Heart Failure

Universal definitions and data standards have now been established for clinical research involving cardiovascular endpoints, according to a report published online Dec. 29 in both the Journal of the American College of Cardiology and Circulation.

The American College of Cardiology/American Heart Association Task Force on Clinical Data Standards, in collaboration with the Food and Drug Administration and the Standardized Data Collection for Cardiovascular Trials Initiative (SCTI), described the standards as “a first step in developing a universal language for clinical trials and other types of health-related research.” The aim is to make patient data regarding CV endpoints as consistent as possible across electronic health records, clinical trial databases, registries, drug/device surveillance programs, and other health-related research, to facilitate information sharing, said Dr. Karen A. Hicks, chair of the task force’s writing committee to develop cardiovascular endpoints data standards, and her associates.

©Petr Vaclavek/Fotolia.com

The report defines CV endpoints such as cardiovascular cause of death (as opposed to noncardiovascular or undetermined causes of death), MI, hospitalization for unstable angina, TIA, stroke, heart failure event, percutaneous coronary intervention, peripheral vascular intervention, and stent thrombosis. For example, the report notes that the outcome “hospitalization for unstable angina” is frequently assessed in research evaluating the safety of CV therapies, but by necessity involves subjective assessment of the most likely etiology of the symptoms that trigger hospitalization. To clarify that this outcome is truly due to cardiovascular ischemia, the definition must now include the presence of ECG abnormalities, such as deviations in the ST segment, the morphology of ST-segment changes (horizontal or downsloping vs. upsloping), and the magnitude of the deviation.

Similarly, the report’s definition of TIA now emphasizes the patient’s clinical presentation rather than the anatomic location of the lesion, because the availability of imaging modalities varies so much across medical centers. And, because heart failure can result from so many different etiologies, the key element in the definition of a heart failure event now is “the need for a resource-intensive response to failure of the primary therapeutic management strategy.”

“What makes this work unique is that it reviews and refines the terms as developed by the SCTI explicitly for use in reporting clinical trial results and in regulatory submissions, and it delineates where these concepts could or should not be used as the foundational vocabulary in routine clinical care,” Dr. Hicks, a cardiologist at the FDA, and her associates stated.

The SCTI is a working group comprised of experts from academia, professional societies, the FDA, and manufacturers of pharmaceuticals and CV devices. The ACC/AHA task force included 16 people with expertise in internal medicine, cardiovascular medicine, neurology, clinical research, epidemiology, invasive and interventional therapies, outcomes assessment, medical informatics, health information management, and healthcare services research and delivery.

The full report is available from the American College of Cardiology at www.acc.org and from the American Heart Association at www.myamericanheart.org.

This work received no commercial support. Dr. Hicks and her associates volunteered their time and were supported exclusively by the ACC and AHA.

Universal definitions and data standards have now been established for clinical research involving cardiovascular endpoints, according to a report published online Dec. 29 in both the Journal of the American College of Cardiology and Circulation.

The American College of Cardiology/American Heart Association Task Force on Clinical Data Standards, in collaboration with the Food and Drug Administration and the Standardized Data Collection for Cardiovascular Trials Initiative (SCTI), described the standards as “a first step in developing a universal language for clinical trials and other types of health-related research.” The aim is to make patient data regarding CV endpoints as consistent as possible across electronic health records, clinical trial databases, registries, drug/device surveillance programs, and other health-related research, to facilitate information sharing, said Dr. Karen A. Hicks, chair of the task force’s writing committee to develop cardiovascular endpoints data standards, and her associates.

©Petr Vaclavek/Fotolia.com

The report defines CV endpoints such as cardiovascular cause of death (as opposed to noncardiovascular or undetermined causes of death), MI, hospitalization for unstable angina, TIA, stroke, heart failure event, percutaneous coronary intervention, peripheral vascular intervention, and stent thrombosis. For example, the report notes that the outcome “hospitalization for unstable angina” is frequently assessed in research evaluating the safety of CV therapies, but by necessity involves subjective assessment of the most likely etiology of the symptoms that trigger hospitalization. To clarify that this outcome is truly due to cardiovascular ischemia, the definition must now include the presence of ECG abnormalities, such as deviations in the ST segment, the morphology of ST-segment changes (horizontal or downsloping vs. upsloping), and the magnitude of the deviation.

Similarly, the report’s definition of TIA now emphasizes the patient’s clinical presentation rather than the anatomic location of the lesion, because the availability of imaging modalities varies so much across medical centers. And, because heart failure can result from so many different etiologies, the key element in the definition of a heart failure event now is “the need for a resource-intensive response to failure of the primary therapeutic management strategy.”

“What makes this work unique is that it reviews and refines the terms as developed by the SCTI explicitly for use in reporting clinical trial results and in regulatory submissions, and it delineates where these concepts could or should not be used as the foundational vocabulary in routine clinical care,” Dr. Hicks, a cardiologist at the FDA, and her associates stated.

The SCTI is a working group comprised of experts from academia, professional societies, the FDA, and manufacturers of pharmaceuticals and CV devices. The ACC/AHA task force included 16 people with expertise in internal medicine, cardiovascular medicine, neurology, clinical research, epidemiology, invasive and interventional therapies, outcomes assessment, medical informatics, health information management, and healthcare services research and delivery.

The full report is available from the American College of Cardiology at www.acc.org and from the American Heart Association at www.myamericanheart.org.

This work received no commercial support. Dr. Hicks and her associates volunteered their time and were supported exclusively by the ACC and AHA.

Universal definitions and data standards have now been established for clinical research involving cardiovascular endpoints, according to a report published online Dec. 29 in both the Journal of the American College of Cardiology and Circulation.

The American College of Cardiology/American Heart Association Task Force on Clinical Data Standards, in collaboration with the Food and Drug Administration and the Standardized Data Collection for Cardiovascular Trials Initiative (SCTI), described the standards as “a first step in developing a universal language for clinical trials and other types of health-related research.” The aim is to make patient data regarding CV endpoints as consistent as possible across electronic health records, clinical trial databases, registries, drug/device surveillance programs, and other health-related research, to facilitate information sharing, said Dr. Karen A. Hicks, chair of the task force’s writing committee to develop cardiovascular endpoints data standards, and her associates.

©Petr Vaclavek/Fotolia.com

The report defines CV endpoints such as cardiovascular cause of death (as opposed to noncardiovascular or undetermined causes of death), MI, hospitalization for unstable angina, TIA, stroke, heart failure event, percutaneous coronary intervention, peripheral vascular intervention, and stent thrombosis. For example, the report notes that the outcome “hospitalization for unstable angina” is frequently assessed in research evaluating the safety of CV therapies, but by necessity involves subjective assessment of the most likely etiology of the symptoms that trigger hospitalization. To clarify that this outcome is truly due to cardiovascular ischemia, the definition must now include the presence of ECG abnormalities, such as deviations in the ST segment, the morphology of ST-segment changes (horizontal or downsloping vs. upsloping), and the magnitude of the deviation.

Similarly, the report’s definition of TIA now emphasizes the patient’s clinical presentation rather than the anatomic location of the lesion, because the availability of imaging modalities varies so much across medical centers. And, because heart failure can result from so many different etiologies, the key element in the definition of a heart failure event now is “the need for a resource-intensive response to failure of the primary therapeutic management strategy.”

“What makes this work unique is that it reviews and refines the terms as developed by the SCTI explicitly for use in reporting clinical trial results and in regulatory submissions, and it delineates where these concepts could or should not be used as the foundational vocabulary in routine clinical care,” Dr. Hicks, a cardiologist at the FDA, and her associates stated.

The SCTI is a working group comprised of experts from academia, professional societies, the FDA, and manufacturers of pharmaceuticals and CV devices. The ACC/AHA task force included 16 people with expertise in internal medicine, cardiovascular medicine, neurology, clinical research, epidemiology, invasive and interventional therapies, outcomes assessment, medical informatics, health information management, and healthcare services research and delivery.

The full report is available from the American College of Cardiology at www.acc.org and from the American Heart Association at www.myamericanheart.org.

This work received no commercial support. Dr. Hicks and her associates volunteered their time and were supported exclusively by the ACC and AHA.

Can the high-intensity care given acutely ill, high-risk U.S. patients with cardiac disease actually harm them?

Results from an unusual analysis of cardiology-meeting times seem to suggest that sobering possibility. Patient outcomes improved when thousands of high-level, American cardiologists left their practices for a few days each year to attend either of the two major U.S. heart disease meetings.

Researchers led by Dr. Anupam B. Jena of Harvard University, Boston, used Medicare data to examine mortality rates among patients hospitalized for cardiac arrest, heart failure, or acute myocardial infarction during 2002-2011. They focused on patients admitted during the annual meetings of the American College of Cardiology (usually in March) or the American Heart Association (during November).

Mitchel L. Zoler/Frontline Medical News

As controls in their case-control analyses, they used data from patients admitted on similar days of the week during the 3 weeks immediately before or after these two meetings. This gave them roughly 11,000 total patients with cardiac arrest, nearly 134,000 with heart failure, and about 60,000 with acute MI – about 14% of patients in each disease category admitted during a meeting and the other 86% (controls) admitted when there was no meeting.

The results showed some statistically significant differences indicating that patients did better during the meetings, presumably when many cardiologists were away from their hospitals. These associations only occurred at teaching hospitals and among patients at high risk for inpatient mortality. The investigators saw no statistically significant differences, after adjustment, in mortality during meetings among patients treated at nonteaching hospitals or among patients with a low risk for inpatient mortality.

In analyses that adjusted for baseline differences in risk factors, the 30-day mortality rate for patients admitted to teaching hospitals with cardiac arrest was 69% during control dates and 59% during the meetings. Thirty-day mortality for patients admitted with heart failure was 25% during control dates and 18% during the meetings, researchers reported in an article published online on Dec. 22 (JAMA Intern. Med. 2014 [doi:10.1001/jamainternmed.2014.6781]).

Although 30-day mortality among patients admitted with an acute MI did not differ significantly at teaching hospitals between patients who presented during a major meeting and those who did not, the results showed that these similar mortality rates were achieved despite a statistically significant difference in the rate of percutaneous coronary interventions (PCI) that patients received: During the major meetings, 21% of the acute MI patients underwent PCI, but when a meeting was not in progress, the PCI rate jumped to 28% of all acute MI patients.

“One explanation for these findings is that the intensity of care provided during meeting dates is lower, and that for high-risk patients with cardiovascular disease, the harms of this care may unexpectedly outweigh the benefits,” Dr. Jena concluded.

It’s a remarkable and surprising finding, but can it be taken seriously? At least one expert said yes, at least seriously enough to warrant further study and consideration.

An editor’s note published with the new report suggested a plausible explanation for the findings is that “more interventions in high-risk patients with heart failure and cardiac arrest leads to higher mortality.” In her note, Dr. Rita F. Redberg, a cardiologist at the University of California, San Francisco, and editor of JAMA Internal Medicine, concluded, “It is reassuring that patient outcomes do not suffer while many cardiologists are away. More important, this analysis may help us to understand how we could lower mortality throughout the year.”

It will be interesting to see if anyone takes up the challenge to further explore this relationship and tries to find ways to apply throughout the year the protective effect of having fewer teaching-hospital cardiologists around. If a drug had this beneficial effect on mortality, the pharmaceutical industry would be all over it.

mzoler@frontlinemedcom.com 


On Twitter @mitchelzoler

Can the high-intensity care given acutely ill, high-risk U.S. patients with cardiac disease actually harm them?

Results from an unusual analysis of cardiology-meeting times seem to suggest that sobering possibility. Patient outcomes improved when thousands of high-level, American cardiologists left their practices for a few days each year to attend either of the two major U.S. heart disease meetings.

Researchers led by Dr. Anupam B. Jena of Harvard University, Boston, used Medicare data to examine mortality rates among patients hospitalized for cardiac arrest, heart failure, or acute myocardial infarction during 2002-2011. They focused on patients admitted during the annual meetings of the American College of Cardiology (usually in March) or the American Heart Association (during November).

Mitchel L. Zoler/Frontline Medical News

As controls in their case-control analyses, they used data from patients admitted on similar days of the week during the 3 weeks immediately before or after these two meetings. This gave them roughly 11,000 total patients with cardiac arrest, nearly 134,000 with heart failure, and about 60,000 with acute MI – about 14% of patients in each disease category admitted during a meeting and the other 86% (controls) admitted when there was no meeting.

The results showed some statistically significant differences indicating that patients did better during the meetings, presumably when many cardiologists were away from their hospitals. These associations only occurred at teaching hospitals and among patients at high risk for inpatient mortality. The investigators saw no statistically significant differences, after adjustment, in mortality during meetings among patients treated at nonteaching hospitals or among patients with a low risk for inpatient mortality.

In analyses that adjusted for baseline differences in risk factors, the 30-day mortality rate for patients admitted to teaching hospitals with cardiac arrest was 69% during control dates and 59% during the meetings. Thirty-day mortality for patients admitted with heart failure was 25% during control dates and 18% during the meetings, researchers reported in an article published online on Dec. 22 (JAMA Intern. Med. 2014 [doi:10.1001/jamainternmed.2014.6781]).

