Heart Failure

WASHINGTON – Marital status plays an underappreciated role in heart failure prognosis.

Indeed, having a life partner was independently associated with a 12% reduction in the risk of all-cause mortality or hospitalization during a median follow-up of 2.5 years in the randomized HF-ACTION trial, Dr. Robert J. Mentz reported at the annual meeting of the American College of Cardiology.

HF-ACTION (Heart Failure: A Controlled Trial Investigating Outcomes in Exercise Training) was an 82-center, randomized trial examining the effects of exercise training in 2,331 heart failure patients with a left ventricular ejection fraction of 35% or less. The primary outcome has been reported previously (JAMA 2009;301:1439-50). In this new secondary analysis, Dr. Mentz and coinvestigators scrutinized the independent impacts of marital status, education level, and economic status on outcomes.

Of HF-ACTION participants, 61% had a current life partner at baseline, 60% had more than a high school education, and 59% had an annual income of at least $25,000. In a multivariate analysis controlling for demographics, comorbid conditions, heart failure etiology, and other potential confounders, life partner status was independently associated with a 12% lower composite event rate for all-cause mortality/hospitalization; education level and income didn’t have significant prognostic value, according to Dr. Mentz, a cardiologist at Duke University, Durham, N.C.

As this was a secondary analysis, the findings should be considered hypothesis generating. "Future prospective studies of social support interventions may be warranted to improve outcomes in this patient population," he observed.

Modern management of heart failure is complex, and fatigue is a prominent symptom. Possible mechanisms that might explain the observed benefit of life partnership in terms of patient outcomes include having someone at home to make sure the patient is taking medications appropriately. The spouse or life partner can also function as a second set of ears during clinic visits.

"When you’re in the physician’s office and information and instructions are coming at you like water out of a fire hose, your partner is there to write things down and help you remember points," Dr. Mentz noted.

The HF-ACTION trial was sponsored by the National Heart, Lung, and Blood Institute. Dr. Mentz reported having no relevant financial interests.

bjancin@frontlinemedcom.com

WASHINGTON – Marital status plays an underappreciated role in heart failure prognosis.

Indeed, having a life partner was independently associated with a 12% reduction in the risk of all-cause mortality or hospitalization during a median follow-up of 2.5 years in the randomized HF-ACTION trial, Dr. Robert J. Mentz reported at the annual meeting of the American College of Cardiology.

HF-ACTION (Heart Failure: A Controlled Trial Investigating Outcomes in Exercise Training) was an 82-center, randomized trial examining the effects of exercise training in 2,331 heart failure patients with a left ventricular ejection fraction of 35% or less. The primary outcome has been reported previously (JAMA 2009;301:1439-50). In this new secondary analysis, Dr. Mentz and coinvestigators scrutinized the independent impacts of marital status, education level, and economic status on outcomes.

Of HF-ACTION participants, 61% had a current life partner at baseline, 60% had more than a high school education, and 59% had an annual income of at least $25,000. In a multivariate analysis controlling for demographics, comorbid conditions, heart failure etiology, and other potential confounders, life partner status was independently associated with a 12% lower composite event rate for all-cause mortality/hospitalization; education level and income didn’t have significant prognostic value, according to Dr. Mentz, a cardiologist at Duke University, Durham, N.C.

As this was a secondary analysis, the findings should be considered hypothesis generating. "Future prospective studies of social support interventions may be warranted to improve outcomes in this patient population," he observed.

Modern management of heart failure is complex, and fatigue is a prominent symptom. Possible mechanisms that might explain the observed benefit of life partnership in terms of patient outcomes include having someone at home to make sure the patient is taking medications appropriately. The spouse or life partner can also function as a second set of ears during clinic visits.

"When you’re in the physician’s office and information and instructions are coming at you like water out of a fire hose, your partner is there to write things down and help you remember points," Dr. Mentz noted.

The HF-ACTION trial was sponsored by the National Heart, Lung, and Blood Institute. Dr. Mentz reported having no relevant financial interests.

bjancin@frontlinemedcom.com

WASHINGTON – Marital status plays an underappreciated role in heart failure prognosis.

Indeed, having a life partner was independently associated with a 12% reduction in the risk of all-cause mortality or hospitalization during a median follow-up of 2.5 years in the randomized HF-ACTION trial, Dr. Robert J. Mentz reported at the annual meeting of the American College of Cardiology.

HF-ACTION (Heart Failure: A Controlled Trial Investigating Outcomes in Exercise Training) was an 82-center, randomized trial examining the effects of exercise training in 2,331 heart failure patients with a left ventricular ejection fraction of 35% or less. The primary outcome has been reported previously (JAMA 2009;301:1439-50). In this new secondary analysis, Dr. Mentz and coinvestigators scrutinized the independent impacts of marital status, education level, and economic status on outcomes.

Of HF-ACTION participants, 61% had a current life partner at baseline, 60% had more than a high school education, and 59% had an annual income of at least $25,000. In a multivariate analysis controlling for demographics, comorbid conditions, heart failure etiology, and other potential confounders, life partner status was independently associated with a 12% lower composite event rate for all-cause mortality/hospitalization; education level and income didn’t have significant prognostic value, according to Dr. Mentz, a cardiologist at Duke University, Durham, N.C.

As this was a secondary analysis, the findings should be considered hypothesis generating. "Future prospective studies of social support interventions may be warranted to improve outcomes in this patient population," he observed.

Modern management of heart failure is complex, and fatigue is a prominent symptom. Possible mechanisms that might explain the observed benefit of life partnership in terms of patient outcomes include having someone at home to make sure the patient is taking medications appropriately. The spouse or life partner can also function as a second set of ears during clinic visits.

"When you’re in the physician’s office and information and instructions are coming at you like water out of a fire hose, your partner is there to write things down and help you remember points," Dr. Mentz noted.

The HF-ACTION trial was sponsored by the National Heart, Lung, and Blood Institute. Dr. Mentz reported having no relevant financial interests.

bjancin@frontlinemedcom.com

A low-intensity intervention aimed at managing cardiac patients who have concomitant depression or anxiety improved mental-health–related quality of life when compared with usual care, according to a report published online April 14 in JAMA Internal Medicine.

The MOSAIC (Management of Sadness and Anxiety in Cardiology) clinical trial involved 183 patients hospitalized at a single urban academic medical center for acute coronary syndrome, heart failure, or arrhythmia during a 2-year period and who were found to have coexisting depression, generalized anxiety disorder, and/or panic disorder. The mean age of the participants was 60.5 years, 90% were white, 61% were employed, 53% were women (JAMA Intern. Med. 2014 April 14 [doi:10.1001/jamainternmend.2014.739]).

© Jupiterimages/Thinkstockphotos.com

They were randomly assigned to receive either usual care or a telephone-based intervention in which a part-time social work care manager coordinated care among psychiatrists, inpatient medical providers, and outpatient medical providers; provided cognitive-behavioral therapy specific to the patient’s condition; and monitored patient symptoms for the 6-month duration of the intervention, said Dr. Jeff C. Huffman, director of cardiac psychiatry research program at Massachusetts General Hospital, and who is in the department of psychiatry at Harvard Medical School, Boston, and his associates.

Patients in the intervention group showed a significantly greater improvement than did those who received usual care in the primary outcome measure: mental-health-related quality of life (QOL), as measured by the Medical Outcomes Study Short Form-12 Mental Component Score. They also were remarkably more likely to receive treatment deemed "adequate" for their psychiatric disorders (75% vs 7%), and to show significantly greater improvement in Patient Health Questionnaire-9 scores; in overall function, as measured on the Duke Activity Status Index; and in health care–related QOL, as measured by EuroQol 5-Domain Instrument scores.

No significant differences were found between the two study groups in cardiac readmission rates at 6 months, but the mean time to readmission was significantly longer for the intervention group (92.4 days) than for the usual care group (62.5 days), Dr. Huffman and his associates said.

The investigators noted that their study involved typical patients seen for cardiac care – including many with serious medical issues and some who declined psychiatric treatment – and so should reflect results that would be found in real-world settings. In addition, using a social worker instead of a nurse as care manager and using telephone rather than in-person contacts substantially saved on costs.

However, Dr. Huffman and his colleagues cited several limitations. For example, the study was conducted in an academic medical center with mostly white patients. Also, those who delivered the intervention had experience with that population and with collaborative care programs.

Still, they expressed optimism about the intervention’s potential. "This intervention seems to have substantial promise as an adjunct or alternative to standard [collaborative care] paradigms," they wrote. "We found that a single care manager was able to coordinate care of three psychiatric conditions in patients with a wide range of cardiac diagnoses living within and outside the metropolitan area of the hospital."

This work was supported in part by the American Heart Association. No relevant financial conflicts of interest were reported.

A low-intensity intervention aimed at managing cardiac patients who have concomitant depression or anxiety improved mental-health–related quality of life when compared with usual care, according to a report published online April 14 in JAMA Internal Medicine.

The MOSAIC (Management of Sadness and Anxiety in Cardiology) clinical trial involved 183 patients hospitalized at a single urban academic medical center for acute coronary syndrome, heart failure, or arrhythmia during a 2-year period and who were found to have coexisting depression, generalized anxiety disorder, and/or panic disorder. The mean age of the participants was 60.5 years, 90% were white, 61% were employed, 53% were women (JAMA Intern. Med. 2014 April 14 [doi:10.1001/jamainternmend.2014.739]).

© Jupiterimages/Thinkstockphotos.com

They were randomly assigned to receive either usual care or a telephone-based intervention in which a part-time social work care manager coordinated care among psychiatrists, inpatient medical providers, and outpatient medical providers; provided cognitive-behavioral therapy specific to the patient’s condition; and monitored patient symptoms for the 6-month duration of the intervention, said Dr. Jeff C. Huffman, director of cardiac psychiatry research program at Massachusetts General Hospital, and who is in the department of psychiatry at Harvard Medical School, Boston, and his associates.

