Eichler said. Combining the newly identified 171 people with dementia and the 179 people previously diagnosed resulted in a total of 350 people diagnosed with definite dementia by the MMSE, 75% of the 468 identified as potentially having dementia based on their scores with the DemTect screening tool.

Dr. Eichler had no relevant financial disclosures.

mzoler@frontlinemedcom.com


On Twitter@mitchelzoler

WASHINGTON – A 7-minute screening tool nearly doubled the rate at which primary care physicians could identify elderly patients in their practices with dementia in a German study involving more than 6,800 community-dwelling people.

“Screening can considerably improve the recognition of dementia in primary care,” Dr. Tilly Eichler said at the Alzheimer’s Association International Conference 2015. But she cautioned that further research needs to be done to determine the best ways to identify the specific type of dementia a patient has, and must also follow patients long term to assess the benefits and risks from a more aggressive approach to dementia diagnosis in community-dwelling primary care patients.

Mitchel L. Zoler/Frontline Medical News

The majority of patients identified with dementia in primary care practices had an unspecified cause for their dementia, noted Dr. Eichler, a researcher with the German Center for Neurodegenerative Diseases in Greifswald, Germany.

Dr. Eichler and her associates arranged for 136 German primary care physicians to administer the DemTect screening tool (Int J Geriatr Psychiatry. 2004 Feb;19(2):136-43), a five-part test that takes about 7 minutes to administer, to screen 6,838 community dwellers aged 70 years or older as part of the DelpHi-MV (Dementia: Life- and Person-Centered Help in Mecklenburg–Western Pomerania) study. The DemTect test identified 1,166 people (17%) with potential dementia based on scoring 8 or less on the screening tool. After obtaining informed consent, the researchers performed a detailed assessment of 468 of that population. The 468 people flagged by screening as possibly having dementia were all 70-79 years old, 60% were women, and half of them lived alone.

Medical records for this subgroup showed that 179 (38%) had already been diagnosed with dementia prior to screening based on their scores on the Mini-Mental State Examination (MMSE). Among the remaining 289 people identified by their DemTect score as potentially having dementia, MMSE testing identified another 171 people with dementia, increasing the total of this subgroup diagnosed with dementia by a relative 96%, compared with the 179 patients who had been identified with dementia prior to screening.

Two-thirds of the patients with newly diagnosed dementia had an unspecified form while 18% had Alzheimer’s disease, 14% had vascular dementia, and the remainder had other forms of dementia, Dr. Eichler said. Combining the newly identified 171 people with dementia and the 179 people previously diagnosed resulted in a total of 350 people diagnosed with definite dementia by the MMSE, 75% of the 468 identified as potentially having dementia based on their scores with the DemTect screening tool.

Dr. Eichler had no relevant financial disclosures.

mzoler@frontlinemedcom.com


On Twitter@mitchelzoler

WASHINGTON – Daily treatment with a combined formulation of dextromethorphan and quinidine led to a significant and clinically meaningful cut in agitation episodes among patients with Alzheimer’s disease in a controlled, phase II, 10-week study with 159 patients.

The combined, oral formulation was generally well tolerated, without appearing to cause somnolence or cognitive decline, Dr. Jeffrey L. Cummings reported at the Alzheimer’s Association International Conference 2015.

A treatment that cuts the frequency and severity of agitation in Alzheimer’s disease patients would be very helpful as this is “one of the most difficult symptoms for patients. [Agitation] makes it very difficult to care for a family member with Alzheimer’s disease,” said Dr. Cummings, professor of neurology at the Cleveland Clinic and director of the clinic’s Lou Ruvo Center for Brain Health in Las Vegas.

“Agitation is one of the most disturbing and disabling symptoms associated with Alzheimer’s disease,” commented Mary Sano, Ph.D., professor of psychiatry and director of Alzheimer’s disease research at Mount Sinai Hospital in New York. “Movement on treating this symptom has the potential to make a real difference for Alzheimer’s disease patients and their caregivers,” she said.

