Heart Failure

For patients hospitalized with heart failure, aliskiren added no significant benefit to standard therapy in preventing cardiovascular death or heart failure readmission.

The drug did, however, have some problematic effects on patients with diabetes, including significant increases in the risk of cardiovascular death and heart failure readmission at 6 months and all-cause death at 1 year.

The negative interaction between diabetes and aliskiren – an inhibitor of the angiotensin-renin-aldosterone system (RAAS) – is unclear, according to Dr. Mihai Gheorghiade and colleagues.

"[The issue] may be related to the increased risk of hypotension, hyperkalemia, and worsening renal function with the study drug," wrote Dr. Gheorghiade of Northwestern University, St. Louis, Mo., and his colleagues. The conclusions were published in the March 10 issue of JAMA and simultaneously presented at the annual meeting of the American College of Cardiology in San Francisco (JAMA 2013;309:doi10.1001/jama.2013.1954).

The randomized, placebo-controlled ASTRONAUT trial compared 6-and 12-month outcomes of aliskiren plus standard therapy to standard therapy alone in patients hospitalized with heart failure. 

The study randomized 1,639 patients; 1,615 were included in the final efficacy analysis. Patients in the investigational arm received 150 mg aliskiren daily in addition to standard treatment. Standard treatment was at the treating physician’s discretion, and could include, among others, diuretics, digoxin, ACE inhibitors, angiotensin receptor blockers, and beta-blockers. The study enrolled patients from 2009-2011; the median follow-up was 11 months

The patients were a mean of 65 years old. Their mean left ventricular ejection fraction was 28%, and mean estimated glomerular filtration rate was 67 mL/min/1.73 m³.  Nearly half (41%) had diabetes.

At admission, the mean N-terminal pro–brain natriuretic peptide (NT-proBNP) level was 4,239 pg/mL. Other drugs taken at baseline included diuretics (96%), beta-blockers (82%), ACE inhibitors or ARBs (84%), and mineralocorticoid antagonists (57%).

The primary efficacy endpoint was a combination of cardiovascular death or heart failure readmission within 6 months. This occurred in 201 (25%) of the aliskiren group and 214 (26%) of the placebo group – a nonsignificant difference. Nor were there significant differences when CV death and readmission were examined separately.

The main secondary endpoint was the composite of cardiovascular death or heart failure readmission at 12 months; again, there was no significant between-group difference (35% vs. 37%), although the events were numerically less in the aliskiren group than the control group (283 vs. 301). Parsing down the number of first cardiovascular events after treatment, the investigators did find that myocardial infarction was significantly less common in the aliskiren group (2% vs. 5%; HR 0.93; P = 0.009).

A subgroup analysis found that the drug was especially problematic for patients with diabetes. Compared to patients without the disorder who had standard treatment, diabetic patients who took aliskiren were 16% more likely to experience cardiovascular death or heart failure readmission by 6 months, and 64% more likely to experience all-cause death by 12 months.

During the treatment period, death occurred in 24% of patients with diabetes who took aliskiren, compared with 17% who took placebo – also a significant difference.

"In contrast, the rates of death among patients without a history [of diabetes] were 15% and 20% in the aliskiren and placebo groups, respectively," the authors wrote.

A number of adverse events were significantly higher in the aliskiren group, including hyperkalemia (14% vs. 13%) and severe hyperkalemia (8% vs. 5%). Hyperkalemia-related events occurred in 21% of the aliskiren group and 17% of the control group. Hypotension was also more common in the aliskiren group (17% vs. 13%). Decreased eGFR was significantly more common among those taking the study drug (11% vs. 9%), as were events potentially related to renal dysfunction (17% vs. 12%).

"The results of the ASTRONAUT study do not support the routine administration of aliskiren in addition to standard therapy, to patients hospitalized for worsening chronic heart failure," the investigators concluded, adding that the subgroup analysis was "consistent with previous reports of poor outcomes  with the use of aliskiren in patients with diabetes already taking RAAS inhibitors."

Further studies will be necessary to evaluate renin inhibiting drugs in patients with diabetes, they added.

Dr. Gheorghiade reported financial relationships with 32 pharmaceutical companies, including Novartis Pharma AG, the study sponsor.

For patients hospitalized with heart failure, aliskiren added no significant benefit to standard therapy in preventing cardiovascular death or heart failure readmission.

The drug did, however, have some problematic effects on patients with diabetes, including significant increases in the risk of cardiovascular death and heart failure readmission at 6 months and all-cause death at 1 year.

The negative interaction between diabetes and aliskiren – an inhibitor of the angiotensin-renin-aldosterone system (RAAS) – is unclear, according to Dr. Mihai Gheorghiade and colleagues.

"[The issue] may be related to the increased risk of hypotension, hyperkalemia, and worsening renal function with the study drug," wrote Dr. Gheorghiade of Northwestern University, St. Louis, Mo., and his colleagues. The conclusions were published in the March 10 issue of JAMA and simultaneously presented at the annual meeting of the American College of Cardiology in San Francisco (JAMA 2013;309:doi10.1001/jama.2013.1954).

The randomized, placebo-controlled ASTRONAUT trial compared 6-and 12-month outcomes of aliskiren plus standard therapy to standard therapy alone in patients hospitalized with heart failure. 

The study randomized 1,639 patients; 1,615 were included in the final efficacy analysis. Patients in the investigational arm received 150 mg aliskiren daily in addition to standard treatment. Standard treatment was at the treating physician’s discretion, and could include, among others, diuretics, digoxin, ACE inhibitors, angiotensin receptor blockers, and beta-blockers. The study enrolled patients from 2009-2011; the median follow-up was 11 months

The patients were a mean of 65 years old. Their mean left ventricular ejection fraction was 28%, and mean estimated glomerular filtration rate was 67 mL/min/1.73 m³.  Nearly half (41%) had diabetes.

At admission, the mean N-terminal pro–brain natriuretic peptide (NT-proBNP) level was 4,239 pg/mL. Other drugs taken at baseline included diuretics (96%), beta-blockers (82%), ACE inhibitors or ARBs (84%), and mineralocorticoid antagonists (57%).

The primary efficacy endpoint was a combination of cardiovascular death or heart failure readmission within 6 months. This occurred in 201 (25%) of the aliskiren group and 214 (26%) of the placebo group – a nonsignificant difference. Nor were there significant differences when CV death and readmission were examined separately.

The main secondary endpoint was the composite of cardiovascular death or heart failure readmission at 12 months; again, there was no significant between-group difference (35% vs. 37%), although the events were numerically less in the aliskiren group than the control group (283 vs. 301). Parsing down the number of first cardiovascular events after treatment, the investigators did find that myocardial infarction was significantly less common in the aliskiren group (2% vs. 5%; HR 0.93; P = 0.009).

A subgroup analysis found that the drug was especially problematic for patients with diabetes. Compared to patients without the disorder who had standard treatment, diabetic patients who took aliskiren were 16% more likely to experience cardiovascular death or heart failure readmission by 6 months, and 64% more likely to experience all-cause death by 12 months.

During the treatment period, death occurred in 24% of patients with diabetes who took aliskiren, compared with 17% who took placebo – also a significant difference.

"In contrast, the rates of death among patients without a history [of diabetes] were 15% and 20% in the aliskiren and placebo groups, respectively," the authors wrote.

A number of adverse events were significantly higher in the aliskiren group, including hyperkalemia (14% vs. 13%) and severe hyperkalemia (8% vs. 5%). Hyperkalemia-related events occurred in 21% of the aliskiren group and 17% of the control group. Hypotension was also more common in the aliskiren group (17% vs. 13%). Decreased eGFR was significantly more common among those taking the study drug (11% vs. 9%), as were events potentially related to renal dysfunction (17% vs. 12%).

"The results of the ASTRONAUT study do not support the routine administration of aliskiren in addition to standard therapy, to patients hospitalized for worsening chronic heart failure," the investigators concluded, adding that the subgroup analysis was "consistent with previous reports of poor outcomes  with the use of aliskiren in patients with diabetes already taking RAAS inhibitors."

Further studies will be necessary to evaluate renin inhibiting drugs in patients with diabetes, they added.

Dr. Gheorghiade reported financial relationships with 32 pharmaceutical companies, including Novartis Pharma AG, the study sponsor.

For patients hospitalized with heart failure, aliskiren added no significant benefit to standard therapy in preventing cardiovascular death or heart failure readmission.

The drug did, however, have some problematic effects on patients with diabetes, including significant increases in the risk of cardiovascular death and heart failure readmission at 6 months and all-cause death at 1 year.

The negative interaction between diabetes and aliskiren – an inhibitor of the angiotensin-renin-aldosterone system (RAAS) – is unclear, according to Dr. Mihai Gheorghiade and colleagues.

"[The issue] may be related to the increased risk of hypotension, hyperkalemia, and worsening renal function with the study drug," wrote Dr. Gheorghiade of Northwestern University, St. Louis, Mo., and his colleagues. The conclusions were published in the March 10 issue of JAMA and simultaneously presented at the annual meeting of the American College of Cardiology in San Francisco (JAMA 2013;309:doi10.1001/jama.2013.1954).

The randomized, placebo-controlled ASTRONAUT trial compared 6-and 12-month outcomes of aliskiren plus standard therapy to standard therapy alone in patients hospitalized with heart failure. 

The study randomized 1,639 patients; 1,615 were included in the final efficacy analysis. Patients in the investigational arm received 150 mg aliskiren daily in addition to standard treatment. Standard treatment was at the treating physician’s discretion, and could include, among others, diuretics, digoxin, ACE inhibitors, angiotensin receptor blockers, and beta-blockers. The study enrolled patients from 2009-2011; the median follow-up was 11 months

The patients were a mean of 65 years old. Their mean left ventricular ejection fraction was 28%, and mean estimated glomerular filtration rate was 67 mL/min/1.73 m³.  Nearly half (41%) had diabetes.

At admission, the mean N-terminal pro–brain natriuretic peptide (NT-proBNP) level was 4,239 pg/mL. Other drugs taken at baseline included diuretics (96%), beta-blockers (82%), ACE inhibitors or ARBs (84%), and mineralocorticoid antagonists (57%).

The primary efficacy endpoint was a combination of cardiovascular death or heart failure readmission within 6 months. This occurred in 201 (25%) of the aliskiren group and 214 (26%) of the placebo group – a nonsignificant difference. Nor were there significant differences when CV death and readmission were examined separately.

The main secondary endpoint was the composite of cardiovascular death or heart failure readmission at 12 months; again, there was no significant between-group difference (35% vs. 37%), although the events were numerically less in the aliskiren group than the control group (283 vs. 301). Parsing down the number of first cardiovascular events after treatment, the investigators did find that myocardial infarction was significantly less common in the aliskiren group (2% vs. 5%; HR 0.93; P = 0.009).

A subgroup analysis found that the drug was especially problematic for patients with diabetes. Compared to patients without the disorder who had standard treatment, diabetic patients who took aliskiren were 16% more likely to experience cardiovascular death or heart failure readmission by 6 months, and 64% more likely to experience all-cause death by 12 months.

During the treatment period, death occurred in 24% of patients with diabetes who took aliskiren, compared with 17% who took placebo – also a significant difference.

"In contrast, the rates of death among patients without a history [of diabetes] were 15% and 20% in the aliskiren and placebo groups, respectively," the authors wrote.

A number of adverse events were significantly higher in the aliskiren group, including hyperkalemia (14% vs. 13%) and severe hyperkalemia (8% vs. 5%). Hyperkalemia-related events occurred in 21% of the aliskiren group and 17% of the control group. Hypotension was also more common in the aliskiren group (17% vs. 13%). Decreased eGFR was significantly more common among those taking the study drug (11% vs. 9%), as were events potentially related to renal dysfunction (17% vs. 12%).

"The results of the ASTRONAUT study do not support the routine administration of aliskiren in addition to standard therapy, to patients hospitalized for worsening chronic heart failure," the investigators concluded, adding that the subgroup analysis was "consistent with previous reports of poor outcomes  with the use of aliskiren in patients with diabetes already taking RAAS inhibitors."

Further studies will be necessary to evaluate renin inhibiting drugs in patients with diabetes, they added.

Dr. Gheorghiade reported financial relationships with 32 pharmaceutical companies, including Novartis Pharma AG, the study sponsor.

SAN FRANCISCO – Treatment of anemic heart failure patients with the erythropoiesis-stimulating agent darbepoetin alfa failed to produce any clinically meaningful improvements and significantly raised the incidence of ischemic stroke and thrombotic events in a randomized, multicenter trial with more than 2,200 patients.

