Heart Failure

Two large observational "real-world" studies of two different treatments for heart failure failed to confirm the results of clinical trials of those treatments, leaving clinicians to wonder which study findings to trust, according to separate reports in the Nov. 28 issue of JAMA.

In one report, aldosterone antagonists failed to improve mortality or reduce CV readmissions in patients who had heart failure with decreased ejection fraction, after clinical trials had indicated the agents would do so. In another report, renin-angiotensin system antagonists did reduce mortality in patients who had HF with preserved ejection fraction, after clinical trials had indicated the drugs would not do so.

Both research groups called for additional study to clarify the discrepant results.

In the first study, investigators noted that "landmark clinical trials" had shown the aldosterone antagonists spironolactone and eplerenone cut mortality by up to 30% and readmissions for HF by nearly 40% among patients who had heart failure accompanied by reduced ejection fraction. Yet even though these drugs are now recommended for such patients, physicians have been slow to comply.

This may be due in part to uncertainty about the safety and effectiveness of aldosterone antagonists under real-world conditions, where many patients – the elderly, those with diabetes or chronic kidney disease, and those already using other medications predisposing them to hyperkalemia – fall outside the strict inclusion criteria used in clinical trial populations, said Dr. Adrian F. Hernandez of Duke Clinical Research Institute, Durham, N.C., and his associates.

Dr. Hernandez and his colleagues used data from the Get With The Guidelines–HF registry and the Medicare claims database to assess the drugs’ effectiveness in 5,887 patients aged 65 and older who had been discharged from 246 U.S. hospitals with a diagnosis of HF with decreased left ventricular ejection fraction in 2005-2009 and who were eligible for treatment with aldosterone antagonists. Only 1,070 of the study subjects received a prescription for the drugs at discharge.

After 3 years, there were no significant differences in all-cause mortality or in readmission for cardiovascular disorders between patients who were given aldosterone antagonists and patients who were not, the researchers said (JAMA 2012;308:2097-107).

On the down side, treated patients did show a higher rate of rehospitalization for hyperkalemia, usually during the first few weeks after initiating therapy with aldosterone antagonists.

This study wasn’t designed to determine why the results contradicted the "impressive benefits of aldosterone antagonist therapy" reported in "pivotal" efficacy trials as well as in a systematic review of randomized clinical trials of the therapy. But the researchers suggested that it’s possible the drugs have limited effectiveness in older patients in clinical practice, possibly because they may not adhere to treatment as well as subjects in intensely monitored clinical trials.

"Our findings highlight the importance of conducting clinical trials that can be easily generalized to real-world practice and in which the most vulnerable patient groups are well represented," Dr. Hernandez and his colleagues said.

Moreover, "developing protocols and systems that encourage optimal use and monitoring of aldosterone antagonist therapy may help to ensure that the effectiveness of this therapy in clinical practice approaches the efficacy achieved in clinical trials."

The investigators added that in their study, aldosterone antagonists did reduce the rate of rehospitalization for HF, which indicates that further study is needed to clarify the benefits and risks of therapy.

The second JAMA report involved the use of renin-angiotensin system (RAS) antagonists, which includes ACE inhibitors and angiotensin-receptor blockers, for patients who have heart failure with preserved ejection fraction. Three randomized clinical trials had concluded that the agents failed to improve outcomes in such patients, but those trials were marred by flaws such as selection bias, underpowering, and high crossover rates, said Dr. Lars H. Lund of the Karolinska Institutet, Stockholm, and his associates.

Dr. Lund and his colleagues used data from the Swedish Heart Failure Registry to examine RAS antagonists’ effectiveness in a large, unselected patient population. Their main analysis included 16,216 patients from 77 hospitals and 84 primary care outpatient clinics, of whom 77% received RAS antagonists and 23% did not.

Patients who took the drugs showed a 1-year crude survival of 86%, compared with only 69% for patients who didn’t take them. Five-year survival was 55% and 32%, respectively, the investigators said (JAMA 2012;308:2108-117).

The researchers also developed propensity scores using 43 clinically relevant variables at baseline so they could construct age-matched and propensity-matched groups of 3,329 patients who received the drugs at hospital discharge and 3,329 who did not. In this analysis, 1-year survival was 77% for the treated patients vs. 72% for the untreated, and 5-year survival was 36% vs 34%, respectively. These differences were statistically significant and confirmed that the result of the main analysis was accurate, Dr. Lund and his associates said.

They performed one further consistency analysis to affirm their findings, and found a dose-response relationship: the greater the use of RAS antagonists, the greater the reduction in mortality.

Taken together, these findings suggest that RAS antagonists may be beneficial for patients who have HF with preserved ejection fraction, "but this should be confirmed in an appropriately powered randomized trial," they added.

Dr. Hernandez’s study was funded by the Agency for Healthcare Research and Quality; he reported ties to Amylin Pharmaceutical, Johnson & Johnson, AstraZeneca, Corthera, and Sanofi-Aventis, and his associates reported ties to numerous industry sources.

Dr. Lund’s study was funded by the Swedish National Board of Health and Welfare, the Swedish Association of Local Authorities and Regions, the Swedish Society of Cardiology, the Swedish Heart-Lung Foundation, and Astra-Zeneca; he reported ties to AstraZeneca, Thoratec, and HeartWare.

Two large observational "real-world" studies of two different treatments for heart failure failed to confirm the results of clinical trials of those treatments, leaving clinicians to wonder which study findings to trust, according to separate reports in the Nov. 28 issue of JAMA.

In one report, aldosterone antagonists failed to improve mortality or reduce CV readmissions in patients who had heart failure with decreased ejection fraction, after clinical trials had indicated the agents would do so. In another report, renin-angiotensin system antagonists did reduce mortality in patients who had HF with preserved ejection fraction, after clinical trials had indicated the drugs would not do so.

Both research groups called for additional study to clarify the discrepant results.

In the first study, investigators noted that "landmark clinical trials" had shown the aldosterone antagonists spironolactone and eplerenone cut mortality by up to 30% and readmissions for HF by nearly 40% among patients who had heart failure accompanied by reduced ejection fraction. Yet even though these drugs are now recommended for such patients, physicians have been slow to comply.

This may be due in part to uncertainty about the safety and effectiveness of aldosterone antagonists under real-world conditions, where many patients – the elderly, those with diabetes or chronic kidney disease, and those already using other medications predisposing them to hyperkalemia – fall outside the strict inclusion criteria used in clinical trial populations, said Dr. Adrian F. Hernandez of Duke Clinical Research Institute, Durham, N.C., and his associates.

Dr. Hernandez and his colleagues used data from the Get With The Guidelines–HF registry and the Medicare claims database to assess the drugs’ effectiveness in 5,887 patients aged 65 and older who had been discharged from 246 U.S. hospitals with a diagnosis of HF with decreased left ventricular ejection fraction in 2005-2009 and who were eligible for treatment with aldosterone antagonists. Only 1,070 of the study subjects received a prescription for the drugs at discharge.

After 3 years, there were no significant differences in all-cause mortality or in readmission for cardiovascular disorders between patients who were given aldosterone antagonists and patients who were not, the researchers said (JAMA 2012;308:2097-107).

On the down side, treated patients did show a higher rate of rehospitalization for hyperkalemia, usually during the first few weeks after initiating therapy with aldosterone antagonists.

This study wasn’t designed to determine why the results contradicted the "impressive benefits of aldosterone antagonist therapy" reported in "pivotal" efficacy trials as well as in a systematic review of randomized clinical trials of the therapy. But the researchers suggested that it’s possible the drugs have limited effectiveness in older patients in clinical practice, possibly because they may not adhere to treatment as well as subjects in intensely monitored clinical trials.

"Our findings highlight the importance of conducting clinical trials that can be easily generalized to real-world practice and in which the most vulnerable patient groups are well represented," Dr. Hernandez and his colleagues said.

Moreover, "developing protocols and systems that encourage optimal use and monitoring of aldosterone antagonist therapy may help to ensure that the effectiveness of this therapy in clinical practice approaches the efficacy achieved in clinical trials."

The investigators added that in their study, aldosterone antagonists did reduce the rate of rehospitalization for HF, which indicates that further study is needed to clarify the benefits and risks of therapy.

The second JAMA report involved the use of renin-angiotensin system (RAS) antagonists, which includes ACE inhibitors and angiotensin-receptor blockers, for patients who have heart failure with preserved ejection fraction. Three randomized clinical trials had concluded that the agents failed to improve outcomes in such patients, but those trials were marred by flaws such as selection bias, underpowering, and high crossover rates, said Dr. Lars H. Lund of the Karolinska Institutet, Stockholm, and his associates.

Dr. Lund and his colleagues used data from the Swedish Heart Failure Registry to examine RAS antagonists’ effectiveness in a large, unselected patient population. Their main analysis included 16,216 patients from 77 hospitals and 84 primary care outpatient clinics, of whom 77% received RAS antagonists and 23% did not.

Patients who took the drugs showed a 1-year crude survival of 86%, compared with only 69% for patients who didn’t take them. Five-year survival was 55% and 32%, respectively, the investigators said (JAMA 2012;308:2108-117).

The researchers also developed propensity scores using 43 clinically relevant variables at baseline so they could construct age-matched and propensity-matched groups of 3,329 patients who received the drugs at hospital discharge and 3,329 who did not. In this analysis, 1-year survival was 77% for the treated patients vs. 72% for the untreated, and 5-year survival was 36% vs 34%, respectively. These differences were statistically significant and confirmed that the result of the main analysis was accurate, Dr. Lund and his associates said.

They performed one further consistency analysis to affirm their findings, and found a dose-response relationship: the greater the use of RAS antagonists, the greater the reduction in mortality.

Taken together, these findings suggest that RAS antagonists may be beneficial for patients who have HF with preserved ejection fraction, "but this should be confirmed in an appropriately powered randomized trial," they added.

Dr. Hernandez’s study was funded by the Agency for Healthcare Research and Quality; he reported ties to Amylin Pharmaceutical, Johnson & Johnson, AstraZeneca, Corthera, and Sanofi-Aventis, and his associates reported ties to numerous industry sources.

Dr. Lund’s study was funded by the Swedish National Board of Health and Welfare, the Swedish Association of Local Authorities and Regions, the Swedish Society of Cardiology, the Swedish Heart-Lung Foundation, and Astra-Zeneca; he reported ties to AstraZeneca, Thoratec, and HeartWare.

Two large observational "real-world" studies of two different treatments for heart failure failed to confirm the results of clinical trials of those treatments, leaving clinicians to wonder which study findings to trust, according to separate reports in the Nov. 28 issue of JAMA.

In one report, aldosterone antagonists failed to improve mortality or reduce CV readmissions in patients who had heart failure with decreased ejection fraction, after clinical trials had indicated the agents would do so. In another report, renin-angiotensin system antagonists did reduce mortality in patients who had HF with preserved ejection fraction, after clinical trials had indicated the drugs would not do so.

Both research groups called for additional study to clarify the discrepant results.

In the first study, investigators noted that "landmark clinical trials" had shown the aldosterone antagonists spironolactone and eplerenone cut mortality by up to 30% and readmissions for HF by nearly 40% among patients who had heart failure accompanied by reduced ejection fraction. Yet even though these drugs are now recommended for such patients, physicians have been slow to comply.

This may be due in part to uncertainty about the safety and effectiveness of aldosterone antagonists under real-world conditions, where many patients – the elderly, those with diabetes or chronic kidney disease, and those already using other medications predisposing them to hyperkalemia – fall outside the strict inclusion criteria used in clinical trial populations, said Dr. Adrian F. Hernandez of Duke Clinical Research Institute, Durham, N.C., and his associates.

Dr. Hernandez and his colleagues used data from the Get With The Guidelines–HF registry and the Medicare claims database to assess the drugs’ effectiveness in 5,887 patients aged 65 and older who had been discharged from 246 U.S. hospitals with a diagnosis of HF with decreased left ventricular ejection fraction in 2005-2009 and who were eligible for treatment with aldosterone antagonists. Only 1,070 of the study subjects received a prescription for the drugs at discharge.

After 3 years, there were no significant differences in all-cause mortality or in readmission for cardiovascular disorders between patients who were given aldosterone antagonists and patients who were not, the researchers said (JAMA 2012;308:2097-107).

On the down side, treated patients did show a higher rate of rehospitalization for hyperkalemia, usually during the first few weeks after initiating therapy with aldosterone antagonists.

This study wasn’t designed to determine why the results contradicted the "impressive benefits of aldosterone antagonist therapy" reported in "pivotal" efficacy trials as well as in a systematic review of randomized clinical trials of the therapy. But the researchers suggested that it’s possible the drugs have limited effectiveness in older patients in clinical practice, possibly because they may not adhere to treatment as well as subjects in intensely monitored clinical trials.

"Our findings highlight the importance of conducting clinical trials that can be easily generalized to real-world practice and in which the most vulnerable patient groups are well represented," Dr. Hernandez and his colleagues said.

Moreover, "developing protocols and systems that encourage optimal use and monitoring of aldosterone antagonist therapy may help to ensure that the effectiveness of this therapy in clinical practice approaches the efficacy achieved in clinical trials."

The investigators added that in their study, aldosterone antagonists did reduce the rate of rehospitalization for HF, which indicates that further study is needed to clarify the benefits and risks of therapy.

The second JAMA report involved the use of renin-angiotensin system (RAS) antagonists, which includes ACE inhibitors and angiotensin-receptor blockers, for patients who have heart failure with preserved ejection fraction. Three randomized clinical trials had concluded that the agents failed to improve outcomes in such patients, but those trials were marred by flaws such as selection bias, underpowering, and high crossover rates, said Dr. Lars H. Lund of the Karolinska Institutet, Stockholm, and his associates.

Dr. Lund and his colleagues used data from the Swedish Heart Failure Registry to examine RAS antagonists’ effectiveness in a large, unselected patient population. Their main analysis included 16,216 patients from 77 hospitals and 84 primary care outpatient clinics, of whom 77% received RAS antagonists and 23% did not.

Patients who took the drugs showed a 1-year crude survival of 86%, compared with only 69% for patients who didn’t take them. Five-year survival was 55% and 32%, respectively, the investigators said (JAMA 2012;308:2108-117).

The researchers also developed propensity scores using 43 clinically relevant variables at baseline so they could construct age-matched and propensity-matched groups of 3,329 patients who received the drugs at hospital discharge and 3,329 who did not. In this analysis, 1-year survival was 77% for the treated patients vs. 72% for the untreated, and 5-year survival was 36% vs 34%, respectively. These differences were statistically significant and confirmed that the result of the main analysis was accurate, Dr. Lund and his associates said.

They performed one further consistency analysis to affirm their findings, and found a dose-response relationship: the greater the use of RAS antagonists, the greater the reduction in mortality.

Taken together, these findings suggest that RAS antagonists may be beneficial for patients who have HF with preserved ejection fraction, "but this should be confirmed in an appropriately powered randomized trial," they added.