Although 30-day mortality among patients admitted with an acute MI did not differ significantly at teaching hospitals between patients who presented during a major meeting and those who did not, the results showed that these similar mortality rates were achieved despite a statistically significant difference in the rate of percutaneous coronary interventions (PCI) that patients received: During the major meetings, 21% of the acute MI patients underwent PCI, but when a meeting was not in progress, the PCI rate jumped to 28% of all acute MI patients.

“One explanation for these findings is that the intensity of care provided during meeting dates is lower, and that for high-risk patients with cardiovascular disease, the harms of this care may unexpectedly outweigh the benefits,” Dr. Jena concluded.

It’s a remarkable and surprising finding, but can it be taken seriously? At least one expert said yes, at least seriously enough to warrant further study and consideration.

An editor’s note published with the new report suggested a plausible explanation for the findings is that “more interventions in high-risk patients with heart failure and cardiac arrest leads to higher mortality.” In her note, Dr. Rita F. Redberg, a cardiologist at the University of California, San Francisco, and editor of JAMA Internal Medicine, concluded, “It is reassuring that patient outcomes do not suffer while many cardiologists are away. More important, this analysis may help us to understand how we could lower mortality throughout the year.”

It will be interesting to see if anyone takes up the challenge to further explore this relationship and tries to find ways to apply throughout the year the protective effect of having fewer teaching-hospital cardiologists around. If a drug had this beneficial effect on mortality, the pharmaceutical industry would be all over it.

mzoler@frontlinemedcom.com 


On Twitter @mitchelzoler

Can the high-intensity care given acutely ill, high-risk U.S. patients with cardiac disease actually harm them?

Results from an unusual analysis of cardiology-meeting times seem to suggest that sobering possibility. Patient outcomes improved when thousands of high-level, American cardiologists left their practices for a few days each year to attend either of the two major U.S. heart disease meetings.

Researchers led by Dr. Anupam B. Jena of Harvard University, Boston, used Medicare data to examine mortality rates among patients hospitalized for cardiac arrest, heart failure, or acute myocardial infarction during 2002-2011. They focused on patients admitted during the annual meetings of the American College of Cardiology (usually in March) or the American Heart Association (during November).

Mitchel L. Zoler/Frontline Medical News

As controls in their case-control analyses, they used data from patients admitted on similar days of the week during the 3 weeks immediately before or after these two meetings. This gave them roughly 11,000 total patients with cardiac arrest, nearly 134,000 with heart failure, and about 60,000 with acute MI – about 14% of patients in each disease category admitted during a meeting and the other 86% (controls) admitted when there was no meeting.

The results showed some statistically significant differences indicating that patients did better during the meetings, presumably when many cardiologists were away from their hospitals. These associations only occurred at teaching hospitals and among patients at high risk for inpatient mortality. The investigators saw no statistically significant differences, after adjustment, in mortality during meetings among patients treated at nonteaching hospitals or among patients with a low risk for inpatient mortality.

In analyses that adjusted for baseline differences in risk factors, the 30-day mortality rate for patients admitted to teaching hospitals with cardiac arrest was 69% during control dates and 59% during the meetings. Thirty-day mortality for patients admitted with heart failure was 25% during control dates and 18% during the meetings, researchers reported in an article published online on Dec. 22 (JAMA Intern. Med. 2014 [doi:10.1001/jamainternmed.2014.6781]).

Although 30-day mortality among patients admitted with an acute MI did not differ significantly at teaching hospitals between patients who presented during a major meeting and those who did not, the results showed that these similar mortality rates were achieved despite a statistically significant difference in the rate of percutaneous coronary interventions (PCI) that patients received: During the major meetings, 21% of the acute MI patients underwent PCI, but when a meeting was not in progress, the PCI rate jumped to 28% of all acute MI patients.

“One explanation for these findings is that the intensity of care provided during meeting dates is lower, and that for high-risk patients with cardiovascular disease, the harms of this care may unexpectedly outweigh the benefits,” Dr. Jena concluded.

It’s a remarkable and surprising finding, but can it be taken seriously? At least one expert said yes, at least seriously enough to warrant further study and consideration.

An editor’s note published with the new report suggested a plausible explanation for the findings is that “more interventions in high-risk patients with heart failure and cardiac arrest leads to higher mortality.” In her note, Dr. Rita F. Redberg, a cardiologist at the University of California, San Francisco, and editor of JAMA Internal Medicine, concluded, “It is reassuring that patient outcomes do not suffer while many cardiologists are away. More important, this analysis may help us to understand how we could lower mortality throughout the year.”

It will be interesting to see if anyone takes up the challenge to further explore this relationship and tries to find ways to apply throughout the year the protective effect of having fewer teaching-hospital cardiologists around. If a drug had this beneficial effect on mortality, the pharmaceutical industry would be all over it.

mzoler@frontlinemedcom.com 


On Twitter @mitchelzoler

CHICAGO – A novel risk score has been developed for predicting the risk of in-hospital mortality in patients with takotsubo cardiomyopathy.

The new risk score’s unique strength is that it was developed using hospital data on a huge patient population with this rare and incompletely understood cardiac condition: 10,582 patients hospitalized for takotsubo cardiomyopathy in seven U.S. states, Dr. David P. Kao reported at the American Heart Association scientific sessions.

He used multivariate logistic regression analysis to identify seven independent characteristics predictive of mortality in the study population. Their collective area under the curve as predictors was 0.70, which is considered good. And while the overall in-hospital mortality rate was low at 4.4%, it varied enormously depending upon how many of the seven risk factors were present, according to Dr. Kao of the University of Colorado, Denver.

In-hospital mortality ranged from 1.6% in the 2,585 patients with none of the risk factors to 19.6% in those with three or more. The 616 patients with at least three risk factors accounted for 22% of all in-hospital deaths in patients with takotsubo cardiomyopathy in California, New York, New Jersey, Colorado, West Virginia, New Hampshire, and Vermont during 2006-2012.

Intracranial hemorrhage, which was present in 2% of hospitalized takotsubo cardiomyopathy patients, was the most potent predictor both of in-hospital mortality and major adverse events. In multivariate analysis, intracranial hemorrhage was independently associated with a 6.8-fold increased risk of in-hospital mortality. The other mortality risk factors and their associated odds ratios were age 60 years or older, with a 1.8-fold risk; Asian race, 1.8-fold; male sex, 1.9-fold; acute renal failure, 4.1-fold; atrial fibrillation or flutter, 1.7-fold; and stroke, 2.9-fold.

The simple, user-friendly risk score is derived by totaling the number of risk factors present in a given hospitalized patient. The presence of each additional risk factor increased the odds of in-hospital death by 2.2-fold, according to Dr. Kao.

Takotsubo cardiomyopathy is marked by acute, typically rapidly reversible left ventricular dysfunction without evidence of epicardial coronary artery occlusion. It occurs most often in postmenopausal women in response to emotional or physical stress. Indeed, 89% of the more than 10,000 affected patients in this series were women.

Most adverse events in patients with takotsubo cardiomyopathy occur during their first hospitalization for the disorder. In this large series, 22% of patients experienced major adverse events, including ventricular arrhythmias, acute heart failure, cardiogenic shock, pulmonary edema, or ventricular rupture.

In a separate multiple logistic regression analysis, Dr. Kao and coinvestigator Dr. JoAnn Lindenfeld, also of the University of Colorado, identified eight characteristics independently predictive of in-hospital major adverse events. Five of them were also predictors of in-hospital mortality: intracranial hemorrhage, male gender, stroke, atrial fibrillation/flutter, and acute renal failure. The other three were age less than 60, substance abuse, and anemia. The major adverse event rate ranged from 10% in patients with none of the risk factors to 56% in the 242 patients having four or more. The 1,057 patients with three or more risk factors had a 47% major adverse event rate and accounted for 20% of all such events.

Dr. Kao reported having no financial conflicts related to this study.

bjancin@frontlinemedcom.com

CHICAGO – A novel risk score has been developed for predicting the risk of in-hospital mortality in patients with takotsubo cardiomyopathy.

The new risk score’s unique strength is that it was developed using hospital data on a huge patient population with this rare and incompletely understood cardiac condition: 10,582 patients hospitalized for takotsubo cardiomyopathy in seven U.S. states, Dr. David P. Kao reported at the American Heart Association scientific sessions.

He used multivariate logistic regression analysis to identify seven independent characteristics predictive of mortality in the study population. Their collective area under the curve as predictors was 0.70, which is considered good. And while the overall in-hospital mortality rate was low at 4.4%, it varied enormously depending upon how many of the seven risk factors were present, according to Dr. Kao of the University of Colorado, Denver.

In-hospital mortality ranged from 1.6% in the 2,585 patients with none of the risk factors to 19.6% in those with three or more. The 616 patients with at least three risk factors accounted for 22% of all in-hospital deaths in patients with takotsubo cardiomyopathy in California, New York, New Jersey, Colorado, West Virginia, New Hampshire, and Vermont during 2006-2012.

Intracranial hemorrhage, which was present in 2% of hospitalized takotsubo cardiomyopathy patients, was the most potent predictor both of in-hospital mortality and major adverse events. In multivariate analysis, intracranial hemorrhage was independently associated with a 6.8-fold increased risk of in-hospital mortality. The other mortality risk factors and their associated odds ratios were age 60 years or older, with a 1.8-fold risk; Asian race, 1.8-fold; male sex, 1.9-fold; acute renal failure, 4.1-fold; atrial fibrillation or flutter, 1.7-fold; and stroke, 2.9-fold.

The simple, user-friendly risk score is derived by totaling the number of risk factors present in a given hospitalized patient. The presence of each additional risk factor increased the odds of in-hospital death by 2.2-fold, according to Dr. Kao.

Takotsubo cardiomyopathy is marked by acute, typically rapidly reversible left ventricular dysfunction without evidence of epicardial coronary artery occlusion. It occurs most often in postmenopausal women in response to emotional or physical stress. Indeed, 89% of the more than 10,000 affected patients in this series were women.

Most adverse events in patients with takotsubo cardiomyopathy occur during their first hospitalization for the disorder. In this large series, 22% of patients experienced major adverse events, including ventricular arrhythmias, acute heart failure, cardiogenic shock, pulmonary edema, or ventricular rupture.

In a separate multiple logistic regression analysis, Dr. Kao and coinvestigator Dr. JoAnn Lindenfeld, also of the University of Colorado, identified eight characteristics independently predictive of in-hospital major adverse events. Five of them were also predictors of in-hospital mortality: intracranial hemorrhage, male gender, stroke, atrial fibrillation/flutter, and acute renal failure. The other three were age less than 60, substance abuse, and anemia. The major adverse event rate ranged from 10% in patients with none of the risk factors to 56% in the 242 patients having four or more. The 1,057 patients with three or more risk factors had a 47% major adverse event rate and accounted for 20% of all such events.

Dr. Kao reported having no financial conflicts related to this study.

bjancin@frontlinemedcom.com

CHICAGO – A novel risk score has been developed for predicting the risk of in-hospital mortality in patients with takotsubo cardiomyopathy.

The new risk score’s unique strength is that it was developed using hospital data on a huge patient population with this rare and incompletely understood cardiac condition: 10,582 patients hospitalized for takotsubo cardiomyopathy in seven U.S. states, Dr. David P. Kao reported at the American Heart Association scientific sessions.

He used multivariate logistic regression analysis to identify seven independent characteristics predictive of mortality in the study population. Their collective area under the curve as predictors was 0.70, which is considered good. And while the overall in-hospital mortality rate was low at 4.4%, it varied enormously depending upon how many of the seven risk factors were present, according to Dr. Kao of the University of Colorado, Denver.

In-hospital mortality ranged from 1.6% in the 2,585 patients with none of the risk factors to 19.6% in those with three or more. The 616 patients with at least three risk factors accounted for 22% of all in-hospital deaths in patients with takotsubo cardiomyopathy in California, New York, New Jersey, Colorado, West Virginia, New Hampshire, and Vermont during 2006-2012.

Intracranial hemorrhage, which was present in 2% of hospitalized takotsubo cardiomyopathy patients, was the most potent predictor both of in-hospital mortality and major adverse events. In multivariate analysis, intracranial hemorrhage was independently associated with a 6.8-fold increased risk of in-hospital mortality. The other mortality risk factors and their associated odds ratios were age 60 years or older, with a 1.8-fold risk; Asian race, 1.8-fold; male sex, 1.9-fold; acute renal failure, 4.1-fold; atrial fibrillation or flutter, 1.7-fold; and stroke, 2.9-fold.

The simple, user-friendly risk score is derived by totaling the number of risk factors present in a given hospitalized patient. The presence of each additional risk factor increased the odds of in-hospital death by 2.2-fold, according to Dr. Kao.

Takotsubo cardiomyopathy is marked by acute, typically rapidly reversible left ventricular dysfunction without evidence of epicardial coronary artery occlusion. It occurs most often in postmenopausal women in response to emotional or physical stress. Indeed, 89% of the more than 10,000 affected patients in this series were women.

