AHA Scientific Sessions 2012

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.

The maxim that diabetes is a coronary risk equivalent is falling out of favor.

Some experts now say that while diabetes raises a patient’s risk for developing cardiovascular events, it doesn’t pack nearly the same punch as a history of coronary disease.

One reason for this disconnect may be widespread use of statins, which seem to blunt the impact of hyperglycemia on cardiovascular disease by damping down the low-density lipoprotein (LDL) cholesterol part of the risk equation.

©Science; used with permission

At the American Heart Association Scientific Sessions in Los Angeles, Toronto endocrinologist Dr. Lawrence Leiter ran through the up-and-down history of diabetes as a coronary-disease risk equivalent. He traced the origin of the idea to a 1998 report that analyzed data from Finland showed that the rate of a future myocardial infarction (MI) in patients with diabetes but no history of MI (about 20% over 7 years) was strikingly similar to the rate seen in patients with a history of MI but no diabetes (N. Engl. J. Med. 1998;339:229-34).

While results from some subsequent studies supported this pattern and led to the risk-equivalent concept getting enshrined in the official U.S. 2002 cholesterol-treatment guidelines, a larger number of studies showed something else: Patients with a history of MI had a substantially higher rate of subsequent MIs or cardiovascular deaths than patients with diabetes but no coronary disease history. For example, Dr. Leiter cited recent study results that analyzed outcomes of more than 1.2 million Alberta, Canada, residents over 4 years (Lancet 2012;380:807-14).

Patients with a prior MI had new MIs at a rate of 19/1,000 person-years of follow-up, compared with a rate of 5/1,000 person-years’ follow-up in patients with a history of diabetes and no prior MI.

Dr. Leiter said the misleading 1998 result that launched the risk-equivalent canard may have happened because the study was in Finland, a country with a high rate of coronary disease (and, he could have added, lots of people with high LDL levels). "The risk of cardiovascular disease in patients with diabetes is high, although not to the point that diabetes is a coronary disease risk equivalent," he said. But he still strongly endorsed using statins to reduce whatever elevated risk a patient with diabetes has. "Given that the price of statins has fallen and the safety of statins is remarkably good, one could argue that you don’t need to risk stratify diabetics to decide who to put on a statin."

More evidence of a diabetes and cardiovascular disease disconnect came in a separate talk at the meeting by Dr. Thomas Pearson, a Rochester, N.Y., preventive medicine specialist, who addressed this paradox: If diabetes and cardiovascular disease are so tightly linked, why over the past 40 years has the prevalence of obesity and diabetes in the United States soared while cardiovascular disease rates fell?

Statins are why, Dr. Pearson said, and perhaps some diet improvement, too.

"LDL is the primary determinant of atherosclerosis; reduced levels [of LDL] negate the effects of diabetes and other obesity-related risk factors," he said.

Dr. Pearson cited a 2005 study of data collected during 1960-2000 by the U.S. National Health Examination Survey that showed among obese Americans (with a body mass index of 30 kg/m² or more) levels of elevated total cholesterol (240 mg/dL or greater) fell by more than half, from a 39% prevalence in 1960 to an 18% prevalence in 2000.

He also pointed to an epidemiologic study he collaborated on that examined LDL levels and diabetes prevalence on the Caribbean island of Grenada. Coronary disease is essentially nonexistent in Grenada, no cardiologists practice there, and Dr. Pearson said "I spent 3 years looking and never found a person with an MI."

That situation exists even though the average body mass index among middle-aged women is 30 kg/m² (meaning that half of the women are obese), and 16% of men and 30% of women who are 55-64 years old have diabetes. But their average LDL cholesterol level is around 130 mg/dL, a relatively low level.

"Grenada is a low-LDL population that can apparently brush off diabetes," he told me. The implications go far beyond the small island nation: "If you can get your LDL cholesterol under control, the other things, like diabetes and hypertension, don’t mean as much," at least for macrovascular disease like MIs. Low LDL means no atherosclerosis, so "you don’t have diabetes, obesity, or hypertension acting on an atherosclerotic substrate."

–Mitchel L. Zoler (on Twitter @mitchelzoler)

The maxim that diabetes is a coronary risk equivalent is falling out of favor.

Some experts now say that while diabetes raises a patient’s risk for developing cardiovascular events, it doesn’t pack nearly the same punch as a history of coronary disease.

One reason for this disconnect may be widespread use of statins, which seem to blunt the impact of hyperglycemia on cardiovascular disease by damping down the low-density lipoprotein (LDL) cholesterol part of the risk equation.

©Science; used with permission

At the American Heart Association Scientific Sessions in Los Angeles, Toronto endocrinologist Dr. Lawrence Leiter ran through the up-and-down history of diabetes as a coronary-disease risk equivalent. He traced the origin of the idea to a 1998 report that analyzed data from Finland showed that the rate of a future myocardial infarction (MI) in patients with diabetes but no history of MI (about 20% over 7 years) was strikingly similar to the rate seen in patients with a history of MI but no diabetes (N. Engl. J. Med. 1998;339:229-34).

While results from some subsequent studies supported this pattern and led to the risk-equivalent concept getting enshrined in the official U.S. 2002 cholesterol-treatment guidelines, a larger number of studies showed something else: Patients with a history of MI had a substantially higher rate of subsequent MIs or cardiovascular deaths than patients with diabetes but no coronary disease history. For example, Dr. Leiter cited recent study results that analyzed outcomes of more than 1.2 million Alberta, Canada, residents over 4 years (Lancet 2012;380:807-14).

Patients with a prior MI had new MIs at a rate of 19/1,000 person-years of follow-up, compared with a rate of 5/1,000 person-years’ follow-up in patients with a history of diabetes and no prior MI.

Dr. Leiter said the misleading 1998 result that launched the risk-equivalent canard may have happened because the study was in Finland, a country with a high rate of coronary disease (and, he could have added, lots of people with high LDL levels). "The risk of cardiovascular disease in patients with diabetes is high, although not to the point that diabetes is a coronary disease risk equivalent," he said. But he still strongly endorsed using statins to reduce whatever elevated risk a patient with diabetes has. "Given that the price of statins has fallen and the safety of statins is remarkably good, one could argue that you don’t need to risk stratify diabetics to decide who to put on a statin."

More evidence of a diabetes and cardiovascular disease disconnect came in a separate talk at the meeting by Dr. Thomas Pearson, a Rochester, N.Y., preventive medicine specialist, who addressed this paradox: If diabetes and cardiovascular disease are so tightly linked, why over the past 40 years has the prevalence of obesity and diabetes in the United States soared while cardiovascular disease rates fell?

Statins are why, Dr. Pearson said, and perhaps some diet improvement, too.

"LDL is the primary determinant of atherosclerosis; reduced levels [of LDL] negate the effects of diabetes and other obesity-related risk factors," he said.

Dr. Pearson cited a 2005 study of data collected during 1960-2000 by the U.S. National Health Examination Survey that showed among obese Americans (with a body mass index of 30 kg/m² or more) levels of elevated total cholesterol (240 mg/dL or greater) fell by more than half, from a 39% prevalence in 1960 to an 18% prevalence in 2000.

He also pointed to an epidemiologic study he collaborated on that examined LDL levels and diabetes prevalence on the Caribbean island of Grenada. Coronary disease is essentially nonexistent in Grenada, no cardiologists practice there, and Dr. Pearson said "I spent 3 years looking and never found a person with an MI."

That situation exists even though the average body mass index among middle-aged women is 30 kg/m² (meaning that half of the women are obese), and 16% of men and 30% of women who are 55-64 years old have diabetes. But their average LDL cholesterol level is around 130 mg/dL, a relatively low level.