Dr. Hernandez’s study was funded by the Agency for Healthcare Research and Quality; he reported ties to Amylin Pharmaceutical, Johnson & Johnson, AstraZeneca, Corthera, and Sanofi-Aventis, and his associates reported ties to numerous industry sources.

Dr. Lund’s study was funded by the Swedish National Board of Health and Welfare, the Swedish Association of Local Authorities and Regions, the Swedish Society of Cardiology, the Swedish Heart-Lung Foundation, and Astra-Zeneca; he reported ties to AstraZeneca, Thoratec, and HeartWare.

BERLIN -- A pancreas-only transplant improved cardiac function and morphology in a group of patients with type 1 diabetes.

After 5 years, the patients showed significantly improved posterior wall and interventricular septal thickness, as well as a significantly increased left ventricular ejection fraction, Dr. Margherita Occhipinti said at the annual meeting of the European Societies for the Study of Diabetes.

She reported 5-year follow-up data on 35 patients with type 1 diabetes who underwent the procedure. The patients were a mean of 38 years old and had a mean disease duration of 25 years. Their mean insulin requirement was 43 U/day.

Most of the transplants (74%) were performed with a portal-enteric drain technique; the remainder had systemic-enteric drainage, said Dr. Occhipinti of the University of Pisa (Italy). The majority (77%) had induction therapy with basiliximab; the rest had antithymocyte globulin (rabbit) induction. The maintenance immunosuppressant regimen was a combination of mycophenolate mofetil, tacrolimus, and steroids.

At last follow-up, fasting plasma glucose level had normalized, hemoglobin A_1c level had fallen from 9% to just under 6%, and C-peptide level had increased from under 1 ng/mL to almost 3 ng/mL.

There were no significant changes in either systolic or diastolic blood pressure. However, the number of patients taking ACE inhibitors or angiotensin receptor blockers decreased from 59% to 43%. Total and LDL cholesterol levels decreased significantly, although there were no significant changes in HDL cholesterol or triglycerides.

Cardiac morphology changed significantly, Dr. Occhipinti said, including a significant decrease in posterior wall thickness during diastole, from 8.1 mm to 7.0 mm, and interventricular septum thickness during diastole, from 9.3 mm to 8.7 mm. The left ventricular mass index decreased significantly, from 82 mg/m² to 73 mg/m²; and the left ventricular ejection fraction increased significantly, from 55.3% to 57.9%.

Dr. Occhipinti compared these changes to 2-year findings in a group of 11 control patients who were on a transplant waiting list or who had a failed pancreatic transplant.

In this group, there were no significant changes in HbA_1c, left ventricular ejection fraction, or any of the measures of cardiac morphology.

Dr. Occhipinti said she had no relevant financial disclosures.

BERLIN -- A pancreas-only transplant improved cardiac function and morphology in a group of patients with type 1 diabetes.

After 5 years, the patients showed significantly improved posterior wall and interventricular septal thickness, as well as a significantly increased left ventricular ejection fraction, Dr. Margherita Occhipinti said at the annual meeting of the European Societies for the Study of Diabetes.

She reported 5-year follow-up data on 35 patients with type 1 diabetes who underwent the procedure. The patients were a mean of 38 years old and had a mean disease duration of 25 years. Their mean insulin requirement was 43 U/day.

Most of the transplants (74%) were performed with a portal-enteric drain technique; the remainder had systemic-enteric drainage, said Dr. Occhipinti of the University of Pisa (Italy). The majority (77%) had induction therapy with basiliximab; the rest had antithymocyte globulin (rabbit) induction. The maintenance immunosuppressant regimen was a combination of mycophenolate mofetil, tacrolimus, and steroids.

At last follow-up, fasting plasma glucose level had normalized, hemoglobin A_1c level had fallen from 9% to just under 6%, and C-peptide level had increased from under 1 ng/mL to almost 3 ng/mL.

There were no significant changes in either systolic or diastolic blood pressure. However, the number of patients taking ACE inhibitors or angiotensin receptor blockers decreased from 59% to 43%. Total and LDL cholesterol levels decreased significantly, although there were no significant changes in HDL cholesterol or triglycerides.

Cardiac morphology changed significantly, Dr. Occhipinti said, including a significant decrease in posterior wall thickness during diastole, from 8.1 mm to 7.0 mm, and interventricular septum thickness during diastole, from 9.3 mm to 8.7 mm. The left ventricular mass index decreased significantly, from 82 mg/m² to 73 mg/m²; and the left ventricular ejection fraction increased significantly, from 55.3% to 57.9%.

Dr. Occhipinti compared these changes to 2-year findings in a group of 11 control patients who were on a transplant waiting list or who had a failed pancreatic transplant.

In this group, there were no significant changes in HbA_1c, left ventricular ejection fraction, or any of the measures of cardiac morphology.

Dr. Occhipinti said she had no relevant financial disclosures.

BERLIN -- A pancreas-only transplant improved cardiac function and morphology in a group of patients with type 1 diabetes.

After 5 years, the patients showed significantly improved posterior wall and interventricular septal thickness, as well as a significantly increased left ventricular ejection fraction, Dr. Margherita Occhipinti said at the annual meeting of the European Societies for the Study of Diabetes.

She reported 5-year follow-up data on 35 patients with type 1 diabetes who underwent the procedure. The patients were a mean of 38 years old and had a mean disease duration of 25 years. Their mean insulin requirement was 43 U/day.

Most of the transplants (74%) were performed with a portal-enteric drain technique; the remainder had systemic-enteric drainage, said Dr. Occhipinti of the University of Pisa (Italy). The majority (77%) had induction therapy with basiliximab; the rest had antithymocyte globulin (rabbit) induction. The maintenance immunosuppressant regimen was a combination of mycophenolate mofetil, tacrolimus, and steroids.

At last follow-up, fasting plasma glucose level had normalized, hemoglobin A_1c level had fallen from 9% to just under 6%, and C-peptide level had increased from under 1 ng/mL to almost 3 ng/mL.

There were no significant changes in either systolic or diastolic blood pressure. However, the number of patients taking ACE inhibitors or angiotensin receptor blockers decreased from 59% to 43%. Total and LDL cholesterol levels decreased significantly, although there were no significant changes in HDL cholesterol or triglycerides.

Cardiac morphology changed significantly, Dr. Occhipinti said, including a significant decrease in posterior wall thickness during diastole, from 8.1 mm to 7.0 mm, and interventricular septum thickness during diastole, from 9.3 mm to 8.7 mm. The left ventricular mass index decreased significantly, from 82 mg/m² to 73 mg/m²; and the left ventricular ejection fraction increased significantly, from 55.3% to 57.9%.

Dr. Occhipinti compared these changes to 2-year findings in a group of 11 control patients who were on a transplant waiting list or who had a failed pancreatic transplant.

In this group, there were no significant changes in HbA_1c, left ventricular ejection fraction, or any of the measures of cardiac morphology.

Dr. Occhipinti said she had no relevant financial disclosures.

LOS ANGELES – Cardiac resynchronization therapy may be on the verge of a strong new indication for the prevention of progression of heart failure in patients with atrioventricular block who are not candidates for the device therapy on the basis of current criteria.

Results of the BLOCK-HF trial comparing biventricular pacing using a CRT device to standard right ventricular pacing demonstrated that in patients with AV block and systolic heart failure, biventricular pacing led to a significant 26% reduction in the combined end point of death, heart failure–related urgent care, or deterioration in heart function as defined echocardiographically by more than a 15% increase in the left ventricular end systolic volume index, Dr. Anne B. Curtis reported at the annual scientific sessions of the American Heart Association.

BLOCK-HF (Biventricular Versus Right Ventricular Pacing in Heart Failure Patients With Atrioventricular Block) was a randomized, double-blind, prospective, multicenter study of 691 patients with class I-III heart failure, a left ventricular ejection fraction (LVEF) of 50% or less, and AV block necessitating pacing. None had a class I indication for CRT by current guidelines. All participants received a CRT device programmed for right ventricular pacing only while optimal medical therapy was established, which took 30-60 days. Once that occurred, subjects were randomized double-blind to biventricular or right ventricular pacing. Analysis was by intent-to-treat.

Of those participants, 207 patients received a combined CRT/defibrillator device because they met criteria for a primary prevention implantable cardioverter-defibrillator; the rest got a CRT pacemaker-only device, said Dr. Curtis, BLOCK-HF principal investigator and professor and chair of the department of medicine at the University at Buffalo (N.Y.).

At an average of 36 months’ follow-up, the combined primary end point had occurred in roughly 60% of the biventricular pacing group, representing a 26% relative risk reduction compared with conventional right ventricular pacing. The rate of the two clinical components of the primary end point – mortality and heart failure–related urgent care – was 27% lower in the biventricular pacing group.

Results were the same in patients with a CRT pacing-only device as for those with a CRT/defibrillator, even though those with the CRT/defibrillator had an average LVEF of 33%, compared with an LVEF of 44% in those who got the pacing-only device. Dr. Curtis said that although a formal subgroup analysis based on heart failure functional class is planned, it’s her anecdotal impression that the benefits of biventricular pacing were similar across the board.

A pronounced imbalance in crossovers between the two study arms occurred: 25% of subjects randomized to right ventricular pacing crossed over to biventricular pacing, while 5% assigned to biventricular pacing crossed to right ventricular pacing.

"If anything, this would tend to minimize the differences we found," Dr. Curtis noted.

Roughly 1 million people in the United States have AV block, and there are 6 million individuals with the diagnosis of heart failure.

Discussant Dr. Gerasimos S. Filippatos of the University of Athens declared that the BLOCK-HF results will certainly lead to a reconsideration of current European Society of Cardiology and joint American College of Cardiology/AHA/Heart Rhythm Society guidelines for heart failure patients with heart block.

As a heart failure specialist and nonelectrophysiologist, Dr. Filippatos said he found the procedure-related complication rates notably high: 33% in recipients of CRT pacing-only devices and 17% in those who got a CRT/defibrillator.

Dr. Curtis replied that complication rates are always higher when putting in a left ventricular lead because it’s a more difficult procedure than putting in a right ventricular lead. One of the key points of BLOCK-HF, she added, was to look at whether or not putting patients through the added difficulty of implanting a biventricular pacing device has clear benefits – and the answer is yes.

The BLOCK-HF trial was sponsored by Medtronic. Dr. Curtis reported serving as a consultant to that company and to Biosense Webster, Sanofi-Aventis, and Bristol-Myers Squibb. Dr. Filippatos is a consultant to Novartis.

LOS ANGELES – Cardiac resynchronization therapy may be on the verge of a strong new indication for the prevention of progression of heart failure in patients with atrioventricular block who are not candidates for the device therapy on the basis of current criteria.

Results of the BLOCK-HF trial comparing biventricular pacing using a CRT device to standard right ventricular pacing demonstrated that in patients with AV block and systolic heart failure, biventricular pacing led to a significant 26% reduction in the combined end point of death, heart failure–related urgent care, or deterioration in heart function as defined echocardiographically by more than a 15% increase in the left ventricular end systolic volume index, Dr. Anne B. Curtis reported at the annual scientific sessions of the American Heart Association.

BLOCK-HF (Biventricular Versus Right Ventricular Pacing in Heart Failure Patients With Atrioventricular Block) was a randomized, double-blind, prospective, multicenter study of 691 patients with class I-III heart failure, a left ventricular ejection fraction (LVEF) of 50% or less, and AV block necessitating pacing. None had a class I indication for CRT by current guidelines. All participants received a CRT device programmed for right ventricular pacing only while optimal medical therapy was established, which took 30-60 days. Once that occurred, subjects were randomized double-blind to biventricular or right ventricular pacing. Analysis was by intent-to-treat.

Of those participants, 207 patients received a combined CRT/defibrillator device because they met criteria for a primary prevention implantable cardioverter-defibrillator; the rest got a CRT pacemaker-only device, said Dr. Curtis, BLOCK-HF principal investigator and professor and chair of the department of medicine at the University at Buffalo (N.Y.).

At an average of 36 months’ follow-up, the combined primary end point had occurred in roughly 60% of the biventricular pacing group, representing a 26% relative risk reduction compared with conventional right ventricular pacing. The rate of the two clinical components of the primary end point – mortality and heart failure–related urgent care – was 27% lower in the biventricular pacing group.

Results were the same in patients with a CRT pacing-only device as for those with a CRT/defibrillator, even though those with the CRT/defibrillator had an average LVEF of 33%, compared with an LVEF of 44% in those who got the pacing-only device. Dr. Curtis said that although a formal subgroup analysis based on heart failure functional class is planned, it’s her anecdotal impression that the benefits of biventricular pacing were similar across the board.

A pronounced imbalance in crossovers between the two study arms occurred: 25% of subjects randomized to right ventricular pacing crossed over to biventricular pacing, while 5% assigned to biventricular pacing crossed to right ventricular pacing.

"If anything, this would tend to minimize the differences we found," Dr. Curtis noted.

Roughly 1 million people in the United States have AV block, and there are 6 million individuals with the diagnosis of heart failure.

Discussant Dr. Gerasimos S. Filippatos of the University of Athens declared that the BLOCK-HF results will certainly lead to a reconsideration of current European Society of Cardiology and joint American College of Cardiology/AHA/Heart Rhythm Society guidelines for heart failure patients with heart block.

As a heart failure specialist and nonelectrophysiologist, Dr. Filippatos said he found the procedure-related complication rates notably high: 33% in recipients of CRT pacing-only devices and 17% in those who got a CRT/defibrillator.

Dr. Curtis replied that complication rates are always higher when putting in a left ventricular lead because it’s a more difficult procedure than putting in a right ventricular lead. One of the key points of BLOCK-HF, she added, was to look at whether or not putting patients through the added difficulty of implanting a biventricular pacing device has clear benefits – and the answer is yes.

The BLOCK-HF trial was sponsored by Medtronic. Dr. Curtis reported serving as a consultant to that company and to Biosense Webster, Sanofi-Aventis, and Bristol-Myers Squibb. Dr. Filippatos is a consultant to Novartis.

LOS ANGELES – Cardiac resynchronization therapy may be on the verge of a strong new indication for the prevention of progression of heart failure in patients with atrioventricular block who are not candidates for the device therapy on the basis of current criteria.

Results of the BLOCK-HF trial comparing biventricular pacing using a CRT device to standard right ventricular pacing demonstrated that in patients with AV block and systolic heart failure, biventricular pacing led to a significant 26% reduction in the combined end point of death, heart failure–related urgent care, or deterioration in heart function as defined echocardiographically by more than a 15% increase in the left ventricular end systolic volume index, Dr. Anne B. Curtis reported at the annual scientific sessions of the American Heart Association.

BLOCK-HF (Biventricular Versus Right Ventricular Pacing in Heart Failure Patients With Atrioventricular Block) was a randomized, double-blind, prospective, multicenter study of 691 patients with class I-III heart failure, a left ventricular ejection fraction (LVEF) of 50% or less, and AV block necessitating pacing. None had a class I indication for CRT by current guidelines. All participants received a CRT device programmed for right ventricular pacing only while optimal medical therapy was established, which took 30-60 days. Once that occurred, subjects were randomized double-blind to biventricular or right ventricular pacing. Analysis was by intent-to-treat.