Most adverse events in patients with takotsubo cardiomyopathy occur during their first hospitalization for the disorder. In this large series, 22% of patients experienced major adverse events, including ventricular arrhythmias, acute heart failure, cardiogenic shock, pulmonary edema, or ventricular rupture.

In a separate multiple logistic regression analysis, Dr. Kao and coinvestigator Dr. JoAnn Lindenfeld, also of the University of Colorado, identified eight characteristics independently predictive of in-hospital major adverse events. Five of them were also predictors of in-hospital mortality: intracranial hemorrhage, male gender, stroke, atrial fibrillation/flutter, and acute renal failure. The other three were age less than 60, substance abuse, and anemia. The major adverse event rate ranged from 10% in patients with none of the risk factors to 56% in the 242 patients having four or more. The 1,057 patients with three or more risk factors had a 47% major adverse event rate and accounted for 20% of all such events.

Dr. Kao reported having no financial conflicts related to this study.

bjancin@frontlinemedcom.com

VIENNA – Bedside echocardiography has become a key part of quickly assessing patients with acute heart failure to decide the best management strategy.

But bedside echo images often are challenging to interpret, so physicians performing an initial work-up of an acute heart failure patient need training in a basic echocardiography examination, Dr. Nuno Cardim said in an interview during the annual meeting of the European Association of Cardiovascular Imaging.

Known as Focused Cardiac Ultrasound (FoCUS), this triage-level exam is distinct from a comprehensive echocardiography assessment. Instead, FoCUS addresses some basic, yes-or-no, present-or-absent questions regarding systolic function, hypovolemia, tamponade, pleural effusion, and pulmonary embolus.

In a position paper and then in practice recommendations issued in 2014, the European Association of Cardiovascular Imaging acknowledged that use of FoCUS in acute heart failure patients was “irreversible,” said Dr. Cardim, professor and director of echocardiography and cardiac imaging at Hospital da Luz in Lisbon.

Cardiologists and echocardiography specialists need to make sure that FoCUS training is available to all physicians who might see suspected acute heart failure patients in emergency medicine settings, Dr. Cardim said.

Dr. Cardim had no disclosures.

mzoler@frontlinemedcom.com

On Twitter @mitchelzoler

VIENNA – Bedside echocardiography has become a key part of quickly assessing patients with acute heart failure to decide the best management strategy.

But bedside echo images often are challenging to interpret, so physicians performing an initial work-up of an acute heart failure patient need training in a basic echocardiography examination, Dr. Nuno Cardim said in an interview during the annual meeting of the European Association of Cardiovascular Imaging.

Known as Focused Cardiac Ultrasound (FoCUS), this triage-level exam is distinct from a comprehensive echocardiography assessment. Instead, FoCUS addresses some basic, yes-or-no, present-or-absent questions regarding systolic function, hypovolemia, tamponade, pleural effusion, and pulmonary embolus.

In a position paper and then in practice recommendations issued in 2014, the European Association of Cardiovascular Imaging acknowledged that use of FoCUS in acute heart failure patients was “irreversible,” said Dr. Cardim, professor and director of echocardiography and cardiac imaging at Hospital da Luz in Lisbon.

Cardiologists and echocardiography specialists need to make sure that FoCUS training is available to all physicians who might see suspected acute heart failure patients in emergency medicine settings, Dr. Cardim said.

Dr. Cardim had no disclosures.

mzoler@frontlinemedcom.com

On Twitter @mitchelzoler

VIENNA – Bedside echocardiography has become a key part of quickly assessing patients with acute heart failure to decide the best management strategy.

But bedside echo images often are challenging to interpret, so physicians performing an initial work-up of an acute heart failure patient need training in a basic echocardiography examination, Dr. Nuno Cardim said in an interview during the annual meeting of the European Association of Cardiovascular Imaging.

Known as Focused Cardiac Ultrasound (FoCUS), this triage-level exam is distinct from a comprehensive echocardiography assessment. Instead, FoCUS addresses some basic, yes-or-no, present-or-absent questions regarding systolic function, hypovolemia, tamponade, pleural effusion, and pulmonary embolus.

In a position paper and then in practice recommendations issued in 2014, the European Association of Cardiovascular Imaging acknowledged that use of FoCUS in acute heart failure patients was “irreversible,” said Dr. Cardim, professor and director of echocardiography and cardiac imaging at Hospital da Luz in Lisbon.

Cardiologists and echocardiography specialists need to make sure that FoCUS training is available to all physicians who might see suspected acute heart failure patients in emergency medicine settings, Dr. Cardim said.

Dr. Cardim had no disclosures.

mzoler@frontlinemedcom.com

On Twitter @mitchelzoler

CHICAGO – Early results from a randomized trial cast doubt on the benefits of routinely repairing a leaky mitral valve during coronary artery bypass grafting in patients with moderate ischemic mitral regurgitation.

At 1 year, there was no significant difference between patients undergoing CABG alone or CABG plus mitral repair in the primary endpoint of left ventricular reverse modeling, as defined by changes in LV end-systolic volume index (LVESVI) at 1 year (z score 0.50).

Both groups achieved significant reductions in LVESVI, with a median reduction of about 6 mL/m² from baseline, Dr. Robert Michler, chair of cardiovascular and thoracic surgery at Montefiore Medical Center, New York, reported at the American Heart Association scientific sessions.

At 1 year, patients who underwent CABG and mitral valve repair had significantly less residual moderate or severe mitral regurgitation (11% vs. 31%; P < .001).

On the other hand, the combination procedure was associated with significantly higher rates of any neurologic event (9.6% vs. 3.1%; P = .03), longer cross-clamp (117 vs. 74 minutes) and cardiopulmonary bypass times (163 vs. 106 minutes; P values both < .001), and longer ICU (4.8 vs. 4.0 days; P = .006) and hospital length of stay (11.3 vs. 9.4 days; P = .002), according to the results, also published online (N. Engl. J. Med. 2014 [doi: 10.1056/NEJMoa1410490]).

“The trial did not demonstrate a clinically meaningful advantage to the routine addition of mitral valve repair to CABG,” Dr. Michler said, on behalf of the Cardiothoracic Surgical Trials Network investigators.

The 2014 AHA/American College of Cardiology mitral valve guidelines give a weak class IIb recommendation for mitral valve repair for patients with chronic mitral regurgitation (MR) who are undergoing other cardiac surgery, he noted.

The study evenly randomized 301 patients with moderate ischemic mitral regurgitation to CABG alone or CABG plus valve repair with an undersized ring (average, 28.3 mm for men and 27.1 mm for women).

The mean LVESVI at baseline was 54.8 mL/m² in the CABG-alone group and 59.6 mL/m² in the combined procedure group.

At 12 months, mean LVESVIs were 46.1 mL/m² and 49.6 mL/m², respectively.

The trial lacked a clinical primary endpoint, and longer follow-up is ongoing to determine whether the lower incidence of moderate or severe MR at 1 year will translate into a net clinical benefit for patients undergoing CABG plus mitral repair, Dr. Michler said.

Designated discussant Dr. David Adams, director of Mount Sinai Hospital’s mitral valve repair reference center in New York, cautioned the audience on the length of the study and called for a full 5 years of follow-up rather than the 2 years as planned.

“Ischemic mitral regurgitation is a disease that hurts you over time. That’s in patients that have had MI, had previous CABG, had attempted mitral valve repair, and had PCI [percutaneous coronary intervention]. So we need much longer term follow-up of this very important data set to really understand its implications,” he said.

In light of roughly half of the patients being in heart failure at baseline, session cochair Dr. Robert Bonow, vice chair of medicine, Northwestern University, Chicago, questioned whether there were differences in outcomes related to changes in baseline ejection fraction (EF) or whether improvement in EF in patients with low EF correlated with reduction in mitral regurgitation with CABG alone.

What is known right now is that mean LVEF increased to the same degree after CABG in both groups, Dr. Michler responded. This was true despite this being a “sick population of patients,” with more than half having diabetes, 50% with heart failure, 20% with renal insufficiency, 10% with prior stroke, and a mean ejection fraction of 40% in both groups.

“What we have yet to identify and plan to explore is the correlation between reverse ventricular remodeling, ejection fraction, and outcome, meaning both the degree of mitral regurgitation and whether there is any signal with respect to repeat hospitalizations, heart failure, or possibly even mortality,” Dr. Michler said.

Both Dr. Michler and Dr. Adams remarked that surgery was extremely safe for the CABG alone and CABG plus MR groups, as reflected by the low mortality at 30 days (2.7% vs. 1.3%) and 1 year (7.3% vs. 6.7%).

The composite endpoint of major adverse cardiac or cerebrovascular events was also similar between groups.

The trial was funded by the National Institutes of Health and the Canadian Institutes for Health Research. Dr. Michler reported grant support from NIH during the conduct of the study. Dr. Adams reported coinventing a mitral valve repair ring.

pwendling@frontlinemedcom.com

CHICAGO – Early results from a randomized trial cast doubt on the benefits of routinely repairing a leaky mitral valve during coronary artery bypass grafting in patients with moderate ischemic mitral regurgitation.

At 1 year, there was no significant difference between patients undergoing CABG alone or CABG plus mitral repair in the primary endpoint of left ventricular reverse modeling, as defined by changes in LV end-systolic volume index (LVESVI) at 1 year (z score 0.50).

Both groups achieved significant reductions in LVESVI, with a median reduction of about 6 mL/m² from baseline, Dr. Robert Michler, chair of cardiovascular and thoracic surgery at Montefiore Medical Center, New York, reported at the American Heart Association scientific sessions.

At 1 year, patients who underwent CABG and mitral valve repair had significantly less residual moderate or severe mitral regurgitation (11% vs. 31%; P < .001).

On the other hand, the combination procedure was associated with significantly higher rates of any neurologic event (9.6% vs. 3.1%; P = .03), longer cross-clamp (117 vs. 74 minutes) and cardiopulmonary bypass times (163 vs. 106 minutes; P values both < .001), and longer ICU (4.8 vs. 4.0 days; P = .006) and hospital length of stay (11.3 vs. 9.4 days; P = .002), according to the results, also published online (N. Engl. J. Med. 2014 [doi: 10.1056/NEJMoa1410490]).

“The trial did not demonstrate a clinically meaningful advantage to the routine addition of mitral valve repair to CABG,” Dr. Michler said, on behalf of the Cardiothoracic Surgical Trials Network investigators.

The 2014 AHA/American College of Cardiology mitral valve guidelines give a weak class IIb recommendation for mitral valve repair for patients with chronic mitral regurgitation (MR) who are undergoing other cardiac surgery, he noted.

The study evenly randomized 301 patients with moderate ischemic mitral regurgitation to CABG alone or CABG plus valve repair with an undersized ring (average, 28.3 mm for men and 27.1 mm for women).

The mean LVESVI at baseline was 54.8 mL/m² in the CABG-alone group and 59.6 mL/m² in the combined procedure group.

At 12 months, mean LVESVIs were 46.1 mL/m² and 49.6 mL/m², respectively.

The trial lacked a clinical primary endpoint, and longer follow-up is ongoing to determine whether the lower incidence of moderate or severe MR at 1 year will translate into a net clinical benefit for patients undergoing CABG plus mitral repair, Dr. Michler said.

Designated discussant Dr. David Adams, director of Mount Sinai Hospital’s mitral valve repair reference center in New York, cautioned the audience on the length of the study and called for a full 5 years of follow-up rather than the 2 years as planned.

“Ischemic mitral regurgitation is a disease that hurts you over time. That’s in patients that have had MI, had previous CABG, had attempted mitral valve repair, and had PCI [percutaneous coronary intervention]. So we need much longer term follow-up of this very important data set to really understand its implications,” he said.

In light of roughly half of the patients being in heart failure at baseline, session cochair Dr. Robert Bonow, vice chair of medicine, Northwestern University, Chicago, questioned whether there were differences in outcomes related to changes in baseline ejection fraction (EF) or whether improvement in EF in patients with low EF correlated with reduction in mitral regurgitation with CABG alone.

What is known right now is that mean LVEF increased to the same degree after CABG in both groups, Dr. Michler responded. This was true despite this being a “sick population of patients,” with more than half having diabetes, 50% with heart failure, 20% with renal insufficiency, 10% with prior stroke, and a mean ejection fraction of 40% in both groups.

“What we have yet to identify and plan to explore is the correlation between reverse ventricular remodeling, ejection fraction, and outcome, meaning both the degree of mitral regurgitation and whether there is any signal with respect to repeat hospitalizations, heart failure, or possibly even mortality,” Dr. Michler said.

Both Dr. Michler and Dr. Adams remarked that surgery was extremely safe for the CABG alone and CABG plus MR groups, as reflected by the low mortality at 30 days (2.7% vs. 1.3%) and 1 year (7.3% vs. 6.7%).

The composite endpoint of major adverse cardiac or cerebrovascular events was also similar between groups.

