Heart Failure

TORONTO — The rate at which eligible, appropriate patients with a low left ventricular ejection fraction miss out on getting an implantable cardioverter defibrillator might be lower than most people think.

After ineligible patients and those who refused the device were accounted for, the “true miss” rate, or rate of patients with ejection fractions of 35% or less who failed to get an ICD was 7% in a random sample of 228 patients who underwent echocardiography scanning during 2005–2007 at Jefferson Medical College, Philadelphia.

However, the ICD implant rate in large, observational studies has usually been reported as about 25%–40% in patients with ejection fractions of 35% or less, Dr. Shaw Natan said while presenting a poster at the 14th World Congress on Heart Disease.

At Jefferson, the implant rate in the 228 patients who were the focus of this study was 42%, suggesting a miss rate of 68%. But assessing each patient individually showed that in most cases there was a good reason for the omission,” said Dr. Natan, a cardiologist formerly at Jefferson and now at St. Elizabeth's Medical Center in Boston, in an interview.

The 228 patients in the sample had an average age of 66 (range 29–96), and 68% were men. Their average LVEF was 21%.

Among the 132 patients in the sample who did not get an ICD, 89 (39% of the total) were ineligible: 34 had an inadequate trial of medical treatment or revascularization, 19 died, 17 had a life expectancy of less than 1 year or dementia, 10 were lost to follow-up, and 9 had other reasons.

Of the remaining 43 patients who were eligible for an ICD, 27 declined the device when it was offered. This left 16 patients (7% of the total number of patients evaluated) who were true misses for an ICD: They had no contraindications and were willing to receive treatment.

TORONTO — The rate at which eligible, appropriate patients with a low left ventricular ejection fraction miss out on getting an implantable cardioverter defibrillator might be lower than most people think.

After ineligible patients and those who refused the device were accounted for, the “true miss” rate, or rate of patients with ejection fractions of 35% or less who failed to get an ICD was 7% in a random sample of 228 patients who underwent echocardiography scanning during 2005–2007 at Jefferson Medical College, Philadelphia.

However, the ICD implant rate in large, observational studies has usually been reported as about 25%–40% in patients with ejection fractions of 35% or less, Dr. Shaw Natan said while presenting a poster at the 14th World Congress on Heart Disease.

At Jefferson, the implant rate in the 228 patients who were the focus of this study was 42%, suggesting a miss rate of 68%. But assessing each patient individually showed that in most cases there was a good reason for the omission,” said Dr. Natan, a cardiologist formerly at Jefferson and now at St. Elizabeth's Medical Center in Boston, in an interview.

The 228 patients in the sample had an average age of 66 (range 29–96), and 68% were men. Their average LVEF was 21%.

Among the 132 patients in the sample who did not get an ICD, 89 (39% of the total) were ineligible: 34 had an inadequate trial of medical treatment or revascularization, 19 died, 17 had a life expectancy of less than 1 year or dementia, 10 were lost to follow-up, and 9 had other reasons.

Of the remaining 43 patients who were eligible for an ICD, 27 declined the device when it was offered. This left 16 patients (7% of the total number of patients evaluated) who were true misses for an ICD: They had no contraindications and were willing to receive treatment.

TORONTO — The rate at which eligible, appropriate patients with a low left ventricular ejection fraction miss out on getting an implantable cardioverter defibrillator might be lower than most people think.

After ineligible patients and those who refused the device were accounted for, the “true miss” rate, or rate of patients with ejection fractions of 35% or less who failed to get an ICD was 7% in a random sample of 228 patients who underwent echocardiography scanning during 2005–2007 at Jefferson Medical College, Philadelphia.

However, the ICD implant rate in large, observational studies has usually been reported as about 25%–40% in patients with ejection fractions of 35% or less, Dr. Shaw Natan said while presenting a poster at the 14th World Congress on Heart Disease.

At Jefferson, the implant rate in the 228 patients who were the focus of this study was 42%, suggesting a miss rate of 68%. But assessing each patient individually showed that in most cases there was a good reason for the omission,” said Dr. Natan, a cardiologist formerly at Jefferson and now at St. Elizabeth's Medical Center in Boston, in an interview.

The 228 patients in the sample had an average age of 66 (range 29–96), and 68% were men. Their average LVEF was 21%.

Among the 132 patients in the sample who did not get an ICD, 89 (39% of the total) were ineligible: 34 had an inadequate trial of medical treatment or revascularization, 19 died, 17 had a life expectancy of less than 1 year or dementia, 10 were lost to follow-up, and 9 had other reasons.