 “Our findings do not support the use of erythropoiesis-stimulating agents to reduced cardiovascular morbidity and mortality in patients with systolic heart failure and mild-to-moderately severe anemia,” Dr. Karl Swedberg said on March 10 at the annual meeting of the American College of Cardiology.

Patients with heart failure also often have anemia, and results from small studies had suggested that increasing patients’ hemoglobin levels could improve their functional capacity. In addition, results from observational studies had shown worse outcomes in heart failure patients with hemoglobin levels less than 12.0 g/dL, and that a 1.0 g/dL change in hemoglobin level linked with a difference of 15-20 percentage points in all-cause mortality.

But the results of the current study called into question whether anemia plays any primary role in worsened outcomes.

Treatment with darbepoetin had “questionable clinical impact and increased thromboembolic events.” The treatment also significantly linked with an increased rate of ischemic cerebrovascular disorders that was “worrying. Our findings suggest that the hemoglobin level, like other surrogates, is simply a marker of poor prognosis in heart failure rather than a therapeutic target," said Dr. Swedberg, professor of medicine at the University of Gothenburg, Sweden. Simultaneously with his report at the meeting, the findings were also published online (N. Engl. J. Med. 2013; 368: doi:10.1056/NEJMoa1214865).

The Reduction of Events by Darbepoetin Alfa in Heart Failure (RED-HF) trial enrolled 2,278 patients with New York Heart Association class II-IV heart failure and a hemoglobin level of 9.0-12.0 g/dL at 453 sites in 33 countries during June 2006–May 2012. All patients also had a left ventricular ejection fraction of 40% or less. The study excluded patients with iron deficiency (transferrin saturation of less than 15%), evidence or bleeding or other causes of anemia, and patients with a high serum creatinine level or blood pressure above 160/100 mm Hg. The median age of the enrolled patients was 72 years, 65% had class III or IV heart failure, and their median ejection fraction was 31%. Median hemoglobin at entry was 11.2 g/dL.

The 1,136 patients assigned to receive darbepoetin injections began at a dose of 0.75 mcg/kg body weight once every 2 weeks; once they achieved a hemoglobin level of 13.0 g/dL treatment scaled back to once monthly, and treatment was continued to maintain a hemoglobin level of 13.0-14.5 g/dL. The difference in hemoglobin levels between these patients and the 1,142 randomized to the placebo control group became statistically significant after 1 month and remained significant through the study, which had a median follow-up of 28 months. The median monthly darbepoetin dosage was 167 mcg. When patients’ transferrin saturation fell below 20% they received supplemental iron.

The study’s primary endpoint was the combined rate of all-cause death and hospitalization for worsening heart failure. This occurred in 51% of the patients treated with darbepoetin alfa and 50% of those who received placebo, a difference that was not statistically significant. The result was consistent across all subgroups examined, and was not affected by adjustment for baseline differences between the two treatment arms. Total mortality was also similar between the two groups, 42% in the darbepoetin-treated patients and 40% in the controls.

The total number of hospitalizations for heart failure was 572 in the darbepoetin arm and 695 among the placebo patients, a difference that just missed being statistically significant (P = 0.06).

The overall Summary Score of the Kansas City Cardiomyopathy Questionnaire, a measure of quality of life in heart failure patients, was 6.68 in the darbepoetin-treated patients and 4.48 in the placebo patients, an average 2.2 point difference that was statistically significant. But the percent of patients with at least a 5-point increase in their score over baseline – a clinically meaningful increase – was 53% in the darbepoetin group and 48% in the placebo arm, a difference that fell short of statistical significant (P = 0.06).

The rate of study drug discontinuations due to adverse events was similar in the two arms. The rate of any embolic and thrombotic event was 14% in the darbepoetin patients and 10% in the placebo patients, a statistically significant difference. The rate of ischemic cerebrovascular events was 5% in the darbepoetin arm and 3% in the placebo arm, a statistically significant difference, although the overall rate of all cerebrovascular disorders – ischemic or hemorrhagic – was not significantly different between the two treatment groups. Episodes of septic shock were also significantly more frequent in the darbepoetin-treatment patients.

Dr. Swedberg cautioned against extrapolating the lack of benefit from darbepoetin in this patient population to other types of patients with anemia.

"I would be very careful to extend our findings to other situations because heart failure is a very special situation, with a lot of neurohormonal activation on top of other effects on the cardiorenal axis," he said. In addition, he stressed that the findings should not dissuade clinicians from administering an erythropoiesis-stimulating agent to patients with systolic heart failure and more severe anemia.

The RED-HF study was sponsored by Amgen, the company that market darbepoetin alfa (Aranesp). Dr. Swedberg said that he has been a consultant to and lecturer on behalf of Amgen as well as Novartis and Servier.

SAN FRANCISCO – Treatment of anemic heart failure patients with the erythropoiesis-stimulating agent darbepoetin alfa failed to produce any clinically meaningful improvements and significantly raised the incidence of ischemic stroke and thrombotic events in a randomized, multicenter trial with more than 2,200 patients.

 “Our findings do not support the use of erythropoiesis-stimulating agents to reduced cardiovascular morbidity and mortality in patients with systolic heart failure and mild-to-moderately severe anemia,” Dr. Karl Swedberg said on March 10 at the annual meeting of the American College of Cardiology.

Patients with heart failure also often have anemia, and results from small studies had suggested that increasing patients’ hemoglobin levels could improve their functional capacity. In addition, results from observational studies had shown worse outcomes in heart failure patients with hemoglobin levels less than 12.0 g/dL, and that a 1.0 g/dL change in hemoglobin level linked with a difference of 15-20 percentage points in all-cause mortality.

But the results of the current study called into question whether anemia plays any primary role in worsened outcomes.

Treatment with darbepoetin had “questionable clinical impact and increased thromboembolic events.” The treatment also significantly linked with an increased rate of ischemic cerebrovascular disorders that was “worrying. Our findings suggest that the hemoglobin level, like other surrogates, is simply a marker of poor prognosis in heart failure rather than a therapeutic target," said Dr. Swedberg, professor of medicine at the University of Gothenburg, Sweden. Simultaneously with his report at the meeting, the findings were also published online (N. Engl. J. Med. 2013; 368: doi:10.1056/NEJMoa1214865).

The Reduction of Events by Darbepoetin Alfa in Heart Failure (RED-HF) trial enrolled 2,278 patients with New York Heart Association class II-IV heart failure and a hemoglobin level of 9.0-12.0 g/dL at 453 sites in 33 countries during June 2006–May 2012. All patients also had a left ventricular ejection fraction of 40% or less. The study excluded patients with iron deficiency (transferrin saturation of less than 15%), evidence or bleeding or other causes of anemia, and patients with a high serum creatinine level or blood pressure above 160/100 mm Hg. The median age of the enrolled patients was 72 years, 65% had class III or IV heart failure, and their median ejection fraction was 31%. Median hemoglobin at entry was 11.2 g/dL.

The 1,136 patients assigned to receive darbepoetin injections began at a dose of 0.75 mcg/kg body weight once every 2 weeks; once they achieved a hemoglobin level of 13.0 g/dL treatment scaled back to once monthly, and treatment was continued to maintain a hemoglobin level of 13.0-14.5 g/dL. The difference in hemoglobin levels between these patients and the 1,142 randomized to the placebo control group became statistically significant after 1 month and remained significant through the study, which had a median follow-up of 28 months. The median monthly darbepoetin dosage was 167 mcg. When patients’ transferrin saturation fell below 20% they received supplemental iron.

The study’s primary endpoint was the combined rate of all-cause death and hospitalization for worsening heart failure. This occurred in 51% of the patients treated with darbepoetin alfa and 50% of those who received placebo, a difference that was not statistically significant. The result was consistent across all subgroups examined, and was not affected by adjustment for baseline differences between the two treatment arms. Total mortality was also similar between the two groups, 42% in the darbepoetin-treated patients and 40% in the controls.

The total number of hospitalizations for heart failure was 572 in the darbepoetin arm and 695 among the placebo patients, a difference that just missed being statistically significant (P = 0.06).

The overall Summary Score of the Kansas City Cardiomyopathy Questionnaire, a measure of quality of life in heart failure patients, was 6.68 in the darbepoetin-treated patients and 4.48 in the placebo patients, an average 2.2 point difference that was statistically significant. But the percent of patients with at least a 5-point increase in their score over baseline – a clinically meaningful increase – was 53% in the darbepoetin group and 48% in the placebo arm, a difference that fell short of statistical significant (P = 0.06).

The rate of study drug discontinuations due to adverse events was similar in the two arms. The rate of any embolic and thrombotic event was 14% in the darbepoetin patients and 10% in the placebo patients, a statistically significant difference. The rate of ischemic cerebrovascular events was 5% in the darbepoetin arm and 3% in the placebo arm, a statistically significant difference, although the overall rate of all cerebrovascular disorders – ischemic or hemorrhagic – was not significantly different between the two treatment groups. Episodes of septic shock were also significantly more frequent in the darbepoetin-treatment patients.

Dr. Swedberg cautioned against extrapolating the lack of benefit from darbepoetin in this patient population to other types of patients with anemia.

"I would be very careful to extend our findings to other situations because heart failure is a very special situation, with a lot of neurohormonal activation on top of other effects on the cardiorenal axis," he said. In addition, he stressed that the findings should not dissuade clinicians from administering an erythropoiesis-stimulating agent to patients with systolic heart failure and more severe anemia.

The RED-HF study was sponsored by Amgen, the company that market darbepoetin alfa (Aranesp). Dr. Swedberg said that he has been a consultant to and lecturer on behalf of Amgen as well as Novartis and Servier.

SAN FRANCISCO – Treatment of anemic heart failure patients with the erythropoiesis-stimulating agent darbepoetin alfa failed to produce any clinically meaningful improvements and significantly raised the incidence of ischemic stroke and thrombotic events in a randomized, multicenter trial with more than 2,200 patients.

 “Our findings do not support the use of erythropoiesis-stimulating agents to reduced cardiovascular morbidity and mortality in patients with systolic heart failure and mild-to-moderately severe anemia,” Dr. Karl Swedberg said on March 10 at the annual meeting of the American College of Cardiology.

Patients with heart failure also often have anemia, and results from small studies had suggested that increasing patients’ hemoglobin levels could improve their functional capacity. In addition, results from observational studies had shown worse outcomes in heart failure patients with hemoglobin levels less than 12.0 g/dL, and that a 1.0 g/dL change in hemoglobin level linked with a difference of 15-20 percentage points in all-cause mortality.

But the results of the current study called into question whether anemia plays any primary role in worsened outcomes.

Treatment with darbepoetin had “questionable clinical impact and increased thromboembolic events.” The treatment also significantly linked with an increased rate of ischemic cerebrovascular disorders that was “worrying. Our findings suggest that the hemoglobin level, like other surrogates, is simply a marker of poor prognosis in heart failure rather than a therapeutic target," said Dr. Swedberg, professor of medicine at the University of Gothenburg, Sweden. Simultaneously with his report at the meeting, the findings were also published online (N. Engl. J. Med. 2013; 368: doi:10.1056/NEJMoa1214865).

The Reduction of Events by Darbepoetin Alfa in Heart Failure (RED-HF) trial enrolled 2,278 patients with New York Heart Association class II-IV heart failure and a hemoglobin level of 9.0-12.0 g/dL at 453 sites in 33 countries during June 2006–May 2012. All patients also had a left ventricular ejection fraction of 40% or less. The study excluded patients with iron deficiency (transferrin saturation of less than 15%), evidence or bleeding or other causes of anemia, and patients with a high serum creatinine level or blood pressure above 160/100 mm Hg. The median age of the enrolled patients was 72 years, 65% had class III or IV heart failure, and their median ejection fraction was 31%. Median hemoglobin at entry was 11.2 g/dL.

The 1,136 patients assigned to receive darbepoetin injections began at a dose of 0.75 mcg/kg body weight once every 2 weeks; once they achieved a hemoglobin level of 13.0 g/dL treatment scaled back to once monthly, and treatment was continued to maintain a hemoglobin level of 13.0-14.5 g/dL. The difference in hemoglobin levels between these patients and the 1,142 randomized to the placebo control group became statistically significant after 1 month and remained significant through the study, which had a median follow-up of 28 months. The median monthly darbepoetin dosage was 167 mcg. When patients’ transferrin saturation fell below 20% they received supplemental iron.