The trial was funded by the National Institutes of Health and the Canadian Institutes for Health Research. Dr. Michler reported grant support from NIH during the conduct of the study. Dr. Adams reported coinventing a mitral valve repair ring.

pwendling@frontlinemedcom.com

CHICAGO – Early results from a randomized trial cast doubt on the benefits of routinely repairing a leaky mitral valve during coronary artery bypass grafting in patients with moderate ischemic mitral regurgitation.

At 1 year, there was no significant difference between patients undergoing CABG alone or CABG plus mitral repair in the primary endpoint of left ventricular reverse modeling, as defined by changes in LV end-systolic volume index (LVESVI) at 1 year (z score 0.50).

Both groups achieved significant reductions in LVESVI, with a median reduction of about 6 mL/m² from baseline, Dr. Robert Michler, chair of cardiovascular and thoracic surgery at Montefiore Medical Center, New York, reported at the American Heart Association scientific sessions.

At 1 year, patients who underwent CABG and mitral valve repair had significantly less residual moderate or severe mitral regurgitation (11% vs. 31%; P < .001).

On the other hand, the combination procedure was associated with significantly higher rates of any neurologic event (9.6% vs. 3.1%; P = .03), longer cross-clamp (117 vs. 74 minutes) and cardiopulmonary bypass times (163 vs. 106 minutes; P values both < .001), and longer ICU (4.8 vs. 4.0 days; P = .006) and hospital length of stay (11.3 vs. 9.4 days; P = .002), according to the results, also published online (N. Engl. J. Med. 2014 [doi: 10.1056/NEJMoa1410490]).

“The trial did not demonstrate a clinically meaningful advantage to the routine addition of mitral valve repair to CABG,” Dr. Michler said, on behalf of the Cardiothoracic Surgical Trials Network investigators.

The 2014 AHA/American College of Cardiology mitral valve guidelines give a weak class IIb recommendation for mitral valve repair for patients with chronic mitral regurgitation (MR) who are undergoing other cardiac surgery, he noted.

The study evenly randomized 301 patients with moderate ischemic mitral regurgitation to CABG alone or CABG plus valve repair with an undersized ring (average, 28.3 mm for men and 27.1 mm for women).

The mean LVESVI at baseline was 54.8 mL/m² in the CABG-alone group and 59.6 mL/m² in the combined procedure group.

At 12 months, mean LVESVIs were 46.1 mL/m² and 49.6 mL/m², respectively.

The trial lacked a clinical primary endpoint, and longer follow-up is ongoing to determine whether the lower incidence of moderate or severe MR at 1 year will translate into a net clinical benefit for patients undergoing CABG plus mitral repair, Dr. Michler said.

Designated discussant Dr. David Adams, director of Mount Sinai Hospital’s mitral valve repair reference center in New York, cautioned the audience on the length of the study and called for a full 5 years of follow-up rather than the 2 years as planned.

“Ischemic mitral regurgitation is a disease that hurts you over time. That’s in patients that have had MI, had previous CABG, had attempted mitral valve repair, and had PCI [percutaneous coronary intervention]. So we need much longer term follow-up of this very important data set to really understand its implications,” he said.

In light of roughly half of the patients being in heart failure at baseline, session cochair Dr. Robert Bonow, vice chair of medicine, Northwestern University, Chicago, questioned whether there were differences in outcomes related to changes in baseline ejection fraction (EF) or whether improvement in EF in patients with low EF correlated with reduction in mitral regurgitation with CABG alone.

What is known right now is that mean LVEF increased to the same degree after CABG in both groups, Dr. Michler responded. This was true despite this being a “sick population of patients,” with more than half having diabetes, 50% with heart failure, 20% with renal insufficiency, 10% with prior stroke, and a mean ejection fraction of 40% in both groups.

“What we have yet to identify and plan to explore is the correlation between reverse ventricular remodeling, ejection fraction, and outcome, meaning both the degree of mitral regurgitation and whether there is any signal with respect to repeat hospitalizations, heart failure, or possibly even mortality,” Dr. Michler said.

Both Dr. Michler and Dr. Adams remarked that surgery was extremely safe for the CABG alone and CABG plus MR groups, as reflected by the low mortality at 30 days (2.7% vs. 1.3%) and 1 year (7.3% vs. 6.7%).

The composite endpoint of major adverse cardiac or cerebrovascular events was also similar between groups.

The trial was funded by the National Institutes of Health and the Canadian Institutes for Health Research. Dr. Michler reported grant support from NIH during the conduct of the study. Dr. Adams reported coinventing a mitral valve repair ring.

pwendling@frontlinemedcom.com

CHICAGO – A year of losartan had no effect on left ventricular mass in patients with overt hypertrophic cardiomyopathy, compared with placebo, in the INHERIT trial.

The angiotensin receptor blocker did not alter any secondary endpoint, including maximal wall thickness, left ventricular fibrosis, diastolic function, and exercise capacity.

There also was no significant change in symptoms or resting left ventricular outflow tract (LVOT) gradient, Dr. Anna Axelsson reported at the American Heart Association scientific sessions.

Patrice Wendling/Frontline Medical News

Current therapies for hypertrophic cardiomyopathy (HCM) are palliative for symptoms only.

Losartan is known to reduce heart wall thickening in patients with hypertension, but is only used with caution in patients with HCM because of a suspicion of deleterious side effects.

INHERIT was initiated based on promising effects with angiotensin receptor blockade in animal and human studies, said Dr. Axelsson of Rigshospitalet, University of Copenhagen, and Harvard Medical School, Boston.

Losartan (Cozaar) has been shown to prevent the development of hypertrophy and fibrosis in HCM mice when started in the prehypertrophic phase. Candesartan (Atacand) use in humans was associated with regression of LV hypertrophy and improvement in LV function and exercise capacity in a small pilot study (J. Mol. Diagn. 2009;11:35-41).

INHERIT (Inhibition of the Renin Angiotensin System With Losartan in Patients With Hypertrophic Cardiomyopathy) evenly allocated 133 adults with overt HCM to daily losartan 100 mg or placebo for 12 months. LV mass was 108 g/m² in the placebo group and 105 g/m² in the losartan group, and 83% of patients had fibrosis.

Of the 124 patients completing the study, 93% were compliant (> 80%,) as assessed by pill count. Corroborating this was a significant decrease in blood pressure in the losartan group compared with the placebo group (P value = .001), Dr. Axelsson said.

At 12 months, both groups had a small decrease from baseline in LV mass, as assessed by magnetic resonance imaging or computed tomography, but the difference between groups was not statistically significant or clinically relevant (mean difference 1 g/m²), she said.

Adverse events were few, and comparable between the losartan and control groups. Sudden cardiac death occurred in two patients on placebo. One patient in each group had worsening of New York Heart Association class. Two controls and one losartan-treated patient had increases in LVOT gradient of at least 10 mm Hg. One patient discontinued losartan because of angioedema and two discontinued because of unspecified symptoms leading to withdrawal of consent.

“The observed safety suggests that losartan may be used for other indications in patients with obstructive physiology,” Dr. Axelsson said.

When asked whether clinicians can conclude that it’s safe to give patients with obstructive physiology a vasodilator, Dr. Axelsson said, “perhaps it shouldn’t be considered such a contraindication anymore, but it should still be done cautiously.”

Invited discussant Dr. Euan Ashley of Stanford (Calif.) University, said that only 15% of patients in the trial had an LVOT gradient of more than 30 mm Hg at baseline, “so to try and extrapolate that vasodilators are safe in older hypertrophics may be going too far.”

Patrice Wendling/Frontline Medical News

Finally, Dr. Axelsson said the overall results do not “close the door” to treatment with angiotensin receptor blockers in HCM, and that future trials may determine whether ARBs can prevent development of disease in preclinical or earlier stages of HCM.

The ongoing VANISH trial is evaluating valsartan (Diovan) in younger patients with early sarcomeric HCM. Also, the Liberty-HCM study will evaluate the effects of the investigational late sodium channel inhibitor, GS-6615, in patients aged 18-65 years, with symptomatic HCM.

INHERIT was funded by the Danish Heart Foundation and several other Danish research organizations. Dr. Axelsson holds stock with AstraZeneca.

pwendling@frontlinemedcom.com

CHICAGO – A year of losartan had no effect on left ventricular mass in patients with overt hypertrophic cardiomyopathy, compared with placebo, in the INHERIT trial.

The angiotensin receptor blocker did not alter any secondary endpoint, including maximal wall thickness, left ventricular fibrosis, diastolic function, and exercise capacity.

There also was no significant change in symptoms or resting left ventricular outflow tract (LVOT) gradient, Dr. Anna Axelsson reported at the American Heart Association scientific sessions.

Patrice Wendling/Frontline Medical News

Current therapies for hypertrophic cardiomyopathy (HCM) are palliative for symptoms only.

Losartan is known to reduce heart wall thickening in patients with hypertension, but is only used with caution in patients with HCM because of a suspicion of deleterious side effects.

INHERIT was initiated based on promising effects with angiotensin receptor blockade in animal and human studies, said Dr. Axelsson of Rigshospitalet, University of Copenhagen, and Harvard Medical School, Boston.

Losartan (Cozaar) has been shown to prevent the development of hypertrophy and fibrosis in HCM mice when started in the prehypertrophic phase. Candesartan (Atacand) use in humans was associated with regression of LV hypertrophy and improvement in LV function and exercise capacity in a small pilot study (J. Mol. Diagn. 2009;11:35-41).

INHERIT (Inhibition of the Renin Angiotensin System With Losartan in Patients With Hypertrophic Cardiomyopathy) evenly allocated 133 adults with overt HCM to daily losartan 100 mg or placebo for 12 months. LV mass was 108 g/m² in the placebo group and 105 g/m² in the losartan group, and 83% of patients had fibrosis.

Of the 124 patients completing the study, 93% were compliant (> 80%,) as assessed by pill count. Corroborating this was a significant decrease in blood pressure in the losartan group compared with the placebo group (P value = .001), Dr. Axelsson said.

At 12 months, both groups had a small decrease from baseline in LV mass, as assessed by magnetic resonance imaging or computed tomography, but the difference between groups was not statistically significant or clinically relevant (mean difference 1 g/m²), she said.

Adverse events were few, and comparable between the losartan and control groups. Sudden cardiac death occurred in two patients on placebo. One patient in each group had worsening of New York Heart Association class. Two controls and one losartan-treated patient had increases in LVOT gradient of at least 10 mm Hg. One patient discontinued losartan because of angioedema and two discontinued because of unspecified symptoms leading to withdrawal of consent.

“The observed safety suggests that losartan may be used for other indications in patients with obstructive physiology,” Dr. Axelsson said.

When asked whether clinicians can conclude that it’s safe to give patients with obstructive physiology a vasodilator, Dr. Axelsson said, “perhaps it shouldn’t be considered such a contraindication anymore, but it should still be done cautiously.”

Invited discussant Dr. Euan Ashley of Stanford (Calif.) University, said that only 15% of patients in the trial had an LVOT gradient of more than 30 mm Hg at baseline, “so to try and extrapolate that vasodilators are safe in older hypertrophics may be going too far.”

Patrice Wendling/Frontline Medical News

Finally, Dr. Axelsson said the overall results do not “close the door” to treatment with angiotensin receptor blockers in HCM, and that future trials may determine whether ARBs can prevent development of disease in preclinical or earlier stages of HCM.

The ongoing VANISH trial is evaluating valsartan (Diovan) in younger patients with early sarcomeric HCM. Also, the Liberty-HCM study will evaluate the effects of the investigational late sodium channel inhibitor, GS-6615, in patients aged 18-65 years, with symptomatic HCM.

INHERIT was funded by the Danish Heart Foundation and several other Danish research organizations. Dr. Axelsson holds stock with AstraZeneca.

pwendling@frontlinemedcom.com

CHICAGO – A year of losartan had no effect on left ventricular mass in patients with overt hypertrophic cardiomyopathy, compared with placebo, in the INHERIT trial.

The angiotensin receptor blocker did not alter any secondary endpoint, including maximal wall thickness, left ventricular fibrosis, diastolic function, and exercise capacity.

There also was no significant change in symptoms or resting left ventricular outflow tract (LVOT) gradient, Dr. Anna Axelsson reported at the American Heart Association scientific sessions.

Patrice Wendling/Frontline Medical News

Current therapies for hypertrophic cardiomyopathy (HCM) are palliative for symptoms only.

Losartan is known to reduce heart wall thickening in patients with hypertension, but is only used with caution in patients with HCM because of a suspicion of deleterious side effects.

INHERIT was initiated based on promising effects with angiotensin receptor blockade in animal and human studies, said Dr. Axelsson of Rigshospitalet, University of Copenhagen, and Harvard Medical School, Boston.

Losartan (Cozaar) has been shown to prevent the development of hypertrophy and fibrosis in HCM mice when started in the prehypertrophic phase. Candesartan (Atacand) use in humans was associated with regression of LV hypertrophy and improvement in LV function and exercise capacity in a small pilot study (J. Mol. Diagn. 2009;11:35-41).