"Grenada is a low-LDL population that can apparently brush off diabetes," he told me. The implications go far beyond the small island nation: "If you can get your LDL cholesterol under control, the other things, like diabetes and hypertension, don’t mean as much," at least for macrovascular disease like MIs. Low LDL means no atherosclerosis, so "you don’t have diabetes, obesity, or hypertension acting on an atherosclerotic substrate."

–Mitchel L. Zoler (on Twitter @mitchelzoler)

The maxim that diabetes is a coronary risk equivalent is falling out of favor.

Some experts now say that while diabetes raises a patient’s risk for developing cardiovascular events, it doesn’t pack nearly the same punch as a history of coronary disease.

One reason for this disconnect may be widespread use of statins, which seem to blunt the impact of hyperglycemia on cardiovascular disease by damping down the low-density lipoprotein (LDL) cholesterol part of the risk equation.

©Science; used with permission

At the American Heart Association Scientific Sessions in Los Angeles, Toronto endocrinologist Dr. Lawrence Leiter ran through the up-and-down history of diabetes as a coronary-disease risk equivalent. He traced the origin of the idea to a 1998 report that analyzed data from Finland showed that the rate of a future myocardial infarction (MI) in patients with diabetes but no history of MI (about 20% over 7 years) was strikingly similar to the rate seen in patients with a history of MI but no diabetes (N. Engl. J. Med. 1998;339:229-34).

While results from some subsequent studies supported this pattern and led to the risk-equivalent concept getting enshrined in the official U.S. 2002 cholesterol-treatment guidelines, a larger number of studies showed something else: Patients with a history of MI had a substantially higher rate of subsequent MIs or cardiovascular deaths than patients with diabetes but no coronary disease history. For example, Dr. Leiter cited recent study results that analyzed outcomes of more than 1.2 million Alberta, Canada, residents over 4 years (Lancet 2012;380:807-14).

Patients with a prior MI had new MIs at a rate of 19/1,000 person-years of follow-up, compared with a rate of 5/1,000 person-years’ follow-up in patients with a history of diabetes and no prior MI.

Dr. Leiter said the misleading 1998 result that launched the risk-equivalent canard may have happened because the study was in Finland, a country with a high rate of coronary disease (and, he could have added, lots of people with high LDL levels). "The risk of cardiovascular disease in patients with diabetes is high, although not to the point that diabetes is a coronary disease risk equivalent," he said. But he still strongly endorsed using statins to reduce whatever elevated risk a patient with diabetes has. "Given that the price of statins has fallen and the safety of statins is remarkably good, one could argue that you don’t need to risk stratify diabetics to decide who to put on a statin."

More evidence of a diabetes and cardiovascular disease disconnect came in a separate talk at the meeting by Dr. Thomas Pearson, a Rochester, N.Y., preventive medicine specialist, who addressed this paradox: If diabetes and cardiovascular disease are so tightly linked, why over the past 40 years has the prevalence of obesity and diabetes in the United States soared while cardiovascular disease rates fell?

Statins are why, Dr. Pearson said, and perhaps some diet improvement, too.

"LDL is the primary determinant of atherosclerosis; reduced levels [of LDL] negate the effects of diabetes and other obesity-related risk factors," he said.

Dr. Pearson cited a 2005 study of data collected during 1960-2000 by the U.S. National Health Examination Survey that showed among obese Americans (with a body mass index of 30 kg/m² or more) levels of elevated total cholesterol (240 mg/dL or greater) fell by more than half, from a 39% prevalence in 1960 to an 18% prevalence in 2000.

He also pointed to an epidemiologic study he collaborated on that examined LDL levels and diabetes prevalence on the Caribbean island of Grenada. Coronary disease is essentially nonexistent in Grenada, no cardiologists practice there, and Dr. Pearson said "I spent 3 years looking and never found a person with an MI."

That situation exists even though the average body mass index among middle-aged women is 30 kg/m² (meaning that half of the women are obese), and 16% of men and 30% of women who are 55-64 years old have diabetes. But their average LDL cholesterol level is around 130 mg/dL, a relatively low level.

"Grenada is a low-LDL population that can apparently brush off diabetes," he told me. The implications go far beyond the small island nation: "If you can get your LDL cholesterol under control, the other things, like diabetes and hypertension, don’t mean as much," at least for macrovascular disease like MIs. Low LDL means no atherosclerosis, so "you don’t have diabetes, obesity, or hypertension acting on an atherosclerotic substrate."

–Mitchel L. Zoler (on Twitter @mitchelzoler)

LOS ANGELES – Pregnancy loss is strongly associated with increased risks of three different clinical forms of atherosclerotic disease over the subsequent 15 years, a study of more than 1 million Danish pregnant women has shown.

"This is the largest-ever study on the occurrence of atherosclerotic disease after pregnancy loss. This study, taken together with previous studies, implies a possible common underlying pathology linking pregnancy losses and atherosclerosis," said Dr. Mattis F. Ranthe of the Statens Serum Institute, Copenhagen.

The study used Denmark’s comprehensive national cradle-to-the-grave health care registry to track all 1,031,279 Danes who were free of a history of cardiovascular disease at the time they became pregnant during 1977-1988. A total of 8,191 women had one or more stillbirths. There were 151,808 women with one miscarriage, 28,398 with two miscarriages, 5,979 with three, and 2,406 women with four or more miscarriages.

The three expressions of atherosclerosis under study were acute MI, cerebral infarction, and renovascular hypertension. During more than 15 million person-years of follow-up through the registry, there were 2,798 cases of MI, 4,053 cerebral infarcts, and 1,269 diagnoses of renovascular hypertension, Dr. Ranthe reported at the annual scientific sessions of the American Heart Association.

A history of even a single stillbirth was associated with a 2.69-fold increased incidence rate ratio for subsequent MI, a 1.74-fold increase in cerebral infarction, and a 2.42-fold increase in renovascular hypertension after adjustment for age, number of live births, and calendar year.

A robust dose-response relationship was evident between the number of miscarriages and atherosclerotic disease risk. Women with a history of a single miscarriage had an adjusted 1.11-fold increased risk of MI, a 1.13-fold increase in cerebral infarction, and a 1.15-fold greater risk of developing renovascular hypertension during follow-up than did women with no miscarriages. These 11%-15% increases in relative risk were all strongly significant, given the large numbers.

With two miscarriages, the risks of MI, cerebral infarct, and renovascular hypertension were increased 1.18-fold, 1.22-fold, and 1.12-fold, respectively. With a history of three miscarriages, the risks were 0.85, 1.43, and 1.78. And with 4 or more miscarriages, the incidence rate ratio for MI was increased 2.08-fold, that for cerebral infarct was 1.89-fold, and for renovascular hypertension it was 3.78-fold greater than in women with no miscarriages.

Further adjustment for diabetes, smoking, thrombophilia, and polycystic ovarian syndrome left these estimates unchanged.

The risk of each of the three forms of atherosclerosis climbed by 10%-20% with each additional miscarriage. However, the risk wasn’t evenly spread across all age groups. Rather, the risk of developing atherosclerotic disease within the next 15 years was greatest in the youngest women who miscarried. The risk associated with miscarriage late in the period of childbearing potential was far less, the physician noted.

That observation raised a red flag for one audience member.

"If you have younger women of childbearing years having myocardial infarctions earlier on, one tends to think that mechanistically it may be atherosclerosis, but it may actually be due to other issues involving connective tissue diseases. I’d be cautious in using atherosclerosis as a broad pathophysiologic explanation," she said.

Dr. Ranthe agreed.

He reported having no financial conflicts related to this study, which was funded by the Danish Heart Foundation.

LOS ANGELES – Pregnancy loss is strongly associated with increased risks of three different clinical forms of atherosclerotic disease over the subsequent 15 years, a study of more than 1 million Danish pregnant women has shown.

"This is the largest-ever study on the occurrence of atherosclerotic disease after pregnancy loss. This study, taken together with previous studies, implies a possible common underlying pathology linking pregnancy losses and atherosclerosis," said Dr. Mattis F. Ranthe of the Statens Serum Institute, Copenhagen.