The study’s primary endpoint was the combined rate of all-cause death and hospitalization for worsening heart failure. This occurred in 51% of the patients treated with darbepoetin alfa and 50% of those who received placebo, a difference that was not statistically significant. The result was consistent across all subgroups examined, and was not affected by adjustment for baseline differences between the two treatment arms. Total mortality was also similar between the two groups, 42% in the darbepoetin-treated patients and 40% in the controls.

The total number of hospitalizations for heart failure was 572 in the darbepoetin arm and 695 among the placebo patients, a difference that just missed being statistically significant (P = 0.06).

The overall Summary Score of the Kansas City Cardiomyopathy Questionnaire, a measure of quality of life in heart failure patients, was 6.68 in the darbepoetin-treated patients and 4.48 in the placebo patients, an average 2.2 point difference that was statistically significant. But the percent of patients with at least a 5-point increase in their score over baseline – a clinically meaningful increase – was 53% in the darbepoetin group and 48% in the placebo arm, a difference that fell short of statistical significant (P = 0.06).

The rate of study drug discontinuations due to adverse events was similar in the two arms. The rate of any embolic and thrombotic event was 14% in the darbepoetin patients and 10% in the placebo patients, a statistically significant difference. The rate of ischemic cerebrovascular events was 5% in the darbepoetin arm and 3% in the placebo arm, a statistically significant difference, although the overall rate of all cerebrovascular disorders – ischemic or hemorrhagic – was not significantly different between the two treatment groups. Episodes of septic shock were also significantly more frequent in the darbepoetin-treatment patients.

Dr. Swedberg cautioned against extrapolating the lack of benefit from darbepoetin in this patient population to other types of patients with anemia.

"I would be very careful to extend our findings to other situations because heart failure is a very special situation, with a lot of neurohormonal activation on top of other effects on the cardiorenal axis," he said. In addition, he stressed that the findings should not dissuade clinicians from administering an erythropoiesis-stimulating agent to patients with systolic heart failure and more severe anemia.

The RED-HF study was sponsored by Amgen, the company that market darbepoetin alfa (Aranesp). Dr. Swedberg said that he has been a consultant to and lecturer on behalf of Amgen as well as Novartis and Servier.

Spironolactone significantly improved left ventricular diastolic function and remodeling in a 1-year study of ambulatory patients who had heart failure with preserved ejection fraction, but that benefit did not translate into improvements in HF symptoms or quality of life, according to a report in the Feb. 27 issue of JAMA.

In the multicenter, double-blind Aldosterone Receptor Blockade in Diastolic HF (Aldo-DHF) clinical trial, 213 men and women aged 50 and older were randomly assigned to receive daily oral spironolactone and 209 to receive a matching placebo for 1 year. Patients on spironolactone had significantly increased LV ejection fraction, decreased LV end-diastolic diameter and LV mass index, and reduced systolic blood pressure, reported Dr. Burkert M. Pieske, professor and head of the department of cardiology at Medical University of Graz, Austria, and his associates.

Mitchel L. Zoler/IMNG Medical Media

The drug failed to improve HF symptoms, exercise capacity, depressive symptoms, or quality of life, compared with placebo. "Our study population may have been too young or too healthy, or the treatment period may have been too short, for observing a translation of improved diastolic function into a clinical benefit," the investigators said (JAMA 2013;309:781-91).

These results were presented at the annual meeting of the European Society of Cardiology in Munich last summer, and reported by this newspaper.

Experts reacting to the news at the meeting expressed similar misgivings.

"It was not all good news. Patients had an increase in their potassium level, and even more concerning, they had a reduction in their glomerular filtration rate, an average reduction of about 5 mL/min," commented Dr. Stefan D. Anker, professor of medicine at Charité Medical University in Berlin. In addition, the distance walked on the 6-minute walk test was "slightly decreased with spironolactone. Even though it was a small change of 15 m, it was statistically significant," he noted. On top of all this, "worsening of anemia was seen in patients," he added.

Mitchel L. Zoler/IMNG Medical Media

Study discussant Dr. John G.F. Cleland said that although the Aldo-DHF study adds important new information on the progression of diastolic heart failure as seen in the control group, it wasn’t really was a study of diastolic heart failure. Few of the patients were on diuretic drugs, at entry they had fairly normal levels of NT-proBNP, they had mild abnormalities detected by echocardiography, and they exhibited mild deficits in cardiopulmonary exercise testing, said Dr. Cleland, professor of cardiology at the University of Hull, Kingston-upon-Hull, England.

Aldo-DHF was supported by the German-Austrian Heart Failure Study Group and the German Competence Network of Heart Failure. Dr. Edelmann and his associates reported numerous ties to industry sources.

cardnews@elsevier.com

Spironolactone significantly improved left ventricular diastolic function and remodeling in a 1-year study of ambulatory patients who had heart failure with preserved ejection fraction, but that benefit did not translate into improvements in HF symptoms or quality of life, according to a report in the Feb. 27 issue of JAMA.

In the multicenter, double-blind Aldosterone Receptor Blockade in Diastolic HF (Aldo-DHF) clinical trial, 213 men and women aged 50 and older were randomly assigned to receive daily oral spironolactone and 209 to receive a matching placebo for 1 year. Patients on spironolactone had significantly increased LV ejection fraction, decreased LV end-diastolic diameter and LV mass index, and reduced systolic blood pressure, reported Dr. Burkert M. Pieske, professor and head of the department of cardiology at Medical University of Graz, Austria, and his associates.

Mitchel L. Zoler/IMNG Medical Media

The drug failed to improve HF symptoms, exercise capacity, depressive symptoms, or quality of life, compared with placebo. "Our study population may have been too young or too healthy, or the treatment period may have been too short, for observing a translation of improved diastolic function into a clinical benefit," the investigators said (JAMA 2013;309:781-91).

These results were presented at the annual meeting of the European Society of Cardiology in Munich last summer, and reported by this newspaper.

Experts reacting to the news at the meeting expressed similar misgivings.

"It was not all good news. Patients had an increase in their potassium level, and even more concerning, they had a reduction in their glomerular filtration rate, an average reduction of about 5 mL/min," commented Dr. Stefan D. Anker, professor of medicine at Charité Medical University in Berlin. In addition, the distance walked on the 6-minute walk test was "slightly decreased with spironolactone. Even though it was a small change of 15 m, it was statistically significant," he noted. On top of all this, "worsening of anemia was seen in patients," he added.

Mitchel L. Zoler/IMNG Medical Media

Study discussant Dr. John G.F. Cleland said that although the Aldo-DHF study adds important new information on the progression of diastolic heart failure as seen in the control group, it wasn’t really was a study of diastolic heart failure. Few of the patients were on diuretic drugs, at entry they had fairly normal levels of NT-proBNP, they had mild abnormalities detected by echocardiography, and they exhibited mild deficits in cardiopulmonary exercise testing, said Dr. Cleland, professor of cardiology at the University of Hull, Kingston-upon-Hull, England.

Aldo-DHF was supported by the German-Austrian Heart Failure Study Group and the German Competence Network of Heart Failure. Dr. Edelmann and his associates reported numerous ties to industry sources.

cardnews@elsevier.com

Spironolactone significantly improved left ventricular diastolic function and remodeling in a 1-year study of ambulatory patients who had heart failure with preserved ejection fraction, but that benefit did not translate into improvements in HF symptoms or quality of life, according to a report in the Feb. 27 issue of JAMA.

In the multicenter, double-blind Aldosterone Receptor Blockade in Diastolic HF (Aldo-DHF) clinical trial, 213 men and women aged 50 and older were randomly assigned to receive daily oral spironolactone and 209 to receive a matching placebo for 1 year. Patients on spironolactone had significantly increased LV ejection fraction, decreased LV end-diastolic diameter and LV mass index, and reduced systolic blood pressure, reported Dr. Burkert M. Pieske, professor and head of the department of cardiology at Medical University of Graz, Austria, and his associates.

Mitchel L. Zoler/IMNG Medical Media

The drug failed to improve HF symptoms, exercise capacity, depressive symptoms, or quality of life, compared with placebo. "Our study population may have been too young or too healthy, or the treatment period may have been too short, for observing a translation of improved diastolic function into a clinical benefit," the investigators said (JAMA 2013;309:781-91).

These results were presented at the annual meeting of the European Society of Cardiology in Munich last summer, and reported by this newspaper.

Experts reacting to the news at the meeting expressed similar misgivings.

"It was not all good news. Patients had an increase in their potassium level, and even more concerning, they had a reduction in their glomerular filtration rate, an average reduction of about 5 mL/min," commented Dr. Stefan D. Anker, professor of medicine at Charité Medical University in Berlin. In addition, the distance walked on the 6-minute walk test was "slightly decreased with spironolactone. Even though it was a small change of 15 m, it was statistically significant," he noted. On top of all this, "worsening of anemia was seen in patients," he added.

Mitchel L. Zoler/IMNG Medical Media

Study discussant Dr. John G.F. Cleland said that although the Aldo-DHF study adds important new information on the progression of diastolic heart failure as seen in the control group, it wasn’t really was a study of diastolic heart failure. Few of the patients were on diuretic drugs, at entry they had fairly normal levels of NT-proBNP, they had mild abnormalities detected by echocardiography, and they exhibited mild deficits in cardiopulmonary exercise testing, said Dr. Cleland, professor of cardiology at the University of Hull, Kingston-upon-Hull, England.

Aldo-DHF was supported by the German-Austrian Heart Failure Study Group and the German Competence Network of Heart Failure. Dr. Edelmann and his associates reported numerous ties to industry sources.

cardnews@elsevier.com

The Centers for Medicare and Medicaid Services is revisiting the National Coverage Determination for ventricular assist devices.

CMS is seeking public comment on the clinical evidence supporting identification of patients whose outcomes would improve with ventricular assist device (VAD) placement, health care teams, and hospital standards that would optimize patient outcomes, including evidence to support the current requirement for certification of hospitals implanting VADs for destination therapy.

CMS added that it is particularly interested in comments that include clinical studies and other scientific information that provides evidence for improvement in short-and long-erm outcomes with VADs.

"My own personal opinion is that it’s a good thing that they’ve reopened the NCD," said Dr. Lee Goldberg, medical director of the heart failure and transplantation program at the University of Pennsylvania, Philadelphia.

"For one, the technology has really changed, the experience of the centers and physicians have changed over time ... and the criteria to certify various centers and surgeons involved is somewhat archaic and arbitrary, so tightening that up in the context of updating evidence and approach makes sense." The challenge, he added, is that there’s not enough clinical data to answer all of the CMS questions and inquiries.

The NCD reopening, announced on Feb. 7, follows a Medicare advisory group meeting in November that aimed to review the available evidence on the management of heart failure using VADs, including the value of VAD-specific certification for various facilities, and patient selection and outcomes.

During the Medicare Advisory (MEDCAC) meeting, heart societies and prominent heart failure experts discussed the state of VAD research. The panel stressed the importance of multidisciplinary heart teams and said that there’s not enough data to show that the indications for VADs can be expanded to include lower-risk patients.

Dr. Sean Pinney, who spoke at the MEDCAC meeting on behalf of the Heart Failure Society of America, said that the society supported the NCD and did "not endorse any change in the current patient selection criteria which derive from prospective randomized trials." He added that there’s a need for more well-controlled clinical trials, including those that would examine "less sick" patients.

CMS will accept comments for 30 days on the reopened NCD, and various entities, including the American College of Cardiology, are expected to submit comments. "We want to make sure that we’re putting forth things that are most important to impact CMS decision making," said Dr. Goldberg, chair of the ACC’s heart failure and transplant council. "For instance, the appropriate certification of hospitals, appropriate utilization of a heart care team. ... Also, currently we know transplant is superior to VAD therapy for long-term survival and therefore we want to ensure that patients do have access to transplant evaluation."

The CMS review includes VADs used for bridge-to-transplant and as destination therapy. It does not include devices that are used for temporary, in-hospital use.

The reconsideration was requested by Det Norske Veritas Healthcare Inc. (DNV) to include the DNV mechanical circulatory support certification program as an acceptable credential for facilities that qualify for Medicare reimbursement.

The 140 U.S. centers that place LVADs were expected to implant nearly 3,000 devices in 2012. Nearly 4,600 patients have received an LVAD since 2010.

"I personally think that they’re going to try and tighten up [the requirements] a little bit," said Dr. Goldberg. "And try to understand who’s too sick, and where’s the appropriate cut-off, and to try and maximize or improve long-term outcomes for VAD patients. Whether they’ll be able to come up with something that’s better than what we have, I don’t know." It’s too soon to tell whether the NCD reconsideration will have an impact on procedure volumes, he added.