INHERIT (Inhibition of the Renin Angiotensin System With Losartan in Patients With Hypertrophic Cardiomyopathy) evenly allocated 133 adults with overt HCM to daily losartan 100 mg or placebo for 12 months. LV mass was 108 g/m² in the placebo group and 105 g/m² in the losartan group, and 83% of patients had fibrosis.

Of the 124 patients completing the study, 93% were compliant (> 80%,) as assessed by pill count. Corroborating this was a significant decrease in blood pressure in the losartan group compared with the placebo group (P value = .001), Dr. Axelsson said.

At 12 months, both groups had a small decrease from baseline in LV mass, as assessed by magnetic resonance imaging or computed tomography, but the difference between groups was not statistically significant or clinically relevant (mean difference 1 g/m²), she said.

Adverse events were few, and comparable between the losartan and control groups. Sudden cardiac death occurred in two patients on placebo. One patient in each group had worsening of New York Heart Association class. Two controls and one losartan-treated patient had increases in LVOT gradient of at least 10 mm Hg. One patient discontinued losartan because of angioedema and two discontinued because of unspecified symptoms leading to withdrawal of consent.

“The observed safety suggests that losartan may be used for other indications in patients with obstructive physiology,” Dr. Axelsson said.

When asked whether clinicians can conclude that it’s safe to give patients with obstructive physiology a vasodilator, Dr. Axelsson said, “perhaps it shouldn’t be considered such a contraindication anymore, but it should still be done cautiously.”

Invited discussant Dr. Euan Ashley of Stanford (Calif.) University, said that only 15% of patients in the trial had an LVOT gradient of more than 30 mm Hg at baseline, “so to try and extrapolate that vasodilators are safe in older hypertrophics may be going too far.”

Patrice Wendling/Frontline Medical News

Finally, Dr. Axelsson said the overall results do not “close the door” to treatment with angiotensin receptor blockers in HCM, and that future trials may determine whether ARBs can prevent development of disease in preclinical or earlier stages of HCM.

The ongoing VANISH trial is evaluating valsartan (Diovan) in younger patients with early sarcomeric HCM. Also, the Liberty-HCM study will evaluate the effects of the investigational late sodium channel inhibitor, GS-6615, in patients aged 18-65 years, with symptomatic HCM.

INHERIT was funded by the Danish Heart Foundation and several other Danish research organizations. Dr. Axelsson holds stock with AstraZeneca.

pwendling@frontlinemedcom.com

CHICAGO – Something smells fishy about the results from Russia and Georgia in the TOPCAT trial, according to a study reappraisal conducted by the trial’s leaders.

TOPCAT (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist) was a randomized, double-blind, placebo-controlled trial of spironolactone for the treatment of heart failure with preserved ejection fraction (HFpEF) in 3,445 patients in six countries. The primary outcome was negative, as presented at last year’s AHA scientific sessions and later published (N. Engl. J. Med. 2014;370:1383-92). However, a new post hoc analysis casts doubt on the validity of the results reported from Russia and Georgia, countries that contributed 49% of TOPCAT participants, Dr. Marc A. Pfeffer reported at the American Heart Association scientific sessions.

The patient outcomes reported from Russia and Georgia were spectacularly at odds with those reported from the United States, Canada, Argentina, and Brazil. Upon careful scrutiny, it appears likely that many Russian and Georgian patients either did not actually have HFpEF or were not taking their spironolactone. And if the results from the two Eastern European countries are put aside, then spironolactone markedly reduced the rate of the primary composite outcome – cardiovascular death or hospitalization for management of heart failure – in the 1,767 study participants in the Americas.

Indeed, the primary composite outcome occurred in 27.3% of spironolactone-treated subjects in the Western Hemisphere during a mean 3.3 years of follow-up, for an event rate of 10.4 per 100 patient-years, compared with rates of 31.8% and 12.6 per 100 patient-years in placebo-treated controls. That translates to a highly significant, 18% relative risk reduction (P = .026) in the primary outcome in spironolactone-treated HFpEF patients in the Americas. Cardiovascular mortality was reduced by 26% and heart failure hospitalization was reduced by 18%, according to Dr. Pfeffer, professor of medicine at Harvard University, Boston.

A post hoc analysis such as this would ordinarily be viewed as hypothesis-generating and nondefinitive. But this is a special situation, according to the cardiologist, who noted that guidelines offer no recommendations for the treatment of HFpEF, which now accounts for roughly 50% of all cases of heart failure.

“HFpEF is a growing part of the heart failure syndrome; it’s a frustrating part of the heart failure syndrome. And if we can improve the prognosis of the 40%-50% of people with symptomatic HFpEF by stating that our observation in the Americas was that spironolactone was associated with reduced cardiovascular deaths as well as hospitalizations for heart failure, then this should be taken into account. Since we don’t have other things we can do for these patients, I bring this to your attention,” Dr. Pfeffer said.

Among the major tip-offs that the Russian/Georgian TOPCAT data were dodgy was the post hoc finding that all-cause mortality, irrespective of treatment, was 21.8% in the Americas but a mere 8.4% in Eastern Europe.

“When I look at anyone’s clinical trial, if I want to ask about the severity of illness, I go to all-cause mortality. And here it was markedly different,” he observed.

Indeed, life-table analyses showed that the Russian/Georgian HFpEF subjects had a life expectancy typical of the region’s general population, whereas death rates for HFpEF enrollees from the Americas were several-fold higher than expected for age- and gender-matched controls.

Discussant Dr. Judith S. Hochman issued the usual caveats about the hazards of drawing conclusions from post hoc analyses of overall negative clinical trials, but then went on to agree with Dr. Pfeffer’s conclusions.

“I conclude, as does Dr. Pfeffer, that it’s reasonable to try mineralocorticoid receptor antagonists for symptomatic HFpEF patients with anticipated risks similar to those enrolled in the Americas. ... This is a growing condition and we have no other treatments,” said Dr. Hochman, professor and associate director of cardiology at New York University.

A key factor in her thinking was the mechanistic plausibility of the differential subgroup treatment effects, she added. For example, hyperkalemia – a well-known side effect of spironolactone – was 3.5-fold more common in patients randomized to spironolactone than in placebo patients in the Americas, as would be expected; but hyperkalemia was equally infrequent in both treatment arms in Russia and Georgia. Conversely, hypokalemia was 49% less likely with spironolactone than placebo in the Americas, yet there was no difference in the incidence of this side effect according to treatment status in Eastern Europe.

Moreover, systolic blood pressure fell by a placebo-subtracted 4.2 mm Hg at 1 year in spironolactone-treated patients in the Americas but was unchanged in Russian and Georgian patients. And while doubling of creatinine levels to above normal range was 60% more common with spironolactone than placebo in the Americas, rates were identical in the two treatment arms in Russia and Georgia.

“There was a physiologic response to spironolactone that paralleled an apparent outcome response,” Dr. Hochman concluded.

As for the discordant Eastern European data, she observed that confirming the diagnosis of HFpEF may be difficult: “Dyspnea, orthopnea, fatigue, lower extremity edema – all of these may be caused by other conditions. So it’s very complicated.”

In contrast to heart failure with reduced ejection fraction, which has seen enormous treatment advances in recent years, not much progress has been made in HFpEF. For that to occur, Dr. Hochman said, it will be essential to come up with refined, objective diagnostic criteria for use in clinical trials. Perhaps echocardiographic findings or elevated natriuretic peptide levels will fill that role, she added.

However, Dr. Pfeffer said that, much to his disappointment, he and other investigators have not seen a consistent correlation between higher baseline brain natriuretic peptide levels and greater clinical response to mineralocorticoid receptor antagonist therapy.

Asked what sort of oversight he and the other TOPCAT leaders had over the Russian and Georgian study sites, Dr. Pfeffer replied that the National Institutes of Health–sponsored study was underfunded for such monitoring.

“As one of the leaders of the trial, there are a lot of things that I would have wished to have done differently,” he said. “I have to stand here and say the amount that you get is inadequate to do what happens in industry-sponsored trials if there’s a perceived problem.”

Both Dr. Pfeffer and Dr. Hochman emphasized the critical importance of careful monitoring of serum potassium and creatinine when prescribing spironolactone in patients with HFpEF. But with regular monitoring, Dr. Pfeffer observed, the risk of major elevations is reassuringly low. For example, with monitoring of serum creatinine at every clinic visit and dose change as per TOPCAT protocol, the incidence of a level of 3.0 mg/dL or more was 10% with spironolactone and not significantly different at 9% with placebo in the Americas.

Dr. Pfeffer reported having received consultant fees from 20 pharmaceutical or medical device companies.

bjancin@frontlinemedcom.com

CHICAGO – Something smells fishy about the results from Russia and Georgia in the TOPCAT trial, according to a study reappraisal conducted by the trial’s leaders.

TOPCAT (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist) was a randomized, double-blind, placebo-controlled trial of spironolactone for the treatment of heart failure with preserved ejection fraction (HFpEF) in 3,445 patients in six countries. The primary outcome was negative, as presented at last year’s AHA scientific sessions and later published (N. Engl. J. Med. 2014;370:1383-92). However, a new post hoc analysis casts doubt on the validity of the results reported from Russia and Georgia, countries that contributed 49% of TOPCAT participants, Dr. Marc A. Pfeffer reported at the American Heart Association scientific sessions.

The patient outcomes reported from Russia and Georgia were spectacularly at odds with those reported from the United States, Canada, Argentina, and Brazil. Upon careful scrutiny, it appears likely that many Russian and Georgian patients either did not actually have HFpEF or were not taking their spironolactone. And if the results from the two Eastern European countries are put aside, then spironolactone markedly reduced the rate of the primary composite outcome – cardiovascular death or hospitalization for management of heart failure – in the 1,767 study participants in the Americas.

Indeed, the primary composite outcome occurred in 27.3% of spironolactone-treated subjects in the Western Hemisphere during a mean 3.3 years of follow-up, for an event rate of 10.4 per 100 patient-years, compared with rates of 31.8% and 12.6 per 100 patient-years in placebo-treated controls. That translates to a highly significant, 18% relative risk reduction (P = .026) in the primary outcome in spironolactone-treated HFpEF patients in the Americas. Cardiovascular mortality was reduced by 26% and heart failure hospitalization was reduced by 18%, according to Dr. Pfeffer, professor of medicine at Harvard University, Boston.

A post hoc analysis such as this would ordinarily be viewed as hypothesis-generating and nondefinitive. But this is a special situation, according to the cardiologist, who noted that guidelines offer no recommendations for the treatment of HFpEF, which now accounts for roughly 50% of all cases of heart failure.

“HFpEF is a growing part of the heart failure syndrome; it’s a frustrating part of the heart failure syndrome. And if we can improve the prognosis of the 40%-50% of people with symptomatic HFpEF by stating that our observation in the Americas was that spironolactone was associated with reduced cardiovascular deaths as well as hospitalizations for heart failure, then this should be taken into account. Since we don’t have other things we can do for these patients, I bring this to your attention,” Dr. Pfeffer said.

Among the major tip-offs that the Russian/Georgian TOPCAT data were dodgy was the post hoc finding that all-cause mortality, irrespective of treatment, was 21.8% in the Americas but a mere 8.4% in Eastern Europe.

“When I look at anyone’s clinical trial, if I want to ask about the severity of illness, I go to all-cause mortality. And here it was markedly different,” he observed.

Indeed, life-table analyses showed that the Russian/Georgian HFpEF subjects had a life expectancy typical of the region’s general population, whereas death rates for HFpEF enrollees from the Americas were several-fold higher than expected for age- and gender-matched controls.

Discussant Dr. Judith S. Hochman issued the usual caveats about the hazards of drawing conclusions from post hoc analyses of overall negative clinical trials, but then went on to agree with Dr. Pfeffer’s conclusions.

“I conclude, as does Dr. Pfeffer, that it’s reasonable to try mineralocorticoid receptor antagonists for symptomatic HFpEF patients with anticipated risks similar to those enrolled in the Americas. ... This is a growing condition and we have no other treatments,” said Dr. Hochman, professor and associate director of cardiology at New York University.

A key factor in her thinking was the mechanistic plausibility of the differential subgroup treatment effects, she added. For example, hyperkalemia – a well-known side effect of spironolactone – was 3.5-fold more common in patients randomized to spironolactone than in placebo patients in the Americas, as would be expected; but hyperkalemia was equally infrequent in both treatment arms in Russia and Georgia. Conversely, hypokalemia was 49% less likely with spironolactone than placebo in the Americas, yet there was no difference in the incidence of this side effect according to treatment status in Eastern Europe.

Moreover, systolic blood pressure fell by a placebo-subtracted 4.2 mm Hg at 1 year in spironolactone-treated patients in the Americas but was unchanged in Russian and Georgian patients. And while doubling of creatinine levels to above normal range was 60% more common with spironolactone than placebo in the Americas, rates were identical in the two treatment arms in Russia and Georgia.

“There was a physiologic response to spironolactone that paralleled an apparent outcome response,” Dr. Hochman concluded.

As for the discordant Eastern European data, she observed that confirming the diagnosis of HFpEF may be difficult: “Dyspnea, orthopnea, fatigue, lower extremity edema – all of these may be caused by other conditions. So it’s very complicated.”