Patients in the intervention group showed a significantly greater improvement than did those who received usual care in the primary outcome measure: mental-health-related quality of life (QOL), as measured by the Medical Outcomes Study Short Form-12 Mental Component Score. They also were remarkably more likely to receive treatment deemed "adequate" for their psychiatric disorders (75% vs 7%), and to show significantly greater improvement in Patient Health Questionnaire-9 scores; in overall function, as measured on the Duke Activity Status Index; and in health care–related QOL, as measured by EuroQol 5-Domain Instrument scores.

No significant differences were found between the two study groups in cardiac readmission rates at 6 months, but the mean time to readmission was significantly longer for the intervention group (92.4 days) than for the usual care group (62.5 days), Dr. Huffman and his associates said.

The investigators noted that their study involved typical patients seen for cardiac care – including many with serious medical issues and some who declined psychiatric treatment – and so should reflect results that would be found in real-world settings. In addition, using a social worker instead of a nurse as care manager and using telephone rather than in-person contacts substantially saved on costs.

However, Dr. Huffman and his colleagues cited several limitations. For example, the study was conducted in an academic medical center with mostly white patients. Also, those who delivered the intervention had experience with that population and with collaborative care programs.

Still, they expressed optimism about the intervention’s potential. "This intervention seems to have substantial promise as an adjunct or alternative to standard [collaborative care] paradigms," they wrote. "We found that a single care manager was able to coordinate care of three psychiatric conditions in patients with a wide range of cardiac diagnoses living within and outside the metropolitan area of the hospital."

This work was supported in part by the American Heart Association. No relevant financial conflicts of interest were reported.

A low-intensity intervention aimed at managing cardiac patients who have concomitant depression or anxiety improved mental-health–related quality of life when compared with usual care, according to a report published online April 14 in JAMA Internal Medicine.

The MOSAIC (Management of Sadness and Anxiety in Cardiology) clinical trial involved 183 patients hospitalized at a single urban academic medical center for acute coronary syndrome, heart failure, or arrhythmia during a 2-year period and who were found to have coexisting depression, generalized anxiety disorder, and/or panic disorder. The mean age of the participants was 60.5 years, 90% were white, 61% were employed, 53% were women (JAMA Intern. Med. 2014 April 14 [doi:10.1001/jamainternmend.2014.739]).

© Jupiterimages/Thinkstockphotos.com

They were randomly assigned to receive either usual care or a telephone-based intervention in which a part-time social work care manager coordinated care among psychiatrists, inpatient medical providers, and outpatient medical providers; provided cognitive-behavioral therapy specific to the patient’s condition; and monitored patient symptoms for the 6-month duration of the intervention, said Dr. Jeff C. Huffman, director of cardiac psychiatry research program at Massachusetts General Hospital, and who is in the department of psychiatry at Harvard Medical School, Boston, and his associates.

Patients in the intervention group showed a significantly greater improvement than did those who received usual care in the primary outcome measure: mental-health-related quality of life (QOL), as measured by the Medical Outcomes Study Short Form-12 Mental Component Score. They also were remarkably more likely to receive treatment deemed "adequate" for their psychiatric disorders (75% vs 7%), and to show significantly greater improvement in Patient Health Questionnaire-9 scores; in overall function, as measured on the Duke Activity Status Index; and in health care–related QOL, as measured by EuroQol 5-Domain Instrument scores.

No significant differences were found between the two study groups in cardiac readmission rates at 6 months, but the mean time to readmission was significantly longer for the intervention group (92.4 days) than for the usual care group (62.5 days), Dr. Huffman and his associates said.

The investigators noted that their study involved typical patients seen for cardiac care – including many with serious medical issues and some who declined psychiatric treatment – and so should reflect results that would be found in real-world settings. In addition, using a social worker instead of a nurse as care manager and using telephone rather than in-person contacts substantially saved on costs.

However, Dr. Huffman and his colleagues cited several limitations. For example, the study was conducted in an academic medical center with mostly white patients. Also, those who delivered the intervention had experience with that population and with collaborative care programs.

Still, they expressed optimism about the intervention’s potential. "This intervention seems to have substantial promise as an adjunct or alternative to standard [collaborative care] paradigms," they wrote. "We found that a single care manager was able to coordinate care of three psychiatric conditions in patients with a wide range of cardiac diagnoses living within and outside the metropolitan area of the hospital."

This work was supported in part by the American Heart Association. No relevant financial conflicts of interest were reported.

The approval of cardiac resynchronization pacemakers and defibrillators manufactured by Medtronic has been expanded to include patients with atrioventricular block and less severe heart failure, the Food and Drug Administration announced on April 10.

The approval applies to two cardiac resynchronization pacemakers (CRT-Ps) and eight cardiac resynchronization defibrillators (CRT-Ds), and was based on the results of the BLOCK-HF study, according to the FDA statement.

The use of these devices "can delay the occurrence of heart failure–related urgent care visits for people who meet these new criteria," Christy Foreman, director of the office of device evaluation in the FDA’s Center for Devices and Radiological Health, said in the statement.

Previously, Medtronic CRT devices were approved for patients with moderate to severe heart failure (New York Heart Association class III and IV), and in April 2012, the FDA approved an expanded indication for Medtronic’s CRT-Ds to treat certain mildly symptomatic heart failure patients – before the addition of patients with atrioventricular block. The expanded approval includes patients with AV block and left ventricular systolic dysfunction, and allows patients with NYHA class I, II, and III with AV block and an ejection fraction of 50% or less to receive biventricular pacing with these devices, according to the Medtronic press release announcing the approval.

In the BLOCK-HF trial of 918 patients with an indication for pacing with AV block, NYHA class I, II, or III heart failure, and a left ventricular ejection fraction of 50% or less, patients were randomized to treatment with right ventricular or biventricular pacing. Those who required defibrillation therapy received an implantable cardioverter-defibrillator, and the others received a cardiac resynchronization pacemaker. Over an average of about 3 years, those in the biventricular pacing group showed a highly significant 26% reduction in risk of a composite of all-cause mortality, an urgent care visit for heart failure requiring intravenous therapy, or a 15% or greater increase in the left ventricular end-systolic volume index (the primary endpoint), compared with patients who had right ventricular pacing (N. Engl. J. Med. 2013;368:1585-93).

The 10 devices are the Consulta CRT-P, Consulta CRT-D, Syncra CRT-P, Maximo II CRT-D, Concerto II CRT-D, Viva XT CRT-D, Viva S CRT-D, Protecta CRT-D, Protecta XT CRT-D, and Brava CRT-D.

emechcatie@frontlinemedcom.com

The approval of cardiac resynchronization pacemakers and defibrillators manufactured by Medtronic has been expanded to include patients with atrioventricular block and less severe heart failure, the Food and Drug Administration announced on April 10.

The approval applies to two cardiac resynchronization pacemakers (CRT-Ps) and eight cardiac resynchronization defibrillators (CRT-Ds), and was based on the results of the BLOCK-HF study, according to the FDA statement.

The use of these devices "can delay the occurrence of heart failure–related urgent care visits for people who meet these new criteria," Christy Foreman, director of the office of device evaluation in the FDA’s Center for Devices and Radiological Health, said in the statement.

Previously, Medtronic CRT devices were approved for patients with moderate to severe heart failure (New York Heart Association class III and IV), and in April 2012, the FDA approved an expanded indication for Medtronic’s CRT-Ds to treat certain mildly symptomatic heart failure patients – before the addition of patients with atrioventricular block. The expanded approval includes patients with AV block and left ventricular systolic dysfunction, and allows patients with NYHA class I, II, and III with AV block and an ejection fraction of 50% or less to receive biventricular pacing with these devices, according to the Medtronic press release announcing the approval.

In the BLOCK-HF trial of 918 patients with an indication for pacing with AV block, NYHA class I, II, or III heart failure, and a left ventricular ejection fraction of 50% or less, patients were randomized to treatment with right ventricular or biventricular pacing. Those who required defibrillation therapy received an implantable cardioverter-defibrillator, and the others received a cardiac resynchronization pacemaker. Over an average of about 3 years, those in the biventricular pacing group showed a highly significant 26% reduction in risk of a composite of all-cause mortality, an urgent care visit for heart failure requiring intravenous therapy, or a 15% or greater increase in the left ventricular end-systolic volume index (the primary endpoint), compared with patients who had right ventricular pacing (N. Engl. J. Med. 2013;368:1585-93).

The 10 devices are the Consulta CRT-P, Consulta CRT-D, Syncra CRT-P, Maximo II CRT-D, Concerto II CRT-D, Viva XT CRT-D, Viva S CRT-D, Protecta CRT-D, Protecta XT CRT-D, and Brava CRT-D.

emechcatie@frontlinemedcom.com

The approval of cardiac resynchronization pacemakers and defibrillators manufactured by Medtronic has been expanded to include patients with atrioventricular block and less severe heart failure, the Food and Drug Administration announced on April 10.

The approval applies to two cardiac resynchronization pacemakers (CRT-Ps) and eight cardiac resynchronization defibrillators (CRT-Ds), and was based on the results of the BLOCK-HF study, according to the FDA statement.

The use of these devices "can delay the occurrence of heart failure–related urgent care visits for people who meet these new criteria," Christy Foreman, director of the office of device evaluation in the FDA’s Center for Devices and Radiological Health, said in the statement.

Previously, Medtronic CRT devices were approved for patients with moderate to severe heart failure (New York Heart Association class III and IV), and in April 2012, the FDA approved an expanded indication for Medtronic’s CRT-Ds to treat certain mildly symptomatic heart failure patients – before the addition of patients with atrioventricular block. The expanded approval includes patients with AV block and left ventricular systolic dysfunction, and allows patients with NYHA class I, II, and III with AV block and an ejection fraction of 50% or less to receive biventricular pacing with these devices, according to the Medtronic press release announcing the approval.