Of the remaining 43 patients who were eligible for an ICD, 27 declined the device when it was offered. This left 16 patients (7% of the total number of patients evaluated) who were true misses for an ICD: They had no contraindications and were willing to receive treatment.

TORONTO — In patients with mild heart failure, cardiac resynchronization therapy improved composite clinical response scores at 18 months, was associated with left ventricular reverse remodeling, reduced the risk of heart failure hospitalization, and lowered the combined risk of morbidity and mortality, compared with optimal medical therapy.

The 18-month data from the European cohort of the Resynchronization Reverses Remodeling in Systolic Left Ventricular Dysfunction (REVERSE) trial supported secondary conclusions from the previously reported 12-month analysis, which, although it indicated that the trial missed its primary clinical composite end point, showed evidence of remodeling and clinical benefit with CRT in mild heart failure (HF).

“Ongoing CRT trials in New York Heart Association class I and II patients may confirm these observations and expand the indication for CRT to this population of heart failure patients,” said Dr. William T. Abraham, who presented the data at the annual meeting of the Heart Failure Society of America.

The REVERSE trial was a multinational prospective effort involving 610 patients with mild or asymptomatic HF and ventricular dyssynchrony. All patients received a CRT device in addition to optimal medical therapy; 191 were randomized to have the device turned on and 419 were randomized to have it turned off.

Eligible patients had left ventricular ejection fractions below 40%, had QRS durations of at least 120 milliseconds, and were already on optimal medical therapy.

The study's main results were published online in the Journal of the American College of Cardiology in September (doi:10.1016/j.jacc.2008.08.027

At this meeting, Dr. Abraham presented the 18-month results from 262 patients in the European cohort, for whom follow-up is continuing to 24 months. These patients, he noted, differed significantly from the North American cohort in their baseline characteristics: They were younger, less likely to have ischemic cardiomyopathy, and less likely to have an implantable cardioverter defibrillator. The European patients had similar ejection fractions to the North American cohort, but had a bit more left ventricular enlargement and slightly longer QRS durations.

In this study population the primary end point significantly favored CRT therapy at 18 months, reported Dr. Abraham, director of the division of cardiovascular medicine at the Ohio State University, Columbus. The proportion of patients who had worsened at 18 months was 29% in the control group vs. 15% in the CRT group, a highly significant difference.

LVESVI improvements seen at 12 months were sustained at 18 months. Also, left ventricular end-diastolic volume index and ejection fraction were both improved in CRT patients, compared with controls.

Furthermore, all-cause mortality did not differ between treatments, while a “remarkable” 58% reduction was seen in the risk of HF hospitalization in the CRT group at 18 months. The absolute rates of hospitalization at 18 months were 13.5% in the control arm and 5.5% in the CRT arm. The combined risk of first HF hospitalization and death was reduced 50% with CRT. Rates of non-HF hospitalization were identical in the CRT on and off groups.

These results “show that there is a favorable impact on remodeling that continues beyond 12 months and that there is a favorable impact on heart failure outcomes … and no signal of an adverse effect on mortality,” commented Dr. William G. Stevenson of Brigham and Women's Hospital in Boston.

REVERSE was sponsored by Medtronic Inc. Dr. Abraham reports research grants, speaker honoraria, and consulting fees from Medtronic, St. Jude Medical Inc., and Biotronik GmbH.

TORONTO — In patients with mild heart failure, cardiac resynchronization therapy improved composite clinical response scores at 18 months, was associated with left ventricular reverse remodeling, reduced the risk of heart failure hospitalization, and lowered the combined risk of morbidity and mortality, compared with optimal medical therapy.

The 18-month data from the European cohort of the Resynchronization Reverses Remodeling in Systolic Left Ventricular Dysfunction (REVERSE) trial supported secondary conclusions from the previously reported 12-month analysis, which, although it indicated that the trial missed its primary clinical composite end point, showed evidence of remodeling and clinical benefit with CRT in mild heart failure (HF).

“Ongoing CRT trials in New York Heart Association class I and II patients may confirm these observations and expand the indication for CRT to this population of heart failure patients,” said Dr. William T. Abraham, who presented the data at the annual meeting of the Heart Failure Society of America.

The REVERSE trial was a multinational prospective effort involving 610 patients with mild or asymptomatic HF and ventricular dyssynchrony. All patients received a CRT device in addition to optimal medical therapy; 191 were randomized to have the device turned on and 419 were randomized to have it turned off.