The study used Denmark’s comprehensive national cradle-to-the-grave health care registry to track all 1,031,279 Danes who were free of a history of cardiovascular disease at the time they became pregnant during 1977-1988. A total of 8,191 women had one or more stillbirths. There were 151,808 women with one miscarriage, 28,398 with two miscarriages, 5,979 with three, and 2,406 women with four or more miscarriages.

The three expressions of atherosclerosis under study were acute MI, cerebral infarction, and renovascular hypertension. During more than 15 million person-years of follow-up through the registry, there were 2,798 cases of MI, 4,053 cerebral infarcts, and 1,269 diagnoses of renovascular hypertension, Dr. Ranthe reported at the annual scientific sessions of the American Heart Association.

A history of even a single stillbirth was associated with a 2.69-fold increased incidence rate ratio for subsequent MI, a 1.74-fold increase in cerebral infarction, and a 2.42-fold increase in renovascular hypertension after adjustment for age, number of live births, and calendar year.

A robust dose-response relationship was evident between the number of miscarriages and atherosclerotic disease risk. Women with a history of a single miscarriage had an adjusted 1.11-fold increased risk of MI, a 1.13-fold increase in cerebral infarction, and a 1.15-fold greater risk of developing renovascular hypertension during follow-up than did women with no miscarriages. These 11%-15% increases in relative risk were all strongly significant, given the large numbers.

With two miscarriages, the risks of MI, cerebral infarct, and renovascular hypertension were increased 1.18-fold, 1.22-fold, and 1.12-fold, respectively. With a history of three miscarriages, the risks were 0.85, 1.43, and 1.78. And with 4 or more miscarriages, the incidence rate ratio for MI was increased 2.08-fold, that for cerebral infarct was 1.89-fold, and for renovascular hypertension it was 3.78-fold greater than in women with no miscarriages.

Further adjustment for diabetes, smoking, thrombophilia, and polycystic ovarian syndrome left these estimates unchanged.

The risk of each of the three forms of atherosclerosis climbed by 10%-20% with each additional miscarriage. However, the risk wasn’t evenly spread across all age groups. Rather, the risk of developing atherosclerotic disease within the next 15 years was greatest in the youngest women who miscarried. The risk associated with miscarriage late in the period of childbearing potential was far less, the physician noted.

That observation raised a red flag for one audience member.

"If you have younger women of childbearing years having myocardial infarctions earlier on, one tends to think that mechanistically it may be atherosclerosis, but it may actually be due to other issues involving connective tissue diseases. I’d be cautious in using atherosclerosis as a broad pathophysiologic explanation," she said.

Dr. Ranthe agreed.

He reported having no financial conflicts related to this study, which was funded by the Danish Heart Foundation.

LOS ANGELES – Pregnancy loss is strongly associated with increased risks of three different clinical forms of atherosclerotic disease over the subsequent 15 years, a study of more than 1 million Danish pregnant women has shown.

"This is the largest-ever study on the occurrence of atherosclerotic disease after pregnancy loss. This study, taken together with previous studies, implies a possible common underlying pathology linking pregnancy losses and atherosclerosis," said Dr. Mattis F. Ranthe of the Statens Serum Institute, Copenhagen.

The study used Denmark’s comprehensive national cradle-to-the-grave health care registry to track all 1,031,279 Danes who were free of a history of cardiovascular disease at the time they became pregnant during 1977-1988. A total of 8,191 women had one or more stillbirths. There were 151,808 women with one miscarriage, 28,398 with two miscarriages, 5,979 with three, and 2,406 women with four or more miscarriages.

The three expressions of atherosclerosis under study were acute MI, cerebral infarction, and renovascular hypertension. During more than 15 million person-years of follow-up through the registry, there were 2,798 cases of MI, 4,053 cerebral infarcts, and 1,269 diagnoses of renovascular hypertension, Dr. Ranthe reported at the annual scientific sessions of the American Heart Association.

A history of even a single stillbirth was associated with a 2.69-fold increased incidence rate ratio for subsequent MI, a 1.74-fold increase in cerebral infarction, and a 2.42-fold increase in renovascular hypertension after adjustment for age, number of live births, and calendar year.

A robust dose-response relationship was evident between the number of miscarriages and atherosclerotic disease risk. Women with a history of a single miscarriage had an adjusted 1.11-fold increased risk of MI, a 1.13-fold increase in cerebral infarction, and a 1.15-fold greater risk of developing renovascular hypertension during follow-up than did women with no miscarriages. These 11%-15% increases in relative risk were all strongly significant, given the large numbers.

With two miscarriages, the risks of MI, cerebral infarct, and renovascular hypertension were increased 1.18-fold, 1.22-fold, and 1.12-fold, respectively. With a history of three miscarriages, the risks were 0.85, 1.43, and 1.78. And with 4 or more miscarriages, the incidence rate ratio for MI was increased 2.08-fold, that for cerebral infarct was 1.89-fold, and for renovascular hypertension it was 3.78-fold greater than in women with no miscarriages.

Further adjustment for diabetes, smoking, thrombophilia, and polycystic ovarian syndrome left these estimates unchanged.

The risk of each of the three forms of atherosclerosis climbed by 10%-20% with each additional miscarriage. However, the risk wasn’t evenly spread across all age groups. Rather, the risk of developing atherosclerotic disease within the next 15 years was greatest in the youngest women who miscarried. The risk associated with miscarriage late in the period of childbearing potential was far less, the physician noted.

That observation raised a red flag for one audience member.

"If you have younger women of childbearing years having myocardial infarctions earlier on, one tends to think that mechanistically it may be atherosclerosis, but it may actually be due to other issues involving connective tissue diseases. I’d be cautious in using atherosclerosis as a broad pathophysiologic explanation," she said.

Dr. Ranthe agreed.

He reported having no financial conflicts related to this study, which was funded by the Danish Heart Foundation.

The remarkable reductions of low-density lipoprotein cholesterol levels in several recent phase II trials using antibodies to PCSK9 triggered speculation on how low LDL should go for optimal patient outcomes.

The short answer is that, for secondary prevention of cardiovascular disease, patients may benefit from a goal substantially below the current level of less than 70 mg/dL – perhaps down to below 50 mg/dL and maybe even below 40 mg/dL. The new drug class of antibodies against the PCSK9 human protein that regulates LDL receptors seems capable of safely producing LDL levels that low when used with a potent statin regimen.

Courtesy Wikimedia/Urban/Creative Commons License

The benefit, as well as safety, of serum LDL cholesterol levels so low remains to be proven and won’t be so for a few more years, but those were the some of the LDL levels seen in the phase II anti-PCSK9 data reported earlier this month at the scientific sessions of the American Heart Association in Los Angeles.

The meeting included four reports from phase II studies of the anti-PCSK9 antibody made by Amgen, which involved a total of 981 patients who received some dosage of the drug. When administered on top of maximal dosages of statin or, in a few patients, ezetimibe, the highest antibody dosages – by subcutaneous injection every 2 weeks – produced LDL cuts of as much as 66%. As a result, a large fraction of patients on the antibody reached the sub–70-mg/dL LDL goal.

One AHA report analyzed data from a phase II study with 474 antibody-treated patients in terms of how many fell below 70 mg/dL while on the antibody. The highest dosage tested brought 90% of patients to goal, compared with virtually none at the start. Average LDL fell to 47 mg/dL and some patients dropped as low as 16 mg/dL.

What might LDL levels like these mean? In an invited discussion of the PCSK9 antibody results at the meeting, Dutch lipidologist John Kastelein – who called the results a "triumph of LDL goal attainment" and also marveled at the clean safety performance of the Amgen antibody – presented an analysis of data from more than 38,000 patients who received a statin in eight major statin-efficacy trials reported over the past 18 years. The results showed a steady drop in cardiovascular disease events at lower and lower LDL levels.