Dr. Goldberg and Dr. Pinney had no relevant disclosures.

n.miller@elsevier.com

On Twitter @NaseemSMiller

The Centers for Medicare and Medicaid Services is revisiting the National Coverage Determination for ventricular assist devices.

CMS is seeking public comment on the clinical evidence supporting identification of patients whose outcomes would improve with ventricular assist device (VAD) placement, health care teams, and hospital standards that would optimize patient outcomes, including evidence to support the current requirement for certification of hospitals implanting VADs for destination therapy.

CMS added that it is particularly interested in comments that include clinical studies and other scientific information that provides evidence for improvement in short-and long-erm outcomes with VADs.

"My own personal opinion is that it’s a good thing that they’ve reopened the NCD," said Dr. Lee Goldberg, medical director of the heart failure and transplantation program at the University of Pennsylvania, Philadelphia.

"For one, the technology has really changed, the experience of the centers and physicians have changed over time ... and the criteria to certify various centers and surgeons involved is somewhat archaic and arbitrary, so tightening that up in the context of updating evidence and approach makes sense." The challenge, he added, is that there’s not enough clinical data to answer all of the CMS questions and inquiries.

The NCD reopening, announced on Feb. 7, follows a Medicare advisory group meeting in November that aimed to review the available evidence on the management of heart failure using VADs, including the value of VAD-specific certification for various facilities, and patient selection and outcomes.

During the Medicare Advisory (MEDCAC) meeting, heart societies and prominent heart failure experts discussed the state of VAD research. The panel stressed the importance of multidisciplinary heart teams and said that there’s not enough data to show that the indications for VADs can be expanded to include lower-risk patients.

Dr. Sean Pinney, who spoke at the MEDCAC meeting on behalf of the Heart Failure Society of America, said that the society supported the NCD and did "not endorse any change in the current patient selection criteria which derive from prospective randomized trials." He added that there’s a need for more well-controlled clinical trials, including those that would examine "less sick" patients.

CMS will accept comments for 30 days on the reopened NCD, and various entities, including the American College of Cardiology, are expected to submit comments. "We want to make sure that we’re putting forth things that are most important to impact CMS decision making," said Dr. Goldberg, chair of the ACC’s heart failure and transplant council. "For instance, the appropriate certification of hospitals, appropriate utilization of a heart care team. ... Also, currently we know transplant is superior to VAD therapy for long-term survival and therefore we want to ensure that patients do have access to transplant evaluation."

The CMS review includes VADs used for bridge-to-transplant and as destination therapy. It does not include devices that are used for temporary, in-hospital use.

The reconsideration was requested by Det Norske Veritas Healthcare Inc. (DNV) to include the DNV mechanical circulatory support certification program as an acceptable credential for facilities that qualify for Medicare reimbursement.

The 140 U.S. centers that place LVADs were expected to implant nearly 3,000 devices in 2012. Nearly 4,600 patients have received an LVAD since 2010.

"I personally think that they’re going to try and tighten up [the requirements] a little bit," said Dr. Goldberg. "And try to understand who’s too sick, and where’s the appropriate cut-off, and to try and maximize or improve long-term outcomes for VAD patients. Whether they’ll be able to come up with something that’s better than what we have, I don’t know." It’s too soon to tell whether the NCD reconsideration will have an impact on procedure volumes, he added.

Dr. Goldberg and Dr. Pinney had no relevant disclosures.

n.miller@elsevier.com

On Twitter @NaseemSMiller

The Centers for Medicare and Medicaid Services is revisiting the National Coverage Determination for ventricular assist devices.

CMS is seeking public comment on the clinical evidence supporting identification of patients whose outcomes would improve with ventricular assist device (VAD) placement, health care teams, and hospital standards that would optimize patient outcomes, including evidence to support the current requirement for certification of hospitals implanting VADs for destination therapy.

CMS added that it is particularly interested in comments that include clinical studies and other scientific information that provides evidence for improvement in short-and long-erm outcomes with VADs.

"My own personal opinion is that it’s a good thing that they’ve reopened the NCD," said Dr. Lee Goldberg, medical director of the heart failure and transplantation program at the University of Pennsylvania, Philadelphia.

"For one, the technology has really changed, the experience of the centers and physicians have changed over time ... and the criteria to certify various centers and surgeons involved is somewhat archaic and arbitrary, so tightening that up in the context of updating evidence and approach makes sense." The challenge, he added, is that there’s not enough clinical data to answer all of the CMS questions and inquiries.

The NCD reopening, announced on Feb. 7, follows a Medicare advisory group meeting in November that aimed to review the available evidence on the management of heart failure using VADs, including the value of VAD-specific certification for various facilities, and patient selection and outcomes.

During the Medicare Advisory (MEDCAC) meeting, heart societies and prominent heart failure experts discussed the state of VAD research. The panel stressed the importance of multidisciplinary heart teams and said that there’s not enough data to show that the indications for VADs can be expanded to include lower-risk patients.

Dr. Sean Pinney, who spoke at the MEDCAC meeting on behalf of the Heart Failure Society of America, said that the society supported the NCD and did "not endorse any change in the current patient selection criteria which derive from prospective randomized trials." He added that there’s a need for more well-controlled clinical trials, including those that would examine "less sick" patients.

CMS will accept comments for 30 days on the reopened NCD, and various entities, including the American College of Cardiology, are expected to submit comments. "We want to make sure that we’re putting forth things that are most important to impact CMS decision making," said Dr. Goldberg, chair of the ACC’s heart failure and transplant council. "For instance, the appropriate certification of hospitals, appropriate utilization of a heart care team. ... Also, currently we know transplant is superior to VAD therapy for long-term survival and therefore we want to ensure that patients do have access to transplant evaluation."

The CMS review includes VADs used for bridge-to-transplant and as destination therapy. It does not include devices that are used for temporary, in-hospital use.

The reconsideration was requested by Det Norske Veritas Healthcare Inc. (DNV) to include the DNV mechanical circulatory support certification program as an acceptable credential for facilities that qualify for Medicare reimbursement.

The 140 U.S. centers that place LVADs were expected to implant nearly 3,000 devices in 2012. Nearly 4,600 patients have received an LVAD since 2010.

"I personally think that they’re going to try and tighten up [the requirements] a little bit," said Dr. Goldberg. "And try to understand who’s too sick, and where’s the appropriate cut-off, and to try and maximize or improve long-term outcomes for VAD patients. Whether they’ll be able to come up with something that’s better than what we have, I don’t know." It’s too soon to tell whether the NCD reconsideration will have an impact on procedure volumes, he added.

Dr. Goldberg and Dr. Pinney had no relevant disclosures.

n.miller@elsevier.com

On Twitter @NaseemSMiller

LOS ANGELES – A strategy of catheter ablation–based rhythm control in patients with long-standing persistent atrial fibrillation plus heart failure improved cardiopulmonary exercise capacity, quality of life, and neurohormonal status, compared with pharmacologic rate control in a single-center randomized trial.

The majority of improvement seen in these endpoints in the ARC-HF (Catheter Ablation Versus Medical Rate Control for Atrial Fibrillation in Patients With Heart Failure) trial occurred 3-12 months after the initial ablation procedure, Dr. David G. Jones reported at the annual scientific sessions of the American Heart Association.

"This may reflect progressive amelioration of the heart failure syndrome. And our findings may also have prognostic significance," said Dr. Jones of Imperial College London.

Indeed, although clinical outcomes weren’t included in the relatively small ARC-HF study, they were reported in the recently published 1,620-patient HF-ACTION (Exercise Training Program to Improve Clinical Outcomes in Individuals With Congestive Heart Failure) trial (Circ. Heart Fail. 2012;5:579-85). And HF-ACTION showed that every 6% increase in peak oxygen uptake (VO₂) was associated with an 8% lower risk of the combined endpoint of cardiovascular mortality or heart failure hospitalization and a 7% reduction in all-cause mortality.

"By comparison, ours was close to a 20% increase in peak VO₂ at 1 year with ablation therapy," Dr. Jones observed.

The ARC-HF trial included 51 patients with continuous persistent atrial fibrillation (AF) for an average of 24 months, symptomatic systolic heart failure, and a left ventricular ejection fraction of 35% or less. Because it has been unclear whether restoration of sinus rhythm or pharmacologic rate control is the optimal management strategy in patients with AF and the common comorbidity of heart failure, the investigators randomized participants to catheter ablation of the arrhythmia or to rate control.

The primary endpoint was the change in peak VO₂ at 12 months from a baseline of roughly 17 mL/kg per minute. Peak VO₂ increased by a mean of 2.0 mL/kg per minute in the 25 patients in the ablation group while declining over time in the rate control group, for an impressive 12-month intergroup difference of 3.07 mL/kg per minute.

The ablation group also displayed significant improvements in quality of life as measured by the Minnesota Living With Heart Failure Questionnaire, as well as neurohormonal status as reflected in a reduction in brain natriuretic peptide levels. Data on other cardiac biomarkers are still being analyzed.

A significant reduction in baseline left atrial dilation was documented in the ablation group at 6 months and maintained at 12 months. The ablation group showed a nonsignificant trend toward improved left ventricular ejection fraction.

Dr. Jones stressed that the ablation procedures were long and challenging. They averaged 333 minutes in duration, including mapping, with fully 80 minutes of fluoroscopy time and 82 minutes of actual ablation.

Seven patients experienced recurrent atrial arrhythmias post ablation; five of them underwent a second ablation procedure and one had a third. The single-procedure success rate in achieving sinus rhythm at 12 months was 72%, with a multiprocedure success rate of 92%.

Of the 26 patients in the rate control group, 2 were in sinus rhythm at 12 months (including 1 patient who crossed over to catheter ablation), and 23 of the remaining 24 were optimally rate controlled, with a resting heart rate below 80 beats per minute and a maximum heart rate below 110 bpm during a 6-minute walk test.

Discussant Dr. Karl-Heinz Kuck called the ARC-HF results "remarkable." So much so, in fact, that he doesn’t think catheter ablation can be recommended for now in patients with long-standing persistent AF and heart failure, because the single-center ARC-HF results are out of step with those reported in observational series. Better, he said, to wait for the results of ongoing, much larger multicenter randomized trials, including CASTLE-AF as well as AMICA, for which he serves as principal investigator.

Among Dr. Kuck’s concerns was the whopping 2.0-mL/kg per minute increase in peak VO₂ reported in ARC-HF. To put that in perspective, the major randomized trials of cardiac resynchronization therapy and cardiac contractility modulation therapy for heart failure achieved increases of only 0.7-1.0 mL/kg per minute.

Also, a recent report from Dr. Kuck and his coinvestigators in the Hamburg Sequential Ablation Group, which involved 202 patients who underwent catheter ablation for long-standing persistent AF, showed only 36% were in sinus rhythm at 12 months after a single procedure and 60% after multiple procedures. Those success rates are substantially lower than in ARC-HF, noted Dr. Kuck, head of the cardiology department at St. Georg Hospital, Hamburg, Germany.

The 5-year success rates in the large Hamburg series were 20% and 45% after single and multiple ablation procedures, respectively. Success rates were far better in patients with a history of less than 2 years of persistent AF than in those who were arrhythmic for longer (J. Am. Coll. Cardiol. 2012;60:1921-9).

The ARC-HF study was supported by research grants from the Royal Brompton & Harefield NHS Foundation Trust. Dr. Jones reported having no financial conflicts. Dr. Kuck is on the speakers bureaus for Biosense Webster, Medtronic, St. Jude Medical, Abbott, Cardiofocus, and Biotronik.

b.jancin@elsevier.com

LOS ANGELES – A strategy of catheter ablation–based rhythm control in patients with long-standing persistent atrial fibrillation plus heart failure improved cardiopulmonary exercise capacity, quality of life, and neurohormonal status, compared with pharmacologic rate control in a single-center randomized trial.

The majority of improvement seen in these endpoints in the ARC-HF (Catheter Ablation Versus Medical Rate Control for Atrial Fibrillation in Patients With Heart Failure) trial occurred 3-12 months after the initial ablation procedure, Dr. David G. Jones reported at the annual scientific sessions of the American Heart Association.

"This may reflect progressive amelioration of the heart failure syndrome. And our findings may also have prognostic significance," said Dr. Jones of Imperial College London.