Eligible patients had left ventricular ejection fractions below 40%, had QRS durations of at least 120 milliseconds, and were already on optimal medical therapy.

The study's main results were published online in the Journal of the American College of Cardiology in September (doi:10.1016/j.jacc.2008.08.027

At this meeting, Dr. Abraham presented the 18-month results from 262 patients in the European cohort, for whom follow-up is continuing to 24 months. These patients, he noted, differed significantly from the North American cohort in their baseline characteristics: They were younger, less likely to have ischemic cardiomyopathy, and less likely to have an implantable cardioverter defibrillator. The European patients had similar ejection fractions to the North American cohort, but had a bit more left ventricular enlargement and slightly longer QRS durations.

In this study population the primary end point significantly favored CRT therapy at 18 months, reported Dr. Abraham, director of the division of cardiovascular medicine at the Ohio State University, Columbus. The proportion of patients who had worsened at 18 months was 29% in the control group vs. 15% in the CRT group, a highly significant difference.

LVESVI improvements seen at 12 months were sustained at 18 months. Also, left ventricular end-diastolic volume index and ejection fraction were both improved in CRT patients, compared with controls.

Furthermore, all-cause mortality did not differ between treatments, while a “remarkable” 58% reduction was seen in the risk of HF hospitalization in the CRT group at 18 months. The absolute rates of hospitalization at 18 months were 13.5% in the control arm and 5.5% in the CRT arm. The combined risk of first HF hospitalization and death was reduced 50% with CRT. Rates of non-HF hospitalization were identical in the CRT on and off groups.

These results “show that there is a favorable impact on remodeling that continues beyond 12 months and that there is a favorable impact on heart failure outcomes … and no signal of an adverse effect on mortality,” commented Dr. William G. Stevenson of Brigham and Women's Hospital in Boston.

REVERSE was sponsored by Medtronic Inc. Dr. Abraham reports research grants, speaker honoraria, and consulting fees from Medtronic, St. Jude Medical Inc., and Biotronik GmbH.

TORONTO — In patients with mild heart failure, cardiac resynchronization therapy improved composite clinical response scores at 18 months, was associated with left ventricular reverse remodeling, reduced the risk of heart failure hospitalization, and lowered the combined risk of morbidity and mortality, compared with optimal medical therapy.

The 18-month data from the European cohort of the Resynchronization Reverses Remodeling in Systolic Left Ventricular Dysfunction (REVERSE) trial supported secondary conclusions from the previously reported 12-month analysis, which, although it indicated that the trial missed its primary clinical composite end point, showed evidence of remodeling and clinical benefit with CRT in mild heart failure (HF).

“Ongoing CRT trials in New York Heart Association class I and II patients may confirm these observations and expand the indication for CRT to this population of heart failure patients,” said Dr. William T. Abraham, who presented the data at the annual meeting of the Heart Failure Society of America.

The REVERSE trial was a multinational prospective effort involving 610 patients with mild or asymptomatic HF and ventricular dyssynchrony. All patients received a CRT device in addition to optimal medical therapy; 191 were randomized to have the device turned on and 419 were randomized to have it turned off.

Eligible patients had left ventricular ejection fractions below 40%, had QRS durations of at least 120 milliseconds, and were already on optimal medical therapy.

The study's main results were published online in the Journal of the American College of Cardiology in September (doi:10.1016/j.jacc.2008.08.027

At this meeting, Dr. Abraham presented the 18-month results from 262 patients in the European cohort, for whom follow-up is continuing to 24 months. These patients, he noted, differed significantly from the North American cohort in their baseline characteristics: They were younger, less likely to have ischemic cardiomyopathy, and less likely to have an implantable cardioverter defibrillator. The European patients had similar ejection fractions to the North American cohort, but had a bit more left ventricular enlargement and slightly longer QRS durations.

In this study population the primary end point significantly favored CRT therapy at 18 months, reported Dr. Abraham, director of the division of cardiovascular medicine at the Ohio State University, Columbus. The proportion of patients who had worsened at 18 months was 29% in the control group vs. 15% in the CRT group, a highly significant difference.

LVESVI improvements seen at 12 months were sustained at 18 months. Also, left ventricular end-diastolic volume index and ejection fraction were both improved in CRT patients, compared with controls.