In the BLOCK-HF trial of 918 patients with an indication for pacing with AV block, NYHA class I, II, or III heart failure, and a left ventricular ejection fraction of 50% or less, patients were randomized to treatment with right ventricular or biventricular pacing. Those who required defibrillation therapy received an implantable cardioverter-defibrillator, and the others received a cardiac resynchronization pacemaker. Over an average of about 3 years, those in the biventricular pacing group showed a highly significant 26% reduction in risk of a composite of all-cause mortality, an urgent care visit for heart failure requiring intravenous therapy, or a 15% or greater increase in the left ventricular end-systolic volume index (the primary endpoint), compared with patients who had right ventricular pacing (N. Engl. J. Med. 2013;368:1585-93).

The 10 devices are the Consulta CRT-P, Consulta CRT-D, Syncra CRT-P, Maximo II CRT-D, Concerto II CRT-D, Viva XT CRT-D, Viva S CRT-D, Protecta CRT-D, Protecta XT CRT-D, and Brava CRT-D.

emechcatie@frontlinemedcom.com

Results of TOPCAT, one of the most talked about heart failure trials in recent years, have been published. There were no obvious surprises: Spironolactone is no more beneficial than placebo for patients who have heart failure with preserved ejection fraction.

Mineralocorticoid-receptor antagonists like spironolactone are known to reduce overall mortality and hospitalizations for HF in patients who have reduced ejection fraction, but their effect on patients with preserved ejection fraction "has not been rigorously tested" until now.

The TOPCAT (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist) study was a phase III, double-blind trial involving 3,445 patients treated at 233 sites in the United States, Canada, Brazil, Argentina, Russia, and Georgia. Patients were randomly assigned to receive either spironolactone (1,722 participants) or placebo (1,723 participants) and followed for a mean of 3.3 years, said Dr. Bertram Pitt of the University of Michigan, Ann Arbor, and his associates in a report published online April 9 in the New England Journal of Medicine.

The primary outcome measure – a composite of death from cardiovascular causes, aborted cardiac arrest, or hospitalization for HF – occurred in 18.6% of patients given spironolactone and 20.4% of those given placebo. This corresponds to incidences of 5.9 events per 100 person-years with active treatment and 6.6 events per 100 person-years with placebo. Both differences were nonsignificant.

There also were no significant differences between the two study groups in time to death from any cause, time to hospitalization for any reason, cause of death, frequency of hospitalization for any reason, and rates of myocardial infarction or stroke, the investigators said (N. Engl. J. Med. 2014 April 9 [doi: 10.1056/NEJMoa1313731]).

In contrast, the 17% reduction in the rate of hospitalization for HFpEF in the spironolactone group relative to controls was significant (P = .04). Moreover, the spironolactone-treated patients had a collective 394 HFpEF hospitalizations, markedly fewer than the 475 in controls. This translated to hospitalization for HFpEF occurring at a rate of 3.8 per 100 person-years in patients randomized to spironolactone, compared with 4.6 per 100 person-years in placebo-treated controls.

The mystifyingly neutral results of this large international trial, presented in November at the annual meeting of the American Heart Association, coincided with a rapidly increasing incidence and awareness of heart failure with preserved ejection fraction, or HFpEF.

Speculation has focused on the differences in treatment response in two areas: geographical location and enrollment criteria.

Geographical differences in event rates have led some to conclude that patients in Eastern Europe just weren’t sick enough to be enrolled. Among patients in the placebo group, the primary endpoint of death or heart failure hospitalization during follow-up occurred at a rate of 12.6 events per 100 patient-years among the 881 patients treated in the four Western Hemisphere countries, and at a rate of 2.3 events per 100 patient-years among the 842 patients treated in Russia or Georgia, a greater than fivefold difference between the two subgroups.

"As a whole, the patients in Russia and Georgia had a lower event rate and were certainly less severely ill than the other patients, but they supposedly still had heart failure," Dr. Scott D. Solomon, professor of medicine at Harvard Medical School and director of noninvasive cardiology at Brigham and Women’s Hospital, Boston, said in an earlier interview. "Defining this disorder is difficult, and when a patient has signs and symptoms of heart failure and preserved ejection fraction, you may not be certain that heart failure is causing the symptoms. That’s why many people think that we should use another criterion" to define HFpEF in trials, such as elevated serum level of some form of natriuretic peptide, said Dr. Solomon, a TOPCAT coinvestigator.

By design, patients could enter TOPCAT either because of a recent heart failure hospitalization, which is how 72% of patients got in, or by having a threshold level of natriuretic peptide, the way the remaining 28% entered the study. Within the subgroup enrolled by natriuretic peptide level, spironolactone treatment had a statistically significant effect in reducing the primary endpoint, while in the other 72% the drug produced no discernable benefit over placebo.

The neutral results of TOPCAT represent more than another failed treatment trial; they underscore the heterogeneity of patients diagnosed with HFpEF.

TOPCAT was supported by the National Heart, Lung, and Blood Institute. Dr. Pitt reported ties to AuraSense Therapeutics, Relypsa, and other companies. His associates reported ties to numerous industry sources. Dr. Solomon has financial ties to Novartis and more than 10 other drug and device companies.

Results of TOPCAT, one of the most talked about heart failure trials in recent years, have been published. There were no obvious surprises: Spironolactone is no more beneficial than placebo for patients who have heart failure with preserved ejection fraction.

Mineralocorticoid-receptor antagonists like spironolactone are known to reduce overall mortality and hospitalizations for HF in patients who have reduced ejection fraction, but their effect on patients with preserved ejection fraction "has not been rigorously tested" until now.

The TOPCAT (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist) study was a phase III, double-blind trial involving 3,445 patients treated at 233 sites in the United States, Canada, Brazil, Argentina, Russia, and Georgia. Patients were randomly assigned to receive either spironolactone (1,722 participants) or placebo (1,723 participants) and followed for a mean of 3.3 years, said Dr. Bertram Pitt of the University of Michigan, Ann Arbor, and his associates in a report published online April 9 in the New England Journal of Medicine.

The primary outcome measure – a composite of death from cardiovascular causes, aborted cardiac arrest, or hospitalization for HF – occurred in 18.6% of patients given spironolactone and 20.4% of those given placebo. This corresponds to incidences of 5.9 events per 100 person-years with active treatment and 6.6 events per 100 person-years with placebo. Both differences were nonsignificant.

There also were no significant differences between the two study groups in time to death from any cause, time to hospitalization for any reason, cause of death, frequency of hospitalization for any reason, and rates of myocardial infarction or stroke, the investigators said (N. Engl. J. Med. 2014 April 9 [doi: 10.1056/NEJMoa1313731]).

In contrast, the 17% reduction in the rate of hospitalization for HFpEF in the spironolactone group relative to controls was significant (P = .04). Moreover, the spironolactone-treated patients had a collective 394 HFpEF hospitalizations, markedly fewer than the 475 in controls. This translated to hospitalization for HFpEF occurring at a rate of 3.8 per 100 person-years in patients randomized to spironolactone, compared with 4.6 per 100 person-years in placebo-treated controls.

The mystifyingly neutral results of this large international trial, presented in November at the annual meeting of the American Heart Association, coincided with a rapidly increasing incidence and awareness of heart failure with preserved ejection fraction, or HFpEF.

Speculation has focused on the differences in treatment response in two areas: geographical location and enrollment criteria.

Geographical differences in event rates have led some to conclude that patients in Eastern Europe just weren’t sick enough to be enrolled. Among patients in the placebo group, the primary endpoint of death or heart failure hospitalization during follow-up occurred at a rate of 12.6 events per 100 patient-years among the 881 patients treated in the four Western Hemisphere countries, and at a rate of 2.3 events per 100 patient-years among the 842 patients treated in Russia or Georgia, a greater than fivefold difference between the two subgroups.

"As a whole, the patients in Russia and Georgia had a lower event rate and were certainly less severely ill than the other patients, but they supposedly still had heart failure," Dr. Scott D. Solomon, professor of medicine at Harvard Medical School and director of noninvasive cardiology at Brigham and Women’s Hospital, Boston, said in an earlier interview. "Defining this disorder is difficult, and when a patient has signs and symptoms of heart failure and preserved ejection fraction, you may not be certain that heart failure is causing the symptoms. That’s why many people think that we should use another criterion" to define HFpEF in trials, such as elevated serum level of some form of natriuretic peptide, said Dr. Solomon, a TOPCAT coinvestigator.

By design, patients could enter TOPCAT either because of a recent heart failure hospitalization, which is how 72% of patients got in, or by having a threshold level of natriuretic peptide, the way the remaining 28% entered the study. Within the subgroup enrolled by natriuretic peptide level, spironolactone treatment had a statistically significant effect in reducing the primary endpoint, while in the other 72% the drug produced no discernable benefit over placebo.

The neutral results of TOPCAT represent more than another failed treatment trial; they underscore the heterogeneity of patients diagnosed with HFpEF.

TOPCAT was supported by the National Heart, Lung, and Blood Institute. Dr. Pitt reported ties to AuraSense Therapeutics, Relypsa, and other companies. His associates reported ties to numerous industry sources. Dr. Solomon has financial ties to Novartis and more than 10 other drug and device companies.

Results of TOPCAT, one of the most talked about heart failure trials in recent years, have been published. There were no obvious surprises: Spironolactone is no more beneficial than placebo for patients who have heart failure with preserved ejection fraction.

Mineralocorticoid-receptor antagonists like spironolactone are known to reduce overall mortality and hospitalizations for HF in patients who have reduced ejection fraction, but their effect on patients with preserved ejection fraction "has not been rigorously tested" until now.