Indeed, although clinical outcomes weren’t included in the relatively small ARC-HF study, they were reported in the recently published 1,620-patient HF-ACTION (Exercise Training Program to Improve Clinical Outcomes in Individuals With Congestive Heart Failure) trial (Circ. Heart Fail. 2012;5:579-85). And HF-ACTION showed that every 6% increase in peak oxygen uptake (VO₂) was associated with an 8% lower risk of the combined endpoint of cardiovascular mortality or heart failure hospitalization and a 7% reduction in all-cause mortality.

"By comparison, ours was close to a 20% increase in peak VO₂ at 1 year with ablation therapy," Dr. Jones observed.

The ARC-HF trial included 51 patients with continuous persistent atrial fibrillation (AF) for an average of 24 months, symptomatic systolic heart failure, and a left ventricular ejection fraction of 35% or less. Because it has been unclear whether restoration of sinus rhythm or pharmacologic rate control is the optimal management strategy in patients with AF and the common comorbidity of heart failure, the investigators randomized participants to catheter ablation of the arrhythmia or to rate control.

The primary endpoint was the change in peak VO₂ at 12 months from a baseline of roughly 17 mL/kg per minute. Peak VO₂ increased by a mean of 2.0 mL/kg per minute in the 25 patients in the ablation group while declining over time in the rate control group, for an impressive 12-month intergroup difference of 3.07 mL/kg per minute.

The ablation group also displayed significant improvements in quality of life as measured by the Minnesota Living With Heart Failure Questionnaire, as well as neurohormonal status as reflected in a reduction in brain natriuretic peptide levels. Data on other cardiac biomarkers are still being analyzed.

A significant reduction in baseline left atrial dilation was documented in the ablation group at 6 months and maintained at 12 months. The ablation group showed a nonsignificant trend toward improved left ventricular ejection fraction.

Dr. Jones stressed that the ablation procedures were long and challenging. They averaged 333 minutes in duration, including mapping, with fully 80 minutes of fluoroscopy time and 82 minutes of actual ablation.

Seven patients experienced recurrent atrial arrhythmias post ablation; five of them underwent a second ablation procedure and one had a third. The single-procedure success rate in achieving sinus rhythm at 12 months was 72%, with a multiprocedure success rate of 92%.

Of the 26 patients in the rate control group, 2 were in sinus rhythm at 12 months (including 1 patient who crossed over to catheter ablation), and 23 of the remaining 24 were optimally rate controlled, with a resting heart rate below 80 beats per minute and a maximum heart rate below 110 bpm during a 6-minute walk test.

Discussant Dr. Karl-Heinz Kuck called the ARC-HF results "remarkable." So much so, in fact, that he doesn’t think catheter ablation can be recommended for now in patients with long-standing persistent AF and heart failure, because the single-center ARC-HF results are out of step with those reported in observational series. Better, he said, to wait for the results of ongoing, much larger multicenter randomized trials, including CASTLE-AF as well as AMICA, for which he serves as principal investigator.

Among Dr. Kuck’s concerns was the whopping 2.0-mL/kg per minute increase in peak VO₂ reported in ARC-HF. To put that in perspective, the major randomized trials of cardiac resynchronization therapy and cardiac contractility modulation therapy for heart failure achieved increases of only 0.7-1.0 mL/kg per minute.

Also, a recent report from Dr. Kuck and his coinvestigators in the Hamburg Sequential Ablation Group, which involved 202 patients who underwent catheter ablation for long-standing persistent AF, showed only 36% were in sinus rhythm at 12 months after a single procedure and 60% after multiple procedures. Those success rates are substantially lower than in ARC-HF, noted Dr. Kuck, head of the cardiology department at St. Georg Hospital, Hamburg, Germany.

The 5-year success rates in the large Hamburg series were 20% and 45% after single and multiple ablation procedures, respectively. Success rates were far better in patients with a history of less than 2 years of persistent AF than in those who were arrhythmic for longer (J. Am. Coll. Cardiol. 2012;60:1921-9).

The ARC-HF study was supported by research grants from the Royal Brompton & Harefield NHS Foundation Trust. Dr. Jones reported having no financial conflicts. Dr. Kuck is on the speakers bureaus for Biosense Webster, Medtronic, St. Jude Medical, Abbott, Cardiofocus, and Biotronik.

b.jancin@elsevier.com

LOS ANGELES – A strategy of catheter ablation–based rhythm control in patients with long-standing persistent atrial fibrillation plus heart failure improved cardiopulmonary exercise capacity, quality of life, and neurohormonal status, compared with pharmacologic rate control in a single-center randomized trial.

The majority of improvement seen in these endpoints in the ARC-HF (Catheter Ablation Versus Medical Rate Control for Atrial Fibrillation in Patients With Heart Failure) trial occurred 3-12 months after the initial ablation procedure, Dr. David G. Jones reported at the annual scientific sessions of the American Heart Association.

"This may reflect progressive amelioration of the heart failure syndrome. And our findings may also have prognostic significance," said Dr. Jones of Imperial College London.

Indeed, although clinical outcomes weren’t included in the relatively small ARC-HF study, they were reported in the recently published 1,620-patient HF-ACTION (Exercise Training Program to Improve Clinical Outcomes in Individuals With Congestive Heart Failure) trial (Circ. Heart Fail. 2012;5:579-85). And HF-ACTION showed that every 6% increase in peak oxygen uptake (VO₂) was associated with an 8% lower risk of the combined endpoint of cardiovascular mortality or heart failure hospitalization and a 7% reduction in all-cause mortality.

"By comparison, ours was close to a 20% increase in peak VO₂ at 1 year with ablation therapy," Dr. Jones observed.

The ARC-HF trial included 51 patients with continuous persistent atrial fibrillation (AF) for an average of 24 months, symptomatic systolic heart failure, and a left ventricular ejection fraction of 35% or less. Because it has been unclear whether restoration of sinus rhythm or pharmacologic rate control is the optimal management strategy in patients with AF and the common comorbidity of heart failure, the investigators randomized participants to catheter ablation of the arrhythmia or to rate control.

The primary endpoint was the change in peak VO₂ at 12 months from a baseline of roughly 17 mL/kg per minute. Peak VO₂ increased by a mean of 2.0 mL/kg per minute in the 25 patients in the ablation group while declining over time in the rate control group, for an impressive 12-month intergroup difference of 3.07 mL/kg per minute.

The ablation group also displayed significant improvements in quality of life as measured by the Minnesota Living With Heart Failure Questionnaire, as well as neurohormonal status as reflected in a reduction in brain natriuretic peptide levels. Data on other cardiac biomarkers are still being analyzed.

A significant reduction in baseline left atrial dilation was documented in the ablation group at 6 months and maintained at 12 months. The ablation group showed a nonsignificant trend toward improved left ventricular ejection fraction.

Dr. Jones stressed that the ablation procedures were long and challenging. They averaged 333 minutes in duration, including mapping, with fully 80 minutes of fluoroscopy time and 82 minutes of actual ablation.

Seven patients experienced recurrent atrial arrhythmias post ablation; five of them underwent a second ablation procedure and one had a third. The single-procedure success rate in achieving sinus rhythm at 12 months was 72%, with a multiprocedure success rate of 92%.

Of the 26 patients in the rate control group, 2 were in sinus rhythm at 12 months (including 1 patient who crossed over to catheter ablation), and 23 of the remaining 24 were optimally rate controlled, with a resting heart rate below 80 beats per minute and a maximum heart rate below 110 bpm during a 6-minute walk test.

Discussant Dr. Karl-Heinz Kuck called the ARC-HF results "remarkable." So much so, in fact, that he doesn’t think catheter ablation can be recommended for now in patients with long-standing persistent AF and heart failure, because the single-center ARC-HF results are out of step with those reported in observational series. Better, he said, to wait for the results of ongoing, much larger multicenter randomized trials, including CASTLE-AF as well as AMICA, for which he serves as principal investigator.

Among Dr. Kuck’s concerns was the whopping 2.0-mL/kg per minute increase in peak VO₂ reported in ARC-HF. To put that in perspective, the major randomized trials of cardiac resynchronization therapy and cardiac contractility modulation therapy for heart failure achieved increases of only 0.7-1.0 mL/kg per minute.

Also, a recent report from Dr. Kuck and his coinvestigators in the Hamburg Sequential Ablation Group, which involved 202 patients who underwent catheter ablation for long-standing persistent AF, showed only 36% were in sinus rhythm at 12 months after a single procedure and 60% after multiple procedures. Those success rates are substantially lower than in ARC-HF, noted Dr. Kuck, head of the cardiology department at St. Georg Hospital, Hamburg, Germany.

The 5-year success rates in the large Hamburg series were 20% and 45% after single and multiple ablation procedures, respectively. Success rates were far better in patients with a history of less than 2 years of persistent AF than in those who were arrhythmic for longer (J. Am. Coll. Cardiol. 2012;60:1921-9).

The ARC-HF study was supported by research grants from the Royal Brompton & Harefield NHS Foundation Trust. Dr. Jones reported having no financial conflicts. Dr. Kuck is on the speakers bureaus for Biosense Webster, Medtronic, St. Jude Medical, Abbott, Cardiofocus, and Biotronik.

b.jancin@elsevier.com

As a further sign of how much mechanical circulatory support for advanced heart failure has matured, the International Society of Heart and Lung Transplantation issued on Jan. 10 the first comprehensive guidelines for all phases of evaluating, implanting, and managing patients who receive left ventricular assist devices or related equipment.

"Traditionally management of patients with mechanical circulatory support [MCS] was very center specific, but because the number of treated patients has increased, and because patients now live with these devices for years, we reached a point where we needed best practices guidelines, an expert consensus on what is the best way to approach this treatment" said Dr. Salpy V. Pamboukian, a cardiologist and one of three cochairs of the guidelines-writing project.

"When MSC started, the role of the devices was as a bridge to heart transplantation, but the field has evolved over the past decade and now MCS for destination therapy has opened a new array of patients who could benefit from these devices," said Dr. Pamboukian, medical director of the MCS device program at the University of Alabama, Birmingham. "We hope these guidelines will serve as a springboard for further research into the long-term management of these patients," she said in an interview.

"As pumps improve and the number of patients with advanced heart failure increases more and more patients will receive a ventricular assist device [VAD], and heart transplant will grow less relevant. These guidelines are much more comprehensive [than anything previously published] and they represent the opinions of the physicians, surgeons, nurses, and other providers who care for these patients," said Dr. David S. Feldman, a cardiologist who is director of the heart failure, VAD, and cardiac transplantation program at the Minneapolis Heart Institute at Abbott Northwestern Hospital, and another cochair of the guidelines committee.

The guidelines, which took about 3 years to produce, came from a committee of 35 health care providers, with initial review by three independent experts followed by additional peer review and then a period of open comment from the society’s membership. The 146-page document consists of more than 250 individual recommendations presented in five sections: patient selection; risk management prior to surgery; intraoperative procedures and immediate postoperative management; in-patient management during the immediate postoperative period; and long-term outpatient management (J. Heart Lung Transplant. 2013;32:157-87).

The writing committee admitted up front in the paper that most of the recommendations are consensus opinions with no clear evidence base. "It’s a limitation," admitted Dr. Pamboukian, "but you need a common approach to patients. Even a busy center may put in 50 or 60 VADs a year. Hopefully, a result of the guidelines is that they will help centers get together and produce the critical mass of patients needed to conduct meaningful trials. It was time to get something on paper; the new guidelines are what we will now work off of." But despite an absence of evidence on which to base many recommendations, "I was pleasantly surprised that there was more consensus than controversy. There was more commonality in our approaches than differences," she added.

The most limited number of recommendations came from the third task force of the panel, which handled intraoperative procedures and immediate postoperative care. Though this section runs 17 pages and deals with topics such as anesthesia, implantation techniques, establishing hemostasis, performing concomitant procedures, methods for explantation, and management of postoperative hemodynamics and bleeding, it contains just three specific recommendations, all dealing with anesthesia. "There are essentially no studies that have looked at how to make things better in the surgical suite," explained Dr. Feldman.

"It’s very challenging to standardize a surgical procedure," added Dr. Pamboukian. "We tried to summarize useful practices, but consensus-based recommendations are difficult to do."

Another topic the guidelines finesse is patient selection. The field is currently trying to sort out the best stage of advanced heart failure for patients to receive mechanical circulatory support. "You’d be amazed at the disparity of who gets these devices now," Dr. Feldman said. In addition, the guideline writing committee decided to defer definitive choices until results are available from a large study starting later this year. The study, Evaluation of VAD Intervention Before Inotropic Therapy (REVIVE-IT), will examine the outcomes of patients with advanced New York Heart Association stage III heart failure who receive a VAD. "It didn’t seem appropriate to address this because of the trial," he added.