In contrast to heart failure with reduced ejection fraction, which has seen enormous treatment advances in recent years, not much progress has been made in HFpEF. For that to occur, Dr. Hochman said, it will be essential to come up with refined, objective diagnostic criteria for use in clinical trials. Perhaps echocardiographic findings or elevated natriuretic peptide levels will fill that role, she added.

However, Dr. Pfeffer said that, much to his disappointment, he and other investigators have not seen a consistent correlation between higher baseline brain natriuretic peptide levels and greater clinical response to mineralocorticoid receptor antagonist therapy.

Asked what sort of oversight he and the other TOPCAT leaders had over the Russian and Georgian study sites, Dr. Pfeffer replied that the National Institutes of Health–sponsored study was underfunded for such monitoring.

“As one of the leaders of the trial, there are a lot of things that I would have wished to have done differently,” he said. “I have to stand here and say the amount that you get is inadequate to do what happens in industry-sponsored trials if there’s a perceived problem.”

Both Dr. Pfeffer and Dr. Hochman emphasized the critical importance of careful monitoring of serum potassium and creatinine when prescribing spironolactone in patients with HFpEF. But with regular monitoring, Dr. Pfeffer observed, the risk of major elevations is reassuringly low. For example, with monitoring of serum creatinine at every clinic visit and dose change as per TOPCAT protocol, the incidence of a level of 3.0 mg/dL or more was 10% with spironolactone and not significantly different at 9% with placebo in the Americas.

Dr. Pfeffer reported having received consultant fees from 20 pharmaceutical or medical device companies.

bjancin@frontlinemedcom.com

CHICAGO – Something smells fishy about the results from Russia and Georgia in the TOPCAT trial, according to a study reappraisal conducted by the trial’s leaders.

TOPCAT (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist) was a randomized, double-blind, placebo-controlled trial of spironolactone for the treatment of heart failure with preserved ejection fraction (HFpEF) in 3,445 patients in six countries. The primary outcome was negative, as presented at last year’s AHA scientific sessions and later published (N. Engl. J. Med. 2014;370:1383-92). However, a new post hoc analysis casts doubt on the validity of the results reported from Russia and Georgia, countries that contributed 49% of TOPCAT participants, Dr. Marc A. Pfeffer reported at the American Heart Association scientific sessions.

The patient outcomes reported from Russia and Georgia were spectacularly at odds with those reported from the United States, Canada, Argentina, and Brazil. Upon careful scrutiny, it appears likely that many Russian and Georgian patients either did not actually have HFpEF or were not taking their spironolactone. And if the results from the two Eastern European countries are put aside, then spironolactone markedly reduced the rate of the primary composite outcome – cardiovascular death or hospitalization for management of heart failure – in the 1,767 study participants in the Americas.

Indeed, the primary composite outcome occurred in 27.3% of spironolactone-treated subjects in the Western Hemisphere during a mean 3.3 years of follow-up, for an event rate of 10.4 per 100 patient-years, compared with rates of 31.8% and 12.6 per 100 patient-years in placebo-treated controls. That translates to a highly significant, 18% relative risk reduction (P = .026) in the primary outcome in spironolactone-treated HFpEF patients in the Americas. Cardiovascular mortality was reduced by 26% and heart failure hospitalization was reduced by 18%, according to Dr. Pfeffer, professor of medicine at Harvard University, Boston.

A post hoc analysis such as this would ordinarily be viewed as hypothesis-generating and nondefinitive. But this is a special situation, according to the cardiologist, who noted that guidelines offer no recommendations for the treatment of HFpEF, which now accounts for roughly 50% of all cases of heart failure.

“HFpEF is a growing part of the heart failure syndrome; it’s a frustrating part of the heart failure syndrome. And if we can improve the prognosis of the 40%-50% of people with symptomatic HFpEF by stating that our observation in the Americas was that spironolactone was associated with reduced cardiovascular deaths as well as hospitalizations for heart failure, then this should be taken into account. Since we don’t have other things we can do for these patients, I bring this to your attention,” Dr. Pfeffer said.

Among the major tip-offs that the Russian/Georgian TOPCAT data were dodgy was the post hoc finding that all-cause mortality, irrespective of treatment, was 21.8% in the Americas but a mere 8.4% in Eastern Europe.

“When I look at anyone’s clinical trial, if I want to ask about the severity of illness, I go to all-cause mortality. And here it was markedly different,” he observed.

Indeed, life-table analyses showed that the Russian/Georgian HFpEF subjects had a life expectancy typical of the region’s general population, whereas death rates for HFpEF enrollees from the Americas were several-fold higher than expected for age- and gender-matched controls.

Discussant Dr. Judith S. Hochman issued the usual caveats about the hazards of drawing conclusions from post hoc analyses of overall negative clinical trials, but then went on to agree with Dr. Pfeffer’s conclusions.

“I conclude, as does Dr. Pfeffer, that it’s reasonable to try mineralocorticoid receptor antagonists for symptomatic HFpEF patients with anticipated risks similar to those enrolled in the Americas. ... This is a growing condition and we have no other treatments,” said Dr. Hochman, professor and associate director of cardiology at New York University.

A key factor in her thinking was the mechanistic plausibility of the differential subgroup treatment effects, she added. For example, hyperkalemia – a well-known side effect of spironolactone – was 3.5-fold more common in patients randomized to spironolactone than in placebo patients in the Americas, as would be expected; but hyperkalemia was equally infrequent in both treatment arms in Russia and Georgia. Conversely, hypokalemia was 49% less likely with spironolactone than placebo in the Americas, yet there was no difference in the incidence of this side effect according to treatment status in Eastern Europe.

Moreover, systolic blood pressure fell by a placebo-subtracted 4.2 mm Hg at 1 year in spironolactone-treated patients in the Americas but was unchanged in Russian and Georgian patients. And while doubling of creatinine levels to above normal range was 60% more common with spironolactone than placebo in the Americas, rates were identical in the two treatment arms in Russia and Georgia.

“There was a physiologic response to spironolactone that paralleled an apparent outcome response,” Dr. Hochman concluded.

As for the discordant Eastern European data, she observed that confirming the diagnosis of HFpEF may be difficult: “Dyspnea, orthopnea, fatigue, lower extremity edema – all of these may be caused by other conditions. So it’s very complicated.”

In contrast to heart failure with reduced ejection fraction, which has seen enormous treatment advances in recent years, not much progress has been made in HFpEF. For that to occur, Dr. Hochman said, it will be essential to come up with refined, objective diagnostic criteria for use in clinical trials. Perhaps echocardiographic findings or elevated natriuretic peptide levels will fill that role, she added.

However, Dr. Pfeffer said that, much to his disappointment, he and other investigators have not seen a consistent correlation between higher baseline brain natriuretic peptide levels and greater clinical response to mineralocorticoid receptor antagonist therapy.

Asked what sort of oversight he and the other TOPCAT leaders had over the Russian and Georgian study sites, Dr. Pfeffer replied that the National Institutes of Health–sponsored study was underfunded for such monitoring.

“As one of the leaders of the trial, there are a lot of things that I would have wished to have done differently,” he said. “I have to stand here and say the amount that you get is inadequate to do what happens in industry-sponsored trials if there’s a perceived problem.”

Both Dr. Pfeffer and Dr. Hochman emphasized the critical importance of careful monitoring of serum potassium and creatinine when prescribing spironolactone in patients with HFpEF. But with regular monitoring, Dr. Pfeffer observed, the risk of major elevations is reassuringly low. For example, with monitoring of serum creatinine at every clinic visit and dose change as per TOPCAT protocol, the incidence of a level of 3.0 mg/dL or more was 10% with spironolactone and not significantly different at 9% with placebo in the Americas.

Dr. Pfeffer reported having received consultant fees from 20 pharmaceutical or medical device companies.

bjancin@frontlinemedcom.com

LAS VEGAS – Percutaneous ventricular restoration using the Parachute device in patients with ischemic dilated cardiomyopathy had a promisingly low 26% combined rate of all-cause mortality and heart failure hospitalization at 1 year in the PARACHUTE III trial, according to Dr. William T. Abraham

PARACHUTE III was a European postmarketing study. And while the composite endpoint of all-cause mortality and heart failure hospitalization was a prespecified secondary outcome in that study, it’s the primary endpoint in the ongoing pivotal U.S. phase III PARACHUTE IV trial headed by Dr. Abraham.

Courtesy of CardioKinetix, Inc.

What’s encouraging about the PARACHUTE III result is that the 26% rate of the combined endpoint is in line with the PARACHUTE IV investigators’ assumption for outcomes in the ongoing U.S. trial, which will randomize roughly 500 patients to device therapy plus optimal medical therapy or optimal medical therapy alone, he reported at the annual meeting of the Heart Failure Society of America.

“The PARACHUTE III results are reassuring. In historical controls, the expected rate [of all-cause mortality and heart failure hospitalization] in this kind of population at 1 year is about 35%,” according to Dr. Abraham, professor of internal medicine, physiology, and cell biology and director of the division of cardiovascular medicine at Ohio State University, Columbus.

Plus, technical improvements in device design and percutaneous implantation technique have been made since PARACHUTE III and are incorporated in PARACHUTE IV. These improvements could drive the composite endpoint rate in the ongoing U.S. trial even lower, he continued. For example, while the 1-year major complication rate in the European postmarketing study was 11%, thus far it’s less than 8% in the U.S. experience.

The proprietary Parachute device is so named because, when deployed, it looks like an upside-down parachute. It is intended for patients with ischemic dilated cardiomyopathy secondary to anteroapical MI. The goal of this device therapy is to attenuate or reverse progression of heart failure in this high-risk population.

The Parachute device has two proposed mechanisms of action, the cardiologist explained. One involves ventricular restoration via ventricular partitioning to reduce wall stress in the upper chamber as well as fostering a return to a more normal, elliptical shape to the heart. Dr. Abraham termed the other mechanism a trampoline effect, in which the compliant device encourages replacement of eccentric apical wall motion with more synchronized wall motion throughout the cardiac cycle.

The device, comprised mainly of a fluoropolymer membrane and a nitinol frame, is implanted percutaneously retrograde across the aortic valve. It is placed in the apex of the left ventricle.

The European Union PARACHUTE III postmarketing study was a single-arm study including 100 consecutive symptomatic patients in 10 countries. Their baseline left ventricular ejection fraction was 28%. Device implantation was accomplished in 97 of the 100 patients, with a mean 94-minute procedure duration and 23 minutes of fluoroscopy time.

The primary study endpoint was a safety outcome: the 1-year rate of procedure- and/or device-related adverse events. The 7% rate included several cases of left ventricular perforation as well as aortic or mitral valve damage.

“The rates and distribution of these events are comparable to other structural heart disease interventions, such as transcatheter aortic valve replacement, and might be considered an acceptable postmarketing result,” Dr. Abraham commented.

There was a 3.2% stroke rate through 1 year and a 9.5% mortality rate.

Hemodynamic improvements were seen in both systolic and diastolic function. The left atrial volume index improved from 42.5 to 38.3 mL/m², indicative of favorable remodeling. The improvement in systolic function was expressed in an increased contractility index.

Moreover, left ventricular end-systolic volume index improved over the course of the year from 84 to 70.5 mL/m², while left ventricular end-diastolic volume index also improved, from 117.3 to 99.1 mL/m².

Eighty percent of patients maintained or improved their 6-minute walk distance. On average, patients improved their walk distance by 25 m from a mean baseline of 372 m. Similarly, 80% of patients maintained or improved their baseline New York Heart Association functional class.

Discussant Dr. James C. Fang called the Parachute device “an important investigational therapeutic option. ” He urged cardiologists to enroll patients in PARACHUTE IV in order to learn whether the percutaneous device therapy will indeed enable patients to live longer and/or avoid hospitalizations for heart failure.

The improvements in myocardial contractility and left atrial volume documented in PARACHUTE III are particularly encouraging, added Dr. Fang, professor of internal medicine and chief of the division of cardiovascular medicine at the University of Utah, Salt Lake City.

Dr. Abraham reported serving as a consultant to CardioKinetix, which sponsors the PARACHUTE IV trial.

bjancin@frontlinemedcom.com

LAS VEGAS – Percutaneous ventricular restoration using the Parachute device in patients with ischemic dilated cardiomyopathy had a promisingly low 26% combined rate of all-cause mortality and heart failure hospitalization at 1 year in the PARACHUTE III trial, according to Dr. William T. Abraham

PARACHUTE III was a European postmarketing study. And while the composite endpoint of all-cause mortality and heart failure hospitalization was a prespecified secondary outcome in that study, it’s the primary endpoint in the ongoing pivotal U.S. phase III PARACHUTE IV trial headed by Dr. Abraham.

Courtesy of CardioKinetix, Inc.

What’s encouraging about the PARACHUTE III result is that the 26% rate of the combined endpoint is in line with the PARACHUTE IV investigators’ assumption for outcomes in the ongoing U.S. trial, which will randomize roughly 500 patients to device therapy plus optimal medical therapy or optimal medical therapy alone, he reported at the annual meeting of the Heart Failure Society of America.