The TOPCAT (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist) study was a phase III, double-blind trial involving 3,445 patients treated at 233 sites in the United States, Canada, Brazil, Argentina, Russia, and Georgia. Patients were randomly assigned to receive either spironolactone (1,722 participants) or placebo (1,723 participants) and followed for a mean of 3.3 years, said Dr. Bertram Pitt of the University of Michigan, Ann Arbor, and his associates in a report published online April 9 in the New England Journal of Medicine.

The primary outcome measure – a composite of death from cardiovascular causes, aborted cardiac arrest, or hospitalization for HF – occurred in 18.6% of patients given spironolactone and 20.4% of those given placebo. This corresponds to incidences of 5.9 events per 100 person-years with active treatment and 6.6 events per 100 person-years with placebo. Both differences were nonsignificant.

There also were no significant differences between the two study groups in time to death from any cause, time to hospitalization for any reason, cause of death, frequency of hospitalization for any reason, and rates of myocardial infarction or stroke, the investigators said (N. Engl. J. Med. 2014 April 9 [doi: 10.1056/NEJMoa1313731]).

In contrast, the 17% reduction in the rate of hospitalization for HFpEF in the spironolactone group relative to controls was significant (P = .04). Moreover, the spironolactone-treated patients had a collective 394 HFpEF hospitalizations, markedly fewer than the 475 in controls. This translated to hospitalization for HFpEF occurring at a rate of 3.8 per 100 person-years in patients randomized to spironolactone, compared with 4.6 per 100 person-years in placebo-treated controls.

The mystifyingly neutral results of this large international trial, presented in November at the annual meeting of the American Heart Association, coincided with a rapidly increasing incidence and awareness of heart failure with preserved ejection fraction, or HFpEF.

Speculation has focused on the differences in treatment response in two areas: geographical location and enrollment criteria.

Geographical differences in event rates have led some to conclude that patients in Eastern Europe just weren’t sick enough to be enrolled. Among patients in the placebo group, the primary endpoint of death or heart failure hospitalization during follow-up occurred at a rate of 12.6 events per 100 patient-years among the 881 patients treated in the four Western Hemisphere countries, and at a rate of 2.3 events per 100 patient-years among the 842 patients treated in Russia or Georgia, a greater than fivefold difference between the two subgroups.

"As a whole, the patients in Russia and Georgia had a lower event rate and were certainly less severely ill than the other patients, but they supposedly still had heart failure," Dr. Scott D. Solomon, professor of medicine at Harvard Medical School and director of noninvasive cardiology at Brigham and Women’s Hospital, Boston, said in an earlier interview. "Defining this disorder is difficult, and when a patient has signs and symptoms of heart failure and preserved ejection fraction, you may not be certain that heart failure is causing the symptoms. That’s why many people think that we should use another criterion" to define HFpEF in trials, such as elevated serum level of some form of natriuretic peptide, said Dr. Solomon, a TOPCAT coinvestigator.

By design, patients could enter TOPCAT either because of a recent heart failure hospitalization, which is how 72% of patients got in, or by having a threshold level of natriuretic peptide, the way the remaining 28% entered the study. Within the subgroup enrolled by natriuretic peptide level, spironolactone treatment had a statistically significant effect in reducing the primary endpoint, while in the other 72% the drug produced no discernable benefit over placebo.

The neutral results of TOPCAT represent more than another failed treatment trial; they underscore the heterogeneity of patients diagnosed with HFpEF.

TOPCAT was supported by the National Heart, Lung, and Blood Institute. Dr. Pitt reported ties to AuraSense Therapeutics, Relypsa, and other companies. His associates reported ties to numerous industry sources. Dr. Solomon has financial ties to Novartis and more than 10 other drug and device companies.

WASHINGTON – Another annual meeting of the American College of Cardiology has drawn to a close, and aside from the seemingly endless rain (and brief snow flurries), a lot of interesting discourse took place.

In the heart failure discipline, we have to a large degree become incrementalists: Although there were no blockbusters, important data on renal denervation were released, and corridor discussions about serelaxin and ivabradine were animated. At a time of ICD-10 rollouts, electronic health record (EHR) struggles, board recertification challenges, accreditation, precertification, compliance mandates, and more, it was a delight to be a cognitive cardiologist again. For a few precious moments, we could own our profession again.

©Hoard11/Thinkstockphotos.com

We saw no hospital administrators; we did not receive any missives about the (lack of) timeliness of closing encounters in EHRs; we engaged in real peer-to-peer interactions with real peers, unlike the shadow variant we deal with during an appeal of an insurance coverage decision.

And then it was over, ironically with the sun shining. It’s now back to work, but perhaps with renewed purpose. Let’s find ways to reestablish facts on the ground: Our patients and the decisions we make about our patients come first. Research and teaching do, too. Hospital administrators? Send them to a very long annual meeting. And hope that they forget to pack umbrellas.

Dr. Hauptman is professor of internal medicine and assistant dean of clinical-translational research at Saint Louis University and director of heart failure at Saint Louis University Hospital.

WASHINGTON – Another annual meeting of the American College of Cardiology has drawn to a close, and aside from the seemingly endless rain (and brief snow flurries), a lot of interesting discourse took place.

In the heart failure discipline, we have to a large degree become incrementalists: Although there were no blockbusters, important data on renal denervation were released, and corridor discussions about serelaxin and ivabradine were animated. At a time of ICD-10 rollouts, electronic health record (EHR) struggles, board recertification challenges, accreditation, precertification, compliance mandates, and more, it was a delight to be a cognitive cardiologist again. For a few precious moments, we could own our profession again.

©Hoard11/Thinkstockphotos.com

We saw no hospital administrators; we did not receive any missives about the (lack of) timeliness of closing encounters in EHRs; we engaged in real peer-to-peer interactions with real peers, unlike the shadow variant we deal with during an appeal of an insurance coverage decision.

And then it was over, ironically with the sun shining. It’s now back to work, but perhaps with renewed purpose. Let’s find ways to reestablish facts on the ground: Our patients and the decisions we make about our patients come first. Research and teaching do, too. Hospital administrators? Send them to a very long annual meeting. And hope that they forget to pack umbrellas.

Dr. Hauptman is professor of internal medicine and assistant dean of clinical-translational research at Saint Louis University and director of heart failure at Saint Louis University Hospital.

WASHINGTON – Another annual meeting of the American College of Cardiology has drawn to a close, and aside from the seemingly endless rain (and brief snow flurries), a lot of interesting discourse took place.

In the heart failure discipline, we have to a large degree become incrementalists: Although there were no blockbusters, important data on renal denervation were released, and corridor discussions about serelaxin and ivabradine were animated. At a time of ICD-10 rollouts, electronic health record (EHR) struggles, board recertification challenges, accreditation, precertification, compliance mandates, and more, it was a delight to be a cognitive cardiologist again. For a few precious moments, we could own our profession again.

©Hoard11/Thinkstockphotos.com

We saw no hospital administrators; we did not receive any missives about the (lack of) timeliness of closing encounters in EHRs; we engaged in real peer-to-peer interactions with real peers, unlike the shadow variant we deal with during an appeal of an insurance coverage decision.

And then it was over, ironically with the sun shining. It’s now back to work, but perhaps with renewed purpose. Let’s find ways to reestablish facts on the ground: Our patients and the decisions we make about our patients come first. Research and teaching do, too. Hospital administrators? Send them to a very long annual meeting. And hope that they forget to pack umbrellas.

Dr. Hauptman is professor of internal medicine and assistant dean of clinical-translational research at Saint Louis University and director of heart failure at Saint Louis University Hospital.

Treatment with metformin failed to show any positive effects on left ventricular function in diabetes-free patients who presented with ST-segment elevation MI, according to the results of a double-blind, placebo-controlled study.

The study in 380 patients undergoing primary percutaneous coronary intervention – 191 of whom were given metformin and 189 of whom were given placebo – found no significant effects of twice-daily metformin (500 mg) on left ventricular ejection fraction (LVEF) after 4 months of treatment, and there was no significant difference in the incidence of major cardiac events between the two groups, Dr. Chris P. H. Lexis said at the annual meeting of the American College of Cardiology.

Specifically, at 4 months, all patients were alive and none were lost to follow-up. LVEF was 53.1% in the metformin group, compared with 54.8% in the placebo group. NT-proBNP concentration was 167 ng/L in the metformin group and 167 ng/L in the placebo group. Major adverse cardiovascular events were observed in six patients (3.1%) in the metformin group and in two patients (1.1%) in the placebo group. Creatinine concentration (79 micromol/L vs. 79 micromol/L) and glycated hemoglobin (5.9% vs. 5.9%) were not significantly different between both groups. No cases of lactic acidosis were observed, according to the investigators.

Up to half of patients who experience an ST-segment elevation MI (STEMI) develop left ventricular dysfunction, which is the strongest predictor of adverse outcomes, such as heart failure.

Findings from previous animal studies had suggested that metformin may have favorable effects on ventricular function, possibly through enhanced phosphorylation of AMP-activated protein kinase causing changes in intracellular pathways and altering mitochondrial function, in turn resulting in improved systolic and diastolic function.

"Data from experimental studies have suggested that administration of metformin before and during ischemia reperfusion might affect these protective pathways and preserve left ventricular function, independent of glycometabolic state," according to Dr. Lexis of the University of Groningen, the Netherlands, and his associates, in a paper simultaneously published online in JAMA (2014 March 31 [doi:10.1001/jama.2014.3315]).

"Moreover, in observational studies of patients with acute myocardial infarction, concurrent treatment with metformin was associated with lower peak values of CK [creatine kinase], myocardial band of CK, and troponins and with improved survival after STEMI in patients with type 2 diabetes, compared with other antihyperglycemic strategies."

Treatment with metformin failed to show any positive effects on left ventricular function in diabetes-free patients who presented with ST-segment elevation MI, according to the results of a double-blind, placebo-controlled study.