Both Dr. Pamboukian and Dr. Feldman agreed that the newly released guidelines will likely be in place for only a couple of years before a revision comes out, testament to the rapid changes in this field. Dr. Feldman cited new VADs from at least two manufacturers expected to enter first-in-man studies this year, and the continued snowballing of VAD implantation rates. The most recent 2012 numbers (through Sept. 30, 2012) from the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) showed nearly 2,000 VADS getting implanted into U.S. patients last year, the highest annual rate ever.

"Because the field is growing, a lot of new centers want to establish programs. We want this treatment to reach as many appropriate patients as possible, but we want it to grow responsibly. These guidelines help establish the best practices, and help ensure that patients get the best care wherever they go," Dr. Pamboukian said.

Dr. Pamboukian said that she had no disclosures. Dr. Feldman said that he has received research support from Terumo.

As a further sign of how much mechanical circulatory support for advanced heart failure has matured, the International Society of Heart and Lung Transplantation issued on Jan. 10 the first comprehensive guidelines for all phases of evaluating, implanting, and managing patients who receive left ventricular assist devices or related equipment.

"Traditionally management of patients with mechanical circulatory support [MCS] was very center specific, but because the number of treated patients has increased, and because patients now live with these devices for years, we reached a point where we needed best practices guidelines, an expert consensus on what is the best way to approach this treatment" said Dr. Salpy V. Pamboukian, a cardiologist and one of three cochairs of the guidelines-writing project.

"When MSC started, the role of the devices was as a bridge to heart transplantation, but the field has evolved over the past decade and now MCS for destination therapy has opened a new array of patients who could benefit from these devices," said Dr. Pamboukian, medical director of the MCS device program at the University of Alabama, Birmingham. "We hope these guidelines will serve as a springboard for further research into the long-term management of these patients," she said in an interview.

"As pumps improve and the number of patients with advanced heart failure increases more and more patients will receive a ventricular assist device [VAD], and heart transplant will grow less relevant. These guidelines are much more comprehensive [than anything previously published] and they represent the opinions of the physicians, surgeons, nurses, and other providers who care for these patients," said Dr. David S. Feldman, a cardiologist who is director of the heart failure, VAD, and cardiac transplantation program at the Minneapolis Heart Institute at Abbott Northwestern Hospital, and another cochair of the guidelines committee.

The guidelines, which took about 3 years to produce, came from a committee of 35 health care providers, with initial review by three independent experts followed by additional peer review and then a period of open comment from the society’s membership. The 146-page document consists of more than 250 individual recommendations presented in five sections: patient selection; risk management prior to surgery; intraoperative procedures and immediate postoperative management; in-patient management during the immediate postoperative period; and long-term outpatient management (J. Heart Lung Transplant. 2013;32:157-87).

The writing committee admitted up front in the paper that most of the recommendations are consensus opinions with no clear evidence base. "It’s a limitation," admitted Dr. Pamboukian, "but you need a common approach to patients. Even a busy center may put in 50 or 60 VADs a year. Hopefully, a result of the guidelines is that they will help centers get together and produce the critical mass of patients needed to conduct meaningful trials. It was time to get something on paper; the new guidelines are what we will now work off of." But despite an absence of evidence on which to base many recommendations, "I was pleasantly surprised that there was more consensus than controversy. There was more commonality in our approaches than differences," she added.

The most limited number of recommendations came from the third task force of the panel, which handled intraoperative procedures and immediate postoperative care. Though this section runs 17 pages and deals with topics such as anesthesia, implantation techniques, establishing hemostasis, performing concomitant procedures, methods for explantation, and management of postoperative hemodynamics and bleeding, it contains just three specific recommendations, all dealing with anesthesia. "There are essentially no studies that have looked at how to make things better in the surgical suite," explained Dr. Feldman.

"It’s very challenging to standardize a surgical procedure," added Dr. Pamboukian. "We tried to summarize useful practices, but consensus-based recommendations are difficult to do."

Another topic the guidelines finesse is patient selection. The field is currently trying to sort out the best stage of advanced heart failure for patients to receive mechanical circulatory support. "You’d be amazed at the disparity of who gets these devices now," Dr. Feldman said. In addition, the guideline writing committee decided to defer definitive choices until results are available from a large study starting later this year. The study, Evaluation of VAD Intervention Before Inotropic Therapy (REVIVE-IT), will examine the outcomes of patients with advanced New York Heart Association stage III heart failure who receive a VAD. "It didn’t seem appropriate to address this because of the trial," he added.

Both Dr. Pamboukian and Dr. Feldman agreed that the newly released guidelines will likely be in place for only a couple of years before a revision comes out, testament to the rapid changes in this field. Dr. Feldman cited new VADs from at least two manufacturers expected to enter first-in-man studies this year, and the continued snowballing of VAD implantation rates. The most recent 2012 numbers (through Sept. 30, 2012) from the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) showed nearly 2,000 VADS getting implanted into U.S. patients last year, the highest annual rate ever.

"Because the field is growing, a lot of new centers want to establish programs. We want this treatment to reach as many appropriate patients as possible, but we want it to grow responsibly. These guidelines help establish the best practices, and help ensure that patients get the best care wherever they go," Dr. Pamboukian said.

Dr. Pamboukian said that she had no disclosures. Dr. Feldman said that he has received research support from Terumo.

As a further sign of how much mechanical circulatory support for advanced heart failure has matured, the International Society of Heart and Lung Transplantation issued on Jan. 10 the first comprehensive guidelines for all phases of evaluating, implanting, and managing patients who receive left ventricular assist devices or related equipment.

"Traditionally management of patients with mechanical circulatory support [MCS] was very center specific, but because the number of treated patients has increased, and because patients now live with these devices for years, we reached a point where we needed best practices guidelines, an expert consensus on what is the best way to approach this treatment" said Dr. Salpy V. Pamboukian, a cardiologist and one of three cochairs of the guidelines-writing project.

"When MSC started, the role of the devices was as a bridge to heart transplantation, but the field has evolved over the past decade and now MCS for destination therapy has opened a new array of patients who could benefit from these devices," said Dr. Pamboukian, medical director of the MCS device program at the University of Alabama, Birmingham. "We hope these guidelines will serve as a springboard for further research into the long-term management of these patients," she said in an interview.

"As pumps improve and the number of patients with advanced heart failure increases more and more patients will receive a ventricular assist device [VAD], and heart transplant will grow less relevant. These guidelines are much more comprehensive [than anything previously published] and they represent the opinions of the physicians, surgeons, nurses, and other providers who care for these patients," said Dr. David S. Feldman, a cardiologist who is director of the heart failure, VAD, and cardiac transplantation program at the Minneapolis Heart Institute at Abbott Northwestern Hospital, and another cochair of the guidelines committee.

The guidelines, which took about 3 years to produce, came from a committee of 35 health care providers, with initial review by three independent experts followed by additional peer review and then a period of open comment from the society’s membership. The 146-page document consists of more than 250 individual recommendations presented in five sections: patient selection; risk management prior to surgery; intraoperative procedures and immediate postoperative management; in-patient management during the immediate postoperative period; and long-term outpatient management (J. Heart Lung Transplant. 2013;32:157-87).

The writing committee admitted up front in the paper that most of the recommendations are consensus opinions with no clear evidence base. "It’s a limitation," admitted Dr. Pamboukian, "but you need a common approach to patients. Even a busy center may put in 50 or 60 VADs a year. Hopefully, a result of the guidelines is that they will help centers get together and produce the critical mass of patients needed to conduct meaningful trials. It was time to get something on paper; the new guidelines are what we will now work off of." But despite an absence of evidence on which to base many recommendations, "I was pleasantly surprised that there was more consensus than controversy. There was more commonality in our approaches than differences," she added.

The most limited number of recommendations came from the third task force of the panel, which handled intraoperative procedures and immediate postoperative care. Though this section runs 17 pages and deals with topics such as anesthesia, implantation techniques, establishing hemostasis, performing concomitant procedures, methods for explantation, and management of postoperative hemodynamics and bleeding, it contains just three specific recommendations, all dealing with anesthesia. "There are essentially no studies that have looked at how to make things better in the surgical suite," explained Dr. Feldman.

"It’s very challenging to standardize a surgical procedure," added Dr. Pamboukian. "We tried to summarize useful practices, but consensus-based recommendations are difficult to do."

Another topic the guidelines finesse is patient selection. The field is currently trying to sort out the best stage of advanced heart failure for patients to receive mechanical circulatory support. "You’d be amazed at the disparity of who gets these devices now," Dr. Feldman said. In addition, the guideline writing committee decided to defer definitive choices until results are available from a large study starting later this year. The study, Evaluation of VAD Intervention Before Inotropic Therapy (REVIVE-IT), will examine the outcomes of patients with advanced New York Heart Association stage III heart failure who receive a VAD. "It didn’t seem appropriate to address this because of the trial," he added.

Both Dr. Pamboukian and Dr. Feldman agreed that the newly released guidelines will likely be in place for only a couple of years before a revision comes out, testament to the rapid changes in this field. Dr. Feldman cited new VADs from at least two manufacturers expected to enter first-in-man studies this year, and the continued snowballing of VAD implantation rates. The most recent 2012 numbers (through Sept. 30, 2012) from the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) showed nearly 2,000 VADS getting implanted into U.S. patients last year, the highest annual rate ever.

"Because the field is growing, a lot of new centers want to establish programs. We want this treatment to reach as many appropriate patients as possible, but we want it to grow responsibly. These guidelines help establish the best practices, and help ensure that patients get the best care wherever they go," Dr. Pamboukian said.

Dr. Pamboukian said that she had no disclosures. Dr. Feldman said that he has received research support from Terumo.

LOS ANGELES – Oral vitamin D₃ may have a future as adjunctive therapy in patients with heart failure, according to Dr. Rebecca S. Boxer.

Six months of oral vitamin D₃ therapy at 50,000 IU/wk resulted in a 37% decrease in serum aldosterone level in a randomized, double-blind, placebo-controlled trial conducted in vitamin D–deficient patients with heart failure.

Moreover, parathyroid hormone levels, which were elevated at baseline, fell by 41% in the active treatment arm, she reported at the annual scientific sessions of the American Heart Association.

The study involved 64 patients with New York Heart Association class II-IV heart failure, all having a baseline serum vitamin D level below 20 ng/mL. All participants were on maximum tolerated doses of standard heart failure medications. The patients were randomized to oral vitamin D₃ at 50,000 IU/wk plus 400 mg of calcium citrate twice daily for 6 months or to calcium plus placebo.

Mean serum vitamin D levels climbed from 19 ng/mL to 60 ng/mL in treated patients while remaining unchanged over time in controls.

Serum aldosterone levels fell from 10.0 ng/mL to 6.3 ng/dL in the active treatment group and remained static in controls. The mean serum parathyroid hormone level dropped from 62.3 pg/mL to 37.1 pg/mL with vitamin D therapy but stayed steady in controls, said Dr. Boxer of Case Western Reserve University, Cleveland.

The primary endpoint in this randomized trial was change in aerobic capacity; vitamin D supplementation had no effect on this endpoint. Nor did it have any significant impact on heart failure symptoms, echocardiographic findings, body weight, blood pressure, serum renin, or C-reactive protein levels in this relatively small study.

Nonetheless, the finding of a moderate reduction in serum aldosterone level indicates that the effects of vitamin D₃ on the renin-angiotensin-aldosterone system (RAAS) in patients with heart failure warrants further study, including assessment of possible long-term clinical benefit.

Dr. Boxer pointed out that serum aldosterone level in patients with heart failure predicts mortality. And aldosterone blockade with an aldosterone antagonist has been shown to improve clinical outcomes in heart failure patients with a depressed left ventricular ejection fraction in RALES, the Randomized Aldactone Evaluation Study (N. Engl. J. Med. 1999;341:709-17) and EPHESUS, the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (N. Engl. J. Med. 2003;348:1309-21). Aldosterone blockade is also actively under study in heart failure patients with preserved systolic function in the ongoing TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) study, due to report results next year.

"There may be certain patient groups that could greatly benefit from vitamin D₃ therapy, particularly patients who may not be able to tolerate RAAS blockade or those who have aldosterone escape," she said.