Of those participants, 207 patients received a combined CRT/defibrillator device because they met criteria for a primary prevention implantable cardioverter-defibrillator; the rest got a CRT pacemaker-only device, said Dr. Curtis, BLOCK-HF principal investigator and professor and chair of the department of medicine at the University at Buffalo (N.Y.).

At an average of 36 months’ follow-up, the combined primary end point had occurred in roughly 60% of the biventricular pacing group, representing a 26% relative risk reduction compared with conventional right ventricular pacing. The rate of the two clinical components of the primary end point – mortality and heart failure–related urgent care – was 27% lower in the biventricular pacing group.

Results were the same in patients with a CRT pacing-only device as for those with a CRT/defibrillator, even though those with the CRT/defibrillator had an average LVEF of 33%, compared with an LVEF of 44% in those who got the pacing-only device. Dr. Curtis said that although a formal subgroup analysis based on heart failure functional class is planned, it’s her anecdotal impression that the benefits of biventricular pacing were similar across the board.

A pronounced imbalance in crossovers between the two study arms occurred: 25% of subjects randomized to right ventricular pacing crossed over to biventricular pacing, while 5% assigned to biventricular pacing crossed to right ventricular pacing.

"If anything, this would tend to minimize the differences we found," Dr. Curtis noted.

Roughly 1 million people in the United States have AV block, and there are 6 million individuals with the diagnosis of heart failure.

Discussant Dr. Gerasimos S. Filippatos of the University of Athens declared that the BLOCK-HF results will certainly lead to a reconsideration of current European Society of Cardiology and joint American College of Cardiology/AHA/Heart Rhythm Society guidelines for heart failure patients with heart block.

As a heart failure specialist and nonelectrophysiologist, Dr. Filippatos said he found the procedure-related complication rates notably high: 33% in recipients of CRT pacing-only devices and 17% in those who got a CRT/defibrillator.

Dr. Curtis replied that complication rates are always higher when putting in a left ventricular lead because it’s a more difficult procedure than putting in a right ventricular lead. One of the key points of BLOCK-HF, she added, was to look at whether or not putting patients through the added difficulty of implanting a biventricular pacing device has clear benefits – and the answer is yes.

The BLOCK-HF trial was sponsored by Medtronic. Dr. Curtis reported serving as a consultant to that company and to Biosense Webster, Sanofi-Aventis, and Bristol-Myers Squibb. Dr. Filippatos is a consultant to Novartis.

LOS ANGELES – In terms of preserving exercise capacity and lowering elevated N-terminal pro-B-type natriuretic peptide levels, calcium channel blockers outperformed beta-blockers for rate control in patients with permanent atrial fibrillation.

The findings were noted in the RATAF (Norwegian Rate Control in Atrial Fibrillation) trial, a randomized, crossover, investigator-blinded study. RATAF also showed that diltiazem and verapamil significantly reduced arrhythmia-related symptoms, while carvedilol and metoprolol did not. Moreover, mean 24-hour ventricular heart rate was significantly lower during calcium channel blocker therapy than when subjects were on beta-blockers, according to Dr. Sarah Reinvik Ulimoen, of Baerum Hospital in Rud, Norway.

"Treatment with calcium channel blockers for rate control in atrial fibrillation should be considered more often in patients not needing a beta-blocker – that is, in patients without systolic heart failure or coronary heart disease," she said at the annual scientific sessions of the American Heart Association.

She reported on 60 RATAF participants with permanent AF, a normal left ventricular ejection fraction, and no coronary heart disease. The subjects received for 3 weeks each and in random sequence, once-daily diltiazem at 360 mg, verapamil at 240 mg, metoprolol at 100 mg, and carvedilol at 25 mg. At baseline and on the final day of each 3-week-long treatment period, the patients performed a bicycle ergometer maximal cardiopulmonary exercise test with measurement of peak oxygen uptake.

Blood samples for measurement of N-terminal pro-B-type natriuretic peptide (NT-proBNP) were taken at rest, peak exercise, and recovery. NT-proBNP is a biomarker widely utilized in the diagnosis and monitoring of heart failure. In addition, NT-proBNP is known to be elevated in patients with AF, even if they have normal systolic function.

The two calcium channel blockers preserved patients’ exercise capacity: Mean VO_2max on the bike was 23.1 mL/kg per minute at baseline, 23.7 mL/kg per minute while subjects were on diltiazem, and 23.1 mL/kg per minute when they were on verapamil.

In contrast, mean VO_2max was significantly reduced relative to baseline when patients were on beta-blocker therapy: 21.1 mL/kg per minute with metoprolol and 20.0 mL/kg per minute with carvedilol.

Mean NT-proBNP levels at rest were 1,039 pg/mL at baseline and significantly lower during calcium channel blocker therapy: 831 pg/mL while patients were on diltiazem and 897 pg/mL on verapamil. When patients were on a beta-blocker, however, their resting NT-proBNP was significantly greater than at baseline: 1,332 pg/mL for metoprolol and 1,205 pg/mL for carvedilol.

The same relationships seen when NT-proBNP was measured at rest held true when the biomarker was measured at peak exercise or during recovery: Mean levels were significantly reduced compared with baseline if patients were on calcium channel blockers for rate control, and significantly elevated above baseline while they were on beta-blockers. An inverse relationship was evident between exercise capacity and NT-proBNP: As maximum oxygen uptake went down, NT-proBNP levels went up.

Dr. Ulimoen noted that the exact mechanism underlying the increased levels of NT-proBNP in AF is unknown. Possibilities include myocardial stretching, oxidative stress in the atrial wall, and local ischemia. It’s believed that the major source of the NT-proBNP present in AF is the atria, not the ventricles as in heart failure.

As to why beta-blocker therapy was associated with higher levels of the cardiac biomarker, Dr. Ulimoen speculated that perhaps the drugs interfere with relaxation of the heart and thus diastolic filling; it is thought that NT-proBNP levels may reflect left ventricular filling pressure.

The findings she presented at the meeting regarding peak exercise capacity and changes in NT-proBNP were secondary end points in RATAF. The primary outcomes – the four rate control drugs’ effects on arrhythmia-related symptoms and mean 24-hour heart rate – were recently published (Am. J. Cardiol. 2012 [doi: 10.1016/j.amjcard.2012.09.020]).

Dr. Ulimoen reported having no financial conflicts.

LOS ANGELES – In terms of preserving exercise capacity and lowering elevated N-terminal pro-B-type natriuretic peptide levels, calcium channel blockers outperformed beta-blockers for rate control in patients with permanent atrial fibrillation.

The findings were noted in the RATAF (Norwegian Rate Control in Atrial Fibrillation) trial, a randomized, crossover, investigator-blinded study. RATAF also showed that diltiazem and verapamil significantly reduced arrhythmia-related symptoms, while carvedilol and metoprolol did not. Moreover, mean 24-hour ventricular heart rate was significantly lower during calcium channel blocker therapy than when subjects were on beta-blockers, according to Dr. Sarah Reinvik Ulimoen, of Baerum Hospital in Rud, Norway.

"Treatment with calcium channel blockers for rate control in atrial fibrillation should be considered more often in patients not needing a beta-blocker – that is, in patients without systolic heart failure or coronary heart disease," she said at the annual scientific sessions of the American Heart Association.

She reported on 60 RATAF participants with permanent AF, a normal left ventricular ejection fraction, and no coronary heart disease. The subjects received for 3 weeks each and in random sequence, once-daily diltiazem at 360 mg, verapamil at 240 mg, metoprolol at 100 mg, and carvedilol at 25 mg. At baseline and on the final day of each 3-week-long treatment period, the patients performed a bicycle ergometer maximal cardiopulmonary exercise test with measurement of peak oxygen uptake.

Blood samples for measurement of N-terminal pro-B-type natriuretic peptide (NT-proBNP) were taken at rest, peak exercise, and recovery. NT-proBNP is a biomarker widely utilized in the diagnosis and monitoring of heart failure. In addition, NT-proBNP is known to be elevated in patients with AF, even if they have normal systolic function.

The two calcium channel blockers preserved patients’ exercise capacity: Mean VO_2max on the bike was 23.1 mL/kg per minute at baseline, 23.7 mL/kg per minute while subjects were on diltiazem, and 23.1 mL/kg per minute when they were on verapamil.

In contrast, mean VO_2max was significantly reduced relative to baseline when patients were on beta-blocker therapy: 21.1 mL/kg per minute with metoprolol and 20.0 mL/kg per minute with carvedilol.

Mean NT-proBNP levels at rest were 1,039 pg/mL at baseline and significantly lower during calcium channel blocker therapy: 831 pg/mL while patients were on diltiazem and 897 pg/mL on verapamil. When patients were on a beta-blocker, however, their resting NT-proBNP was significantly greater than at baseline: 1,332 pg/mL for metoprolol and 1,205 pg/mL for carvedilol.

The same relationships seen when NT-proBNP was measured at rest held true when the biomarker was measured at peak exercise or during recovery: Mean levels were significantly reduced compared with baseline if patients were on calcium channel blockers for rate control, and significantly elevated above baseline while they were on beta-blockers. An inverse relationship was evident between exercise capacity and NT-proBNP: As maximum oxygen uptake went down, NT-proBNP levels went up.

Dr. Ulimoen noted that the exact mechanism underlying the increased levels of NT-proBNP in AF is unknown. Possibilities include myocardial stretching, oxidative stress in the atrial wall, and local ischemia. It’s believed that the major source of the NT-proBNP present in AF is the atria, not the ventricles as in heart failure.

As to why beta-blocker therapy was associated with higher levels of the cardiac biomarker, Dr. Ulimoen speculated that perhaps the drugs interfere with relaxation of the heart and thus diastolic filling; it is thought that NT-proBNP levels may reflect left ventricular filling pressure.

The findings she presented at the meeting regarding peak exercise capacity and changes in NT-proBNP were secondary end points in RATAF. The primary outcomes – the four rate control drugs’ effects on arrhythmia-related symptoms and mean 24-hour heart rate – were recently published (Am. J. Cardiol. 2012 [doi: 10.1016/j.amjcard.2012.09.020]).

Dr. Ulimoen reported having no financial conflicts.

LOS ANGELES – In terms of preserving exercise capacity and lowering elevated N-terminal pro-B-type natriuretic peptide levels, calcium channel blockers outperformed beta-blockers for rate control in patients with permanent atrial fibrillation.

The findings were noted in the RATAF (Norwegian Rate Control in Atrial Fibrillation) trial, a randomized, crossover, investigator-blinded study. RATAF also showed that diltiazem and verapamil significantly reduced arrhythmia-related symptoms, while carvedilol and metoprolol did not. Moreover, mean 24-hour ventricular heart rate was significantly lower during calcium channel blocker therapy than when subjects were on beta-blockers, according to Dr. Sarah Reinvik Ulimoen, of Baerum Hospital in Rud, Norway.

"Treatment with calcium channel blockers for rate control in atrial fibrillation should be considered more often in patients not needing a beta-blocker – that is, in patients without systolic heart failure or coronary heart disease," she said at the annual scientific sessions of the American Heart Association.

She reported on 60 RATAF participants with permanent AF, a normal left ventricular ejection fraction, and no coronary heart disease. The subjects received for 3 weeks each and in random sequence, once-daily diltiazem at 360 mg, verapamil at 240 mg, metoprolol at 100 mg, and carvedilol at 25 mg. At baseline and on the final day of each 3-week-long treatment period, the patients performed a bicycle ergometer maximal cardiopulmonary exercise test with measurement of peak oxygen uptake.

Blood samples for measurement of N-terminal pro-B-type natriuretic peptide (NT-proBNP) were taken at rest, peak exercise, and recovery. NT-proBNP is a biomarker widely utilized in the diagnosis and monitoring of heart failure. In addition, NT-proBNP is known to be elevated in patients with AF, even if they have normal systolic function.

The two calcium channel blockers preserved patients’ exercise capacity: Mean VO_2max on the bike was 23.1 mL/kg per minute at baseline, 23.7 mL/kg per minute while subjects were on diltiazem, and 23.1 mL/kg per minute when they were on verapamil.

In contrast, mean VO_2max was significantly reduced relative to baseline when patients were on beta-blocker therapy: 21.1 mL/kg per minute with metoprolol and 20.0 mL/kg per minute with carvedilol.

Mean NT-proBNP levels at rest were 1,039 pg/mL at baseline and significantly lower during calcium channel blocker therapy: 831 pg/mL while patients were on diltiazem and 897 pg/mL on verapamil. When patients were on a beta-blocker, however, their resting NT-proBNP was significantly greater than at baseline: 1,332 pg/mL for metoprolol and 1,205 pg/mL for carvedilol.

The same relationships seen when NT-proBNP was measured at rest held true when the biomarker was measured at peak exercise or during recovery: Mean levels were significantly reduced compared with baseline if patients were on calcium channel blockers for rate control, and significantly elevated above baseline while they were on beta-blockers. An inverse relationship was evident between exercise capacity and NT-proBNP: As maximum oxygen uptake went down, NT-proBNP levels went up.

Dr. Ulimoen noted that the exact mechanism underlying the increased levels of NT-proBNP in AF is unknown. Possibilities include myocardial stretching, oxidative stress in the atrial wall, and local ischemia. It’s believed that the major source of the NT-proBNP present in AF is the atria, not the ventricles as in heart failure.

As to why beta-blocker therapy was associated with higher levels of the cardiac biomarker, Dr. Ulimoen speculated that perhaps the drugs interfere with relaxation of the heart and thus diastolic filling; it is thought that NT-proBNP levels may reflect left ventricular filling pressure.

The findings she presented at the meeting regarding peak exercise capacity and changes in NT-proBNP were secondary end points in RATAF. The primary outcomes – the four rate control drugs’ effects on arrhythmia-related symptoms and mean 24-hour heart rate – were recently published (Am. J. Cardiol. 2012 [doi: 10.1016/j.amjcard.2012.09.020]).

Dr. Ulimoen reported having no financial conflicts.

CHICAGO -- Mitral valve endocarditis is a medical-surgical problem that demands a team approach, and the landscape of the disease has changed significantly for the worst in the recent past, according to a presentation at Heart Valve Summit 2012.

"If you’re lucky enough to have a valve infection with the Strep viridans microorganism, you’re likely to do well," said Dr. Patrick T. O’Gara, director of clinical cardiology at Brigham and Women’s Hospital, Boston.

CDC/Dr. Mike Miller

On the other hand, patients who’ve been infected with any other type of organism, particularly Staph aureus or its increasingly frequent relative methicillin-resistant Staph aureus, could be in real trouble.

"There’s no question that these organisms are smarter than we are and can lead to destruction of the valve and death of the patient, despite our best intentions," said Dr. O’Gara. He described the evolving epidemiology, natural history, and indications for surgery for this disease to this educational program of the American Association for Thoracic Surgery (AATS) and the American College of Cardiology Foundation (ACCF).