Patients reaching an LDL of 70-100 mg/dL, for example, had about a 16% rate of CVD events during follow-up. Among those who reached 50-70 mg/dL, the event rate dropped to about 12%, for those who hit 30-50 mg/dL the rate fell to about 5%, and those who slipped to an LDL level below 30 mg/dL had about a 2.5% event rate during follow-up.

The event rates "go down, down, down," as patients near what has been proposed as the true "physiologic" LDL serum level, about 25 mg/dL, Dr. Kastelein said.

Why was the target LDL goal set at 70 mg/dL? "Guideline writers looked at the evidence available" in 2004, when the Adult Treatment Panel III guideline group set its most aggressive goal of less than 70 mg/dL. "They saw where the intensive statin trials had gotten, mostly with 80-mg/day atorvastatin, to LDLs down to 65, 70, 75 mg/dL , so they picked 70 mg/dL as a reasonable target. But now we can get people into the 40s," Dr. Nihar Desai, a cardiologist at Brigham and Women’s Hospital in Boston, said to me after giving one of the anti-PCSK9 reports at the meeting.

Will driving LDLs levels that low help? Dr. Kastelein’s data from more than 38,000 statin-treated patients show that it could, but now it needs to be proved prospectively. A few days ago, Regeneron, one of the companies developing an anti-PCSK9 antibody, announced that its 18,000-patient, phase III trial had begun enrolling patients. A big trial of the Amgen antibody will probably start early next year. Results from both these studies should answer the question in about 3 years.

The remarkable reductions of low-density lipoprotein cholesterol levels in several recent phase II trials using antibodies to PCSK9 triggered speculation on how low LDL should go for optimal patient outcomes.

The short answer is that, for secondary prevention of cardiovascular disease, patients may benefit from a goal substantially below the current level of less than 70 mg/dL – perhaps down to below 50 mg/dL and maybe even below 40 mg/dL. The new drug class of antibodies against the PCSK9 human protein that regulates LDL receptors seems capable of safely producing LDL levels that low when used with a potent statin regimen.

Courtesy Wikimedia/Urban/Creative Commons License

The benefit, as well as safety, of serum LDL cholesterol levels so low remains to be proven and won’t be so for a few more years, but those were the some of the LDL levels seen in the phase II anti-PCSK9 data reported earlier this month at the scientific sessions of the American Heart Association in Los Angeles.

The meeting included four reports from phase II studies of the anti-PCSK9 antibody made by Amgen, which involved a total of 981 patients who received some dosage of the drug. When administered on top of maximal dosages of statin or, in a few patients, ezetimibe, the highest antibody dosages – by subcutaneous injection every 2 weeks – produced LDL cuts of as much as 66%. As a result, a large fraction of patients on the antibody reached the sub–70-mg/dL LDL goal.

One AHA report analyzed data from a phase II study with 474 antibody-treated patients in terms of how many fell below 70 mg/dL while on the antibody. The highest dosage tested brought 90% of patients to goal, compared with virtually none at the start. Average LDL fell to 47 mg/dL and some patients dropped as low as 16 mg/dL.

What might LDL levels like these mean? In an invited discussion of the PCSK9 antibody results at the meeting, Dutch lipidologist John Kastelein – who called the results a "triumph of LDL goal attainment" and also marveled at the clean safety performance of the Amgen antibody – presented an analysis of data from more than 38,000 patients who received a statin in eight major statin-efficacy trials reported over the past 18 years. The results showed a steady drop in cardiovascular disease events at lower and lower LDL levels.

Patients reaching an LDL of 70-100 mg/dL, for example, had about a 16% rate of CVD events during follow-up. Among those who reached 50-70 mg/dL, the event rate dropped to about 12%, for those who hit 30-50 mg/dL the rate fell to about 5%, and those who slipped to an LDL level below 30 mg/dL had about a 2.5% event rate during follow-up.

The event rates "go down, down, down," as patients near what has been proposed as the true "physiologic" LDL serum level, about 25 mg/dL, Dr. Kastelein said.

Why was the target LDL goal set at 70 mg/dL? "Guideline writers looked at the evidence available" in 2004, when the Adult Treatment Panel III guideline group set its most aggressive goal of less than 70 mg/dL. "They saw where the intensive statin trials had gotten, mostly with 80-mg/day atorvastatin, to LDLs down to 65, 70, 75 mg/dL , so they picked 70 mg/dL as a reasonable target. But now we can get people into the 40s," Dr. Nihar Desai, a cardiologist at Brigham and Women’s Hospital in Boston, said to me after giving one of the anti-PCSK9 reports at the meeting.

Will driving LDLs levels that low help? Dr. Kastelein’s data from more than 38,000 statin-treated patients show that it could, but now it needs to be proved prospectively. A few days ago, Regeneron, one of the companies developing an anti-PCSK9 antibody, announced that its 18,000-patient, phase III trial had begun enrolling patients. A big trial of the Amgen antibody will probably start early next year. Results from both these studies should answer the question in about 3 years.

The remarkable reductions of low-density lipoprotein cholesterol levels in several recent phase II trials using antibodies to PCSK9 triggered speculation on how low LDL should go for optimal patient outcomes.

The short answer is that, for secondary prevention of cardiovascular disease, patients may benefit from a goal substantially below the current level of less than 70 mg/dL – perhaps down to below 50 mg/dL and maybe even below 40 mg/dL. The new drug class of antibodies against the PCSK9 human protein that regulates LDL receptors seems capable of safely producing LDL levels that low when used with a potent statin regimen.

Courtesy Wikimedia/Urban/Creative Commons License

The benefit, as well as safety, of serum LDL cholesterol levels so low remains to be proven and won’t be so for a few more years, but those were the some of the LDL levels seen in the phase II anti-PCSK9 data reported earlier this month at the scientific sessions of the American Heart Association in Los Angeles.

The meeting included four reports from phase II studies of the anti-PCSK9 antibody made by Amgen, which involved a total of 981 patients who received some dosage of the drug. When administered on top of maximal dosages of statin or, in a few patients, ezetimibe, the highest antibody dosages – by subcutaneous injection every 2 weeks – produced LDL cuts of as much as 66%. As a result, a large fraction of patients on the antibody reached the sub–70-mg/dL LDL goal.

One AHA report analyzed data from a phase II study with 474 antibody-treated patients in terms of how many fell below 70 mg/dL while on the antibody. The highest dosage tested brought 90% of patients to goal, compared with virtually none at the start. Average LDL fell to 47 mg/dL and some patients dropped as low as 16 mg/dL.

What might LDL levels like these mean? In an invited discussion of the PCSK9 antibody results at the meeting, Dutch lipidologist John Kastelein – who called the results a "triumph of LDL goal attainment" and also marveled at the clean safety performance of the Amgen antibody – presented an analysis of data from more than 38,000 patients who received a statin in eight major statin-efficacy trials reported over the past 18 years. The results showed a steady drop in cardiovascular disease events at lower and lower LDL levels.

Patients reaching an LDL of 70-100 mg/dL, for example, had about a 16% rate of CVD events during follow-up. Among those who reached 50-70 mg/dL, the event rate dropped to about 12%, for those who hit 30-50 mg/dL the rate fell to about 5%, and those who slipped to an LDL level below 30 mg/dL had about a 2.5% event rate during follow-up.

The event rates "go down, down, down," as patients near what has been proposed as the true "physiologic" LDL serum level, about 25 mg/dL, Dr. Kastelein said.

Why was the target LDL goal set at 70 mg/dL? "Guideline writers looked at the evidence available" in 2004, when the Adult Treatment Panel III guideline group set its most aggressive goal of less than 70 mg/dL. "They saw where the intensive statin trials had gotten, mostly with 80-mg/day atorvastatin, to LDLs down to 65, 70, 75 mg/dL , so they picked 70 mg/dL as a reasonable target. But now we can get people into the 40s," Dr. Nihar Desai, a cardiologist at Brigham and Women’s Hospital in Boston, said to me after giving one of the anti-PCSK9 reports at the meeting.