The mechanism by which oral vitamin D₃ reduces serum aldosterone is unknown. The mechanism is clearly non–renin-dependent, given that serum renin level remained unchanged. In vitro studies suggest that vitamin D might act through a direct effect on steroidogenesis in adrenal cortical cells, Dr. Boxer said.

The study was funded by the American Heart Association. Dr. Boxer reported having no relevant financial conflicts.

b.jancin@elsevier.com

LOS ANGELES – Oral vitamin D₃ may have a future as adjunctive therapy in patients with heart failure, according to Dr. Rebecca S. Boxer.

Six months of oral vitamin D₃ therapy at 50,000 IU/wk resulted in a 37% decrease in serum aldosterone level in a randomized, double-blind, placebo-controlled trial conducted in vitamin D–deficient patients with heart failure.

Moreover, parathyroid hormone levels, which were elevated at baseline, fell by 41% in the active treatment arm, she reported at the annual scientific sessions of the American Heart Association.

The study involved 64 patients with New York Heart Association class II-IV heart failure, all having a baseline serum vitamin D level below 20 ng/mL. All participants were on maximum tolerated doses of standard heart failure medications. The patients were randomized to oral vitamin D₃ at 50,000 IU/wk plus 400 mg of calcium citrate twice daily for 6 months or to calcium plus placebo.

Mean serum vitamin D levels climbed from 19 ng/mL to 60 ng/mL in treated patients while remaining unchanged over time in controls.

Serum aldosterone levels fell from 10.0 ng/mL to 6.3 ng/dL in the active treatment group and remained static in controls. The mean serum parathyroid hormone level dropped from 62.3 pg/mL to 37.1 pg/mL with vitamin D therapy but stayed steady in controls, said Dr. Boxer of Case Western Reserve University, Cleveland.

The primary endpoint in this randomized trial was change in aerobic capacity; vitamin D supplementation had no effect on this endpoint. Nor did it have any significant impact on heart failure symptoms, echocardiographic findings, body weight, blood pressure, serum renin, or C-reactive protein levels in this relatively small study.

Nonetheless, the finding of a moderate reduction in serum aldosterone level indicates that the effects of vitamin D₃ on the renin-angiotensin-aldosterone system (RAAS) in patients with heart failure warrants further study, including assessment of possible long-term clinical benefit.

Dr. Boxer pointed out that serum aldosterone level in patients with heart failure predicts mortality. And aldosterone blockade with an aldosterone antagonist has been shown to improve clinical outcomes in heart failure patients with a depressed left ventricular ejection fraction in RALES, the Randomized Aldactone Evaluation Study (N. Engl. J. Med. 1999;341:709-17) and EPHESUS, the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (N. Engl. J. Med. 2003;348:1309-21). Aldosterone blockade is also actively under study in heart failure patients with preserved systolic function in the ongoing TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) study, due to report results next year.

"There may be certain patient groups that could greatly benefit from vitamin D₃ therapy, particularly patients who may not be able to tolerate RAAS blockade or those who have aldosterone escape," she said.

The mechanism by which oral vitamin D₃ reduces serum aldosterone is unknown. The mechanism is clearly non–renin-dependent, given that serum renin level remained unchanged. In vitro studies suggest that vitamin D might act through a direct effect on steroidogenesis in adrenal cortical cells, Dr. Boxer said.

The study was funded by the American Heart Association. Dr. Boxer reported having no relevant financial conflicts.

b.jancin@elsevier.com

LOS ANGELES – Oral vitamin D₃ may have a future as adjunctive therapy in patients with heart failure, according to Dr. Rebecca S. Boxer.

Six months of oral vitamin D₃ therapy at 50,000 IU/wk resulted in a 37% decrease in serum aldosterone level in a randomized, double-blind, placebo-controlled trial conducted in vitamin D–deficient patients with heart failure.

Moreover, parathyroid hormone levels, which were elevated at baseline, fell by 41% in the active treatment arm, she reported at the annual scientific sessions of the American Heart Association.

The study involved 64 patients with New York Heart Association class II-IV heart failure, all having a baseline serum vitamin D level below 20 ng/mL. All participants were on maximum tolerated doses of standard heart failure medications. The patients were randomized to oral vitamin D₃ at 50,000 IU/wk plus 400 mg of calcium citrate twice daily for 6 months or to calcium plus placebo.

Mean serum vitamin D levels climbed from 19 ng/mL to 60 ng/mL in treated patients while remaining unchanged over time in controls.

Serum aldosterone levels fell from 10.0 ng/mL to 6.3 ng/dL in the active treatment group and remained static in controls. The mean serum parathyroid hormone level dropped from 62.3 pg/mL to 37.1 pg/mL with vitamin D therapy but stayed steady in controls, said Dr. Boxer of Case Western Reserve University, Cleveland.

The primary endpoint in this randomized trial was change in aerobic capacity; vitamin D supplementation had no effect on this endpoint. Nor did it have any significant impact on heart failure symptoms, echocardiographic findings, body weight, blood pressure, serum renin, or C-reactive protein levels in this relatively small study.

Nonetheless, the finding of a moderate reduction in serum aldosterone level indicates that the effects of vitamin D₃ on the renin-angiotensin-aldosterone system (RAAS) in patients with heart failure warrants further study, including assessment of possible long-term clinical benefit.

Dr. Boxer pointed out that serum aldosterone level in patients with heart failure predicts mortality. And aldosterone blockade with an aldosterone antagonist has been shown to improve clinical outcomes in heart failure patients with a depressed left ventricular ejection fraction in RALES, the Randomized Aldactone Evaluation Study (N. Engl. J. Med. 1999;341:709-17) and EPHESUS, the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (N. Engl. J. Med. 2003;348:1309-21). Aldosterone blockade is also actively under study in heart failure patients with preserved systolic function in the ongoing TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) study, due to report results next year.

"There may be certain patient groups that could greatly benefit from vitamin D₃ therapy, particularly patients who may not be able to tolerate RAAS blockade or those who have aldosterone escape," she said.

The mechanism by which oral vitamin D₃ reduces serum aldosterone is unknown. The mechanism is clearly non–renin-dependent, given that serum renin level remained unchanged. In vitro studies suggest that vitamin D might act through a direct effect on steroidogenesis in adrenal cortical cells, Dr. Boxer said.

The study was funded by the American Heart Association. Dr. Boxer reported having no relevant financial conflicts.

b.jancin@elsevier.com

SAN DIEGO – Levels of calcium, phosphorus, and parathyroid hormone are poorer in patients with heart failure at each stage of chronic kidney disease, results from a large study showed.

The finding "raises more questions than it answers," Dr. Claudine T. Jurkovitz said in an interview during a poster session at Kidney Week 2012. "The question is, are these patients less well managed for their metabolic bone disease than the patients without HF? If so, why? Is it because their HF is so severe, or is it because the nephrologists count on cardiologists or primary care physicians to treat the patients’ metabolic bone disease also? And do cardiologists identify metabolic bone disease in patients with HF?"

Doug Brunk/IMNG Medical Media

Dr. Jurkovitz, a physician scientist with Christiana Care Health System in Newark, Del., and her associates compared the management of CKD-associated metabolic bone disease between patients with and without HF who were treated at a local nephrology practice between 2000 and 2010. They evaluated the medical records of 11,883 patients with CKD stage 3 and above, and excluded dialysis and transplant patients. The researchers calculated average calcium, phosphorus, and intact parathyroid hormone (iPTH) by radioimmunoassay for each patient, and used multilinear regressions to determine the effects of CKD and HF on calcium, phosphorus, and iPTH after controlling for age, race, and gender.

The mean follow-up of the 11,883 patients was 4 years. Of these, nearly one-quarter (24%) had HF at baseline, while 76% had stage 3 CKD, 22% had stage 4 CKD, and 2% had stage 5 CKD. Patients with HF were slightly older, with a mean of 69 years, than were their counterparts without HF, who had a mean 66 years.

Dr. Jurkovitz and her associates found that the adjusted mean for calcium was significantly lower in patients with HF at each CKD stage. The interaction between CKD and HF was statistically significant. The adjusted means for phosphorus and iPTH were significantly higher in patients with HF at each CKD stage, while the interactions between CKD and HF were not significant.

"Physicians need to be concerned about the management of chronic kidney disease in their patients with HF, and the management of metabolic bone disease addressed on a case by case basis in a dialogue between the cardiologists, nephrologists, and primary care physicians," she concluded.

The meeting was sponsored by the American Society of Nephrology. Dr. Jurkovitz said that she had no relevant financial conflicts to disclose.

SAN DIEGO – Levels of calcium, phosphorus, and parathyroid hormone are poorer in patients with heart failure at each stage of chronic kidney disease, results from a large study showed.

The finding "raises more questions than it answers," Dr. Claudine T. Jurkovitz said in an interview during a poster session at Kidney Week 2012. "The question is, are these patients less well managed for their metabolic bone disease than the patients without HF? If so, why? Is it because their HF is so severe, or is it because the nephrologists count on cardiologists or primary care physicians to treat the patients’ metabolic bone disease also? And do cardiologists identify metabolic bone disease in patients with HF?"

Doug Brunk/IMNG Medical Media

Dr. Jurkovitz, a physician scientist with Christiana Care Health System in Newark, Del., and her associates compared the management of CKD-associated metabolic bone disease between patients with and without HF who were treated at a local nephrology practice between 2000 and 2010. They evaluated the medical records of 11,883 patients with CKD stage 3 and above, and excluded dialysis and transplant patients. The researchers calculated average calcium, phosphorus, and intact parathyroid hormone (iPTH) by radioimmunoassay for each patient, and used multilinear regressions to determine the effects of CKD and HF on calcium, phosphorus, and iPTH after controlling for age, race, and gender.

The mean follow-up of the 11,883 patients was 4 years. Of these, nearly one-quarter (24%) had HF at baseline, while 76% had stage 3 CKD, 22% had stage 4 CKD, and 2% had stage 5 CKD. Patients with HF were slightly older, with a mean of 69 years, than were their counterparts without HF, who had a mean 66 years.

Dr. Jurkovitz and her associates found that the adjusted mean for calcium was significantly lower in patients with HF at each CKD stage. The interaction between CKD and HF was statistically significant. The adjusted means for phosphorus and iPTH were significantly higher in patients with HF at each CKD stage, while the interactions between CKD and HF were not significant.

"Physicians need to be concerned about the management of chronic kidney disease in their patients with HF, and the management of metabolic bone disease addressed on a case by case basis in a dialogue between the cardiologists, nephrologists, and primary care physicians," she concluded.

The meeting was sponsored by the American Society of Nephrology. Dr. Jurkovitz said that she had no relevant financial conflicts to disclose.

SAN DIEGO – Levels of calcium, phosphorus, and parathyroid hormone are poorer in patients with heart failure at each stage of chronic kidney disease, results from a large study showed.

The finding "raises more questions than it answers," Dr. Claudine T. Jurkovitz said in an interview during a poster session at Kidney Week 2012. "The question is, are these patients less well managed for their metabolic bone disease than the patients without HF? If so, why? Is it because their HF is so severe, or is it because the nephrologists count on cardiologists or primary care physicians to treat the patients’ metabolic bone disease also? And do cardiologists identify metabolic bone disease in patients with HF?"

Doug Brunk/IMNG Medical Media

Dr. Jurkovitz, a physician scientist with Christiana Care Health System in Newark, Del., and her associates compared the management of CKD-associated metabolic bone disease between patients with and without HF who were treated at a local nephrology practice between 2000 and 2010. They evaluated the medical records of 11,883 patients with CKD stage 3 and above, and excluded dialysis and transplant patients. The researchers calculated average calcium, phosphorus, and intact parathyroid hormone (iPTH) by radioimmunoassay for each patient, and used multilinear regressions to determine the effects of CKD and HF on calcium, phosphorus, and iPTH after controlling for age, race, and gender.

The mean follow-up of the 11,883 patients was 4 years. Of these, nearly one-quarter (24%) had HF at baseline, while 76% had stage 3 CKD, 22% had stage 4 CKD, and 2% had stage 5 CKD. Patients with HF were slightly older, with a mean of 69 years, than were their counterparts without HF, who had a mean 66 years.

Dr. Jurkovitz and her associates found that the adjusted mean for calcium was significantly lower in patients with HF at each CKD stage. The interaction between CKD and HF was statistically significant. The adjusted means for phosphorus and iPTH were significantly higher in patients with HF at each CKD stage, while the interactions between CKD and HF were not significant.

"Physicians need to be concerned about the management of chronic kidney disease in their patients with HF, and the management of metabolic bone disease addressed on a case by case basis in a dialogue between the cardiologists, nephrologists, and primary care physicians," she concluded.