"Unfortunately, despite our best efforts, and worldwide, among centers with an interest in the care of patients with endocarditis, 6-month mortality rates still approach 25%," he said. This is close to the mortality rate of a type A aortic dissection, so it is by no means trivial. Early surgery is now performed on many who present with the disease in early stages, and perioperative mortality is 12%-20%.

It is a challenge to manage a patient who is asymptomatic with respect to heart failure but who has a large mobile vegetation involving the anterior mitral leaflet, said Dr. O’Gara. Vegetations in this location are the most prone to embolize.

"This is the common question now posed to consulting cardiologists: Does my patient require early surgery for prevention of embolic complications? We don’t really get asked too much any more: ‘Does my patient need early surgery because they’ve developed heart failure?’ I guess we’re much more confident in proceeding under those circumstances."

He discussed considerations for surgery, including the level of local surgical expertise. The intervention is complex and delicate. "This is not something for the faint of heart," said Dr. O’Gara.

In the early time frame following presentation, there is a relationship between the size of the vegetation and the risk of embolization.

The risk of stroke drops rapidly after initiation of antimicrobial therapy. Patients who develop stroke as a complication of endocarditis typically do so the day before, the day of, or the day after presentation, he said. Stroke risk continues to drop quickly in the first 2 weeks after initiation of antibiotics, and by week 5 it’s almost nil.

"If you’re thinking about intervention for prevention of stroke, it makes sense to do so in the first week, after identification of a patient at risk with a large mobile vegetation. It makes much less sense to do so in weeks 2 or 3."

The size of the vegetation alone may dictate mortality. A size of 1.5 cm or greater is associated with increased risk of death at 1 year in the setting of native valve endocarditis.

The good news is that event-free survival rates have been shown to be much better for those who undergo surgery in the first 7 days after presentation with high-risk native, left-sided endocarditis. In-hospital mortality as a function of early surgery appears to have declined over the course of time.

"So, in summary, I think for our management considerations, it’s early diagnosis, risk stratification, a heart team approach, consider early surgery, particularly if you have the operative expertise. The early risk of re-infection in implanted prosthetic material is very low," Dr. O’Gara said.

Dr. O’Gara disclosed ties with the Data Safety Monitoring Board and Lantheus Medical Imaging.

CHICAGO -- Mitral valve endocarditis is a medical-surgical problem that demands a team approach, and the landscape of the disease has changed significantly for the worst in the recent past, according to a presentation at Heart Valve Summit 2012.

"If you’re lucky enough to have a valve infection with the Strep viridans microorganism, you’re likely to do well," said Dr. Patrick T. O’Gara, director of clinical cardiology at Brigham and Women’s Hospital, Boston.

CDC/Dr. Mike Miller

On the other hand, patients who’ve been infected with any other type of organism, particularly Staph aureus or its increasingly frequent relative methicillin-resistant Staph aureus, could be in real trouble.

"There’s no question that these organisms are smarter than we are and can lead to destruction of the valve and death of the patient, despite our best intentions," said Dr. O’Gara. He described the evolving epidemiology, natural history, and indications for surgery for this disease to this educational program of the American Association for Thoracic Surgery (AATS) and the American College of Cardiology Foundation (ACCF).

"Unfortunately, despite our best efforts, and worldwide, among centers with an interest in the care of patients with endocarditis, 6-month mortality rates still approach 25%," he said. This is close to the mortality rate of a type A aortic dissection, so it is by no means trivial. Early surgery is now performed on many who present with the disease in early stages, and perioperative mortality is 12%-20%.

It is a challenge to manage a patient who is asymptomatic with respect to heart failure but who has a large mobile vegetation involving the anterior mitral leaflet, said Dr. O’Gara. Vegetations in this location are the most prone to embolize.

"This is the common question now posed to consulting cardiologists: Does my patient require early surgery for prevention of embolic complications? We don’t really get asked too much any more: ‘Does my patient need early surgery because they’ve developed heart failure?’ I guess we’re much more confident in proceeding under those circumstances."

He discussed considerations for surgery, including the level of local surgical expertise. The intervention is complex and delicate. "This is not something for the faint of heart," said Dr. O’Gara.

In the early time frame following presentation, there is a relationship between the size of the vegetation and the risk of embolization.

The risk of stroke drops rapidly after initiation of antimicrobial therapy. Patients who develop stroke as a complication of endocarditis typically do so the day before, the day of, or the day after presentation, he said. Stroke risk continues to drop quickly in the first 2 weeks after initiation of antibiotics, and by week 5 it’s almost nil.

"If you’re thinking about intervention for prevention of stroke, it makes sense to do so in the first week, after identification of a patient at risk with a large mobile vegetation. It makes much less sense to do so in weeks 2 or 3."

The size of the vegetation alone may dictate mortality. A size of 1.5 cm or greater is associated with increased risk of death at 1 year in the setting of native valve endocarditis.

The good news is that event-free survival rates have been shown to be much better for those who undergo surgery in the first 7 days after presentation with high-risk native, left-sided endocarditis. In-hospital mortality as a function of early surgery appears to have declined over the course of time.

"So, in summary, I think for our management considerations, it’s early diagnosis, risk stratification, a heart team approach, consider early surgery, particularly if you have the operative expertise. The early risk of re-infection in implanted prosthetic material is very low," Dr. O’Gara said.

Dr. O’Gara disclosed ties with the Data Safety Monitoring Board and Lantheus Medical Imaging.

CHICAGO -- Mitral valve endocarditis is a medical-surgical problem that demands a team approach, and the landscape of the disease has changed significantly for the worst in the recent past, according to a presentation at Heart Valve Summit 2012.

"If you’re lucky enough to have a valve infection with the Strep viridans microorganism, you’re likely to do well," said Dr. Patrick T. O’Gara, director of clinical cardiology at Brigham and Women’s Hospital, Boston.

CDC/Dr. Mike Miller

On the other hand, patients who’ve been infected with any other type of organism, particularly Staph aureus or its increasingly frequent relative methicillin-resistant Staph aureus, could be in real trouble.

"There’s no question that these organisms are smarter than we are and can lead to destruction of the valve and death of the patient, despite our best intentions," said Dr. O’Gara. He described the evolving epidemiology, natural history, and indications for surgery for this disease to this educational program of the American Association for Thoracic Surgery (AATS) and the American College of Cardiology Foundation (ACCF).

"Unfortunately, despite our best efforts, and worldwide, among centers with an interest in the care of patients with endocarditis, 6-month mortality rates still approach 25%," he said. This is close to the mortality rate of a type A aortic dissection, so it is by no means trivial. Early surgery is now performed on many who present with the disease in early stages, and perioperative mortality is 12%-20%.

It is a challenge to manage a patient who is asymptomatic with respect to heart failure but who has a large mobile vegetation involving the anterior mitral leaflet, said Dr. O’Gara. Vegetations in this location are the most prone to embolize.

"This is the common question now posed to consulting cardiologists: Does my patient require early surgery for prevention of embolic complications? We don’t really get asked too much any more: ‘Does my patient need early surgery because they’ve developed heart failure?’ I guess we’re much more confident in proceeding under those circumstances."

He discussed considerations for surgery, including the level of local surgical expertise. The intervention is complex and delicate. "This is not something for the faint of heart," said Dr. O’Gara.

In the early time frame following presentation, there is a relationship between the size of the vegetation and the risk of embolization.

The risk of stroke drops rapidly after initiation of antimicrobial therapy. Patients who develop stroke as a complication of endocarditis typically do so the day before, the day of, or the day after presentation, he said. Stroke risk continues to drop quickly in the first 2 weeks after initiation of antibiotics, and by week 5 it’s almost nil.

"If you’re thinking about intervention for prevention of stroke, it makes sense to do so in the first week, after identification of a patient at risk with a large mobile vegetation. It makes much less sense to do so in weeks 2 or 3."

The size of the vegetation alone may dictate mortality. A size of 1.5 cm or greater is associated with increased risk of death at 1 year in the setting of native valve endocarditis.

The good news is that event-free survival rates have been shown to be much better for those who undergo surgery in the first 7 days after presentation with high-risk native, left-sided endocarditis. In-hospital mortality as a function of early surgery appears to have declined over the course of time.

"So, in summary, I think for our management considerations, it’s early diagnosis, risk stratification, a heart team approach, consider early surgery, particularly if you have the operative expertise. The early risk of re-infection in implanted prosthetic material is very low," Dr. O’Gara said.

Dr. O’Gara disclosed ties with the Data Safety Monitoring Board and Lantheus Medical Imaging.

LOS ANGELES – The recombinant vasoactive peptide hormone serelaxin showed the potential to be a breakthrough therapy for acute heart failure in a phase III randomized trial.

In the Relaxin in Acute Heart Failure (RELAX-AHF) trial, serelaxin brought greater dyspnea relief than standard treatment plus placebo. It also markedly reduced the risk of worsening heart failure during the index hospitalization, significantly shortened ICU and total hospital lengths of stay, improved biomarkers, and displayed a benign safety profile. Most impressive of all, serelaxin was associated with a highly significant 37% reduction in both cardiovascular and all-cause mortality at follow-up 6 months after administration of a 48-hour infusion, study co-principal investigator Dr. John R. Teerlink reported on Nov. 6 at the annual scientific sessions of the American Heart Association.

These benefits mirror those seen earlier in the phase II Pre-RELAX-AHF study (Lancet 2009;373:1429-39). That study showed an all-cause mortality reduction in the subgroup randomized to the same dose of serelaxin used in the phase III trial, added Dr. Teerlink, professor of medicine at the University of California, San Francisco.

Serelaxin is recombinant human relaxin-2, which is present in both men and women. The hormone rises to pharmacologic levels during pregnancy. During that time, it promotes increased cardiac output, renal blood flow, and arterial compliance.

"Those are exactly the kinds of changes we’d like to see in patients with acute heart failure," Dr. Teerlink explained in describing the rationale for developing the hormone as a novel cardiovascular medication.

Heart failure experts who commented on RELAX-AHF were unanimous in their conviction that the study persuasively demonstrated that serelaxin reduces breathlessness and other signs and symptoms of acute heart failure. They were more cautious regarding the observed mortality benefit.

"My own feeling about this is that it would be very nice to see this finding replicated. If we did replicate this finding it would be an extraordinary advance in the management of acute heart failure, for which we have no disease-modifying or lifesaving therapies," said Dr. John McMurray, professor of medical cardiology at the University of Glasgow.

RELAX-AHF was an international double-blind study that enrolled 1,161 patients hospitalized for acute heart failure. All had dyspnea at rest or with minimal exertion, pulmonary congestion, mild to moderate renal insufficiency, elevated brain natriuretic peptide levels, and a systolic blood pressure greater than 125 mm Hg despite having received at least 40 mg of intravenous furosemide or its equivalent shortly before enrollment. Participants were randomized to intravenous serelaxin at 30 mcg/kg per day for 48 hours or placebo on top of standard management.

The results: The serelaxin-treated group experienced a 19% improvement in the primary end point of patient-reported dyspnea to day 5. They also had a 30% reduction in the relative risk of worsening heart failure events up to day 14, despite roughly 25% less use of intravenous diuretics and other vasoactive drugs than in the placebo group. The average length of the initial hospital stay was 9.6 days in the serelaxin group, and nearly a full day longer at 10.5 days in controls. The serelaxin group averaged 3.5 days in the ICU or coronary care unit, 0.4 days less than the placebo group.

They were less likely than controls to experience a significant rise in creatinine or troponin T at day 2, and more likely to have a substantial decrease in NT-proBNP and liver enzymes.

But the head-turning result was the cardiovascular death rate through day 180: 9.5% with placebo compared with 6.0% with serelaxin, for a 37% reduction in risk. The number of patients who needed to be treated with serelaxin for 48 hours in order to prevent one additional cardiovascular death was 29. All-cause mortality was reduced to a similar extent, with an 11.3% rate in controls, compared with 7.3% with serelaxin.

Rates and types of adverse events overall and serious adverse events were similar in the two study arms.

But not all prespecified end points were met. Most important, in Dr. McMurray’s view, was the serelaxin group’s lack of a reduction in rehospitalizations for heart failure or renal failure during 60 days of follow-up. In chronic heart failure, it’s very unusual to see a treatment that improves survival but does not reduce rehospitalization. Also, 6-month mortality was not a prespecified end point in RELAX-AHF. And the mortality conclusions were based on relatively small numbers.

"In acute heart failure in the past, we’ve been famously misled by small numbers," he said, citing the example of vesnarinone, which in its first randomized trial showed a 62% reduction in all-cause mortality that didn’t hold up in a second, much larger trial.

Dr. Milton Packer drew attention to the impressively short time between hospital admission and the start of serelaxin, which averaged less than 8 hours.

"No trial has ever pulled that off before. And here’s the thing that’s really exciting about RELAX-AHF: If the mortality effect is correct, and if that mortality effect is related to early treatment, that would be transformative in terms of how we think about acute heart failure. It would mean that just as in myocardial infarction, where time is of the essence, it could be that in acute heart failure time is of the essence. So if the mortality effect is true, this trial changes the way we do things," said Dr. Packer, professor and chairman of the department of clinical sciences at the University of Texas Southwestern Medical Center, Dallas.

It’s plausible that decompressing the heart quite early in an episode of acute heart failure, when the heart is being actively distended, reduces myocardial injury and thereby lowers cardiovascular risk long term. The drop in cardiac troponin levels seen with serelaxin therapy is consistent with such a scenario, according to Dr. Packer.

Dr. Gregg Fonarow said in an interview that on the strength of the evidence from RELAX-AHF plus the phase III study, including the absence of any safety concerns, he thinks serelaxin would readily earn Food and Drug Administration approval for the relief of signs and symptoms of acute heart failure. But winning an indication for mortality reduction might require a confirmatory trial.

"To have a drug that relieves symptoms and improves survival in patients hospitalized with acute heart failure would be off-the-charts exciting after 20 years of trial and error," added Dr. Fonarow, professor of medicine and director of the Ahmanson-UCLA Cardiomyopathy Center.

A spokesperson for Novartis, which sponsored RELAX-AHF, told this publication that the company hasn’t yet determined its filing strategy but believes "this is a strong set of data," and has begun discussions with the major regulatory agencies.

Simultaneous with Dr. Teerlink’s presentation, the RELAX-AHF findings were published online (Lancet 2012 Nov. 7 [doi: 10.1016/S0140-6736(12)61855-8]).

The trial was sponsored by Novartis. Dr. Teerlink reported that he has received research grants from and serves as a consultant to Novartis as well as other pharmaceutical and medical device companies. The discussants reported having no financial conflicts.

LOS ANGELES – The recombinant vasoactive peptide hormone serelaxin showed the potential to be a breakthrough therapy for acute heart failure in a phase III randomized trial.

In the Relaxin in Acute Heart Failure (RELAX-AHF) trial, serelaxin brought greater dyspnea relief than standard treatment plus placebo. It also markedly reduced the risk of worsening heart failure during the index hospitalization, significantly shortened ICU and total hospital lengths of stay, improved biomarkers, and displayed a benign safety profile. Most impressive of all, serelaxin was associated with a highly significant 37% reduction in both cardiovascular and all-cause mortality at follow-up 6 months after administration of a 48-hour infusion, study co-principal investigator Dr. John R. Teerlink reported on Nov. 6 at the annual scientific sessions of the American Heart Association.