The study in 380 patients undergoing primary percutaneous coronary intervention – 191 of whom were given metformin and 189 of whom were given placebo – found no significant effects of twice-daily metformin (500 mg) on left ventricular ejection fraction (LVEF) after 4 months of treatment, and there was no significant difference in the incidence of major cardiac events between the two groups, Dr. Chris P. H. Lexis said at the annual meeting of the American College of Cardiology.

Specifically, at 4 months, all patients were alive and none were lost to follow-up. LVEF was 53.1% in the metformin group, compared with 54.8% in the placebo group. NT-proBNP concentration was 167 ng/L in the metformin group and 167 ng/L in the placebo group. Major adverse cardiovascular events were observed in six patients (3.1%) in the metformin group and in two patients (1.1%) in the placebo group. Creatinine concentration (79 micromol/L vs. 79 micromol/L) and glycated hemoglobin (5.9% vs. 5.9%) were not significantly different between both groups. No cases of lactic acidosis were observed, according to the investigators.

Up to half of patients who experience an ST-segment elevation MI (STEMI) develop left ventricular dysfunction, which is the strongest predictor of adverse outcomes, such as heart failure.

Findings from previous animal studies had suggested that metformin may have favorable effects on ventricular function, possibly through enhanced phosphorylation of AMP-activated protein kinase causing changes in intracellular pathways and altering mitochondrial function, in turn resulting in improved systolic and diastolic function.

"Data from experimental studies have suggested that administration of metformin before and during ischemia reperfusion might affect these protective pathways and preserve left ventricular function, independent of glycometabolic state," according to Dr. Lexis of the University of Groningen, the Netherlands, and his associates, in a paper simultaneously published online in JAMA (2014 March 31 [doi:10.1001/jama.2014.3315]).

"Moreover, in observational studies of patients with acute myocardial infarction, concurrent treatment with metformin was associated with lower peak values of CK [creatine kinase], myocardial band of CK, and troponins and with improved survival after STEMI in patients with type 2 diabetes, compared with other antihyperglycemic strategies."

Treatment with metformin failed to show any positive effects on left ventricular function in diabetes-free patients who presented with ST-segment elevation MI, according to the results of a double-blind, placebo-controlled study.

The study in 380 patients undergoing primary percutaneous coronary intervention – 191 of whom were given metformin and 189 of whom were given placebo – found no significant effects of twice-daily metformin (500 mg) on left ventricular ejection fraction (LVEF) after 4 months of treatment, and there was no significant difference in the incidence of major cardiac events between the two groups, Dr. Chris P. H. Lexis said at the annual meeting of the American College of Cardiology.

Specifically, at 4 months, all patients were alive and none were lost to follow-up. LVEF was 53.1% in the metformin group, compared with 54.8% in the placebo group. NT-proBNP concentration was 167 ng/L in the metformin group and 167 ng/L in the placebo group. Major adverse cardiovascular events were observed in six patients (3.1%) in the metformin group and in two patients (1.1%) in the placebo group. Creatinine concentration (79 micromol/L vs. 79 micromol/L) and glycated hemoglobin (5.9% vs. 5.9%) were not significantly different between both groups. No cases of lactic acidosis were observed, according to the investigators.

Up to half of patients who experience an ST-segment elevation MI (STEMI) develop left ventricular dysfunction, which is the strongest predictor of adverse outcomes, such as heart failure.

Findings from previous animal studies had suggested that metformin may have favorable effects on ventricular function, possibly through enhanced phosphorylation of AMP-activated protein kinase causing changes in intracellular pathways and altering mitochondrial function, in turn resulting in improved systolic and diastolic function.

"Data from experimental studies have suggested that administration of metformin before and during ischemia reperfusion might affect these protective pathways and preserve left ventricular function, independent of glycometabolic state," according to Dr. Lexis of the University of Groningen, the Netherlands, and his associates, in a paper simultaneously published online in JAMA (2014 March 31 [doi:10.1001/jama.2014.3315]).

"Moreover, in observational studies of patients with acute myocardial infarction, concurrent treatment with metformin was associated with lower peak values of CK [creatine kinase], myocardial band of CK, and troponins and with improved survival after STEMI in patients with type 2 diabetes, compared with other antihyperglycemic strategies."

WASHINGTON – Patients with acute heart failure who were discharged on an angiotensin converting enzyme inhibitor or an angiotensin receptor blocker were significantly less likely to be readmitted to the hospital within 30 days of discharge than patients who were not prescribed these drugs, in a retrospective study of Medicare beneficiaries.

Using data from the Alabama Heart Failure Project, the study looked at hospital readmission rates in 1,348 patients with acute decompensated heart failure and an ejection fraction under 45%, discharged from 106 hospitals in the United States. Their mean age was 75 years, they had similar renal function, they were on various baseline cardiac medications, and they had no contraindications for angiotensin converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) treatment. Of these patients, 734 were prescribed one of these drugs before discharge.

Nick Piegari/Frontline Medical News

The heart failure readmission and all-cause mortality rates were significantly higher among those who were not started on an ACE inhibitor or ARB before discharge: The 30-day heart failure readmission rate was 14% among those who did not receive an ACE inhibitor or ARB, compared with 7% of those who did – a 48% reduced risk, said Dr. Kumar Sanam, a heart failure fellow at the University of Alabama, Birmingham, at the annual meeting of the American College of Cardiology.

The all-cause readmission rate within 30 days among patients discharged without an ACE inhibitor or ARB was also significantly higher, at 24%, compared with 18% of those discharged with an ACE or an ARB, a relative risk reduction of 26%. The risk of all-cause mortality was reduced by 44% among those prescribed an ACE inhibitor or ARB, Dr. Sanam said.

Under the Affordable Care Act, hospitals will be penalized for above-average, all-cause 30-day readmission rates, he noted, and these findings highlight how the use of treatment recommended in evidence-based guidelines "could be used to reduce a costly health care problem," in the United States, Dr. Sanam said. An estimated one in four patients hospitalized with heart failure return to the hospital within 30 days, and heart failure is the most common cause of 30-day all-cause readmissions, he noted.

Dr. Sanam had no disclosures.

emechcatie@frontlinemedcom.com

WASHINGTON – Patients with acute heart failure who were discharged on an angiotensin converting enzyme inhibitor or an angiotensin receptor blocker were significantly less likely to be readmitted to the hospital within 30 days of discharge than patients who were not prescribed these drugs, in a retrospective study of Medicare beneficiaries.

Using data from the Alabama Heart Failure Project, the study looked at hospital readmission rates in 1,348 patients with acute decompensated heart failure and an ejection fraction under 45%, discharged from 106 hospitals in the United States. Their mean age was 75 years, they had similar renal function, they were on various baseline cardiac medications, and they had no contraindications for angiotensin converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) treatment. Of these patients, 734 were prescribed one of these drugs before discharge.

Nick Piegari/Frontline Medical News

The heart failure readmission and all-cause mortality rates were significantly higher among those who were not started on an ACE inhibitor or ARB before discharge: The 30-day heart failure readmission rate was 14% among those who did not receive an ACE inhibitor or ARB, compared with 7% of those who did – a 48% reduced risk, said Dr. Kumar Sanam, a heart failure fellow at the University of Alabama, Birmingham, at the annual meeting of the American College of Cardiology.

The all-cause readmission rate within 30 days among patients discharged without an ACE inhibitor or ARB was also significantly higher, at 24%, compared with 18% of those discharged with an ACE or an ARB, a relative risk reduction of 26%. The risk of all-cause mortality was reduced by 44% among those prescribed an ACE inhibitor or ARB, Dr. Sanam said.

Under the Affordable Care Act, hospitals will be penalized for above-average, all-cause 30-day readmission rates, he noted, and these findings highlight how the use of treatment recommended in evidence-based guidelines "could be used to reduce a costly health care problem," in the United States, Dr. Sanam said. An estimated one in four patients hospitalized with heart failure return to the hospital within 30 days, and heart failure is the most common cause of 30-day all-cause readmissions, he noted.

Dr. Sanam had no disclosures.

emechcatie@frontlinemedcom.com

WASHINGTON – Patients with acute heart failure who were discharged on an angiotensin converting enzyme inhibitor or an angiotensin receptor blocker were significantly less likely to be readmitted to the hospital within 30 days of discharge than patients who were not prescribed these drugs, in a retrospective study of Medicare beneficiaries.

Using data from the Alabama Heart Failure Project, the study looked at hospital readmission rates in 1,348 patients with acute decompensated heart failure and an ejection fraction under 45%, discharged from 106 hospitals in the United States. Their mean age was 75 years, they had similar renal function, they were on various baseline cardiac medications, and they had no contraindications for angiotensin converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) treatment. Of these patients, 734 were prescribed one of these drugs before discharge.

Nick Piegari/Frontline Medical News

The heart failure readmission and all-cause mortality rates were significantly higher among those who were not started on an ACE inhibitor or ARB before discharge: The 30-day heart failure readmission rate was 14% among those who did not receive an ACE inhibitor or ARB, compared with 7% of those who did – a 48% reduced risk, said Dr. Kumar Sanam, a heart failure fellow at the University of Alabama, Birmingham, at the annual meeting of the American College of Cardiology.

The all-cause readmission rate within 30 days among patients discharged without an ACE inhibitor or ARB was also significantly higher, at 24%, compared with 18% of those discharged with an ACE or an ARB, a relative risk reduction of 26%. The risk of all-cause mortality was reduced by 44% among those prescribed an ACE inhibitor or ARB, Dr. Sanam said.

Under the Affordable Care Act, hospitals will be penalized for above-average, all-cause 30-day readmission rates, he noted, and these findings highlight how the use of treatment recommended in evidence-based guidelines "could be used to reduce a costly health care problem," in the United States, Dr. Sanam said. An estimated one in four patients hospitalized with heart failure return to the hospital within 30 days, and heart failure is the most common cause of 30-day all-cause readmissions, he noted.