The formulation of dextromethorphan and quinidine used in the study already has Food and Drug Administration marketing approval with the brand name Nuedexta for treating pseudobulbar affect (PBA), which can occur in patients with, for example, amyotrophic lateral sclerosis or multiple sclerosis. In addition, the primary active ingredient in the combination, dextromethorphan, appears in many over-the-counter formulations of cough syrup that are labeled to deliver roughly similar dosages of the drug as those used to treat PBA and tested in the current trial to treat agitation. But the OTC formulations of dextromethorphan do not include quinidine, which inhibits dextromethorphan’s metabolism and results in a roughly 20-fold increase in the bioavailability of the active agent, Dr. Cummings explained.

“With quinidine, we can use smaller dosages of dextromethorphan” than might be required if the drug were used by itself and thereby avoid the lethargy that could occur in patients who might require larger dosages of dextromethorphan without quinidine, he said in an interview.

The results he reported came from a study run at 44 U.S. centers that enrolled patients aged 50-90 years with probable Alzheimer’s disease and “meaningful” agitation secondary to their condition who scored at least 4 on a Clinical Global Impression-Severity Scale for Agitation. The researchers excluded patients who had any other cause for their agitation. Enrolled patients averaged 78 years old, somewhat more than half were women, and they had an average score on the Mini-Mental State Examination of about 17. The enrolled patients “looked like the population that you treat for agitation” secondary to Alzheimer’s disease, Dr. Cummings said.

The 93 patients randomized to the investigational treatment started on 20 mg dextromethorphan and 10 mg quinidine administered orally once daily for a week, followed by an up-titration schedule over 2 weeks to reach 30 mg dextromethorphan twice daily plus 10 mg quinidine twice daily, the dosage they continued for an additional 7 weeks. The study design allowed patients to also continue on stable, preexisting regimens of memantine, cholinesterase inhibitors, and psychotropic medications.

After 10 weeks, the 93 patients on dextromethorphan plus quinidine had their average neuropsychiatric inventory domain score for agitation and aggression cut roughly in half, compared with baseline, compared with about a 25% drop in average score among 66 control patients, a statistically significant difference for the study’s primary endpoint, Dr. Cummings reported. The results also showed statistically significant declines in the active-treatment versus control arm in certain secondary efficacy measures, including patient-reported quality of life and caregiver-reported strain.

The active treatment also appeared generally well tolerated, compared with placebo. The most noteworthy safety finding was an increased rate of falls among patients on dextromethorphan plus quinidine, a 9% rate, compared with a 4% rate in the controls, a signal for this adverse effect not previously seen in other studies of dextromethorphan plus quinidine. “We were surprised with the increased falls,” Dr. Cummings said. By chance, patients randomized to the active-treatment arm had an increased history of falls, compared with patients enrolled in the control arm, which may explain the safety finding, he noted. “We will monitor falls very closely in our follow-up studies,” he said.

A separate report at the meeting presented a new analysis of data from an open-label study that examined the same dextromethorphan plus quinidine formulation to treat 134 patients for 12 weeks with PBA secondary to dementia, stroke, or traumatic brain injury. The overall results showed that the combined formulation effectively reduced PBA in all enrolled patients, including those with dementia, a subset that predominantly included Alzheimer’s disease patients. The results also showed a modest 2% rate of falls, said Dr. Rachelle S. Doody, a professor of neurology and director of the Alzheimer’s Disease and Memory Disorders Center at Baylor College of Medicine in Houston. The new findings she reported at the meeting showed that the combined drug formulation worked equally effectively in the subset of patients with dementia, regardless of whether or not they concurrently received treatment with an antidepressant.

Despite availability of the dextromethorphan plus quinidine formulation, clinicians should avoid using it to treat agitation in Alzheimer’s disease patients until data become available from phase III studies that involve at least 6 months of chronic therapy, Dr. Cummings said. “We don’t want to encourage off-label use of the combined formulation until we understand it better when treating agitation in Alzheimer’s disease,” he cautioned.

He also highlighted the difficulty in enrolling Alzheimer’s disease patients with agitation as a significant symptom into trials, which means that completing a phase III trial could take perhaps as long as 2 more years and that FDA approval of this indication could be as long as 3 years off.