Will driving LDLs levels that low help? Dr. Kastelein’s data from more than 38,000 statin-treated patients show that it could, but now it needs to be proved prospectively. A few days ago, Regeneron, one of the companies developing an anti-PCSK9 antibody, announced that its 18,000-patient, phase III trial had begun enrolling patients. A big trial of the Amgen antibody will probably start early next year. Results from both these studies should answer the question in about 3 years.

LOS ANGELES – Cooling to 32° C in comatose survivors of out-of-hospital cardiac arrest secondary to a shockable rhythm yielded markedly better outcomes than did cooling to 34° C in a pilot randomized trial.

Eight of 13 patients with an initial rhythm of ventricular fibrillation or pulseless ventricular tachycardia who were cooled to 32° C (89.6° F) were alive and free of severe dependence 6 months later, compared with just 2 of 13 patients cooled to 34° C (93.2° F).

Bruce Jancin/IMNG Medical Media

None of 10 study participants whose initial rhythm was asystole survived longer than 1 month regardless of which cooling level they received, Dr. Esteban Lopez-de-Sa reported at the annual scientific sessions of the American Heart Association.

Clinical seizures occurred during the first week post cardiac arrest in only 1 of 18 patients cooled at 32° C, compared with 11 of 18 patients cooled to 34° C. On the other hand, seven patients assigned to cooling at 32° developed bradycardia in the first week, compared with two patients cooled to 34°, noted Dr. Lopez-de-Sa, head of the cardiac critical care unit and clinical cardiology at La Paz University Hospital in Madrid.

This randomized trial helps answer an important question: how low to go with therapeutic hypothermia? Current American Heart Association guidelines recommend that comatose survivors of out-of-hospital cardiac arrest undergo therapeutic hypothermia at 32-34° C for 12-24 hours, but the guidelines don’t specify which temperature is better because data have been lacking.

Participants in the Spanish study had a median Glasgow Coma Scale score of 3 upon admission. They were maintained at their assigned target temperature for 24 hours using a feedback device before undergoing 12-24 hours of controlled rewarming.

Dr. Lopez-de-Sa observed that patients successfully resuscitated after out-of-hospital cardiac arrest often have terrible neurologic outcomes, so the 62% rate of survival without severe dependence at 6 months seen in comatose patients with a shockable initial rhythm who were cooled at 32° C in this study is quite encouraging. Freedom from severe dependence was defined as a Barthel Index score of 60 or more out of a possible 100, indicative of an ability to independently perform essential personal care.

Patients were initially cooled with intravenous cold saline. Then they had a catheter placed in the inferior vena cava through a femoral vein attached to the Thermogard XP Temperature Management System manufactured by ZOLL Medical.

Discussant Dr. Graham Nichol noted that many different methods for induction of therapeutic hypothermia exist, including cold water immersion, surface blankets, ice packs, intranasal evaporative cooling, intravenous saline, and intraperitoneal cooling. But no medical device is FDA approved for the induction of hypothermia following resuscitation from cardiac arrest.

"The optimal duration of therapeutic hypothermia, method, and the benefit in the field or in patients with a rhythm other than VF [ventricular fibrillation] remain unclear. I would offer an analogy: For hypothermia in cardiac arrest, ... we are where we were in the 1980s with thrombolytic therapy for myocardial infarction. Most clinicians believe that it works, but there are lots of unanswered questions about timing, dose, and duration," said Dr. Nichol, professor of medicine and director of the University of Washington–Harborview Center for Prehospital Emergency Care, Seattle.

Discussant Dr. Douglas P. Zipes observed that VF and pulseless VT [ventricular tachycardia] are declining as causes of cardiac arrest. Meanwhile, asystole and pulseless electrical activity represent a growing percentage of the cardiac arrest population.

"It’s very distressing that none of the patients in either group who had asystole survived," commented Dr. Zipes, professor emeritus of medicine at Indiana University, Indianapolis.

Dr. Lopez-de-Sa said he believes the therapeutic hypothermia success rate can be improved further in patients with shockable rhythms as well as in those with electromechanical dissociation.

"Probably we need to go to lower temperatures and for longer periods," according to the cardiologist.

Indeed, the superior results seen with cooling to 32° C in the Spanish study may have been due in part to the fact that patients assigned to lower cooling spent more total time in hypothermia, since it took longer to get to their target temperature, he continued.

Animal models indicate that for every 1° C drop in temperature there’s a 6% reduction in cerebral metabolic rate. So lower is probably better in terms of neuroprotection, but only to a point. And that point is 30° C, below which there is a risk of triggering arrhythmias and coagulopathies. Dr. Lopez-de-Sa said that based upon the successful pilot study, he and his coinvestigators are planning a much larger randomized trial, probably comparing 33° C to 31° C.

Simultaneous with Dr. Lopez-de-Sa’s presentation at the meeting, the study findings were published online (Circulation 2012 Nov. 6 [doi: 10.1161/circulationaha.112.136408]).

The study was funded by La Paz University Hospital. Dr. Lopez-de-Sa reported having no financial conflicts. Dr. Nichol receives research funding from Medtronic, ZOLL, Physio-Control, and Cardiac Science.

LOS ANGELES – Cooling to 32° C in comatose survivors of out-of-hospital cardiac arrest secondary to a shockable rhythm yielded markedly better outcomes than did cooling to 34° C in a pilot randomized trial.

Eight of 13 patients with an initial rhythm of ventricular fibrillation or pulseless ventricular tachycardia who were cooled to 32° C (89.6° F) were alive and free of severe dependence 6 months later, compared with just 2 of 13 patients cooled to 34° C (93.2° F).

Bruce Jancin/IMNG Medical Media

None of 10 study participants whose initial rhythm was asystole survived longer than 1 month regardless of which cooling level they received, Dr. Esteban Lopez-de-Sa reported at the annual scientific sessions of the American Heart Association.

Clinical seizures occurred during the first week post cardiac arrest in only 1 of 18 patients cooled at 32° C, compared with 11 of 18 patients cooled to 34° C. On the other hand, seven patients assigned to cooling at 32° developed bradycardia in the first week, compared with two patients cooled to 34°, noted Dr. Lopez-de-Sa, head of the cardiac critical care unit and clinical cardiology at La Paz University Hospital in Madrid.

This randomized trial helps answer an important question: how low to go with therapeutic hypothermia? Current American Heart Association guidelines recommend that comatose survivors of out-of-hospital cardiac arrest undergo therapeutic hypothermia at 32-34° C for 12-24 hours, but the guidelines don’t specify which temperature is better because data have been lacking.

Participants in the Spanish study had a median Glasgow Coma Scale score of 3 upon admission. They were maintained at their assigned target temperature for 24 hours using a feedback device before undergoing 12-24 hours of controlled rewarming.

Dr. Lopez-de-Sa observed that patients successfully resuscitated after out-of-hospital cardiac arrest often have terrible neurologic outcomes, so the 62% rate of survival without severe dependence at 6 months seen in comatose patients with a shockable initial rhythm who were cooled at 32° C in this study is quite encouraging. Freedom from severe dependence was defined as a Barthel Index score of 60 or more out of a possible 100, indicative of an ability to independently perform essential personal care.

Patients were initially cooled with intravenous cold saline. Then they had a catheter placed in the inferior vena cava through a femoral vein attached to the Thermogard XP Temperature Management System manufactured by ZOLL Medical.

Discussant Dr. Graham Nichol noted that many different methods for induction of therapeutic hypothermia exist, including cold water immersion, surface blankets, ice packs, intranasal evaporative cooling, intravenous saline, and intraperitoneal cooling. But no medical device is FDA approved for the induction of hypothermia following resuscitation from cardiac arrest.