These benefits mirror those seen earlier in the phase II Pre-RELAX-AHF study (Lancet 2009;373:1429-39). That study showed an all-cause mortality reduction in the subgroup randomized to the same dose of serelaxin used in the phase III trial, added Dr. Teerlink, professor of medicine at the University of California, San Francisco.

Serelaxin is recombinant human relaxin-2, which is present in both men and women. The hormone rises to pharmacologic levels during pregnancy. During that time, it promotes increased cardiac output, renal blood flow, and arterial compliance.

"Those are exactly the kinds of changes we’d like to see in patients with acute heart failure," Dr. Teerlink explained in describing the rationale for developing the hormone as a novel cardiovascular medication.

Heart failure experts who commented on RELAX-AHF were unanimous in their conviction that the study persuasively demonstrated that serelaxin reduces breathlessness and other signs and symptoms of acute heart failure. They were more cautious regarding the observed mortality benefit.

"My own feeling about this is that it would be very nice to see this finding replicated. If we did replicate this finding it would be an extraordinary advance in the management of acute heart failure, for which we have no disease-modifying or lifesaving therapies," said Dr. John McMurray, professor of medical cardiology at the University of Glasgow.

RELAX-AHF was an international double-blind study that enrolled 1,161 patients hospitalized for acute heart failure. All had dyspnea at rest or with minimal exertion, pulmonary congestion, mild to moderate renal insufficiency, elevated brain natriuretic peptide levels, and a systolic blood pressure greater than 125 mm Hg despite having received at least 40 mg of intravenous furosemide or its equivalent shortly before enrollment. Participants were randomized to intravenous serelaxin at 30 mcg/kg per day for 48 hours or placebo on top of standard management.

The results: The serelaxin-treated group experienced a 19% improvement in the primary end point of patient-reported dyspnea to day 5. They also had a 30% reduction in the relative risk of worsening heart failure events up to day 14, despite roughly 25% less use of intravenous diuretics and other vasoactive drugs than in the placebo group. The average length of the initial hospital stay was 9.6 days in the serelaxin group, and nearly a full day longer at 10.5 days in controls. The serelaxin group averaged 3.5 days in the ICU or coronary care unit, 0.4 days less than the placebo group.

They were less likely than controls to experience a significant rise in creatinine or troponin T at day 2, and more likely to have a substantial decrease in NT-proBNP and liver enzymes.

But the head-turning result was the cardiovascular death rate through day 180: 9.5% with placebo compared with 6.0% with serelaxin, for a 37% reduction in risk. The number of patients who needed to be treated with serelaxin for 48 hours in order to prevent one additional cardiovascular death was 29. All-cause mortality was reduced to a similar extent, with an 11.3% rate in controls, compared with 7.3% with serelaxin.

Rates and types of adverse events overall and serious adverse events were similar in the two study arms.

But not all prespecified end points were met. Most important, in Dr. McMurray’s view, was the serelaxin group’s lack of a reduction in rehospitalizations for heart failure or renal failure during 60 days of follow-up. In chronic heart failure, it’s very unusual to see a treatment that improves survival but does not reduce rehospitalization. Also, 6-month mortality was not a prespecified end point in RELAX-AHF. And the mortality conclusions were based on relatively small numbers.

"In acute heart failure in the past, we’ve been famously misled by small numbers," he said, citing the example of vesnarinone, which in its first randomized trial showed a 62% reduction in all-cause mortality that didn’t hold up in a second, much larger trial.

Dr. Milton Packer drew attention to the impressively short time between hospital admission and the start of serelaxin, which averaged less than 8 hours.

"No trial has ever pulled that off before. And here’s the thing that’s really exciting about RELAX-AHF: If the mortality effect is correct, and if that mortality effect is related to early treatment, that would be transformative in terms of how we think about acute heart failure. It would mean that just as in myocardial infarction, where time is of the essence, it could be that in acute heart failure time is of the essence. So if the mortality effect is true, this trial changes the way we do things," said Dr. Packer, professor and chairman of the department of clinical sciences at the University of Texas Southwestern Medical Center, Dallas.

It’s plausible that decompressing the heart quite early in an episode of acute heart failure, when the heart is being actively distended, reduces myocardial injury and thereby lowers cardiovascular risk long term. The drop in cardiac troponin levels seen with serelaxin therapy is consistent with such a scenario, according to Dr. Packer.

Dr. Gregg Fonarow said in an interview that on the strength of the evidence from RELAX-AHF plus the phase III study, including the absence of any safety concerns, he thinks serelaxin would readily earn Food and Drug Administration approval for the relief of signs and symptoms of acute heart failure. But winning an indication for mortality reduction might require a confirmatory trial.

"To have a drug that relieves symptoms and improves survival in patients hospitalized with acute heart failure would be off-the-charts exciting after 20 years of trial and error," added Dr. Fonarow, professor of medicine and director of the Ahmanson-UCLA Cardiomyopathy Center.

A spokesperson for Novartis, which sponsored RELAX-AHF, told this publication that the company hasn’t yet determined its filing strategy but believes "this is a strong set of data," and has begun discussions with the major regulatory agencies.

Simultaneous with Dr. Teerlink’s presentation, the RELAX-AHF findings were published online (Lancet 2012 Nov. 7 [doi: 10.1016/S0140-6736(12)61855-8]).

The trial was sponsored by Novartis. Dr. Teerlink reported that he has received research grants from and serves as a consultant to Novartis as well as other pharmaceutical and medical device companies. The discussants reported having no financial conflicts.

LOS ANGELES – The recombinant vasoactive peptide hormone serelaxin showed the potential to be a breakthrough therapy for acute heart failure in a phase III randomized trial.

In the Relaxin in Acute Heart Failure (RELAX-AHF) trial, serelaxin brought greater dyspnea relief than standard treatment plus placebo. It also markedly reduced the risk of worsening heart failure during the index hospitalization, significantly shortened ICU and total hospital lengths of stay, improved biomarkers, and displayed a benign safety profile. Most impressive of all, serelaxin was associated with a highly significant 37% reduction in both cardiovascular and all-cause mortality at follow-up 6 months after administration of a 48-hour infusion, study co-principal investigator Dr. John R. Teerlink reported on Nov. 6 at the annual scientific sessions of the American Heart Association.

These benefits mirror those seen earlier in the phase II Pre-RELAX-AHF study (Lancet 2009;373:1429-39). That study showed an all-cause mortality reduction in the subgroup randomized to the same dose of serelaxin used in the phase III trial, added Dr. Teerlink, professor of medicine at the University of California, San Francisco.

Serelaxin is recombinant human relaxin-2, which is present in both men and women. The hormone rises to pharmacologic levels during pregnancy. During that time, it promotes increased cardiac output, renal blood flow, and arterial compliance.

"Those are exactly the kinds of changes we’d like to see in patients with acute heart failure," Dr. Teerlink explained in describing the rationale for developing the hormone as a novel cardiovascular medication.

Heart failure experts who commented on RELAX-AHF were unanimous in their conviction that the study persuasively demonstrated that serelaxin reduces breathlessness and other signs and symptoms of acute heart failure. They were more cautious regarding the observed mortality benefit.

"My own feeling about this is that it would be very nice to see this finding replicated. If we did replicate this finding it would be an extraordinary advance in the management of acute heart failure, for which we have no disease-modifying or lifesaving therapies," said Dr. John McMurray, professor of medical cardiology at the University of Glasgow.

RELAX-AHF was an international double-blind study that enrolled 1,161 patients hospitalized for acute heart failure. All had dyspnea at rest or with minimal exertion, pulmonary congestion, mild to moderate renal insufficiency, elevated brain natriuretic peptide levels, and a systolic blood pressure greater than 125 mm Hg despite having received at least 40 mg of intravenous furosemide or its equivalent shortly before enrollment. Participants were randomized to intravenous serelaxin at 30 mcg/kg per day for 48 hours or placebo on top of standard management.

The results: The serelaxin-treated group experienced a 19% improvement in the primary end point of patient-reported dyspnea to day 5. They also had a 30% reduction in the relative risk of worsening heart failure events up to day 14, despite roughly 25% less use of intravenous diuretics and other vasoactive drugs than in the placebo group. The average length of the initial hospital stay was 9.6 days in the serelaxin group, and nearly a full day longer at 10.5 days in controls. The serelaxin group averaged 3.5 days in the ICU or coronary care unit, 0.4 days less than the placebo group.

They were less likely than controls to experience a significant rise in creatinine or troponin T at day 2, and more likely to have a substantial decrease in NT-proBNP and liver enzymes.

But the head-turning result was the cardiovascular death rate through day 180: 9.5% with placebo compared with 6.0% with serelaxin, for a 37% reduction in risk. The number of patients who needed to be treated with serelaxin for 48 hours in order to prevent one additional cardiovascular death was 29. All-cause mortality was reduced to a similar extent, with an 11.3% rate in controls, compared with 7.3% with serelaxin.

Rates and types of adverse events overall and serious adverse events were similar in the two study arms.

But not all prespecified end points were met. Most important, in Dr. McMurray’s view, was the serelaxin group’s lack of a reduction in rehospitalizations for heart failure or renal failure during 60 days of follow-up. In chronic heart failure, it’s very unusual to see a treatment that improves survival but does not reduce rehospitalization. Also, 6-month mortality was not a prespecified end point in RELAX-AHF. And the mortality conclusions were based on relatively small numbers.

"In acute heart failure in the past, we’ve been famously misled by small numbers," he said, citing the example of vesnarinone, which in its first randomized trial showed a 62% reduction in all-cause mortality that didn’t hold up in a second, much larger trial.

Dr. Milton Packer drew attention to the impressively short time between hospital admission and the start of serelaxin, which averaged less than 8 hours.

"No trial has ever pulled that off before. And here’s the thing that’s really exciting about RELAX-AHF: If the mortality effect is correct, and if that mortality effect is related to early treatment, that would be transformative in terms of how we think about acute heart failure. It would mean that just as in myocardial infarction, where time is of the essence, it could be that in acute heart failure time is of the essence. So if the mortality effect is true, this trial changes the way we do things," said Dr. Packer, professor and chairman of the department of clinical sciences at the University of Texas Southwestern Medical Center, Dallas.

It’s plausible that decompressing the heart quite early in an episode of acute heart failure, when the heart is being actively distended, reduces myocardial injury and thereby lowers cardiovascular risk long term. The drop in cardiac troponin levels seen with serelaxin therapy is consistent with such a scenario, according to Dr. Packer.

Dr. Gregg Fonarow said in an interview that on the strength of the evidence from RELAX-AHF plus the phase III study, including the absence of any safety concerns, he thinks serelaxin would readily earn Food and Drug Administration approval for the relief of signs and symptoms of acute heart failure. But winning an indication for mortality reduction might require a confirmatory trial.

"To have a drug that relieves symptoms and improves survival in patients hospitalized with acute heart failure would be off-the-charts exciting after 20 years of trial and error," added Dr. Fonarow, professor of medicine and director of the Ahmanson-UCLA Cardiomyopathy Center.

A spokesperson for Novartis, which sponsored RELAX-AHF, told this publication that the company hasn’t yet determined its filing strategy but believes "this is a strong set of data," and has begun discussions with the major regulatory agencies.

Simultaneous with Dr. Teerlink’s presentation, the RELAX-AHF findings were published online (Lancet 2012 Nov. 7 [doi: 10.1016/S0140-6736(12)61855-8]).

The trial was sponsored by Novartis. Dr. Teerlink reported that he has received research grants from and serves as a consultant to Novartis as well as other pharmaceutical and medical device companies. The discussants reported having no financial conflicts.

LOS ANGELES – Full left-atrial ablation by the modified Cox MAZE procedure to treat atrial fibrillation led to significant reductions in left atrial function, based on a detailed assessment of 31 patients who underwent this treatment using bilateral bipolar radiofrequency.

The damaging effect of complete left-atrial ablation contrasted with the impact of a less extensive procedure, pulmonary vein isolation, which kept left-atrial function intact and even improved it by some parameters. Opinions split on the implications of these findings.

"Our advice is that left-atrial ablation should be restricted to those cases where pulmonary vein isolation will likely be insufficient" to restore and maintain sinus rhythm, Dr. Marieke G. Compier said as she presented the findings at the annual scientific sessions of the American Heart Association on Nov. 6.

But a cardiac surgeon who heard the results disagreed, contending that the top priority is performing the procedure that will result in durable prevention of atrial fibrillation (AF) recurrence.

"Recurrence of atrial fibrillation is a more important determinant of [successful] clinical outcomes than preserved atrial function," said Dr. Pierre Page, chief of cardiac surgery at the University of Montreal. "The data we have today show that left-atrial ablation is very beneficial," Dr. Page said in an interview.

Dr. Compier and her associates used echocardiography to assess left-atrial function in 31 patients who underwent a modified Cox-MAZE procedure for complete left-atrial ablation using bilateral bipolar radiofrequency, and 31 patients who underwent pulmonary-vein isolation (PVI) only. In the full ablation group, 25 patients had persistent AF and 6 had paroxysmal AF; in the PVI group, 25 patients had paroxysmal disease and 6 had persistent AF. All patients also underwent concurrent coronary artery bypass, valve surgery, or both.

The researchers assessed the efficacy of AF treatment using 24-hour ECG monitoring at 3, 6, and 12 months following surgery. They also used two-dimensional echocardiography to assess left atrial size and function at 3 months and 1 year after surgery.

After 1 year, 68% of the patients who had full ablation and 81% of those who underwent PVI were free of AF and completely off anti-arrhythmic drug treatment; the other patients in each group had AF recurrences. The different long-term success in maintaining sinus rhythm in the two groups probably stemmed from the unbalanced distribution of patients with paroxysmal and persistent AF, said Dr. Compier, a cardiologist in the Heart Center at Leiden (the Netherlands) University Medical Center. "I think this is why full ablation seemed less successful," she said.

After 1 year, echocardiographic examinations showed that patients treated with full ablation had statistically significant reductions in left atrial volume and strain, and 42% of patients had A-wave restoration. Compared with measurements made prior to surgery, strain rate fell by an average of about 50%, peak A-wave dropped by an average of about a third, and average left-atrial ejection fraction and filling fraction each dropped by about 20%. All of these changes were statistically significant, compared with baseline.

In contrast, patients who underwent PVI had no significant change in their strain rate or peak A wave, and their average left-atrial ejection fraction and filling fraction each rose by about 10% compared with baseline, statistically significant differences. A-wave restoration occurred in 87% of the PVI patients.

Stepwise regression analysis of baseline differences between the two study groups showed that the follow-up differences seen in left-atrial size and function were best explained by the different ablation treatments the two groups received, Dr. Compier said.

Dr. Compier said that she had no disclosures.

LOS ANGELES – Full left-atrial ablation by the modified Cox MAZE procedure to treat atrial fibrillation led to significant reductions in left atrial function, based on a detailed assessment of 31 patients who underwent this treatment using bilateral bipolar radiofrequency.