The study was sponsored by Avanir, the company that markets Nuedexta. Dr. Cummings has been a consultant to and has received honoraria from Avanir as well as from several other drug companies. He also owns stock or stock options in several companies developing drugs or other products aimed at Alzheimer’s disease patients. Dr. Sano has been a consultant to Eisai, Eli Lilly, and Takeda. Dr. Doody has been a principal investigator for trials sponsored by Avanir and several other drug companies. She also has been a consultant to several drug companies.

mzoler@frontlinemedcom.com

On Twitter @mitchelzoler

WASHINGTON – Daily treatment with a combined formulation of dextromethorphan and quinidine led to a significant and clinically meaningful cut in agitation episodes among patients with Alzheimer’s disease in a controlled, phase II, 10-week study with 159 patients.

The combined, oral formulation was generally well tolerated, without appearing to cause somnolence or cognitive decline, Dr. Jeffrey L. Cummings reported at the Alzheimer’s Association International Conference 2015.

A treatment that cuts the frequency and severity of agitation in Alzheimer’s disease patients would be very helpful as this is “one of the most difficult symptoms for patients. [Agitation] makes it very difficult to care for a family member with Alzheimer’s disease,” said Dr. Cummings, professor of neurology at the Cleveland Clinic and director of the clinic’s Lou Ruvo Center for Brain Health in Las Vegas.

“Agitation is one of the most disturbing and disabling symptoms associated with Alzheimer’s disease,” commented Mary Sano, Ph.D., professor of psychiatry and director of Alzheimer’s disease research at Mount Sinai Hospital in New York. “Movement on treating this symptom has the potential to make a real difference for Alzheimer’s disease patients and their caregivers,” she said.

The formulation of dextromethorphan and quinidine used in the study already has Food and Drug Administration marketing approval with the brand name Nuedexta for treating pseudobulbar affect (PBA), which can occur in patients with, for example, amyotrophic lateral sclerosis or multiple sclerosis. In addition, the primary active ingredient in the combination, dextromethorphan, appears in many over-the-counter formulations of cough syrup that are labeled to deliver roughly similar dosages of the drug as those used to treat PBA and tested in the current trial to treat agitation. But the OTC formulations of dextromethorphan do not include quinidine, which inhibits dextromethorphan’s metabolism and results in a roughly 20-fold increase in the bioavailability of the active agent, Dr. Cummings explained.

“With quinidine, we can use smaller dosages of dextromethorphan” than might be required if the drug were used by itself and thereby avoid the lethargy that could occur in patients who might require larger dosages of dextromethorphan without quinidine, he said in an interview.

The results he reported came from a study run at 44 U.S. centers that enrolled patients aged 50-90 years with probable Alzheimer’s disease and “meaningful” agitation secondary to their condition who scored at least 4 on a Clinical Global Impression-Severity Scale for Agitation. The researchers excluded patients who had any other cause for their agitation. Enrolled patients averaged 78 years old, somewhat more than half were women, and they had an average score on the Mini-Mental State Examination of about 17. The enrolled patients “looked like the population that you treat for agitation” secondary to Alzheimer’s disease, Dr. Cummings said.

The 93 patients randomized to the investigational treatment started on 20 mg dextromethorphan and 10 mg quinidine administered orally once daily for a week, followed by an up-titration schedule over 2 weeks to reach 30 mg dextromethorphan twice daily plus 10 mg quinidine twice daily, the dosage they continued for an additional 7 weeks. The study design allowed patients to also continue on stable, preexisting regimens of memantine, cholinesterase inhibitors, and psychotropic medications.

After 10 weeks, the 93 patients on dextromethorphan plus quinidine had their average neuropsychiatric inventory domain score for agitation and aggression cut roughly in half, compared with baseline, compared with about a 25% drop in average score among 66 control patients, a statistically significant difference for the study’s primary endpoint, Dr. Cummings reported. The results also showed statistically significant declines in the active-treatment versus control arm in certain secondary efficacy measures, including patient-reported quality of life and caregiver-reported strain.