"The optimal duration of therapeutic hypothermia, method, and the benefit in the field or in patients with a rhythm other than VF [ventricular fibrillation] remain unclear. I would offer an analogy: For hypothermia in cardiac arrest, ... we are where we were in the 1980s with thrombolytic therapy for myocardial infarction. Most clinicians believe that it works, but there are lots of unanswered questions about timing, dose, and duration," said Dr. Nichol, professor of medicine and director of the University of Washington–Harborview Center for Prehospital Emergency Care, Seattle.

Discussant Dr. Douglas P. Zipes observed that VF and pulseless VT [ventricular tachycardia] are declining as causes of cardiac arrest. Meanwhile, asystole and pulseless electrical activity represent a growing percentage of the cardiac arrest population.

"It’s very distressing that none of the patients in either group who had asystole survived," commented Dr. Zipes, professor emeritus of medicine at Indiana University, Indianapolis.

Dr. Lopez-de-Sa said he believes the therapeutic hypothermia success rate can be improved further in patients with shockable rhythms as well as in those with electromechanical dissociation.

"Probably we need to go to lower temperatures and for longer periods," according to the cardiologist.

Indeed, the superior results seen with cooling to 32° C in the Spanish study may have been due in part to the fact that patients assigned to lower cooling spent more total time in hypothermia, since it took longer to get to their target temperature, he continued.

Animal models indicate that for every 1° C drop in temperature there’s a 6% reduction in cerebral metabolic rate. So lower is probably better in terms of neuroprotection, but only to a point. And that point is 30° C, below which there is a risk of triggering arrhythmias and coagulopathies. Dr. Lopez-de-Sa said that based upon the successful pilot study, he and his coinvestigators are planning a much larger randomized trial, probably comparing 33° C to 31° C.

Simultaneous with Dr. Lopez-de-Sa’s presentation at the meeting, the study findings were published online (Circulation 2012 Nov. 6 [doi: 10.1161/circulationaha.112.136408]).

The study was funded by La Paz University Hospital. Dr. Lopez-de-Sa reported having no financial conflicts. Dr. Nichol receives research funding from Medtronic, ZOLL, Physio-Control, and Cardiac Science.

LOS ANGELES – Cooling to 32° C in comatose survivors of out-of-hospital cardiac arrest secondary to a shockable rhythm yielded markedly better outcomes than did cooling to 34° C in a pilot randomized trial.

Eight of 13 patients with an initial rhythm of ventricular fibrillation or pulseless ventricular tachycardia who were cooled to 32° C (89.6° F) were alive and free of severe dependence 6 months later, compared with just 2 of 13 patients cooled to 34° C (93.2° F).

Bruce Jancin/IMNG Medical Media

None of 10 study participants whose initial rhythm was asystole survived longer than 1 month regardless of which cooling level they received, Dr. Esteban Lopez-de-Sa reported at the annual scientific sessions of the American Heart Association.

Clinical seizures occurred during the first week post cardiac arrest in only 1 of 18 patients cooled at 32° C, compared with 11 of 18 patients cooled to 34° C. On the other hand, seven patients assigned to cooling at 32° developed bradycardia in the first week, compared with two patients cooled to 34°, noted Dr. Lopez-de-Sa, head of the cardiac critical care unit and clinical cardiology at La Paz University Hospital in Madrid.

This randomized trial helps answer an important question: how low to go with therapeutic hypothermia? Current American Heart Association guidelines recommend that comatose survivors of out-of-hospital cardiac arrest undergo therapeutic hypothermia at 32-34° C for 12-24 hours, but the guidelines don’t specify which temperature is better because data have been lacking.

Participants in the Spanish study had a median Glasgow Coma Scale score of 3 upon admission. They were maintained at their assigned target temperature for 24 hours using a feedback device before undergoing 12-24 hours of controlled rewarming.

Dr. Lopez-de-Sa observed that patients successfully resuscitated after out-of-hospital cardiac arrest often have terrible neurologic outcomes, so the 62% rate of survival without severe dependence at 6 months seen in comatose patients with a shockable initial rhythm who were cooled at 32° C in this study is quite encouraging. Freedom from severe dependence was defined as a Barthel Index score of 60 or more out of a possible 100, indicative of an ability to independently perform essential personal care.

Patients were initially cooled with intravenous cold saline. Then they had a catheter placed in the inferior vena cava through a femoral vein attached to the Thermogard XP Temperature Management System manufactured by ZOLL Medical.

Discussant Dr. Graham Nichol noted that many different methods for induction of therapeutic hypothermia exist, including cold water immersion, surface blankets, ice packs, intranasal evaporative cooling, intravenous saline, and intraperitoneal cooling. But no medical device is FDA approved for the induction of hypothermia following resuscitation from cardiac arrest.

"The optimal duration of therapeutic hypothermia, method, and the benefit in the field or in patients with a rhythm other than VF [ventricular fibrillation] remain unclear. I would offer an analogy: For hypothermia in cardiac arrest, ... we are where we were in the 1980s with thrombolytic therapy for myocardial infarction. Most clinicians believe that it works, but there are lots of unanswered questions about timing, dose, and duration," said Dr. Nichol, professor of medicine and director of the University of Washington–Harborview Center for Prehospital Emergency Care, Seattle.

Discussant Dr. Douglas P. Zipes observed that VF and pulseless VT [ventricular tachycardia] are declining as causes of cardiac arrest. Meanwhile, asystole and pulseless electrical activity represent a growing percentage of the cardiac arrest population.

"It’s very distressing that none of the patients in either group who had asystole survived," commented Dr. Zipes, professor emeritus of medicine at Indiana University, Indianapolis.

Dr. Lopez-de-Sa said he believes the therapeutic hypothermia success rate can be improved further in patients with shockable rhythms as well as in those with electromechanical dissociation.

"Probably we need to go to lower temperatures and for longer periods," according to the cardiologist.

Indeed, the superior results seen with cooling to 32° C in the Spanish study may have been due in part to the fact that patients assigned to lower cooling spent more total time in hypothermia, since it took longer to get to their target temperature, he continued.

Animal models indicate that for every 1° C drop in temperature there’s a 6% reduction in cerebral metabolic rate. So lower is probably better in terms of neuroprotection, but only to a point. And that point is 30° C, below which there is a risk of triggering arrhythmias and coagulopathies. Dr. Lopez-de-Sa said that based upon the successful pilot study, he and his coinvestigators are planning a much larger randomized trial, probably comparing 33° C to 31° C.

Simultaneous with Dr. Lopez-de-Sa’s presentation at the meeting, the study findings were published online (Circulation 2012 Nov. 6 [doi: 10.1161/circulationaha.112.136408]).

The study was funded by La Paz University Hospital. Dr. Lopez-de-Sa reported having no financial conflicts. Dr. Nichol receives research funding from Medtronic, ZOLL, Physio-Control, and Cardiac Science.

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.

LOS ANGELES – Chelation therapy resulted in a slight reduction in cardiovascular events in patients with coronary artery disease and a prior myocardial infarction, according to a randomized, government-funded trial, but the findings are far from practice changing.

Experts at the annual scientific sessions of the American Heart Association, including the study’s authors, were quick to point out that the results yielded more questions than answers, and called for additional research to confirm or refute the findings.

"Intriguing as the results are, they are unexpected and should not be interpreted as an indication to adopt chelation therapy into clinical practice," said Dr. Elliott Antman, chair of the AHA Scientific Sessions Program Committee, and a cardiologist at Brigham and Women’s Hospital in Boston.

The therapy did not reduce mortality, and a substudy showed that patients did not have any sustained improvement in their quality of life.

Dr. Gervasio A. Lamas, the study’s lead author and a cardiologist at Mount Sinai Medical Center in Miami Beach, said that the trial "does not constitute evidence to recommend the clinical application of chelation therapy."