“The PARACHUTE III results are reassuring. In historical controls, the expected rate [of all-cause mortality and heart failure hospitalization] in this kind of population at 1 year is about 35%,” according to Dr. Abraham, professor of internal medicine, physiology, and cell biology and director of the division of cardiovascular medicine at Ohio State University, Columbus.

Plus, technical improvements in device design and percutaneous implantation technique have been made since PARACHUTE III and are incorporated in PARACHUTE IV. These improvements could drive the composite endpoint rate in the ongoing U.S. trial even lower, he continued. For example, while the 1-year major complication rate in the European postmarketing study was 11%, thus far it’s less than 8% in the U.S. experience.

The proprietary Parachute device is so named because, when deployed, it looks like an upside-down parachute. It is intended for patients with ischemic dilated cardiomyopathy secondary to anteroapical MI. The goal of this device therapy is to attenuate or reverse progression of heart failure in this high-risk population.

The Parachute device has two proposed mechanisms of action, the cardiologist explained. One involves ventricular restoration via ventricular partitioning to reduce wall stress in the upper chamber as well as fostering a return to a more normal, elliptical shape to the heart. Dr. Abraham termed the other mechanism a trampoline effect, in which the compliant device encourages replacement of eccentric apical wall motion with more synchronized wall motion throughout the cardiac cycle.

The device, comprised mainly of a fluoropolymer membrane and a nitinol frame, is implanted percutaneously retrograde across the aortic valve. It is placed in the apex of the left ventricle.

The European Union PARACHUTE III postmarketing study was a single-arm study including 100 consecutive symptomatic patients in 10 countries. Their baseline left ventricular ejection fraction was 28%. Device implantation was accomplished in 97 of the 100 patients, with a mean 94-minute procedure duration and 23 minutes of fluoroscopy time.

The primary study endpoint was a safety outcome: the 1-year rate of procedure- and/or device-related adverse events. The 7% rate included several cases of left ventricular perforation as well as aortic or mitral valve damage.

“The rates and distribution of these events are comparable to other structural heart disease interventions, such as transcatheter aortic valve replacement, and might be considered an acceptable postmarketing result,” Dr. Abraham commented.

There was a 3.2% stroke rate through 1 year and a 9.5% mortality rate.

Hemodynamic improvements were seen in both systolic and diastolic function. The left atrial volume index improved from 42.5 to 38.3 mL/m², indicative of favorable remodeling. The improvement in systolic function was expressed in an increased contractility index.

Moreover, left ventricular end-systolic volume index improved over the course of the year from 84 to 70.5 mL/m², while left ventricular end-diastolic volume index also improved, from 117.3 to 99.1 mL/m².

Eighty percent of patients maintained or improved their 6-minute walk distance. On average, patients improved their walk distance by 25 m from a mean baseline of 372 m. Similarly, 80% of patients maintained or improved their baseline New York Heart Association functional class.

Discussant Dr. James C. Fang called the Parachute device “an important investigational therapeutic option. ” He urged cardiologists to enroll patients in PARACHUTE IV in order to learn whether the percutaneous device therapy will indeed enable patients to live longer and/or avoid hospitalizations for heart failure.

The improvements in myocardial contractility and left atrial volume documented in PARACHUTE III are particularly encouraging, added Dr. Fang, professor of internal medicine and chief of the division of cardiovascular medicine at the University of Utah, Salt Lake City.

Dr. Abraham reported serving as a consultant to CardioKinetix, which sponsors the PARACHUTE IV trial.

bjancin@frontlinemedcom.com

LAS VEGAS – Percutaneous ventricular restoration using the Parachute device in patients with ischemic dilated cardiomyopathy had a promisingly low 26% combined rate of all-cause mortality and heart failure hospitalization at 1 year in the PARACHUTE III trial, according to Dr. William T. Abraham

PARACHUTE III was a European postmarketing study. And while the composite endpoint of all-cause mortality and heart failure hospitalization was a prespecified secondary outcome in that study, it’s the primary endpoint in the ongoing pivotal U.S. phase III PARACHUTE IV trial headed by Dr. Abraham.

Courtesy of CardioKinetix, Inc.

What’s encouraging about the PARACHUTE III result is that the 26% rate of the combined endpoint is in line with the PARACHUTE IV investigators’ assumption for outcomes in the ongoing U.S. trial, which will randomize roughly 500 patients to device therapy plus optimal medical therapy or optimal medical therapy alone, he reported at the annual meeting of the Heart Failure Society of America.

“The PARACHUTE III results are reassuring. In historical controls, the expected rate [of all-cause mortality and heart failure hospitalization] in this kind of population at 1 year is about 35%,” according to Dr. Abraham, professor of internal medicine, physiology, and cell biology and director of the division of cardiovascular medicine at Ohio State University, Columbus.

Plus, technical improvements in device design and percutaneous implantation technique have been made since PARACHUTE III and are incorporated in PARACHUTE IV. These improvements could drive the composite endpoint rate in the ongoing U.S. trial even lower, he continued. For example, while the 1-year major complication rate in the European postmarketing study was 11%, thus far it’s less than 8% in the U.S. experience.

The proprietary Parachute device is so named because, when deployed, it looks like an upside-down parachute. It is intended for patients with ischemic dilated cardiomyopathy secondary to anteroapical MI. The goal of this device therapy is to attenuate or reverse progression of heart failure in this high-risk population.

The Parachute device has two proposed mechanisms of action, the cardiologist explained. One involves ventricular restoration via ventricular partitioning to reduce wall stress in the upper chamber as well as fostering a return to a more normal, elliptical shape to the heart. Dr. Abraham termed the other mechanism a trampoline effect, in which the compliant device encourages replacement of eccentric apical wall motion with more synchronized wall motion throughout the cardiac cycle.

The device, comprised mainly of a fluoropolymer membrane and a nitinol frame, is implanted percutaneously retrograde across the aortic valve. It is placed in the apex of the left ventricle.

The European Union PARACHUTE III postmarketing study was a single-arm study including 100 consecutive symptomatic patients in 10 countries. Their baseline left ventricular ejection fraction was 28%. Device implantation was accomplished in 97 of the 100 patients, with a mean 94-minute procedure duration and 23 minutes of fluoroscopy time.

The primary study endpoint was a safety outcome: the 1-year rate of procedure- and/or device-related adverse events. The 7% rate included several cases of left ventricular perforation as well as aortic or mitral valve damage.

“The rates and distribution of these events are comparable to other structural heart disease interventions, such as transcatheter aortic valve replacement, and might be considered an acceptable postmarketing result,” Dr. Abraham commented.

There was a 3.2% stroke rate through 1 year and a 9.5% mortality rate.

Hemodynamic improvements were seen in both systolic and diastolic function. The left atrial volume index improved from 42.5 to 38.3 mL/m², indicative of favorable remodeling. The improvement in systolic function was expressed in an increased contractility index.

Moreover, left ventricular end-systolic volume index improved over the course of the year from 84 to 70.5 mL/m², while left ventricular end-diastolic volume index also improved, from 117.3 to 99.1 mL/m².

Eighty percent of patients maintained or improved their 6-minute walk distance. On average, patients improved their walk distance by 25 m from a mean baseline of 372 m. Similarly, 80% of patients maintained or improved their baseline New York Heart Association functional class.

Discussant Dr. James C. Fang called the Parachute device “an important investigational therapeutic option. ” He urged cardiologists to enroll patients in PARACHUTE IV in order to learn whether the percutaneous device therapy will indeed enable patients to live longer and/or avoid hospitalizations for heart failure.

The improvements in myocardial contractility and left atrial volume documented in PARACHUTE III are particularly encouraging, added Dr. Fang, professor of internal medicine and chief of the division of cardiovascular medicine at the University of Utah, Salt Lake City.

Dr. Abraham reported serving as a consultant to CardioKinetix, which sponsors the PARACHUTE IV trial.

bjancin@frontlinemedcom.com

PHILADELPHIA – ZS-9, an investigational cation exchanger designed to trap potassium in the gut, effectively and rapidly restores and maintains normokalemia in hyperkalemic patients with diabetes and significant renal impairment, according to a subgroup analysis of data from a randomized, placebo-controlled phase III trial.

Treatment with the first-in-class insoluble, nonabsorbed zirconium silicate, which was designed and engineered to have a three-dimensional crystalline lattice structure that preferentially traps potassium ions, was shown to have clinically and statistically significant benefit at daily oral doses of 5 mg and 10 mg, compared with placebo in the overall study population of 753 patients with hyperkalemia and underlying diabetes, heart failure, or chronic kidney disease.

The current analysis included 366 patients who had diabetes and an estimated glomerular filtration rate less than 60 mL/min/1.73m². The patients, who had baseline potassium levels of 5.0-6.5 mEq/L (mean of 5.3 mEq/L) were randomized to oral ZS-9 at doses of 1.25, 2.5, 5, or 10 g or placebo given three times daily for the first 48 hours. Following this acute phase, those with a potassium level of 3.5-5.0 mEq/L were rerandomized to either the same ZS-9 acute-phase dose once daily for days 3-15 or placebo.

In the subgroup, ZS-9 treatment was associated with a significant decrease in potassium at 48 hours (decreases of -0.45, -0.59, and -0.81 mEq/L in the 2.5-, 5-, and 10-g groups, respectively, compared with +0.24 mEq/L in the placebo group, Dr. Bhupinder Singh reported at the meeting sponsored by the American Society of Nephrology.

During the maintenance phase, patients receiving a 10-g dose of ZS-9 maintained normokalemia (4.5 mEq/L at day 3 vs. 4.6 mEq/L at day 15) vs. placebo (4.4 mEq/L at day 3, vs. 5.1 mEq/L at day 15). Similar results were seen in the 5-mg treatment group, Dr. Singh of Apex Research, Riverside, Calif. said.

“Hyperkalemia is a common and serious complication in patients with diabetes who have chronic kidney disease, particularly those who are treated with renin-angiotensin-aldosterone system (RAAS) inhibitors. Even mild to moderate hyperkalemia has been recently shown to be associated with increased mortality,” Dr. Singh said, noting that concerns about the seriousness of hyperkalemia have likely led to under-prescription of RAAS inhibitors, which have been proven to have cardio- and renoprotective action, but which are associated with hyperkalemia.

In head-to-head in vitro studies, ZS-9 has been shown to be more than 125 times more selective than sodium polystyrene sulfonate (SPS) – the current mainstay of treatment for hyperkalemia), and to have more than 9 times the potassium-binding capacity.

In the current analysis, ZS-9 was associated with a “fairly acute” effect, reducing potassium levels significantly within 1 hour, and to less than 5 mEq/L within 4 hours. The study also was published Nov. 21 in the New England Journal of Medicine (doi:10.1056/NEJMoa1411487).

In both the overall study population and the subgroup with diabetes and chronic kidney disease, ZS-9 discontinuation at the end of the study was associated with recurrence of hyperkalemia, indicating a need for continued use. The adverse event profile was similar in the treatment and placebo groups in both studies.

The findings suggest that long-term treatment with ZS-9 may allow continuation of chronic RAAS inhibition in patients with diabetes and chronic kidney disease, Dr. Sing said, adding that long-term treatment studies are underway.

This study was funded by ZS Pharma Inc., which is developing ZS-9. Dr. Singh is a consultant to ZS Pharma Inc.

PHILADELPHIA – ZS-9, an investigational cation exchanger designed to trap potassium in the gut, effectively and rapidly restores and maintains normokalemia in hyperkalemic patients with diabetes and significant renal impairment, according to a subgroup analysis of data from a randomized, placebo-controlled phase III trial.

Treatment with the first-in-class insoluble, nonabsorbed zirconium silicate, which was designed and engineered to have a three-dimensional crystalline lattice structure that preferentially traps potassium ions, was shown to have clinically and statistically significant benefit at daily oral doses of 5 mg and 10 mg, compared with placebo in the overall study population of 753 patients with hyperkalemia and underlying diabetes, heart failure, or chronic kidney disease.

The current analysis included 366 patients who had diabetes and an estimated glomerular filtration rate less than 60 mL/min/1.73m². The patients, who had baseline potassium levels of 5.0-6.5 mEq/L (mean of 5.3 mEq/L) were randomized to oral ZS-9 at doses of 1.25, 2.5, 5, or 10 g or placebo given three times daily for the first 48 hours. Following this acute phase, those with a potassium level of 3.5-5.0 mEq/L were rerandomized to either the same ZS-9 acute-phase dose once daily for days 3-15 or placebo.

In the subgroup, ZS-9 treatment was associated with a significant decrease in potassium at 48 hours (decreases of -0.45, -0.59, and -0.81 mEq/L in the 2.5-, 5-, and 10-g groups, respectively, compared with +0.24 mEq/L in the placebo group, Dr. Bhupinder Singh reported at the meeting sponsored by the American Society of Nephrology.

During the maintenance phase, patients receiving a 10-g dose of ZS-9 maintained normokalemia (4.5 mEq/L at day 3 vs. 4.6 mEq/L at day 15) vs. placebo (4.4 mEq/L at day 3, vs. 5.1 mEq/L at day 15). Similar results were seen in the 5-mg treatment group, Dr. Singh of Apex Research, Riverside, Calif. said.