The active treatment also appeared generally well tolerated, compared with placebo. The most noteworthy safety finding was an increased rate of falls among patients on dextromethorphan plus quinidine, a 9% rate, compared with a 4% rate in the controls, a signal for this adverse effect not previously seen in other studies of dextromethorphan plus quinidine. “We were surprised with the increased falls,” Dr. Cummings said. By chance, patients randomized to the active-treatment arm had an increased history of falls, compared with patients enrolled in the control arm, which may explain the safety finding, he noted. “We will monitor falls very closely in our follow-up studies,” he said.

A separate report at the meeting presented a new analysis of data from an open-label study that examined the same dextromethorphan plus quinidine formulation to treat 134 patients for 12 weeks with PBA secondary to dementia, stroke, or traumatic brain injury. The overall results showed that the combined formulation effectively reduced PBA in all enrolled patients, including those with dementia, a subset that predominantly included Alzheimer’s disease patients. The results also showed a modest 2% rate of falls, said Dr. Rachelle S. Doody, a professor of neurology and director of the Alzheimer’s Disease and Memory Disorders Center at Baylor College of Medicine in Houston. The new findings she reported at the meeting showed that the combined drug formulation worked equally effectively in the subset of patients with dementia, regardless of whether or not they concurrently received treatment with an antidepressant.

Despite availability of the dextromethorphan plus quinidine formulation, clinicians should avoid using it to treat agitation in Alzheimer’s disease patients until data become available from phase III studies that involve at least 6 months of chronic therapy, Dr. Cummings said. “We don’t want to encourage off-label use of the combined formulation until we understand it better when treating agitation in Alzheimer’s disease,” he cautioned.

He also highlighted the difficulty in enrolling Alzheimer’s disease patients with agitation as a significant symptom into trials, which means that completing a phase III trial could take perhaps as long as 2 more years and that FDA approval of this indication could be as long as 3 years off.

The study was sponsored by Avanir, the company that markets Nuedexta. Dr. Cummings has been a consultant to and has received honoraria from Avanir as well as from several other drug companies. He also owns stock or stock options in several companies developing drugs or other products aimed at Alzheimer’s disease patients. Dr. Sano has been a consultant to Eisai, Eli Lilly, and Takeda. Dr. Doody has been a principal investigator for trials sponsored by Avanir and several other drug companies. She also has been a consultant to several drug companies.

mzoler@frontlinemedcom.com

On Twitter @mitchelzoler

WASHINGTON – Daily treatment with a combined formulation of dextromethorphan and quinidine led to a significant and clinically meaningful cut in agitation episodes among patients with Alzheimer’s disease in a controlled, phase II, 10-week study with 159 patients.

The combined, oral formulation was generally well tolerated, without appearing to cause somnolence or cognitive decline, Dr. Jeffrey L. Cummings reported at the Alzheimer’s Association International Conference 2015.

A treatment that cuts the frequency and severity of agitation in Alzheimer’s disease patients would be very helpful as this is “one of the most difficult symptoms for patients. [Agitation] makes it very difficult to care for a family member with Alzheimer’s disease,” said Dr. Cummings, professor of neurology at the Cleveland Clinic and director of the clinic’s Lou Ruvo Center for Brain Health in Las Vegas.

“Agitation is one of the most disturbing and disabling symptoms associated with Alzheimer’s disease,” commented Mary Sano, Ph.D., professor of psychiatry and director of Alzheimer’s disease research at Mount Sinai Hospital in New York. “Movement on treating this symptom has the potential to make a real difference for Alzheimer’s disease patients and their caregivers,” she said.

The formulation of dextromethorphan and quinidine used in the study already has Food and Drug Administration marketing approval with the brand name Nuedexta for treating pseudobulbar affect (PBA), which can occur in patients with, for example, amyotrophic lateral sclerosis or multiple sclerosis. In addition, the primary active ingredient in the combination, dextromethorphan, appears in many over-the-counter formulations of cough syrup that are labeled to deliver roughly similar dosages of the drug as those used to treat PBA and tested in the current trial to treat agitation. But the OTC formulations of dextromethorphan do not include quinidine, which inhibits dextromethorphan’s metabolism and results in a roughly 20-fold increase in the bioavailability of the active agent, Dr. Cummings explained.