Chelation, which is not approved by the Food and Drug Administration (FDA), is an intravenous therapy in which the synthetic amino acid ethylenediaminetetraacetic acid (EDTA) binds to and extracts metals. The controversial treatment has been around since the 1950s, and research findings have been inconsistent.

In the case of heart disease, the idea is that EDTA binds to the calcium in the arterial plaques.

"But there are no data that show that it happens," said Dr. Sidney Goldstein, professor of medicine at Wayne State University in Detroit, who was not involved in the study. "I wouldn’t put much value on the [trial], because the science is thin or nonexistent," he said about the $30 million NIH-funded study.

TACT (Trial to Assess Chelation Therapy) was a randomized, double-blind, placebo-controlled study that was 20 times larger than previous studies conducted on the controversial treatment (Am. Heart J. 2012;163:7-12).

The trial has had its share of turbulence since it enrolled the first patient in 2003. It was once stopped after the FDA raised concerns about its process and conduct. After taking corrective steps, the investigators had to scale down the study population from nearly 2,400 to 1,700 owing to difficulty enrolling patients.

Researchers randomized and followed the 1,708 post-MI patients for an average of 4 years at 134 sites in the United States and Canada from September 2003 to October 2010. Their goal was to test the benefits and risks of 40 infusions of a 500-mL multicomponent disodium EDTA chelation solution compared with placebo, which was a solution of normal saline and 1.2% dextrose.

A total of 55,222 EDTA and placebo infusions were administered during the trial, each patient receiving 30 weekly infusions followed by 10 maintenance infusions 2-8 weeks apart. Each infusion lasted for about 3 hours.

The primary composite end point was death, MI, stroke, coronary revascularization, and hospitalization for angina. The composite secondary end point was irreversible ischemic events, including cardiovascular death, nonfatal MI, and nonfatal stroke.

Patients were at least 50 years old (mean age, 65 years). The average body mass index for both groups was 30 kg/m², and roughly 30% of each group had diabetes.

Sixty-five percent of the patients completed all 40 infusions, and 76% completed at least 30. Meanwhile, 30% discontinued infusions for several reasons, and 17% percent withdrew consent.

The results showed that 39 fewer patients in the chelation therapy group had a cardiovascular event compared with the placebo group, a nonsignificant difference that was driven largely by coronary revascularization, where there was a 3% difference between the two groups (15% vs. 18%), a "soft end point," according to Dr. Goldstein.

There were no significant benefits for angina (1.5% in the EDTA chelation group vs. 2.1% in the placebo group), mortality (10.4% vs. 10.7%, respectively), MI (6.2% vs. 7.7%), or stroke (1.2% vs. 1.5%).

Seventy-nine patients (12%) discontinued infusions due to adverse events or side effects. Of those, 17 reached an end point, 11 had heart failure, and 7 had cardiac issues, among other reasons.

There were four unexpected severe adverse events, including two deaths, one in each group.

A surprising effect was found in the diabetes subgroup, for which researchers did not have a biological explanation. Diabetes patients had 35 fewer events than the placebo group (P = .002). The difference was minimal in the subgroup with no diabetes.

"Although there were some aspects of the trial that suggested chelation may be beneficial, too many questions remain to recommend chelation as standard therapy at this time," said Dr. David. O. Williams, a cardiologist at Brigham and Women’s Hospital, who was not involved in the study. He pointed out that many patients didn’t receive complete study therapy, and a substantial number dropped out of the trial, which meant that their outcomes didn’t contribute to the follow-up data.

He also said that the primary end point was a composite of many different cardiovascular events, and data for individual events were not available. In addition, there remained an absence of clear biological rationale.

Interest in chelation therapy has been increasing, at least until recently, according to national data. In 2007, nearly 111,000 people received chelation, an almost 68% increase from 2002.

But the procedure can be harmful, especially if infusions occur quickly, causing hypocalcemia. Three of those cases that led to patient death were recorded in a 2006 Centers for Disease Control and Prevention report.

"To suggest that [chelation therapy] is steeped in controversy is an understatement," said Dr. Paul W. Armstrong, professor of medicine at the University of Alberta in Edmonton, who commented on the trial at a press briefing. "We owe the investigators a debt of gratitude for undertaking this subject," he said. But, "the results are hypothesis generating and not practice changing."

The National Center for Complementary and Alternative Medicine and the National Heart, Lung, and Blood Institute funded the study. Dr. Armstrong received research grants from several companies including Boehringer Ingelheim and AstraZeneca. Dr. Antman and Dr. Williams had no relevant disclosures. Dr. Goldstein is the medical editor of Cardiology News.

LOS ANGELES – Chelation therapy resulted in a slight reduction in cardiovascular events in patients with coronary artery disease and a prior myocardial infarction, according to a randomized, government-funded trial, but the findings are far from practice changing.

Experts at the annual scientific sessions of the American Heart Association, including the study’s authors, were quick to point out that the results yielded more questions than answers, and called for additional research to confirm or refute the findings.

"Intriguing as the results are, they are unexpected and should not be interpreted as an indication to adopt chelation therapy into clinical practice," said Dr. Elliott Antman, chair of the AHA Scientific Sessions Program Committee, and a cardiologist at Brigham and Women’s Hospital in Boston.

The therapy did not reduce mortality, and a substudy showed that patients did not have any sustained improvement in their quality of life.

Dr. Gervasio A. Lamas, the study’s lead author and a cardiologist at Mount Sinai Medical Center in Miami Beach, said that the trial "does not constitute evidence to recommend the clinical application of chelation therapy."

Chelation, which is not approved by the Food and Drug Administration (FDA), is an intravenous therapy in which the synthetic amino acid ethylenediaminetetraacetic acid (EDTA) binds to and extracts metals. The controversial treatment has been around since the 1950s, and research findings have been inconsistent.

In the case of heart disease, the idea is that EDTA binds to the calcium in the arterial plaques.

"But there are no data that show that it happens," said Dr. Sidney Goldstein, professor of medicine at Wayne State University in Detroit, who was not involved in the study. "I wouldn’t put much value on the [trial], because the science is thin or nonexistent," he said about the $30 million NIH-funded study.

TACT (Trial to Assess Chelation Therapy) was a randomized, double-blind, placebo-controlled study that was 20 times larger than previous studies conducted on the controversial treatment (Am. Heart J. 2012;163:7-12).

The trial has had its share of turbulence since it enrolled the first patient in 2003. It was once stopped after the FDA raised concerns about its process and conduct. After taking corrective steps, the investigators had to scale down the study population from nearly 2,400 to 1,700 owing to difficulty enrolling patients.

Researchers randomized and followed the 1,708 post-MI patients for an average of 4 years at 134 sites in the United States and Canada from September 2003 to October 2010. Their goal was to test the benefits and risks of 40 infusions of a 500-mL multicomponent disodium EDTA chelation solution compared with placebo, which was a solution of normal saline and 1.2% dextrose.

A total of 55,222 EDTA and placebo infusions were administered during the trial, each patient receiving 30 weekly infusions followed by 10 maintenance infusions 2-8 weeks apart. Each infusion lasted for about 3 hours.

The primary composite end point was death, MI, stroke, coronary revascularization, and hospitalization for angina. The composite secondary end point was irreversible ischemic events, including cardiovascular death, nonfatal MI, and nonfatal stroke.

Patients were at least 50 years old (mean age, 65 years). The average body mass index for both groups was 30 kg/m², and roughly 30% of each group had diabetes.

Sixty-five percent of the patients completed all 40 infusions, and 76% completed at least 30. Meanwhile, 30% discontinued infusions for several reasons, and 17% percent withdrew consent.