“Hyperkalemia is a common and serious complication in patients with diabetes who have chronic kidney disease, particularly those who are treated with renin-angiotensin-aldosterone system (RAAS) inhibitors. Even mild to moderate hyperkalemia has been recently shown to be associated with increased mortality,” Dr. Singh said, noting that concerns about the seriousness of hyperkalemia have likely led to under-prescription of RAAS inhibitors, which have been proven to have cardio- and renoprotective action, but which are associated with hyperkalemia.

In head-to-head in vitro studies, ZS-9 has been shown to be more than 125 times more selective than sodium polystyrene sulfonate (SPS) – the current mainstay of treatment for hyperkalemia), and to have more than 9 times the potassium-binding capacity.

In the current analysis, ZS-9 was associated with a “fairly acute” effect, reducing potassium levels significantly within 1 hour, and to less than 5 mEq/L within 4 hours. The study also was published Nov. 21 in the New England Journal of Medicine (doi:10.1056/NEJMoa1411487).

In both the overall study population and the subgroup with diabetes and chronic kidney disease, ZS-9 discontinuation at the end of the study was associated with recurrence of hyperkalemia, indicating a need for continued use. The adverse event profile was similar in the treatment and placebo groups in both studies.

The findings suggest that long-term treatment with ZS-9 may allow continuation of chronic RAAS inhibition in patients with diabetes and chronic kidney disease, Dr. Sing said, adding that long-term treatment studies are underway.

This study was funded by ZS Pharma Inc., which is developing ZS-9. Dr. Singh is a consultant to ZS Pharma Inc.

PHILADELPHIA – ZS-9, an investigational cation exchanger designed to trap potassium in the gut, effectively and rapidly restores and maintains normokalemia in hyperkalemic patients with diabetes and significant renal impairment, according to a subgroup analysis of data from a randomized, placebo-controlled phase III trial.

Treatment with the first-in-class insoluble, nonabsorbed zirconium silicate, which was designed and engineered to have a three-dimensional crystalline lattice structure that preferentially traps potassium ions, was shown to have clinically and statistically significant benefit at daily oral doses of 5 mg and 10 mg, compared with placebo in the overall study population of 753 patients with hyperkalemia and underlying diabetes, heart failure, or chronic kidney disease.

The current analysis included 366 patients who had diabetes and an estimated glomerular filtration rate less than 60 mL/min/1.73m². The patients, who had baseline potassium levels of 5.0-6.5 mEq/L (mean of 5.3 mEq/L) were randomized to oral ZS-9 at doses of 1.25, 2.5, 5, or 10 g or placebo given three times daily for the first 48 hours. Following this acute phase, those with a potassium level of 3.5-5.0 mEq/L were rerandomized to either the same ZS-9 acute-phase dose once daily for days 3-15 or placebo.

In the subgroup, ZS-9 treatment was associated with a significant decrease in potassium at 48 hours (decreases of -0.45, -0.59, and -0.81 mEq/L in the 2.5-, 5-, and 10-g groups, respectively, compared with +0.24 mEq/L in the placebo group, Dr. Bhupinder Singh reported at the meeting sponsored by the American Society of Nephrology.

During the maintenance phase, patients receiving a 10-g dose of ZS-9 maintained normokalemia (4.5 mEq/L at day 3 vs. 4.6 mEq/L at day 15) vs. placebo (4.4 mEq/L at day 3, vs. 5.1 mEq/L at day 15). Similar results were seen in the 5-mg treatment group, Dr. Singh of Apex Research, Riverside, Calif. said.

“Hyperkalemia is a common and serious complication in patients with diabetes who have chronic kidney disease, particularly those who are treated with renin-angiotensin-aldosterone system (RAAS) inhibitors. Even mild to moderate hyperkalemia has been recently shown to be associated with increased mortality,” Dr. Singh said, noting that concerns about the seriousness of hyperkalemia have likely led to under-prescription of RAAS inhibitors, which have been proven to have cardio- and renoprotective action, but which are associated with hyperkalemia.

In head-to-head in vitro studies, ZS-9 has been shown to be more than 125 times more selective than sodium polystyrene sulfonate (SPS) – the current mainstay of treatment for hyperkalemia), and to have more than 9 times the potassium-binding capacity.

In the current analysis, ZS-9 was associated with a “fairly acute” effect, reducing potassium levels significantly within 1 hour, and to less than 5 mEq/L within 4 hours. The study also was published Nov. 21 in the New England Journal of Medicine (doi:10.1056/NEJMoa1411487).

In both the overall study population and the subgroup with diabetes and chronic kidney disease, ZS-9 discontinuation at the end of the study was associated with recurrence of hyperkalemia, indicating a need for continued use. The adverse event profile was similar in the treatment and placebo groups in both studies.

The findings suggest that long-term treatment with ZS-9 may allow continuation of chronic RAAS inhibition in patients with diabetes and chronic kidney disease, Dr. Sing said, adding that long-term treatment studies are underway.

This study was funded by ZS Pharma Inc., which is developing ZS-9. Dr. Singh is a consultant to ZS Pharma Inc.

The oral drug sodium zirconium cyclosilicate may offer an effective new treatment option for outpatients with mild hyperkalemia, according to results of the phase III, open-label, randomized HARMONIZE trial presented at the American Heart Association scientific sessions.

The sodium-potassium cation exchanger zirconium cyclosilicate reduced potassium levels in 258 patients with mild hyperkalemia to normal levels within 48 hours, compared with placebo, and effectively maintained potassium levels for up to 4 weeks. The findings were published simultaneously in JAMA (JAMA 2014 Nov. 17 [doi: 10.1001/jama.2014.15688]). However, more long-term studies are needed to assess the efficacy and safety of the drug beyond 4 weeks and in patients with more severe hyperkalemia, reported Dr. Mikhail Kosiborod of Saint Luke’s Mid America Heart Institute in Kansas City, Mo., and his colleagues.

In the open-label phase of the study, 258 outpatients with hyperkalemia (serum potassium ≥5.1 mEq/L) were given 10 g of zirconium cyclosilicate three times a day for 48 hours. Mean serum potassium levels significantly declined by 0.2 mEq/L 1 hour after the initial dose and decreased an average 1.1 mEq/L at 48 hours, with 98% (n = 237) of patients achieving normokalemia (3.5-5.0 mEq/L). These patients were then randomized to receive 5 g (n = 45), 10 g (n = 51), or 15 g (n = 56) of zirconium cyclosilicate or placebo (n = 85) daily, and were followed for 28 days.

Zirconium cyclosilicate lowered serum potassium to 4.8, 4.5, and 4.4 mEq/L at 5, 10, and 15 g, respectively, compared with 5.1 mEq/L for placebo. Adverse events were comparable between the treatment and placebo groups, but edema was more common in the 15-g group. Hyperkalemia developed in 10% of the 10-g group and 11% of the 15-g group, compared with no patients in the 5-g or placebo groups.

In an accompanying editorial, Dr. Bradley S. Dixon of the University of Iowa, Iowa City, said the findings suggest that zirconium cyclosilicate may offer an important new treatment for the acute and short-term treatment of outpatients with mild hyperkalemia. “Longer-term studies are needed to assess the clinical benefits and risks that may be related to more extended use of this product, especially among hospitalized patients, as well as those with more severe hyperkalemia, other medical conditions, and other medications that affect potassium homeostasis,” he wrote.

The study was sponsored and funded by ZS Pharma, maker of sodium zirconium cyclosilicate. Dr. Kosiborod reported serving as a consultant for ZS Pharma and as an investigator on the HARMONIZE study. Several coauthors also declared financial interests with ZS Pharma. Dr. Dixon reported financial relationships with multiple companies, but not with ZS Pharma.

The oral drug sodium zirconium cyclosilicate may offer an effective new treatment option for outpatients with mild hyperkalemia, according to results of the phase III, open-label, randomized HARMONIZE trial presented at the American Heart Association scientific sessions.

The sodium-potassium cation exchanger zirconium cyclosilicate reduced potassium levels in 258 patients with mild hyperkalemia to normal levels within 48 hours, compared with placebo, and effectively maintained potassium levels for up to 4 weeks. The findings were published simultaneously in JAMA (JAMA 2014 Nov. 17 [doi: 10.1001/jama.2014.15688]). However, more long-term studies are needed to assess the efficacy and safety of the drug beyond 4 weeks and in patients with more severe hyperkalemia, reported Dr. Mikhail Kosiborod of Saint Luke’s Mid America Heart Institute in Kansas City, Mo., and his colleagues.

In the open-label phase of the study, 258 outpatients with hyperkalemia (serum potassium ≥5.1 mEq/L) were given 10 g of zirconium cyclosilicate three times a day for 48 hours. Mean serum potassium levels significantly declined by 0.2 mEq/L 1 hour after the initial dose and decreased an average 1.1 mEq/L at 48 hours, with 98% (n = 237) of patients achieving normokalemia (3.5-5.0 mEq/L). These patients were then randomized to receive 5 g (n = 45), 10 g (n = 51), or 15 g (n = 56) of zirconium cyclosilicate or placebo (n = 85) daily, and were followed for 28 days.

Zirconium cyclosilicate lowered serum potassium to 4.8, 4.5, and 4.4 mEq/L at 5, 10, and 15 g, respectively, compared with 5.1 mEq/L for placebo. Adverse events were comparable between the treatment and placebo groups, but edema was more common in the 15-g group. Hyperkalemia developed in 10% of the 10-g group and 11% of the 15-g group, compared with no patients in the 5-g or placebo groups.

In an accompanying editorial, Dr. Bradley S. Dixon of the University of Iowa, Iowa City, said the findings suggest that zirconium cyclosilicate may offer an important new treatment for the acute and short-term treatment of outpatients with mild hyperkalemia. “Longer-term studies are needed to assess the clinical benefits and risks that may be related to more extended use of this product, especially among hospitalized patients, as well as those with more severe hyperkalemia, other medical conditions, and other medications that affect potassium homeostasis,” he wrote.

The study was sponsored and funded by ZS Pharma, maker of sodium zirconium cyclosilicate. Dr. Kosiborod reported serving as a consultant for ZS Pharma and as an investigator on the HARMONIZE study. Several coauthors also declared financial interests with ZS Pharma. Dr. Dixon reported financial relationships with multiple companies, but not with ZS Pharma.

The oral drug sodium zirconium cyclosilicate may offer an effective new treatment option for outpatients with mild hyperkalemia, according to results of the phase III, open-label, randomized HARMONIZE trial presented at the American Heart Association scientific sessions.

The sodium-potassium cation exchanger zirconium cyclosilicate reduced potassium levels in 258 patients with mild hyperkalemia to normal levels within 48 hours, compared with placebo, and effectively maintained potassium levels for up to 4 weeks. The findings were published simultaneously in JAMA (JAMA 2014 Nov. 17 [doi: 10.1001/jama.2014.15688]). However, more long-term studies are needed to assess the efficacy and safety of the drug beyond 4 weeks and in patients with more severe hyperkalemia, reported Dr. Mikhail Kosiborod of Saint Luke’s Mid America Heart Institute in Kansas City, Mo., and his colleagues.

In the open-label phase of the study, 258 outpatients with hyperkalemia (serum potassium ≥5.1 mEq/L) were given 10 g of zirconium cyclosilicate three times a day for 48 hours. Mean serum potassium levels significantly declined by 0.2 mEq/L 1 hour after the initial dose and decreased an average 1.1 mEq/L at 48 hours, with 98% (n = 237) of patients achieving normokalemia (3.5-5.0 mEq/L). These patients were then randomized to receive 5 g (n = 45), 10 g (n = 51), or 15 g (n = 56) of zirconium cyclosilicate or placebo (n = 85) daily, and were followed for 28 days.

Zirconium cyclosilicate lowered serum potassium to 4.8, 4.5, and 4.4 mEq/L at 5, 10, and 15 g, respectively, compared with 5.1 mEq/L for placebo. Adverse events were comparable between the treatment and placebo groups, but edema was more common in the 15-g group. Hyperkalemia developed in 10% of the 10-g group and 11% of the 15-g group, compared with no patients in the 5-g or placebo groups.

In an accompanying editorial, Dr. Bradley S. Dixon of the University of Iowa, Iowa City, said the findings suggest that zirconium cyclosilicate may offer an important new treatment for the acute and short-term treatment of outpatients with mild hyperkalemia. “Longer-term studies are needed to assess the clinical benefits and risks that may be related to more extended use of this product, especially among hospitalized patients, as well as those with more severe hyperkalemia, other medical conditions, and other medications that affect potassium homeostasis,” he wrote.

The study was sponsored and funded by ZS Pharma, maker of sodium zirconium cyclosilicate. Dr. Kosiborod reported serving as a consultant for ZS Pharma and as an investigator on the HARMONIZE study. Several coauthors also declared financial interests with ZS Pharma. Dr. Dixon reported financial relationships with multiple companies, but not with ZS Pharma.