“With quinidine, we can use smaller dosages of dextromethorphan” than might be required if the drug were used by itself and thereby avoid the lethargy that could occur in patients who might require larger dosages of dextromethorphan without quinidine, he said in an interview.

The results he reported came from a study run at 44 U.S. centers that enrolled patients aged 50-90 years with probable Alzheimer’s disease and “meaningful” agitation secondary to their condition who scored at least 4 on a Clinical Global Impression-Severity Scale for Agitation. The researchers excluded patients who had any other cause for their agitation. Enrolled patients averaged 78 years old, somewhat more than half were women, and they had an average score on the Mini-Mental State Examination of about 17. The enrolled patients “looked like the population that you treat for agitation” secondary to Alzheimer’s disease, Dr. Cummings said.

The 93 patients randomized to the investigational treatment started on 20 mg dextromethorphan and 10 mg quinidine administered orally once daily for a week, followed by an up-titration schedule over 2 weeks to reach 30 mg dextromethorphan twice daily plus 10 mg quinidine twice daily, the dosage they continued for an additional 7 weeks. The study design allowed patients to also continue on stable, preexisting regimens of memantine, cholinesterase inhibitors, and psychotropic medications.

After 10 weeks, the 93 patients on dextromethorphan plus quinidine had their average neuropsychiatric inventory domain score for agitation and aggression cut roughly in half, compared with baseline, compared with about a 25% drop in average score among 66 control patients, a statistically significant difference for the study’s primary endpoint, Dr. Cummings reported. The results also showed statistically significant declines in the active-treatment versus control arm in certain secondary efficacy measures, including patient-reported quality of life and caregiver-reported strain.

The active treatment also appeared generally well tolerated, compared with placebo. The most noteworthy safety finding was an increased rate of falls among patients on dextromethorphan plus quinidine, a 9% rate, compared with a 4% rate in the controls, a signal for this adverse effect not previously seen in other studies of dextromethorphan plus quinidine. “We were surprised with the increased falls,” Dr. Cummings said. By chance, patients randomized to the active-treatment arm had an increased history of falls, compared with patients enrolled in the control arm, which may explain the safety finding, he noted. “We will monitor falls very closely in our follow-up studies,” he said.

A separate report at the meeting presented a new analysis of data from an open-label study that examined the same dextromethorphan plus quinidine formulation to treat 134 patients for 12 weeks with PBA secondary to dementia, stroke, or traumatic brain injury. The overall results showed that the combined formulation effectively reduced PBA in all enrolled patients, including those with dementia, a subset that predominantly included Alzheimer’s disease patients. The results also showed a modest 2% rate of falls, said Dr. Rachelle S. Doody, a professor of neurology and director of the Alzheimer’s Disease and Memory Disorders Center at Baylor College of Medicine in Houston. The new findings she reported at the meeting showed that the combined drug formulation worked equally effectively in the subset of patients with dementia, regardless of whether or not they concurrently received treatment with an antidepressant.

Despite availability of the dextromethorphan plus quinidine formulation, clinicians should avoid using it to treat agitation in Alzheimer’s disease patients until data become available from phase III studies that involve at least 6 months of chronic therapy, Dr. Cummings said. “We don’t want to encourage off-label use of the combined formulation until we understand it better when treating agitation in Alzheimer’s disease,” he cautioned.

He also highlighted the difficulty in enrolling Alzheimer’s disease patients with agitation as a significant symptom into trials, which means that completing a phase III trial could take perhaps as long as 2 more years and that FDA approval of this indication could be as long as 3 years off.

The study was sponsored by Avanir, the company that markets Nuedexta. Dr. Cummings has been a consultant to and has received honoraria from Avanir as well as from several other drug companies. He also owns stock or stock options in several companies developing drugs or other products aimed at Alzheimer’s disease patients. Dr. Sano has been a consultant to Eisai, Eli Lilly, and Takeda. Dr. Doody has been a principal investigator for trials sponsored by Avanir and several other drug companies. She also has been a consultant to several drug companies.

mzoler@frontlinemedcom.com

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