The results showed that 39 fewer patients in the chelation therapy group had a cardiovascular event compared with the placebo group, a nonsignificant difference that was driven largely by coronary revascularization, where there was a 3% difference between the two groups (15% vs. 18%), a "soft end point," according to Dr. Goldstein.

There were no significant benefits for angina (1.5% in the EDTA chelation group vs. 2.1% in the placebo group), mortality (10.4% vs. 10.7%, respectively), MI (6.2% vs. 7.7%), or stroke (1.2% vs. 1.5%).

Seventy-nine patients (12%) discontinued infusions due to adverse events or side effects. Of those, 17 reached an end point, 11 had heart failure, and 7 had cardiac issues, among other reasons.

There were four unexpected severe adverse events, including two deaths, one in each group.

A surprising effect was found in the diabetes subgroup, for which researchers did not have a biological explanation. Diabetes patients had 35 fewer events than the placebo group (P = .002). The difference was minimal in the subgroup with no diabetes.

"Although there were some aspects of the trial that suggested chelation may be beneficial, too many questions remain to recommend chelation as standard therapy at this time," said Dr. David. O. Williams, a cardiologist at Brigham and Women’s Hospital, who was not involved in the study. He pointed out that many patients didn’t receive complete study therapy, and a substantial number dropped out of the trial, which meant that their outcomes didn’t contribute to the follow-up data.

He also said that the primary end point was a composite of many different cardiovascular events, and data for individual events were not available. In addition, there remained an absence of clear biological rationale.

Interest in chelation therapy has been increasing, at least until recently, according to national data. In 2007, nearly 111,000 people received chelation, an almost 68% increase from 2002.

But the procedure can be harmful, especially if infusions occur quickly, causing hypocalcemia. Three of those cases that led to patient death were recorded in a 2006 Centers for Disease Control and Prevention report.

"To suggest that [chelation therapy] is steeped in controversy is an understatement," said Dr. Paul W. Armstrong, professor of medicine at the University of Alberta in Edmonton, who commented on the trial at a press briefing. "We owe the investigators a debt of gratitude for undertaking this subject," he said. But, "the results are hypothesis generating and not practice changing."

The National Center for Complementary and Alternative Medicine and the National Heart, Lung, and Blood Institute funded the study. Dr. Armstrong received research grants from several companies including Boehringer Ingelheim and AstraZeneca. Dr. Antman and Dr. Williams had no relevant disclosures. Dr. Goldstein is the medical editor of Cardiology News.

LOS ANGELES – Chelation therapy resulted in a slight reduction in cardiovascular events in patients with coronary artery disease and a prior myocardial infarction, according to a randomized, government-funded trial, but the findings are far from practice changing.

Experts at the annual scientific sessions of the American Heart Association, including the study’s authors, were quick to point out that the results yielded more questions than answers, and called for additional research to confirm or refute the findings.

"Intriguing as the results are, they are unexpected and should not be interpreted as an indication to adopt chelation therapy into clinical practice," said Dr. Elliott Antman, chair of the AHA Scientific Sessions Program Committee, and a cardiologist at Brigham and Women’s Hospital in Boston.

The therapy did not reduce mortality, and a substudy showed that patients did not have any sustained improvement in their quality of life.

Dr. Gervasio A. Lamas, the study’s lead author and a cardiologist at Mount Sinai Medical Center in Miami Beach, said that the trial "does not constitute evidence to recommend the clinical application of chelation therapy."

Chelation, which is not approved by the Food and Drug Administration (FDA), is an intravenous therapy in which the synthetic amino acid ethylenediaminetetraacetic acid (EDTA) binds to and extracts metals. The controversial treatment has been around since the 1950s, and research findings have been inconsistent.

In the case of heart disease, the idea is that EDTA binds to the calcium in the arterial plaques.

"But there are no data that show that it happens," said Dr. Sidney Goldstein, professor of medicine at Wayne State University in Detroit, who was not involved in the study. "I wouldn’t put much value on the [trial], because the science is thin or nonexistent," he said about the $30 million NIH-funded study.

TACT (Trial to Assess Chelation Therapy) was a randomized, double-blind, placebo-controlled study that was 20 times larger than previous studies conducted on the controversial treatment (Am. Heart J. 2012;163:7-12).

The trial has had its share of turbulence since it enrolled the first patient in 2003. It was once stopped after the FDA raised concerns about its process and conduct. After taking corrective steps, the investigators had to scale down the study population from nearly 2,400 to 1,700 owing to difficulty enrolling patients.

Researchers randomized and followed the 1,708 post-MI patients for an average of 4 years at 134 sites in the United States and Canada from September 2003 to October 2010. Their goal was to test the benefits and risks of 40 infusions of a 500-mL multicomponent disodium EDTA chelation solution compared with placebo, which was a solution of normal saline and 1.2% dextrose.

A total of 55,222 EDTA and placebo infusions were administered during the trial, each patient receiving 30 weekly infusions followed by 10 maintenance infusions 2-8 weeks apart. Each infusion lasted for about 3 hours.

The primary composite end point was death, MI, stroke, coronary revascularization, and hospitalization for angina. The composite secondary end point was irreversible ischemic events, including cardiovascular death, nonfatal MI, and nonfatal stroke.

Patients were at least 50 years old (mean age, 65 years). The average body mass index for both groups was 30 kg/m², and roughly 30% of each group had diabetes.

Sixty-five percent of the patients completed all 40 infusions, and 76% completed at least 30. Meanwhile, 30% discontinued infusions for several reasons, and 17% percent withdrew consent.

The results showed that 39 fewer patients in the chelation therapy group had a cardiovascular event compared with the placebo group, a nonsignificant difference that was driven largely by coronary revascularization, where there was a 3% difference between the two groups (15% vs. 18%), a "soft end point," according to Dr. Goldstein.

There were no significant benefits for angina (1.5% in the EDTA chelation group vs. 2.1% in the placebo group), mortality (10.4% vs. 10.7%, respectively), MI (6.2% vs. 7.7%), or stroke (1.2% vs. 1.5%).

Seventy-nine patients (12%) discontinued infusions due to adverse events or side effects. Of those, 17 reached an end point, 11 had heart failure, and 7 had cardiac issues, among other reasons.

There were four unexpected severe adverse events, including two deaths, one in each group.

A surprising effect was found in the diabetes subgroup, for which researchers did not have a biological explanation. Diabetes patients had 35 fewer events than the placebo group (P = .002). The difference was minimal in the subgroup with no diabetes.

"Although there were some aspects of the trial that suggested chelation may be beneficial, too many questions remain to recommend chelation as standard therapy at this time," said Dr. David. O. Williams, a cardiologist at Brigham and Women’s Hospital, who was not involved in the study. He pointed out that many patients didn’t receive complete study therapy, and a substantial number dropped out of the trial, which meant that their outcomes didn’t contribute to the follow-up data.

He also said that the primary end point was a composite of many different cardiovascular events, and data for individual events were not available. In addition, there remained an absence of clear biological rationale.

Interest in chelation therapy has been increasing, at least until recently, according to national data. In 2007, nearly 111,000 people received chelation, an almost 68% increase from 2002.

But the procedure can be harmful, especially if infusions occur quickly, causing hypocalcemia. Three of those cases that led to patient death were recorded in a 2006 Centers for Disease Control and Prevention report.

"To suggest that [chelation therapy] is steeped in controversy is an understatement," said Dr. Paul W. Armstrong, professor of medicine at the University of Alberta in Edmonton, who commented on the trial at a press briefing. "We owe the investigators a debt of gratitude for undertaking this subject," he said. But, "the results are hypothesis generating and not practice changing."

The National Center for Complementary and Alternative Medicine and the National Heart, Lung, and Blood Institute funded the study. Dr. Armstrong received research grants from several companies including Boehringer Ingelheim and AstraZeneca. Dr. Antman and Dr. Williams had no relevant disclosures. Dr. Goldstein is the medical editor of Cardiology News.