Dr. Sanam had no disclosures.

emechcatie@frontlinemedcom.com

WASHINGTON, D.C. – Heart failure patients discharged on inexpensive, guideline-recommended drugs were half as likely to be readmitted for the condition within* 30 days, compared with those who weren’t given the drugs, according to a study of the Alabama Heart Failure Project that used Medicare data.

Dr. Kumar Sanam, an advanced heart failure fellow at the University of Alabama, Birmingham, presented the study at the annual meeting of the American College of Cardiology, and sat down with us to discuss the take-home implications of the study.

emechcatie@frontlinemedcom.com

*CORRECTION, 4/22/2014: An earlier version of this story misstated the follow-up period.

WASHINGTON, D.C. – Heart failure patients discharged on inexpensive, guideline-recommended drugs were half as likely to be readmitted for the condition within* 30 days, compared with those who weren’t given the drugs, according to a study of the Alabama Heart Failure Project that used Medicare data.

Dr. Kumar Sanam, an advanced heart failure fellow at the University of Alabama, Birmingham, presented the study at the annual meeting of the American College of Cardiology, and sat down with us to discuss the take-home implications of the study.

emechcatie@frontlinemedcom.com

*CORRECTION, 4/22/2014: An earlier version of this story misstated the follow-up period.

WASHINGTON, D.C. – Heart failure patients discharged on inexpensive, guideline-recommended drugs were half as likely to be readmitted for the condition within* 30 days, compared with those who weren’t given the drugs, according to a study of the Alabama Heart Failure Project that used Medicare data.

Dr. Kumar Sanam, an advanced heart failure fellow at the University of Alabama, Birmingham, presented the study at the annual meeting of the American College of Cardiology, and sat down with us to discuss the take-home implications of the study.

emechcatie@frontlinemedcom.com

*CORRECTION, 4/22/2014: An earlier version of this story misstated the follow-up period.

WASHINGTON – A first in transcatheter aortic valve replacement trials, the CoreValve prosthesis was superior to surgical valve replacement in patients with severe aortic stenosis at increased surgical risk, showing a significantly lower risk of mortality 1 year later.

In the U.S. CoreValve High Risk Study, a prospective randomized controlled study of almost 800 patients, the rate of all-cause mortality at 1 year, the primary endpoint, was 14.2% among those in the transcatheter aortic valve replacement (TAVR) group, compared with 19.1% among those in the surgery group, a statistically significant difference that represented a 26% survival benefit at 1 year for the CoreValve, Dr. David H. Adams reported at the annual meeting of the American College of Cardiology.

Nick Piegari/Frontline Medical News

his is the first prospective, randomized study to show superiority for transcatheter valve therapy over surgery, and "there’s no study or trial that I’m aware of that’s suggested that TAVR patients would have a superior survival outcome," Dr. Adams of Mount Sinai Medical Center, New York, said in an interview. Based on these results, he said he expects that TAVR "will increasingly become the alternative of choice for patients" at this level of risk.

The study was the high-risk arm of the U.S. CoreValve pivotal trial. The CoreValve self-expanding prosthesis was approved in January 2014 by the Food and Drug Administration for use in extreme risk patients, based on the results of the extreme risk cohort of patients.The data from the study in the high-risk trial are being reviewed at the FDA, according to the manufacturer, Medtronic.

The study compared the safety and effectiveness of TAVR with the CoreValve device to surgical valve replacement in 795 patients at 45 U.S. centers. The patients had severe aortic stenosis, had New York Heart Association class II heart failure or higher, and were judged to have at least a 15% risk of death within 30 days after surgery and less than a 50% risk of death or irreversible complications within 30 days after surgery. Their mean age was about age 83 years, almost half were females, most had class NYHA class III HF, and cardiac risk factors included coronary artery disease (in about two-thirds), previous coronary artery bypass surgery (about 30%), a previous MI (about 25%), and almost all had heart failure.

At 1 year, a composite of major adverse cardiovascular and cerebrovascular events (death from any cause, MI, any stroke, or reintervention), a secondary endpoint, was significantly lower among those on TAVR (20.4%) vs. the surgical group (27.3%). The rate of any stroke at 30 days was 4.9% in TAVR patients and 6.2% in the surgical group; and at 1 year, those rates were 8.8% and 12.6%, respectively; neither difference was statistically significant. Of the procedure-related outcomes, major vascular complications and permanent pacemaker implantations were significantly higher in the TAVR group (22.3% at 1 year, vs. 11.3% in the surgical group). In the TAVR group, there were five cases of cardiac perforation; there were no perforations in the surgical group.

Nick Piegari/Frontline Medical News

Patients are being followed through 5 years. The 2-year mortality data are encouraging, with continued separation of the all-cause mortality curves, although the numbers are still small, Dr. Adams said at the meeting.

Among the study limitations was that more patients in the trial refused surgical valve replacement after randomization and the mortality rate within 30 days after surgery was 4.5%, which was lower than the rate specified for inclusion in the study, which was 15% or higher, so the patients may have been at a lower risk than planned, he said.

During the discussion, the inevitable comparisons to the results of the Placement of Aortic Transcatheter Valves A (PARTNER A) study were raised. In PARTNER A, which compared the safety and effectiveness of the balloon-expandable SAPIEN Transcatheter Heart Valve to aortic valve replacement surgery in high risk patients with severe symptomatic aortic stenosis, found no difference in mortality between the two arms and an increase in cerebrovascular events in the TAVR arm.

Dr. Adams said that different characteristics of the device in the two trials are possible explanations as to why the TAVR results were superior to surgery in the CoreValve study, and not in PARTNER A. "The size of the catheter as well as perhaps the self-expanding nature of the device both could help explain that," he said.

While patient risk was assessed differently in the studies, and the Society of Thoracic Surgeons scores of the patients were different, "we’re confident these were patients at increased risk for surgery," he added.

The study was published simultaneously in the New England Journal of Medicine on March 29 (2014 March 29 [doi:10.1056/NEJMoa1400590]).

The study is funded by the CoreValve manufacturer, Medtronic. Dr. Adams disclosed receiving grant support from Medtronic during the conduct of the study and other support from Medtronic and Edwards Lifesciences outside the submitted work.

emechcatie@frontlinemedcom.com

WASHINGTON – A first in transcatheter aortic valve replacement trials, the CoreValve prosthesis was superior to surgical valve replacement in patients with severe aortic stenosis at increased surgical risk, showing a significantly lower risk of mortality 1 year later.

In the U.S. CoreValve High Risk Study, a prospective randomized controlled study of almost 800 patients, the rate of all-cause mortality at 1 year, the primary endpoint, was 14.2% among those in the transcatheter aortic valve replacement (TAVR) group, compared with 19.1% among those in the surgery group, a statistically significant difference that represented a 26% survival benefit at 1 year for the CoreValve, Dr. David H. Adams reported at the annual meeting of the American College of Cardiology.

Nick Piegari/Frontline Medical News

his is the first prospective, randomized study to show superiority for transcatheter valve therapy over surgery, and "there’s no study or trial that I’m aware of that’s suggested that TAVR patients would have a superior survival outcome," Dr. Adams of Mount Sinai Medical Center, New York, said in an interview. Based on these results, he said he expects that TAVR "will increasingly become the alternative of choice for patients" at this level of risk.

The study was the high-risk arm of the U.S. CoreValve pivotal trial. The CoreValve self-expanding prosthesis was approved in January 2014 by the Food and Drug Administration for use in extreme risk patients, based on the results of the extreme risk cohort of patients.The data from the study in the high-risk trial are being reviewed at the FDA, according to the manufacturer, Medtronic.

The study compared the safety and effectiveness of TAVR with the CoreValve device to surgical valve replacement in 795 patients at 45 U.S. centers. The patients had severe aortic stenosis, had New York Heart Association class II heart failure or higher, and were judged to have at least a 15% risk of death within 30 days after surgery and less than a 50% risk of death or irreversible complications within 30 days after surgery. Their mean age was about age 83 years, almost half were females, most had class NYHA class III HF, and cardiac risk factors included coronary artery disease (in about two-thirds), previous coronary artery bypass surgery (about 30%), a previous MI (about 25%), and almost all had heart failure.

At 1 year, a composite of major adverse cardiovascular and cerebrovascular events (death from any cause, MI, any stroke, or reintervention), a secondary endpoint, was significantly lower among those on TAVR (20.4%) vs. the surgical group (27.3%). The rate of any stroke at 30 days was 4.9% in TAVR patients and 6.2% in the surgical group; and at 1 year, those rates were 8.8% and 12.6%, respectively; neither difference was statistically significant. Of the procedure-related outcomes, major vascular complications and permanent pacemaker implantations were significantly higher in the TAVR group (22.3% at 1 year, vs. 11.3% in the surgical group). In the TAVR group, there were five cases of cardiac perforation; there were no perforations in the surgical group.

Nick Piegari/Frontline Medical News

Patients are being followed through 5 years. The 2-year mortality data are encouraging, with continued separation of the all-cause mortality curves, although the numbers are still small, Dr. Adams said at the meeting.

Among the study limitations was that more patients in the trial refused surgical valve replacement after randomization and the mortality rate within 30 days after surgery was 4.5%, which was lower than the rate specified for inclusion in the study, which was 15% or higher, so the patients may have been at a lower risk than planned, he said.

During the discussion, the inevitable comparisons to the results of the Placement of Aortic Transcatheter Valves A (PARTNER A) study were raised. In PARTNER A, which compared the safety and effectiveness of the balloon-expandable SAPIEN Transcatheter Heart Valve to aortic valve replacement surgery in high risk patients with severe symptomatic aortic stenosis, found no difference in mortality between the two arms and an increase in cerebrovascular events in the TAVR arm.

Dr. Adams said that different characteristics of the device in the two trials are possible explanations as to why the TAVR results were superior to surgery in the CoreValve study, and not in PARTNER A. "The size of the catheter as well as perhaps the self-expanding nature of the device both could help explain that," he said.