The damaging effect of complete left-atrial ablation contrasted with the impact of a less extensive procedure, pulmonary vein isolation, which kept left-atrial function intact and even improved it by some parameters. Opinions split on the implications of these findings.

"Our advice is that left-atrial ablation should be restricted to those cases where pulmonary vein isolation will likely be insufficient" to restore and maintain sinus rhythm, Dr. Marieke G. Compier said as she presented the findings at the annual scientific sessions of the American Heart Association on Nov. 6.

But a cardiac surgeon who heard the results disagreed, contending that the top priority is performing the procedure that will result in durable prevention of atrial fibrillation (AF) recurrence.

"Recurrence of atrial fibrillation is a more important determinant of [successful] clinical outcomes than preserved atrial function," said Dr. Pierre Page, chief of cardiac surgery at the University of Montreal. "The data we have today show that left-atrial ablation is very beneficial," Dr. Page said in an interview.

Dr. Compier and her associates used echocardiography to assess left-atrial function in 31 patients who underwent a modified Cox-MAZE procedure for complete left-atrial ablation using bilateral bipolar radiofrequency, and 31 patients who underwent pulmonary-vein isolation (PVI) only. In the full ablation group, 25 patients had persistent AF and 6 had paroxysmal AF; in the PVI group, 25 patients had paroxysmal disease and 6 had persistent AF. All patients also underwent concurrent coronary artery bypass, valve surgery, or both.

The researchers assessed the efficacy of AF treatment using 24-hour ECG monitoring at 3, 6, and 12 months following surgery. They also used two-dimensional echocardiography to assess left atrial size and function at 3 months and 1 year after surgery.

After 1 year, 68% of the patients who had full ablation and 81% of those who underwent PVI were free of AF and completely off anti-arrhythmic drug treatment; the other patients in each group had AF recurrences. The different long-term success in maintaining sinus rhythm in the two groups probably stemmed from the unbalanced distribution of patients with paroxysmal and persistent AF, said Dr. Compier, a cardiologist in the Heart Center at Leiden (the Netherlands) University Medical Center. "I think this is why full ablation seemed less successful," she said.

After 1 year, echocardiographic examinations showed that patients treated with full ablation had statistically significant reductions in left atrial volume and strain, and 42% of patients had A-wave restoration. Compared with measurements made prior to surgery, strain rate fell by an average of about 50%, peak A-wave dropped by an average of about a third, and average left-atrial ejection fraction and filling fraction each dropped by about 20%. All of these changes were statistically significant, compared with baseline.

In contrast, patients who underwent PVI had no significant change in their strain rate or peak A wave, and their average left-atrial ejection fraction and filling fraction each rose by about 10% compared with baseline, statistically significant differences. A-wave restoration occurred in 87% of the PVI patients.

Stepwise regression analysis of baseline differences between the two study groups showed that the follow-up differences seen in left-atrial size and function were best explained by the different ablation treatments the two groups received, Dr. Compier said.

Dr. Compier said that she had no disclosures.

LOS ANGELES – Full left-atrial ablation by the modified Cox MAZE procedure to treat atrial fibrillation led to significant reductions in left atrial function, based on a detailed assessment of 31 patients who underwent this treatment using bilateral bipolar radiofrequency.

The damaging effect of complete left-atrial ablation contrasted with the impact of a less extensive procedure, pulmonary vein isolation, which kept left-atrial function intact and even improved it by some parameters. Opinions split on the implications of these findings.

"Our advice is that left-atrial ablation should be restricted to those cases where pulmonary vein isolation will likely be insufficient" to restore and maintain sinus rhythm, Dr. Marieke G. Compier said as she presented the findings at the annual scientific sessions of the American Heart Association on Nov. 6.

But a cardiac surgeon who heard the results disagreed, contending that the top priority is performing the procedure that will result in durable prevention of atrial fibrillation (AF) recurrence.

"Recurrence of atrial fibrillation is a more important determinant of [successful] clinical outcomes than preserved atrial function," said Dr. Pierre Page, chief of cardiac surgery at the University of Montreal. "The data we have today show that left-atrial ablation is very beneficial," Dr. Page said in an interview.

Dr. Compier and her associates used echocardiography to assess left-atrial function in 31 patients who underwent a modified Cox-MAZE procedure for complete left-atrial ablation using bilateral bipolar radiofrequency, and 31 patients who underwent pulmonary-vein isolation (PVI) only. In the full ablation group, 25 patients had persistent AF and 6 had paroxysmal AF; in the PVI group, 25 patients had paroxysmal disease and 6 had persistent AF. All patients also underwent concurrent coronary artery bypass, valve surgery, or both.

The researchers assessed the efficacy of AF treatment using 24-hour ECG monitoring at 3, 6, and 12 months following surgery. They also used two-dimensional echocardiography to assess left atrial size and function at 3 months and 1 year after surgery.

After 1 year, 68% of the patients who had full ablation and 81% of those who underwent PVI were free of AF and completely off anti-arrhythmic drug treatment; the other patients in each group had AF recurrences. The different long-term success in maintaining sinus rhythm in the two groups probably stemmed from the unbalanced distribution of patients with paroxysmal and persistent AF, said Dr. Compier, a cardiologist in the Heart Center at Leiden (the Netherlands) University Medical Center. "I think this is why full ablation seemed less successful," she said.

After 1 year, echocardiographic examinations showed that patients treated with full ablation had statistically significant reductions in left atrial volume and strain, and 42% of patients had A-wave restoration. Compared with measurements made prior to surgery, strain rate fell by an average of about 50%, peak A-wave dropped by an average of about a third, and average left-atrial ejection fraction and filling fraction each dropped by about 20%. All of these changes were statistically significant, compared with baseline.

In contrast, patients who underwent PVI had no significant change in their strain rate or peak A wave, and their average left-atrial ejection fraction and filling fraction each rose by about 10% compared with baseline, statistically significant differences. A-wave restoration occurred in 87% of the PVI patients.

Stepwise regression analysis of baseline differences between the two study groups showed that the follow-up differences seen in left-atrial size and function were best explained by the different ablation treatments the two groups received, Dr. Compier said.

Dr. Compier said that she had no disclosures.

Intracoronary delivery of bone marrow mononuclear cells to the infarct zone of patients who have undergone percutaneous coronary intervention following an ST-segment elevation myocardial infarction did not improve left ventricular function at 6 months in the TIME trial.

The trial was designed to examine the difference in effect of infusing the bone marrow mononuclear cells (BMCs) into the infarct-related artery at 7 days after PCI and at 3 days, Dr. Jay H. Traverse reported at the annual scientific sessions of the American Heart Association.

Unfortunately, neither of these approaches were any better than placebo infusion at improving the recovery of left ventricular function, improving left ventricular volume, or reducing infarct size at 6 months’ follow-up in this double-blind Timing in Myocardial Infarction Evaluation (TIME) clinical trial, said Dr. Traverse, of the Minneapolis Heart Institute at Abbott Northwestern Hospital.

"However, long-term follow-up of these patients and the development of new composite end points may still reveal a role for this cell type after AMI [acute myocardial infarction]," Dr. Traverse and his associates said in an article published online simultaneously with his presentation (JAMA 2012 Nov. 6 [doi: 10.1001/jama.2012.28726]).

Recent research indicates that the timing of BMC infusion after PCI due to ST-segment elevation myocardial infarction (STEMI) might be critical. In the days following STEMI, there are significant temporal changes in the release of cytokines and growth factors "that may support stem-cell homing and angiogenesis, leading to improved cell survival and engraftment," they noted.

"Conversely, reactive oxygen species and inflammatory cytokines ... released by [damaged] myocardium and circulating inflammatory cells may adversely affect the bone marrow and stem cell function and/or survival." This could in turn impair the quality and potency of BMCs harvested from the patient.

The results of one large study indicated that stem cells harvested 5-7 days after an acute MI performed better than those harvested earlier, but "this important variable has never been evaluated in a prospective trial that randomly selects the day of cell delivery," the researchers said.

The TIME trial was designed to do so.

A total of 132 high-risk patients were enrolled during a 3-year period after they had experienced STEMI, shown a left ventricular ejection fraction (LVEF) of 45% or less, and were slated for PCI with stenting. These subjects were randomly assigned to have stem cell therapy on either day 3 or day 7 after PCI; they underwent bone marrow aspiration on the day of the procedure, and their BMCs were isolated and stored.

After some of these patients were excluded or withdrawn from the study, the remaining 120 patients underwent a second randomization to receive either the autologous BMCs (79 patients) or placebo infusions (41 patients).

The primary end points of TIME were changes in global and regional left ventricular function on MRI scanning at 6 months post PCI. There were no significant differences in these outcomes between subjects who received stem-cell therapy 3 days after PCI and those who received it 7 days after PCI, the investigators reported.

There also were no significant differences among the study groups in secondary outcomes such as reduction in infarct volume or change in ventricular volumes.

However, there also were no significant differences in any outcomes between subjects who received active BMCs and those who received placebo infusions. This may indicate that, contrary to previous findings, BMCs do not improve left ventricular function when administered in the immediate post-STEMI setting.

But it also is possible that "the phenotype and functionality of the BMC product in this population may be an issue," and that allogeneic BMCs procured from younger, healthier donors may have a better regenerative capacity, Dr. Traverse and his colleagues said.

It was encouraging that despite their high risk, these study subjects had few clinical events during follow-up. One death occurred (due to subarachnoid hemorrhage) before stem-cell therapy was administered. Eleven patients required repeat revascularization, and 6 received implantable cardioverter-defibrillators (ICDs). There were no significant differences among the study groups in the rates of these adverse events.

This study was funded by the National Heart, Lung, and Blood Institute. Dr. Traverse reported no financial conflicts of interest, but his associates reported numerous ties to industry sources.

Intracoronary delivery of bone marrow mononuclear cells to the infarct zone of patients who have undergone percutaneous coronary intervention following an ST-segment elevation myocardial infarction did not improve left ventricular function at 6 months in the TIME trial.

The trial was designed to examine the difference in effect of infusing the bone marrow mononuclear cells (BMCs) into the infarct-related artery at 7 days after PCI and at 3 days, Dr. Jay H. Traverse reported at the annual scientific sessions of the American Heart Association.

Unfortunately, neither of these approaches were any better than placebo infusion at improving the recovery of left ventricular function, improving left ventricular volume, or reducing infarct size at 6 months’ follow-up in this double-blind Timing in Myocardial Infarction Evaluation (TIME) clinical trial, said Dr. Traverse, of the Minneapolis Heart Institute at Abbott Northwestern Hospital.

"However, long-term follow-up of these patients and the development of new composite end points may still reveal a role for this cell type after AMI [acute myocardial infarction]," Dr. Traverse and his associates said in an article published online simultaneously with his presentation (JAMA 2012 Nov. 6 [doi: 10.1001/jama.2012.28726]).

Recent research indicates that the timing of BMC infusion after PCI due to ST-segment elevation myocardial infarction (STEMI) might be critical. In the days following STEMI, there are significant temporal changes in the release of cytokines and growth factors "that may support stem-cell homing and angiogenesis, leading to improved cell survival and engraftment," they noted.

"Conversely, reactive oxygen species and inflammatory cytokines ... released by [damaged] myocardium and circulating inflammatory cells may adversely affect the bone marrow and stem cell function and/or survival." This could in turn impair the quality and potency of BMCs harvested from the patient.

The results of one large study indicated that stem cells harvested 5-7 days after an acute MI performed better than those harvested earlier, but "this important variable has never been evaluated in a prospective trial that randomly selects the day of cell delivery," the researchers said.

The TIME trial was designed to do so.

A total of 132 high-risk patients were enrolled during a 3-year period after they had experienced STEMI, shown a left ventricular ejection fraction (LVEF) of 45% or less, and were slated for PCI with stenting. These subjects were randomly assigned to have stem cell therapy on either day 3 or day 7 after PCI; they underwent bone marrow aspiration on the day of the procedure, and their BMCs were isolated and stored.

After some of these patients were excluded or withdrawn from the study, the remaining 120 patients underwent a second randomization to receive either the autologous BMCs (79 patients) or placebo infusions (41 patients).

The primary end points of TIME were changes in global and regional left ventricular function on MRI scanning at 6 months post PCI. There were no significant differences in these outcomes between subjects who received stem-cell therapy 3 days after PCI and those who received it 7 days after PCI, the investigators reported.

There also were no significant differences among the study groups in secondary outcomes such as reduction in infarct volume or change in ventricular volumes.

However, there also were no significant differences in any outcomes between subjects who received active BMCs and those who received placebo infusions. This may indicate that, contrary to previous findings, BMCs do not improve left ventricular function when administered in the immediate post-STEMI setting.

But it also is possible that "the phenotype and functionality of the BMC product in this population may be an issue," and that allogeneic BMCs procured from younger, healthier donors may have a better regenerative capacity, Dr. Traverse and his colleagues said.

It was encouraging that despite their high risk, these study subjects had few clinical events during follow-up. One death occurred (due to subarachnoid hemorrhage) before stem-cell therapy was administered. Eleven patients required repeat revascularization, and 6 received implantable cardioverter-defibrillators (ICDs). There were no significant differences among the study groups in the rates of these adverse events.

This study was funded by the National Heart, Lung, and Blood Institute. Dr. Traverse reported no financial conflicts of interest, but his associates reported numerous ties to industry sources.

Intracoronary delivery of bone marrow mononuclear cells to the infarct zone of patients who have undergone percutaneous coronary intervention following an ST-segment elevation myocardial infarction did not improve left ventricular function at 6 months in the TIME trial.

The trial was designed to examine the difference in effect of infusing the bone marrow mononuclear cells (BMCs) into the infarct-related artery at 7 days after PCI and at 3 days, Dr. Jay H. Traverse reported at the annual scientific sessions of the American Heart Association.

Unfortunately, neither of these approaches were any better than placebo infusion at improving the recovery of left ventricular function, improving left ventricular volume, or reducing infarct size at 6 months’ follow-up in this double-blind Timing in Myocardial Infarction Evaluation (TIME) clinical trial, said Dr. Traverse, of the Minneapolis Heart Institute at Abbott Northwestern Hospital.

"However, long-term follow-up of these patients and the development of new composite end points may still reveal a role for this cell type after AMI [acute myocardial infarction]," Dr. Traverse and his associates said in an article published online simultaneously with his presentation (JAMA 2012 Nov. 6 [doi: 10.1001/jama.2012.28726]).

Recent research indicates that the timing of BMC infusion after PCI due to ST-segment elevation myocardial infarction (STEMI) might be critical. In the days following STEMI, there are significant temporal changes in the release of cytokines and growth factors "that may support stem-cell homing and angiogenesis, leading to improved cell survival and engraftment," they noted.

"Conversely, reactive oxygen species and inflammatory cytokines ... released by [damaged] myocardium and circulating inflammatory cells may adversely affect the bone marrow and stem cell function and/or survival." This could in turn impair the quality and potency of BMCs harvested from the patient.