The meeting was sponsored by the American Society of Nephrology. Dr. Jurkovitz said that she had no relevant financial conflicts to disclose.

LOS ANGELES – Mechanical venovenous ultrafiltration proved inferior to drug therapy in diuretic-responsive patients hospitalized with acute decompensated heart failure and cardiorenal syndrome in a major multicenter randomized trial.

In the Cardiorenal Rescue Study in Acute Decompensated Heart Failure (CARRESS-HF), weight loss due to elimination of excess fluid was similar at 96 hours in the two treatment arms. However, renal function was significantly worse in the ultrafiltration group at that time point, and it remained so even 60 days from baseline, Dr. Bradley A. Bart reported at the annual scientific sessions of the American Heart Association.

Moreover, the combined rate of the secondary end point comprising death or serious adverse events at 6 months was 72% in the ultrafiltration group, compared with 57% in patients treated with a standardized pharmacologic regimen, for an adjusted 50% increased risk in the ultrafiltration group. Serious adverse events included kidney failure, bleeding complications, and problems due to intravenous catheters.

"Neither group was adequately decongested at the time of hospital discharge. This is a challenging group of patients to treat. The 60-day event rates are very high, and better therapies are needed in the future," said Dr. Bart of the Hennepin County Medical Center, Minneapolis.

Acute cardiorenal syndrome occurs in up to one-third of patients with acute decompensated heart failure. The CARRESS-HF trial randomized 188 affected patients who were diuretic responsive to a stepped pharmacologic care algorithm or to ultrafiltration at a rate of 200 mL/hr using the commercially available Aquadex System 100 device manufactured by CHF Solutions.

Both treatment groups lost about 12 pounds through 96 hours. However, while mean serum creatinine was unchanged from baseline in the drug therapy group, it climbed by 0.25 mg/dL in the ultrafiltration group.

Discussant Dr. Milton Packer agreed with the investigators’ conclusion that the study data offer no support for the use of mechanical ultrafiltration in patients who are responsive to diuretics.

"I still think there’s a role for ultrafiltration in patients who are diuretic unresponsive," added Dr. Packer, professor and chairman of the department of clinical sciences at the University of Texas Southwestern Medical Center, Dallas.

He called CARRESS-HF "a really terrific study and an important one." Ultrafiltration can be programmed to pull fluid off of patients more rapidly than is possible with drug therapy. Had mechanical ultrafiltration performed better than well-managed drug therapy in CARRESS-HF, the message to physicians would have been that they shouldn’t spend much time fiddling with diuretic therapy in such patients, but should instead turn to ultrafiltration much earlier during the hospitalization, even in diuretic-responsive patients.

"What is striking about this study is that the difference in renal function was present not only during the ultrafiltration but afterward. That’s something that, frankly speaking, gives us pause. It may be worthwhile in someone who’s diuretic unresponsive; it’s not worthwhile in someone who is diuretic responsive," according to Dr. Packer.

Simultaneous with Dr. Bart’s presentation of the CARRESS-HF results at the AHA conference, the study findings were published online (N. Engl. J. Med. 2012 [doi:10.1056/NEJMoa1210357]).

In an accompanying editorial, Dr. W.H. Wilson Tang of the Cleveland Clinic called the outcomes in CARRESS-HF "overall dismal," with more than one-third of patients dying or being readmitted for acute decompensated heart failure within 60 days, regardless of their treatment arm. But that’s representative of what happens in everyday clinical practice when acute cardiorenal syndrome occurs (N. Engl. J. Med. 2012 [doi:10.1056/NEJMe1212881]).

It’s unclear why serum creatinine rose further and stayed high in the ultrafiltration-treated patients. Dr. Tang speculated that it might be because the mechanical device drew off fluid so rapidly that kidney perfusion was decreased.

"We may even have to confront the possibility that the pressure to reduce hospital length of stay with a strategy of initial aggressive diuresis in patients with acute decompensated heart failure may actually result in an increased incidence of the acute cardiorenal syndrome and cause unwanted consequences. Perhaps slow and steady may ultimately win the race after all," according to Dr. Tang.

CARRESS-HF was sponsored by the National Heart, Lung, and Blood Institute and carried out by the Heart Failure Clinical Research Network. Dr. Bart, Dr. Packer, and Dr. Tang reported having no relevant financial disclosures.

LOS ANGELES – Mechanical venovenous ultrafiltration proved inferior to drug therapy in diuretic-responsive patients hospitalized with acute decompensated heart failure and cardiorenal syndrome in a major multicenter randomized trial.

In the Cardiorenal Rescue Study in Acute Decompensated Heart Failure (CARRESS-HF), weight loss due to elimination of excess fluid was similar at 96 hours in the two treatment arms. However, renal function was significantly worse in the ultrafiltration group at that time point, and it remained so even 60 days from baseline, Dr. Bradley A. Bart reported at the annual scientific sessions of the American Heart Association.

Moreover, the combined rate of the secondary end point comprising death or serious adverse events at 6 months was 72% in the ultrafiltration group, compared with 57% in patients treated with a standardized pharmacologic regimen, for an adjusted 50% increased risk in the ultrafiltration group. Serious adverse events included kidney failure, bleeding complications, and problems due to intravenous catheters.

"Neither group was adequately decongested at the time of hospital discharge. This is a challenging group of patients to treat. The 60-day event rates are very high, and better therapies are needed in the future," said Dr. Bart of the Hennepin County Medical Center, Minneapolis.

Acute cardiorenal syndrome occurs in up to one-third of patients with acute decompensated heart failure. The CARRESS-HF trial randomized 188 affected patients who were diuretic responsive to a stepped pharmacologic care algorithm or to ultrafiltration at a rate of 200 mL/hr using the commercially available Aquadex System 100 device manufactured by CHF Solutions.

Both treatment groups lost about 12 pounds through 96 hours. However, while mean serum creatinine was unchanged from baseline in the drug therapy group, it climbed by 0.25 mg/dL in the ultrafiltration group.

Discussant Dr. Milton Packer agreed with the investigators’ conclusion that the study data offer no support for the use of mechanical ultrafiltration in patients who are responsive to diuretics.

"I still think there’s a role for ultrafiltration in patients who are diuretic unresponsive," added Dr. Packer, professor and chairman of the department of clinical sciences at the University of Texas Southwestern Medical Center, Dallas.

He called CARRESS-HF "a really terrific study and an important one." Ultrafiltration can be programmed to pull fluid off of patients more rapidly than is possible with drug therapy. Had mechanical ultrafiltration performed better than well-managed drug therapy in CARRESS-HF, the message to physicians would have been that they shouldn’t spend much time fiddling with diuretic therapy in such patients, but should instead turn to ultrafiltration much earlier during the hospitalization, even in diuretic-responsive patients.

"What is striking about this study is that the difference in renal function was present not only during the ultrafiltration but afterward. That’s something that, frankly speaking, gives us pause. It may be worthwhile in someone who’s diuretic unresponsive; it’s not worthwhile in someone who is diuretic responsive," according to Dr. Packer.

Simultaneous with Dr. Bart’s presentation of the CARRESS-HF results at the AHA conference, the study findings were published online (N. Engl. J. Med. 2012 [doi:10.1056/NEJMoa1210357]).

In an accompanying editorial, Dr. W.H. Wilson Tang of the Cleveland Clinic called the outcomes in CARRESS-HF "overall dismal," with more than one-third of patients dying or being readmitted for acute decompensated heart failure within 60 days, regardless of their treatment arm. But that’s representative of what happens in everyday clinical practice when acute cardiorenal syndrome occurs (N. Engl. J. Med. 2012 [doi:10.1056/NEJMe1212881]).

It’s unclear why serum creatinine rose further and stayed high in the ultrafiltration-treated patients. Dr. Tang speculated that it might be because the mechanical device drew off fluid so rapidly that kidney perfusion was decreased.

"We may even have to confront the possibility that the pressure to reduce hospital length of stay with a strategy of initial aggressive diuresis in patients with acute decompensated heart failure may actually result in an increased incidence of the acute cardiorenal syndrome and cause unwanted consequences. Perhaps slow and steady may ultimately win the race after all," according to Dr. Tang.

CARRESS-HF was sponsored by the National Heart, Lung, and Blood Institute and carried out by the Heart Failure Clinical Research Network. Dr. Bart, Dr. Packer, and Dr. Tang reported having no relevant financial disclosures.

LOS ANGELES – Mechanical venovenous ultrafiltration proved inferior to drug therapy in diuretic-responsive patients hospitalized with acute decompensated heart failure and cardiorenal syndrome in a major multicenter randomized trial.

In the Cardiorenal Rescue Study in Acute Decompensated Heart Failure (CARRESS-HF), weight loss due to elimination of excess fluid was similar at 96 hours in the two treatment arms. However, renal function was significantly worse in the ultrafiltration group at that time point, and it remained so even 60 days from baseline, Dr. Bradley A. Bart reported at the annual scientific sessions of the American Heart Association.

Moreover, the combined rate of the secondary end point comprising death or serious adverse events at 6 months was 72% in the ultrafiltration group, compared with 57% in patients treated with a standardized pharmacologic regimen, for an adjusted 50% increased risk in the ultrafiltration group. Serious adverse events included kidney failure, bleeding complications, and problems due to intravenous catheters.

"Neither group was adequately decongested at the time of hospital discharge. This is a challenging group of patients to treat. The 60-day event rates are very high, and better therapies are needed in the future," said Dr. Bart of the Hennepin County Medical Center, Minneapolis.

Acute cardiorenal syndrome occurs in up to one-third of patients with acute decompensated heart failure. The CARRESS-HF trial randomized 188 affected patients who were diuretic responsive to a stepped pharmacologic care algorithm or to ultrafiltration at a rate of 200 mL/hr using the commercially available Aquadex System 100 device manufactured by CHF Solutions.

Both treatment groups lost about 12 pounds through 96 hours. However, while mean serum creatinine was unchanged from baseline in the drug therapy group, it climbed by 0.25 mg/dL in the ultrafiltration group.

Discussant Dr. Milton Packer agreed with the investigators’ conclusion that the study data offer no support for the use of mechanical ultrafiltration in patients who are responsive to diuretics.

"I still think there’s a role for ultrafiltration in patients who are diuretic unresponsive," added Dr. Packer, professor and chairman of the department of clinical sciences at the University of Texas Southwestern Medical Center, Dallas.

He called CARRESS-HF "a really terrific study and an important one." Ultrafiltration can be programmed to pull fluid off of patients more rapidly than is possible with drug therapy. Had mechanical ultrafiltration performed better than well-managed drug therapy in CARRESS-HF, the message to physicians would have been that they shouldn’t spend much time fiddling with diuretic therapy in such patients, but should instead turn to ultrafiltration much earlier during the hospitalization, even in diuretic-responsive patients.

"What is striking about this study is that the difference in renal function was present not only during the ultrafiltration but afterward. That’s something that, frankly speaking, gives us pause. It may be worthwhile in someone who’s diuretic unresponsive; it’s not worthwhile in someone who is diuretic responsive," according to Dr. Packer.

Simultaneous with Dr. Bart’s presentation of the CARRESS-HF results at the AHA conference, the study findings were published online (N. Engl. J. Med. 2012 [doi:10.1056/NEJMoa1210357]).

In an accompanying editorial, Dr. W.H. Wilson Tang of the Cleveland Clinic called the outcomes in CARRESS-HF "overall dismal," with more than one-third of patients dying or being readmitted for acute decompensated heart failure within 60 days, regardless of their treatment arm. But that’s representative of what happens in everyday clinical practice when acute cardiorenal syndrome occurs (N. Engl. J. Med. 2012 [doi:10.1056/NEJMe1212881]).

It’s unclear why serum creatinine rose further and stayed high in the ultrafiltration-treated patients. Dr. Tang speculated that it might be because the mechanical device drew off fluid so rapidly that kidney perfusion was decreased.

"We may even have to confront the possibility that the pressure to reduce hospital length of stay with a strategy of initial aggressive diuresis in patients with acute decompensated heart failure may actually result in an increased incidence of the acute cardiorenal syndrome and cause unwanted consequences. Perhaps slow and steady may ultimately win the race after all," according to Dr. Tang.

CARRESS-HF was sponsored by the National Heart, Lung, and Blood Institute and carried out by the Heart Failure Clinical Research Network. Dr. Bart, Dr. Packer, and Dr. Tang reported having no relevant financial disclosures.