While patient risk was assessed differently in the studies, and the Society of Thoracic Surgeons scores of the patients were different, "we’re confident these were patients at increased risk for surgery," he added.

The study was published simultaneously in the New England Journal of Medicine on March 29 (2014 March 29 [doi:10.1056/NEJMoa1400590]).

The study is funded by the CoreValve manufacturer, Medtronic. Dr. Adams disclosed receiving grant support from Medtronic during the conduct of the study and other support from Medtronic and Edwards Lifesciences outside the submitted work.

emechcatie@frontlinemedcom.com

WASHINGTON – A first in transcatheter aortic valve replacement trials, the CoreValve prosthesis was superior to surgical valve replacement in patients with severe aortic stenosis at increased surgical risk, showing a significantly lower risk of mortality 1 year later.

In the U.S. CoreValve High Risk Study, a prospective randomized controlled study of almost 800 patients, the rate of all-cause mortality at 1 year, the primary endpoint, was 14.2% among those in the transcatheter aortic valve replacement (TAVR) group, compared with 19.1% among those in the surgery group, a statistically significant difference that represented a 26% survival benefit at 1 year for the CoreValve, Dr. David H. Adams reported at the annual meeting of the American College of Cardiology.

Nick Piegari/Frontline Medical News

his is the first prospective, randomized study to show superiority for transcatheter valve therapy over surgery, and "there’s no study or trial that I’m aware of that’s suggested that TAVR patients would have a superior survival outcome," Dr. Adams of Mount Sinai Medical Center, New York, said in an interview. Based on these results, he said he expects that TAVR "will increasingly become the alternative of choice for patients" at this level of risk.

The study was the high-risk arm of the U.S. CoreValve pivotal trial. The CoreValve self-expanding prosthesis was approved in January 2014 by the Food and Drug Administration for use in extreme risk patients, based on the results of the extreme risk cohort of patients.The data from the study in the high-risk trial are being reviewed at the FDA, according to the manufacturer, Medtronic.

The study compared the safety and effectiveness of TAVR with the CoreValve device to surgical valve replacement in 795 patients at 45 U.S. centers. The patients had severe aortic stenosis, had New York Heart Association class II heart failure or higher, and were judged to have at least a 15% risk of death within 30 days after surgery and less than a 50% risk of death or irreversible complications within 30 days after surgery. Their mean age was about age 83 years, almost half were females, most had class NYHA class III HF, and cardiac risk factors included coronary artery disease (in about two-thirds), previous coronary artery bypass surgery (about 30%), a previous MI (about 25%), and almost all had heart failure.

At 1 year, a composite of major adverse cardiovascular and cerebrovascular events (death from any cause, MI, any stroke, or reintervention), a secondary endpoint, was significantly lower among those on TAVR (20.4%) vs. the surgical group (27.3%). The rate of any stroke at 30 days was 4.9% in TAVR patients and 6.2% in the surgical group; and at 1 year, those rates were 8.8% and 12.6%, respectively; neither difference was statistically significant. Of the procedure-related outcomes, major vascular complications and permanent pacemaker implantations were significantly higher in the TAVR group (22.3% at 1 year, vs. 11.3% in the surgical group). In the TAVR group, there were five cases of cardiac perforation; there were no perforations in the surgical group.

Nick Piegari/Frontline Medical News

Patients are being followed through 5 years. The 2-year mortality data are encouraging, with continued separation of the all-cause mortality curves, although the numbers are still small, Dr. Adams said at the meeting.

Among the study limitations was that more patients in the trial refused surgical valve replacement after randomization and the mortality rate within 30 days after surgery was 4.5%, which was lower than the rate specified for inclusion in the study, which was 15% or higher, so the patients may have been at a lower risk than planned, he said.

During the discussion, the inevitable comparisons to the results of the Placement of Aortic Transcatheter Valves A (PARTNER A) study were raised. In PARTNER A, which compared the safety and effectiveness of the balloon-expandable SAPIEN Transcatheter Heart Valve to aortic valve replacement surgery in high risk patients with severe symptomatic aortic stenosis, found no difference in mortality between the two arms and an increase in cerebrovascular events in the TAVR arm.

Dr. Adams said that different characteristics of the device in the two trials are possible explanations as to why the TAVR results were superior to surgery in the CoreValve study, and not in PARTNER A. "The size of the catheter as well as perhaps the self-expanding nature of the device both could help explain that," he said.

While patient risk was assessed differently in the studies, and the Society of Thoracic Surgeons scores of the patients were different, "we’re confident these were patients at increased risk for surgery," he added.

The study was published simultaneously in the New England Journal of Medicine on March 29 (2014 March 29 [doi:10.1056/NEJMoa1400590]).

The study is funded by the CoreValve manufacturer, Medtronic. Dr. Adams disclosed receiving grant support from Medtronic during the conduct of the study and other support from Medtronic and Edwards Lifesciences outside the submitted work.

emechcatie@frontlinemedcom.com

SILVER SPRING, MD. – A Food and Drug Administration advisory panel voted 11 to 0 that serelaxin should not be approved for the treatment of acute heart failure, but agreed that the data on the drug were promising and that it should be studied further, at a meeting on March 27.

Members of the FDA’s Cardiovascular and Renal Drugs Advisory Committee agreed there was evidence that serelaxin, a recombinant form of human relaxin-2 hormone that is administered in an intravenous infusion over 48 hours, had a positive effect on worsening heart failure in the phase III RELAX-AHF study. But this was not a primary endpoint of the study, and panelists agreed that the study results were hypothesis-generating and were not sufficient to recommend approval. And because only one of the study’s two primary endpoints was positive, the study did not meet the level required for approval of a drug based on a single trial, several panelists pointed out.

"It’s clear that the drug does have an effect on worsening heart failure, but ... given the limitations on how that was not rigorously defined ... we don’t know how much of the effect was on minor heart failure changes, versus major [changes]," said the panel chair, Dr. A. Michael Lincoff, vice chairman for research in the department of cardiovascular medicine at the Cleveland Clinic. "We need better data on understanding the magnitude of benefit in a rigorous fashion, and the data we have here don’t stand alone as a single trial," he added.

Relaxin, which is present in men and women and increases during the first trimester of pregnancy, "primarily stimulates both the rapid and sustained nitric oxide (NO)-mediated vasodilation pathways," and results in vasodilation within minutes of administration, according to the manufacturer, Novartis Pharmaceuticals. The company’s proposed indication for serelaxin is for improving the symptoms of acute heart failure "through reduction of the rate of worsening of heart failure," based on the results of the phase III RELAX-AHF study, an international randomized, placebo-controlled, double-blind study of 1,161 patients with acute heart failure.

The study compared serelaxin started within 16 hours of hospitalization (at a dose of 30 mcg/kg per day for 48 hours) vs. placebo, plus standard therapy, on two primary endpoints that evaluated the drug’s effect on dyspnea: the Visual Analogue Scale (VAS) dyspnea scale and the Likert dyspnea scale. The area under the curve (AUC), representing the change in patient-reported dyspnea from baseline through day 5, significantly increased among those on serelaxin, compared with those on placebo. But the proportion of patients with moderate to marked improvements in dyspnea, based on the 7-point Likert scale at 6, 12, and 24 hours, however, was not significantly different between the two groups (27% among those on serelaxin vs. 26% among those on placebo).

Novartis also presented data to support serelaxin’s effects on worsening heart failure events through day 5, during which time 6.4% of those on serelaxin had a first episode of worsening heart failure or death within 5 days, vs. almost 12% of those on placebo; and less than 1% of those on serelaxin had recurrent worsening heart failure or death with prior event, vs. 2.6% of those on placebo.

In briefing documents provided before the meeting, the FDA stated that it does not recommend approval of serelaxin, citing various reasons, including the claim in the proposed indication that was "somewhat different" from what was evaluated in the study, as well as the "vague" definition of worsening heart failure in the study.

At the meeting, Dr. Melanie Blank, the FDA’s clinical reviewer, pointed out that the study protocol did not include prespecified criteria, such as signs, symptoms, and lab results, for defining worsening heart failure, and it was left to the investigator to determine whether a patient had worsening heart failure. Cases of worsening heart failure ranged from those that required mechanical ventilation to cases that required only a single 20-mg dose of furosemide, she added. Hypotension was the main safety issue in the study, but most cases were managed by reducing the dose and would not preclude approval, according to the FDA.

Because the study was designed to evaluate the effect of treatment on dyspnea, panelist Dr. Stuart Rich, professor of medicine at the University of Chicago, said "this was more a failure of trial design than it was of the drug itself." He added that that like other panelists, he was enthusiastic about the drug’s potential, and "hopefully, this will be a learning study where the hypotheses will be better thought out, tested, and then proven in a subsequent trial."

In a statement issued after the meeting, Tim Wright, global head of development at Novartis, said that the discussion during the meeting "provided important information that we will address with the FDA as it completes its review," and that the company will "continue to drive our robust clinical trial program and build upon the already established body of evidence." In 2013, Novartis started enrolling patients in RELAX-AHF-2, an international, phase III outcomes study of serelaxin in more than 6,300 patients with acute heart failure; results are expected in 2016.

Serelaxin has not been approved elsewhere. The FDA granted serelaxin fast track status in 2009, and in 2013 it was granted breakthrough therapy designation for reduction of cardiovascular mortality. Breakthrough therapy designation is intended to expedite the development and review of drugs for serious or life-threatening conditions.

In January, the Committee for Medicinal Products for Human Use recommended against approving serelaxin for acute heart failure in Europe, citing issues that included no apparent benefit for short-term relief of dyspnea.

The FDA usually follows the recommendations of its advisory panels. Panelists have been cleared of potential conflicts of interest related to the topic of the meeting. Occasionally, a panelist may be given a waiver, but not at this meeting.

emechcatie@frontlinemedcom.com

SILVER SPRING, MD. – A Food and Drug Administration advisory panel voted 11 to 0 that serelaxin should not be approved for the treatment of acute heart failure, but agreed that the data on the drug were promising and that it should be studied further, at a meeting on March 27.