The results of one large study indicated that stem cells harvested 5-7 days after an acute MI performed better than those harvested earlier, but "this important variable has never been evaluated in a prospective trial that randomly selects the day of cell delivery," the researchers said.

The TIME trial was designed to do so.

A total of 132 high-risk patients were enrolled during a 3-year period after they had experienced STEMI, shown a left ventricular ejection fraction (LVEF) of 45% or less, and were slated for PCI with stenting. These subjects were randomly assigned to have stem cell therapy on either day 3 or day 7 after PCI; they underwent bone marrow aspiration on the day of the procedure, and their BMCs were isolated and stored.

After some of these patients were excluded or withdrawn from the study, the remaining 120 patients underwent a second randomization to receive either the autologous BMCs (79 patients) or placebo infusions (41 patients).

The primary end points of TIME were changes in global and regional left ventricular function on MRI scanning at 6 months post PCI. There were no significant differences in these outcomes between subjects who received stem-cell therapy 3 days after PCI and those who received it 7 days after PCI, the investigators reported.

There also were no significant differences among the study groups in secondary outcomes such as reduction in infarct volume or change in ventricular volumes.

However, there also were no significant differences in any outcomes between subjects who received active BMCs and those who received placebo infusions. This may indicate that, contrary to previous findings, BMCs do not improve left ventricular function when administered in the immediate post-STEMI setting.

But it also is possible that "the phenotype and functionality of the BMC product in this population may be an issue," and that allogeneic BMCs procured from younger, healthier donors may have a better regenerative capacity, Dr. Traverse and his colleagues said.

It was encouraging that despite their high risk, these study subjects had few clinical events during follow-up. One death occurred (due to subarachnoid hemorrhage) before stem-cell therapy was administered. Eleven patients required repeat revascularization, and 6 received implantable cardioverter-defibrillators (ICDs). There were no significant differences among the study groups in the rates of these adverse events.

This study was funded by the National Heart, Lung, and Blood Institute. Dr. Traverse reported no financial conflicts of interest, but his associates reported numerous ties to industry sources.

Allogeneic and autologous stem-cell infusions were found equally safe for ischemic cardiomyopathy in a pilot study comparing the two approaches, Dr. Joshua M. Hare reported at the annual scientific sessions of the American Heart Association.

Transendocardial injections of both types of bone-marrow–derived mesenchymal stem cells produced low rates of adverse events, including immunologic reactions. Both also demonstrated "potential regenerative bioactivity" in patients with chronic left ventricular dysfunction secondary to MI that had occurred years earlier, said Dr. Hare of the Interdisciplinary Stem Cell Institute, University of Miami.

The primary goal of the trial was to establish the safety of allogeneic (donor-derived) stem-cell grafts in the myocardium. Theoretically, they should have an advantage over autologous (self-derived) grafts because they can be stockpiled for immediate use, while autologous grafts must be harvested and grown for several weeks in tissue culture.

In addition, autologous stem cells may be impaired in older patients who have comorbidities, so they may not perform as well when transplanted. Allogeneic stem cells, in contrast, can be taken from younger, healthier donors for optimal performance.

On the other hand, allogeneic mesenchymal stem cells don’t appear to persist as long as autologous stem cells once they are transplanted into the myocardium, possibly because they may be cleared from the body more rapidly due to formation of alloreactive antibodies. So there is some question as to whether their effect will wear off prematurely, Dr. Hare and his associates in the POSEIDON clinical trial said in an article published online simultaneously with the AHA presentation (JAMA 2012 Nov. 6 [doi:10.1001/jama.2012.25321]).

A secondary goal of this phase I/II clinical trial was to assess different doses of stem cells.

In all 30 study subjects, the ventricles had undergone extensive structural remodelling and their function was significantly impaired. All the subjects had heart failure symptoms, impaired 6-minute walk times, and low scores on the Minnesota Living With Heart Failure Questionnaire that measures HF-related quality of life.

All the study subjects underwent bone marrow aspiration from the iliac crest to harvest mesenchymal stem cells 4-6 weeks before undergoing cardiac catheterization. Then they were randomized to receive infusions of either those autologous grafts (15 patients) or allogeneic grafts (15 patients) derived from bone marrow aspirates of healthy donors.

In each of these study groups, subjects were assigned to receive doses of 10 million, 100 million, or 200 million stem cells. These were injected into 10 sites in the infarcted territory of the myocardium during retrograde left heart catheterization.

The primary end point of the study was the incidence of any treatment-related serious adverse event within 1 month of the procedure. This was defined as a composite of death, nonfatal MI, stroke, hospitalization for worsening HF, cardiac perforation, pericardial tamponade, or sustained ventricular arrhythmias.

One subject in each group reached this end point. Both required hospitalization for worsening HF within 30 days. Therefore, there were no differences between the two study groups in the primary end point.

Other, less serious adverse events were slightly more common with autologous than with allogeneic transplants. In particular, events "suggestive of an acute immunogenic reaction, such as fever, urticaria, hemolysis, hypotension, liver dysfunction, and/or thrombocytopenia, did not occur in any patient," the investigators said.

During a further 12 months of follow-up, there was no difference between patients who received allogeneic stem cells and those who received autologous stem cells in the rates of HF or major adverse cardiovascular events. In particular, the rates of arrhythmias, rehospitalization, and worsening HF were either similar between the two study groups or favored the allogeneic-transplant group.

Similarly, the rates of less serious adverse events were slightly higher with autologous than with allogeneic transplants. No ectopic tissue formation was observed in any patient on CT scans of the chest, abdomen, and pelvis.

Regarding the effectiveness of the two transplant approaches, both groups of patients showed equivalent, significant improvements in 6-minute walk times, NYHA class, and HF-related quality of life. Both groups also showed dramatic, 33% reductions in a CT measure of infarct size, as well as decreases in LV systolic and diastolic volumes and increases in ejection fraction.

"Our findings strongly support the ongoing development of allogeneic [stem-cell] therapy," Dr. Hare and his associates said.

Their results must be substantiated in larger phase II studies, given the relatively small sample size, open-label design, and lack of a placebo group in this clinical trial, they added.

And one surprising finding – an inverse dose-response indicating that the lowest dose of stem cells was more effective than the higher doses – was notable. "Future studies are planned to further investigate this important observation," they said.

This study was funded by the National Heart, Lung, and Blood Institute and the National Institutes of Health; Biocardia supplied the cardiac infusion catheters. Dr. Hare reported holding a patent for cardiac cell-based therapy and having ties to Biocardia, Vestion, and Kardia, and his associates reported ties to numerous industry sources.

Allogeneic and autologous stem-cell infusions were found equally safe for ischemic cardiomyopathy in a pilot study comparing the two approaches, Dr. Joshua M. Hare reported at the annual scientific sessions of the American Heart Association.

Transendocardial injections of both types of bone-marrow–derived mesenchymal stem cells produced low rates of adverse events, including immunologic reactions. Both also demonstrated "potential regenerative bioactivity" in patients with chronic left ventricular dysfunction secondary to MI that had occurred years earlier, said Dr. Hare of the Interdisciplinary Stem Cell Institute, University of Miami.

The primary goal of the trial was to establish the safety of allogeneic (donor-derived) stem-cell grafts in the myocardium. Theoretically, they should have an advantage over autologous (self-derived) grafts because they can be stockpiled for immediate use, while autologous grafts must be harvested and grown for several weeks in tissue culture.

In addition, autologous stem cells may be impaired in older patients who have comorbidities, so they may not perform as well when transplanted. Allogeneic stem cells, in contrast, can be taken from younger, healthier donors for optimal performance.

On the other hand, allogeneic mesenchymal stem cells don’t appear to persist as long as autologous stem cells once they are transplanted into the myocardium, possibly because they may be cleared from the body more rapidly due to formation of alloreactive antibodies. So there is some question as to whether their effect will wear off prematurely, Dr. Hare and his associates in the POSEIDON clinical trial said in an article published online simultaneously with the AHA presentation (JAMA 2012 Nov. 6 [doi:10.1001/jama.2012.25321]).

A secondary goal of this phase I/II clinical trial was to assess different doses of stem cells.

In all 30 study subjects, the ventricles had undergone extensive structural remodelling and their function was significantly impaired. All the subjects had heart failure symptoms, impaired 6-minute walk times, and low scores on the Minnesota Living With Heart Failure Questionnaire that measures HF-related quality of life.

All the study subjects underwent bone marrow aspiration from the iliac crest to harvest mesenchymal stem cells 4-6 weeks before undergoing cardiac catheterization. Then they were randomized to receive infusions of either those autologous grafts (15 patients) or allogeneic grafts (15 patients) derived from bone marrow aspirates of healthy donors.

In each of these study groups, subjects were assigned to receive doses of 10 million, 100 million, or 200 million stem cells. These were injected into 10 sites in the infarcted territory of the myocardium during retrograde left heart catheterization.

The primary end point of the study was the incidence of any treatment-related serious adverse event within 1 month of the procedure. This was defined as a composite of death, nonfatal MI, stroke, hospitalization for worsening HF, cardiac perforation, pericardial tamponade, or sustained ventricular arrhythmias.

One subject in each group reached this end point. Both required hospitalization for worsening HF within 30 days. Therefore, there were no differences between the two study groups in the primary end point.

Other, less serious adverse events were slightly more common with autologous than with allogeneic transplants. In particular, events "suggestive of an acute immunogenic reaction, such as fever, urticaria, hemolysis, hypotension, liver dysfunction, and/or thrombocytopenia, did not occur in any patient," the investigators said.

During a further 12 months of follow-up, there was no difference between patients who received allogeneic stem cells and those who received autologous stem cells in the rates of HF or major adverse cardiovascular events. In particular, the rates of arrhythmias, rehospitalization, and worsening HF were either similar between the two study groups or favored the allogeneic-transplant group.

Similarly, the rates of less serious adverse events were slightly higher with autologous than with allogeneic transplants. No ectopic tissue formation was observed in any patient on CT scans of the chest, abdomen, and pelvis.

Regarding the effectiveness of the two transplant approaches, both groups of patients showed equivalent, significant improvements in 6-minute walk times, NYHA class, and HF-related quality of life. Both groups also showed dramatic, 33% reductions in a CT measure of infarct size, as well as decreases in LV systolic and diastolic volumes and increases in ejection fraction.

"Our findings strongly support the ongoing development of allogeneic [stem-cell] therapy," Dr. Hare and his associates said.

Their results must be substantiated in larger phase II studies, given the relatively small sample size, open-label design, and lack of a placebo group in this clinical trial, they added.

And one surprising finding – an inverse dose-response indicating that the lowest dose of stem cells was more effective than the higher doses – was notable. "Future studies are planned to further investigate this important observation," they said.

This study was funded by the National Heart, Lung, and Blood Institute and the National Institutes of Health; Biocardia supplied the cardiac infusion catheters. Dr. Hare reported holding a patent for cardiac cell-based therapy and having ties to Biocardia, Vestion, and Kardia, and his associates reported ties to numerous industry sources.

Allogeneic and autologous stem-cell infusions were found equally safe for ischemic cardiomyopathy in a pilot study comparing the two approaches, Dr. Joshua M. Hare reported at the annual scientific sessions of the American Heart Association.

Transendocardial injections of both types of bone-marrow–derived mesenchymal stem cells produced low rates of adverse events, including immunologic reactions. Both also demonstrated "potential regenerative bioactivity" in patients with chronic left ventricular dysfunction secondary to MI that had occurred years earlier, said Dr. Hare of the Interdisciplinary Stem Cell Institute, University of Miami.

The primary goal of the trial was to establish the safety of allogeneic (donor-derived) stem-cell grafts in the myocardium. Theoretically, they should have an advantage over autologous (self-derived) grafts because they can be stockpiled for immediate use, while autologous grafts must be harvested and grown for several weeks in tissue culture.

In addition, autologous stem cells may be impaired in older patients who have comorbidities, so they may not perform as well when transplanted. Allogeneic stem cells, in contrast, can be taken from younger, healthier donors for optimal performance.

On the other hand, allogeneic mesenchymal stem cells don’t appear to persist as long as autologous stem cells once they are transplanted into the myocardium, possibly because they may be cleared from the body more rapidly due to formation of alloreactive antibodies. So there is some question as to whether their effect will wear off prematurely, Dr. Hare and his associates in the POSEIDON clinical trial said in an article published online simultaneously with the AHA presentation (JAMA 2012 Nov. 6 [doi:10.1001/jama.2012.25321]).

A secondary goal of this phase I/II clinical trial was to assess different doses of stem cells.

In all 30 study subjects, the ventricles had undergone extensive structural remodelling and their function was significantly impaired. All the subjects had heart failure symptoms, impaired 6-minute walk times, and low scores on the Minnesota Living With Heart Failure Questionnaire that measures HF-related quality of life.

All the study subjects underwent bone marrow aspiration from the iliac crest to harvest mesenchymal stem cells 4-6 weeks before undergoing cardiac catheterization. Then they were randomized to receive infusions of either those autologous grafts (15 patients) or allogeneic grafts (15 patients) derived from bone marrow aspirates of healthy donors.

In each of these study groups, subjects were assigned to receive doses of 10 million, 100 million, or 200 million stem cells. These were injected into 10 sites in the infarcted territory of the myocardium during retrograde left heart catheterization.

The primary end point of the study was the incidence of any treatment-related serious adverse event within 1 month of the procedure. This was defined as a composite of death, nonfatal MI, stroke, hospitalization for worsening HF, cardiac perforation, pericardial tamponade, or sustained ventricular arrhythmias.

One subject in each group reached this end point. Both required hospitalization for worsening HF within 30 days. Therefore, there were no differences between the two study groups in the primary end point.

Other, less serious adverse events were slightly more common with autologous than with allogeneic transplants. In particular, events "suggestive of an acute immunogenic reaction, such as fever, urticaria, hemolysis, hypotension, liver dysfunction, and/or thrombocytopenia, did not occur in any patient," the investigators said.

During a further 12 months of follow-up, there was no difference between patients who received allogeneic stem cells and those who received autologous stem cells in the rates of HF or major adverse cardiovascular events. In particular, the rates of arrhythmias, rehospitalization, and worsening HF were either similar between the two study groups or favored the allogeneic-transplant group.

Similarly, the rates of less serious adverse events were slightly higher with autologous than with allogeneic transplants. No ectopic tissue formation was observed in any patient on CT scans of the chest, abdomen, and pelvis.

Regarding the effectiveness of the two transplant approaches, both groups of patients showed equivalent, significant improvements in 6-minute walk times, NYHA class, and HF-related quality of life. Both groups also showed dramatic, 33% reductions in a CT measure of infarct size, as well as decreases in LV systolic and diastolic volumes and increases in ejection fraction.

"Our findings strongly support the ongoing development of allogeneic [stem-cell] therapy," Dr. Hare and his associates said.

Their results must be substantiated in larger phase II studies, given the relatively small sample size, open-label design, and lack of a placebo group in this clinical trial, they added.

And one surprising finding – an inverse dose-response indicating that the lowest dose of stem cells was more effective than the higher doses – was notable. "Future studies are planned to further investigate this important observation," they said.