Members of the FDA’s Cardiovascular and Renal Drugs Advisory Committee agreed there was evidence that serelaxin, a recombinant form of human relaxin-2 hormone that is administered in an intravenous infusion over 48 hours, had a positive effect on worsening heart failure in the phase III RELAX-AHF study. But this was not a primary endpoint of the study, and panelists agreed that the study results were hypothesis-generating and were not sufficient to recommend approval. And because only one of the study’s two primary endpoints was positive, the study did not meet the level required for approval of a drug based on a single trial, several panelists pointed out.

"It’s clear that the drug does have an effect on worsening heart failure, but ... given the limitations on how that was not rigorously defined ... we don’t know how much of the effect was on minor heart failure changes, versus major [changes]," said the panel chair, Dr. A. Michael Lincoff, vice chairman for research in the department of cardiovascular medicine at the Cleveland Clinic. "We need better data on understanding the magnitude of benefit in a rigorous fashion, and the data we have here don’t stand alone as a single trial," he added.

Relaxin, which is present in men and women and increases during the first trimester of pregnancy, "primarily stimulates both the rapid and sustained nitric oxide (NO)-mediated vasodilation pathways," and results in vasodilation within minutes of administration, according to the manufacturer, Novartis Pharmaceuticals. The company’s proposed indication for serelaxin is for improving the symptoms of acute heart failure "through reduction of the rate of worsening of heart failure," based on the results of the phase III RELAX-AHF study, an international randomized, placebo-controlled, double-blind study of 1,161 patients with acute heart failure.

The study compared serelaxin started within 16 hours of hospitalization (at a dose of 30 mcg/kg per day for 48 hours) vs. placebo, plus standard therapy, on two primary endpoints that evaluated the drug’s effect on dyspnea: the Visual Analogue Scale (VAS) dyspnea scale and the Likert dyspnea scale. The area under the curve (AUC), representing the change in patient-reported dyspnea from baseline through day 5, significantly increased among those on serelaxin, compared with those on placebo. But the proportion of patients with moderate to marked improvements in dyspnea, based on the 7-point Likert scale at 6, 12, and 24 hours, however, was not significantly different between the two groups (27% among those on serelaxin vs. 26% among those on placebo).

Novartis also presented data to support serelaxin’s effects on worsening heart failure events through day 5, during which time 6.4% of those on serelaxin had a first episode of worsening heart failure or death within 5 days, vs. almost 12% of those on placebo; and less than 1% of those on serelaxin had recurrent worsening heart failure or death with prior event, vs. 2.6% of those on placebo.

In briefing documents provided before the meeting, the FDA stated that it does not recommend approval of serelaxin, citing various reasons, including the claim in the proposed indication that was "somewhat different" from what was evaluated in the study, as well as the "vague" definition of worsening heart failure in the study.

At the meeting, Dr. Melanie Blank, the FDA’s clinical reviewer, pointed out that the study protocol did not include prespecified criteria, such as signs, symptoms, and lab results, for defining worsening heart failure, and it was left to the investigator to determine whether a patient had worsening heart failure. Cases of worsening heart failure ranged from those that required mechanical ventilation to cases that required only a single 20-mg dose of furosemide, she added. Hypotension was the main safety issue in the study, but most cases were managed by reducing the dose and would not preclude approval, according to the FDA.

Because the study was designed to evaluate the effect of treatment on dyspnea, panelist Dr. Stuart Rich, professor of medicine at the University of Chicago, said "this was more a failure of trial design than it was of the drug itself." He added that that like other panelists, he was enthusiastic about the drug’s potential, and "hopefully, this will be a learning study where the hypotheses will be better thought out, tested, and then proven in a subsequent trial."

In a statement issued after the meeting, Tim Wright, global head of development at Novartis, said that the discussion during the meeting "provided important information that we will address with the FDA as it completes its review," and that the company will "continue to drive our robust clinical trial program and build upon the already established body of evidence." In 2013, Novartis started enrolling patients in RELAX-AHF-2, an international, phase III outcomes study of serelaxin in more than 6,300 patients with acute heart failure; results are expected in 2016.

Serelaxin has not been approved elsewhere. The FDA granted serelaxin fast track status in 2009, and in 2013 it was granted breakthrough therapy designation for reduction of cardiovascular mortality. Breakthrough therapy designation is intended to expedite the development and review of drugs for serious or life-threatening conditions.

In January, the Committee for Medicinal Products for Human Use recommended against approving serelaxin for acute heart failure in Europe, citing issues that included no apparent benefit for short-term relief of dyspnea.

The FDA usually follows the recommendations of its advisory panels. Panelists have been cleared of potential conflicts of interest related to the topic of the meeting. Occasionally, a panelist may be given a waiver, but not at this meeting.

emechcatie@frontlinemedcom.com

SILVER SPRING, MD. – A Food and Drug Administration advisory panel voted 11 to 0 that serelaxin should not be approved for the treatment of acute heart failure, but agreed that the data on the drug were promising and that it should be studied further, at a meeting on March 27.

Members of the FDA’s Cardiovascular and Renal Drugs Advisory Committee agreed there was evidence that serelaxin, a recombinant form of human relaxin-2 hormone that is administered in an intravenous infusion over 48 hours, had a positive effect on worsening heart failure in the phase III RELAX-AHF study. But this was not a primary endpoint of the study, and panelists agreed that the study results were hypothesis-generating and were not sufficient to recommend approval. And because only one of the study’s two primary endpoints was positive, the study did not meet the level required for approval of a drug based on a single trial, several panelists pointed out.

"It’s clear that the drug does have an effect on worsening heart failure, but ... given the limitations on how that was not rigorously defined ... we don’t know how much of the effect was on minor heart failure changes, versus major [changes]," said the panel chair, Dr. A. Michael Lincoff, vice chairman for research in the department of cardiovascular medicine at the Cleveland Clinic. "We need better data on understanding the magnitude of benefit in a rigorous fashion, and the data we have here don’t stand alone as a single trial," he added.

Relaxin, which is present in men and women and increases during the first trimester of pregnancy, "primarily stimulates both the rapid and sustained nitric oxide (NO)-mediated vasodilation pathways," and results in vasodilation within minutes of administration, according to the manufacturer, Novartis Pharmaceuticals. The company’s proposed indication for serelaxin is for improving the symptoms of acute heart failure "through reduction of the rate of worsening of heart failure," based on the results of the phase III RELAX-AHF study, an international randomized, placebo-controlled, double-blind study of 1,161 patients with acute heart failure.

The study compared serelaxin started within 16 hours of hospitalization (at a dose of 30 mcg/kg per day for 48 hours) vs. placebo, plus standard therapy, on two primary endpoints that evaluated the drug’s effect on dyspnea: the Visual Analogue Scale (VAS) dyspnea scale and the Likert dyspnea scale. The area under the curve (AUC), representing the change in patient-reported dyspnea from baseline through day 5, significantly increased among those on serelaxin, compared with those on placebo. But the proportion of patients with moderate to marked improvements in dyspnea, based on the 7-point Likert scale at 6, 12, and 24 hours, however, was not significantly different between the two groups (27% among those on serelaxin vs. 26% among those on placebo).

Novartis also presented data to support serelaxin’s effects on worsening heart failure events through day 5, during which time 6.4% of those on serelaxin had a first episode of worsening heart failure or death within 5 days, vs. almost 12% of those on placebo; and less than 1% of those on serelaxin had recurrent worsening heart failure or death with prior event, vs. 2.6% of those on placebo.

In briefing documents provided before the meeting, the FDA stated that it does not recommend approval of serelaxin, citing various reasons, including the claim in the proposed indication that was "somewhat different" from what was evaluated in the study, as well as the "vague" definition of worsening heart failure in the study.

At the meeting, Dr. Melanie Blank, the FDA’s clinical reviewer, pointed out that the study protocol did not include prespecified criteria, such as signs, symptoms, and lab results, for defining worsening heart failure, and it was left to the investigator to determine whether a patient had worsening heart failure. Cases of worsening heart failure ranged from those that required mechanical ventilation to cases that required only a single 20-mg dose of furosemide, she added. Hypotension was the main safety issue in the study, but most cases were managed by reducing the dose and would not preclude approval, according to the FDA.

Because the study was designed to evaluate the effect of treatment on dyspnea, panelist Dr. Stuart Rich, professor of medicine at the University of Chicago, said "this was more a failure of trial design than it was of the drug itself." He added that that like other panelists, he was enthusiastic about the drug’s potential, and "hopefully, this will be a learning study where the hypotheses will be better thought out, tested, and then proven in a subsequent trial."

In a statement issued after the meeting, Tim Wright, global head of development at Novartis, said that the discussion during the meeting "provided important information that we will address with the FDA as it completes its review," and that the company will "continue to drive our robust clinical trial program and build upon the already established body of evidence." In 2013, Novartis started enrolling patients in RELAX-AHF-2, an international, phase III outcomes study of serelaxin in more than 6,300 patients with acute heart failure; results are expected in 2016.

Serelaxin has not been approved elsewhere. The FDA granted serelaxin fast track status in 2009, and in 2013 it was granted breakthrough therapy designation for reduction of cardiovascular mortality. Breakthrough therapy designation is intended to expedite the development and review of drugs for serious or life-threatening conditions.

In January, the Committee for Medicinal Products for Human Use recommended against approving serelaxin for acute heart failure in Europe, citing issues that included no apparent benefit for short-term relief of dyspnea.

The FDA usually follows the recommendations of its advisory panels. Panelists have been cleared of potential conflicts of interest related to the topic of the meeting. Occasionally, a panelist may be given a waiver, but not at this meeting.

emechcatie@frontlinemedcom.com