This study was funded by the National Heart, Lung, and Blood Institute and the National Institutes of Health; Biocardia supplied the cardiac infusion catheters. Dr. Hare reported holding a patent for cardiac cell-based therapy and having ties to Biocardia, Vestion, and Kardia, and his associates reported ties to numerous industry sources.

SEATTLE – Smartphones may soon be harnessed for monitoring patients with heart failure, offering advantages such as remote assessment and early prediction of decompensation.

A recent survey suggested that 88% of physicians would like to be able to monitor measures of their patients’ health status at home, including many relevant to heart failure. "Those metrics will become more and more available" with smartphone technology, noted Dr. David E. Albert, founder and chief scientific officer of AliveCor Inc., a manufacturer of mobile monitors, including the investigational AliveCor Smartphone System.

Image Courtesy AliveCor

The device is an ECG monitor that is in clinical trials and under review by the Food and Drug Administration. A patient uses a smartphone and an app to record a clinical-quality ECG that is securely stored and processed in cloud computing-based server, and can be accessed by a physician anywhere in the world.

The device can evaluate at least three cardiac indices used in the monitoring of heart failure, according to Dr. Albert: cardiac rhythm, heart rate, and heart rate variability.

When it comes to cardiac rhythm, smartphones can be used to detect arrhythmias such as atrial fibrillation (J. Am. Coll. Cardiol. 2012;59:E726). He recounted the story of a man in Mumbai, India, experiencing asymptomatic ischemia-induced rhythm changes that were recorded with a smartphone. Physicians in Oklahoma City and Los Angeles identified the arrhythmia and notified the patient, who then went to his physician.

The ECG obtained with the smartphone has the same quality as a 12-lead ECG obtained with state-of-the-art equipment in the clinic, he said. Also, data suggest that a daily ECG is second only to implanted devices for detecting atrial fibrillation (Pacing Clin. Electrophysiol. 2007;30:458-62). "So it’s better than a 24-hour Holter, even now, and our very intermittent 7-day Holters."

Heart rate, the second index, may be a key therapeutic target in heart failure. Here, too, the smartphone-assessed heart rate is just as accurate as clinically measured heart rate, with sensitivity exceeding 99% for QRS detection (and thus R to R intervals), putting it on par with the 12-lead ECG, according to Dr. Albert.

Heart rate variability, the third index, potentially could be used as an index to guide the need for intervention before progression to decompensated heart failure.

Decompensation develops through a series of changes beginning with increasing preload and autonomic adaptation, and culminating in weight gain, symptoms, and hospitalization (Curr. Heart Fail. Rep. 2009;6:287-92). "Obviously, we want to operate on the left side of this graph, where filling and autonomic adaptation are the places we can intervene early," he noted.

Short-term heart rate variability obtained during 8 minutes of paced breathing has been shown to predict sudden cardiac death in patients having chronic heart failure (Circulation 2003;107:565-70), and smartphones can readily be used for such measurement.

The timing of events during the cardiac cycle may also be informative, according to Dr. Albert. These events can be assessed with seismocardiography, whereby vibrations in the chest are measured with an accelerometer placed on the sternum (Chest 1991;100:991-3) and can be combined with ECG data to derive the Tei index, a global measure of cardiac performance (J. Cardiol. 1995;26:135-6). Although the necessary data can be collected with a somewhat elaborate laboratory setup (J. Med. Biol. Engineer 2012;32:103-10), they can also be obtained easily with a smartphone placed on the chest.

"We can measure isovolumic contraction time, isovolumic relaxation time, and ejection time, and develop in 30 seconds not only rate, rhythm, variability, but now a modified Tei index, an index of performance, and as many papers have said, an index of preload status," he noted.

"With today’s smartphones, which will only get more powerful, we can evaluate cardiac rhythm, or our patients can. They can evaluate their cardiac rate, their heart rate variability, and probably potentially – unproven yet very interesting – their ventricular performance and their preload status, enabling that [information] to be injected into the network, enabling certainly intervention and maybe self-care," Dr. Albert concluded.

A session attendee said that this new technology "sounds very good. But we know even when [clinical devices] are used just to study time intervals, there were a lot of artifacts, and accuracy was not very easily determined. Certainly, with this kind of platform, there must be problems with accuracy and artifact in recordings."

It is still early in development of this technology, Dr. Albert acknowledged. "But understand that we have processing power that’s quite unbelievable. ... What I can tell you is that we can measure these variables; what I can’t tell you is how valuable they are going to be."

Another attendee expressed concern over the vast amount of data that would be generated and then require analysis. "How far are we going to go before we get to the point where we need a different layer besides the physician, the nurses, the PAs? If you are going to swamp us with this much data, there is no way a busy doctor seeing 20 heart patients a day, going to the cath lab, can possibly figure out so much data, what’s important, what’s not," he said.

Recently, the venture capitalist Vinod Khosla put forth a paper calling for fewer doctors and more algorithms, Dr. Albert replied. "I don’t think we will disenfranchise physicians, but I do believe the power of big data will become more and more important for all of us in the management of all our patients," he predicted.

"Apps will be in our pockets as professionals; they will be in our patients’ pockets. And we must figure out how to utilize them to help us deal with major health care issues of the day."

Dr. Albert disclosed that he is member of the board of directors of, a full-time salaried employee of, and an equity shareholder in AliveCor.

SEATTLE – Smartphones may soon be harnessed for monitoring patients with heart failure, offering advantages such as remote assessment and early prediction of decompensation.

A recent survey suggested that 88% of physicians would like to be able to monitor measures of their patients’ health status at home, including many relevant to heart failure. "Those metrics will become more and more available" with smartphone technology, noted Dr. David E. Albert, founder and chief scientific officer of AliveCor Inc., a manufacturer of mobile monitors, including the investigational AliveCor Smartphone System.

Image Courtesy AliveCor

The device is an ECG monitor that is in clinical trials and under review by the Food and Drug Administration. A patient uses a smartphone and an app to record a clinical-quality ECG that is securely stored and processed in cloud computing-based server, and can be accessed by a physician anywhere in the world.

The device can evaluate at least three cardiac indices used in the monitoring of heart failure, according to Dr. Albert: cardiac rhythm, heart rate, and heart rate variability.

When it comes to cardiac rhythm, smartphones can be used to detect arrhythmias such as atrial fibrillation (J. Am. Coll. Cardiol. 2012;59:E726). He recounted the story of a man in Mumbai, India, experiencing asymptomatic ischemia-induced rhythm changes that were recorded with a smartphone. Physicians in Oklahoma City and Los Angeles identified the arrhythmia and notified the patient, who then went to his physician.

The ECG obtained with the smartphone has the same quality as a 12-lead ECG obtained with state-of-the-art equipment in the clinic, he said. Also, data suggest that a daily ECG is second only to implanted devices for detecting atrial fibrillation (Pacing Clin. Electrophysiol. 2007;30:458-62). "So it’s better than a 24-hour Holter, even now, and our very intermittent 7-day Holters."

Heart rate, the second index, may be a key therapeutic target in heart failure. Here, too, the smartphone-assessed heart rate is just as accurate as clinically measured heart rate, with sensitivity exceeding 99% for QRS detection (and thus R to R intervals), putting it on par with the 12-lead ECG, according to Dr. Albert.

Heart rate variability, the third index, potentially could be used as an index to guide the need for intervention before progression to decompensated heart failure.

Decompensation develops through a series of changes beginning with increasing preload and autonomic adaptation, and culminating in weight gain, symptoms, and hospitalization (Curr. Heart Fail. Rep. 2009;6:287-92). "Obviously, we want to operate on the left side of this graph, where filling and autonomic adaptation are the places we can intervene early," he noted.

Short-term heart rate variability obtained during 8 minutes of paced breathing has been shown to predict sudden cardiac death in patients having chronic heart failure (Circulation 2003;107:565-70), and smartphones can readily be used for such measurement.

The timing of events during the cardiac cycle may also be informative, according to Dr. Albert. These events can be assessed with seismocardiography, whereby vibrations in the chest are measured with an accelerometer placed on the sternum (Chest 1991;100:991-3) and can be combined with ECG data to derive the Tei index, a global measure of cardiac performance (J. Cardiol. 1995;26:135-6). Although the necessary data can be collected with a somewhat elaborate laboratory setup (J. Med. Biol. Engineer 2012;32:103-10), they can also be obtained easily with a smartphone placed on the chest.

"We can measure isovolumic contraction time, isovolumic relaxation time, and ejection time, and develop in 30 seconds not only rate, rhythm, variability, but now a modified Tei index, an index of performance, and as many papers have said, an index of preload status," he noted.

"With today’s smartphones, which will only get more powerful, we can evaluate cardiac rhythm, or our patients can. They can evaluate their cardiac rate, their heart rate variability, and probably potentially – unproven yet very interesting – their ventricular performance and their preload status, enabling that [information] to be injected into the network, enabling certainly intervention and maybe self-care," Dr. Albert concluded.

A session attendee said that this new technology "sounds very good. But we know even when [clinical devices] are used just to study time intervals, there were a lot of artifacts, and accuracy was not very easily determined. Certainly, with this kind of platform, there must be problems with accuracy and artifact in recordings."

It is still early in development of this technology, Dr. Albert acknowledged. "But understand that we have processing power that’s quite unbelievable. ... What I can tell you is that we can measure these variables; what I can’t tell you is how valuable they are going to be."

Another attendee expressed concern over the vast amount of data that would be generated and then require analysis. "How far are we going to go before we get to the point where we need a different layer besides the physician, the nurses, the PAs? If you are going to swamp us with this much data, there is no way a busy doctor seeing 20 heart patients a day, going to the cath lab, can possibly figure out so much data, what’s important, what’s not," he said.

Recently, the venture capitalist Vinod Khosla put forth a paper calling for fewer doctors and more algorithms, Dr. Albert replied. "I don’t think we will disenfranchise physicians, but I do believe the power of big data will become more and more important for all of us in the management of all our patients," he predicted.

"Apps will be in our pockets as professionals; they will be in our patients’ pockets. And we must figure out how to utilize them to help us deal with major health care issues of the day."

Dr. Albert disclosed that he is member of the board of directors of, a full-time salaried employee of, and an equity shareholder in AliveCor.

SEATTLE – Smartphones may soon be harnessed for monitoring patients with heart failure, offering advantages such as remote assessment and early prediction of decompensation.

A recent survey suggested that 88% of physicians would like to be able to monitor measures of their patients’ health status at home, including many relevant to heart failure. "Those metrics will become more and more available" with smartphone technology, noted Dr. David E. Albert, founder and chief scientific officer of AliveCor Inc., a manufacturer of mobile monitors, including the investigational AliveCor Smartphone System.

Image Courtesy AliveCor

The device is an ECG monitor that is in clinical trials and under review by the Food and Drug Administration. A patient uses a smartphone and an app to record a clinical-quality ECG that is securely stored and processed in cloud computing-based server, and can be accessed by a physician anywhere in the world.

The device can evaluate at least three cardiac indices used in the monitoring of heart failure, according to Dr. Albert: cardiac rhythm, heart rate, and heart rate variability.

When it comes to cardiac rhythm, smartphones can be used to detect arrhythmias such as atrial fibrillation (J. Am. Coll. Cardiol. 2012;59:E726). He recounted the story of a man in Mumbai, India, experiencing asymptomatic ischemia-induced rhythm changes that were recorded with a smartphone. Physicians in Oklahoma City and Los Angeles identified the arrhythmia and notified the patient, who then went to his physician.

The ECG obtained with the smartphone has the same quality as a 12-lead ECG obtained with state-of-the-art equipment in the clinic, he said. Also, data suggest that a daily ECG is second only to implanted devices for detecting atrial fibrillation (Pacing Clin. Electrophysiol. 2007;30:458-62). "So it’s better than a 24-hour Holter, even now, and our very intermittent 7-day Holters."

Heart rate, the second index, may be a key therapeutic target in heart failure. Here, too, the smartphone-assessed heart rate is just as accurate as clinically measured heart rate, with sensitivity exceeding 99% for QRS detection (and thus R to R intervals), putting it on par with the 12-lead ECG, according to Dr. Albert.

Heart rate variability, the third index, potentially could be used as an index to guide the need for intervention before progression to decompensated heart failure.

Decompensation develops through a series of changes beginning with increasing preload and autonomic adaptation, and culminating in weight gain, symptoms, and hospitalization (Curr. Heart Fail. Rep. 2009;6:287-92). "Obviously, we want to operate on the left side of this graph, where filling and autonomic adaptation are the places we can intervene early," he noted.

Short-term heart rate variability obtained during 8 minutes of paced breathing has been shown to predict sudden cardiac death in patients having chronic heart failure (Circulation 2003;107:565-70), and smartphones can readily be used for such measurement.

The timing of events during the cardiac cycle may also be informative, according to Dr. Albert. These events can be assessed with seismocardiography, whereby vibrations in the chest are measured with an accelerometer placed on the sternum (Chest 1991;100:991-3) and can be combined with ECG data to derive the Tei index, a global measure of cardiac performance (J. Cardiol. 1995;26:135-6). Although the necessary data can be collected with a somewhat elaborate laboratory setup (J. Med. Biol. Engineer 2012;32:103-10), they can also be obtained easily with a smartphone placed on the chest.

"We can measure isovolumic contraction time, isovolumic relaxation time, and ejection time, and develop in 30 seconds not only rate, rhythm, variability, but now a modified Tei index, an index of performance, and as many papers have said, an index of preload status," he noted.

"With today’s smartphones, which will only get more powerful, we can evaluate cardiac rhythm, or our patients can. They can evaluate their cardiac rate, their heart rate variability, and probably potentially – unproven yet very interesting – their ventricular performance and their preload status, enabling that [information] to be injected into the network, enabling certainly intervention and maybe self-care," Dr. Albert concluded.

A session attendee said that this new technology "sounds very good. But we know even when [clinical devices] are used just to study time intervals, there were a lot of artifacts, and accuracy was not very easily determined. Certainly, with this kind of platform, there must be problems with accuracy and artifact in recordings."

It is still early in development of this technology, Dr. Albert acknowledged. "But understand that we have processing power that’s quite unbelievable. ... What I can tell you is that we can measure these variables; what I can’t tell you is how valuable they are going to be."

Another attendee expressed concern over the vast amount of data that would be generated and then require analysis. "How far are we going to go before we get to the point where we need a different layer besides the physician, the nurses, the PAs? If you are going to swamp us with this much data, there is no way a busy doctor seeing 20 heart patients a day, going to the cath lab, can possibly figure out so much data, what’s important, what’s not," he said.

Recently, the venture capitalist Vinod Khosla put forth a paper calling for fewer doctors and more algorithms, Dr. Albert replied. "I don’t think we will disenfranchise physicians, but I do believe the power of big data will become more and more important for all of us in the management of all our patients," he predicted.

"Apps will be in our pockets as professionals; they will be in our patients’ pockets. And we must figure out how to utilize them to help us deal with major health care issues of the day."

Dr. Albert disclosed that he is member of the board of directors of, a full-time salaried employee of, and an equity shareholder in AliveCor.