Furthermore, all-cause mortality did not differ between treatments, while a “remarkable” 58% reduction was seen in the risk of HF hospitalization in the CRT group at 18 months. The absolute rates of hospitalization at 18 months were 13.5% in the control arm and 5.5% in the CRT arm. The combined risk of first HF hospitalization and death was reduced 50% with CRT. Rates of non-HF hospitalization were identical in the CRT on and off groups.

These results “show that there is a favorable impact on remodeling that continues beyond 12 months and that there is a favorable impact on heart failure outcomes … and no signal of an adverse effect on mortality,” commented Dr. William G. Stevenson of Brigham and Women's Hospital in Boston.

REVERSE was sponsored by Medtronic Inc. Dr. Abraham reports research grants, speaker honoraria, and consulting fees from Medtronic, St. Jude Medical Inc., and Biotronik GmbH.

CHICAGO — Deep vein thrombosis prophylaxis for hospitalized patients with heart failure is recommended in evidence-based guidelines but is often omitted in practice.

“High medical acuity, an increased prevalence of venous thromboembolism [VTE] risk factors, and a low rate of VTE prophylaxis present a triple threat to heart failure patients,” Dr. Gregory Piazza said at the annual meeting of the American College of Cardiology.

He studied 5,451 consecutive patients with ultrasound-confirmed deep vein thrombosis (DVT) in a prospective registry that included 685 patients with a history of heart failure. The heart failure patients were significantly more likely to have VTE risk factors, including acute infection, chronic obstructive pulmonary disease, and immobilization, and they had more comorbid medical conditions (see table). Moreover, 48% of the heart failure patients had been hospitalized recently. Yet only 46% of them had received any VTE prophylaxis, despite the published recommendations of the American College of Chest Physicians and other groups.

“I think heart failure patients find themselves in a catch-22, where all of the comorbid conditions that give them such high medical acuity and put them at such high risk for VTE also put them at high risk for bleeding. So there's a tendency to shy away from pharmacologic prophylaxis with anticoagulants in these patients,” said Dr. Piazza, a cardiovascular medicine fellow at Beth Israel Deaconess Medical Center, Boston. “Also, I think that because heart failure patients have so many comorbid conditions, VTE prophylaxis might fall lower on the priority list of things physicians have to take care of when they're managing these patients.”

Bringing about improvement in the situation will entail making clinicians more aware of the ACCP guidelines recommending VTE prophylaxis. In addition, cardiologists who consult on heart failure patients need to identify VTE prophylaxis on their list of recommendations.

In an interview, Dr. Piazza said future studies will establish whether it's safe and effective for hospitalized heart failure patients to continue on VTE prophylaxis after being discharged home, as is now routine for 4–6 weeks in orthopedic surgery patients.

This issue of VTE prophylaxis in heart failure patients is not going to go away, the physician stressed. “Some studies show VTE risk increases as left ventricular ejection fraction declines, perhaps suggesting that our very advanced heart failure patients are at even higher risk. And as our treatments for coronary disease and heart failure continue to improve, we're going to have many more patients hanging out in the lower ejection fraction ranges,” Dr. Piazza noted.

This study was sponsored by Sanofi Aventis. Dr. Piazza disclosed he has no financial ties with the company.

The catch-22 is, the conditions that increase heart failure patients' VTE risk also increase their bleeding risk. DR. PIAZZA

ELSEVIER GLOBAL MEDICAL NEWS

CHICAGO — Deep vein thrombosis prophylaxis for hospitalized patients with heart failure is recommended in evidence-based guidelines but is often omitted in practice.

“High medical acuity, an increased prevalence of venous thromboembolism [VTE] risk factors, and a low rate of VTE prophylaxis present a triple threat to heart failure patients,” Dr. Gregory Piazza said at the annual meeting of the American College of Cardiology.

He studied 5,451 consecutive patients with ultrasound-confirmed deep vein thrombosis (DVT) in a prospective registry that included 685 patients with a history of heart failure. The heart failure patients were significantly more likely to have VTE risk factors, including acute infection, chronic obstructive pulmonary disease, and immobilization, and they had more comorbid medical conditions (see table). Moreover, 48% of the heart failure patients had been hospitalized recently. Yet only 46% of them had received any VTE prophylaxis, despite the published recommendations of the American College of Chest Physicians and other groups.

“I think heart failure patients find themselves in a catch-22, where all of the comorbid conditions that give them such high medical acuity and put them at such high risk for VTE also put them at high risk for bleeding. So there's a tendency to shy away from pharmacologic prophylaxis with anticoagulants in these patients,” said Dr. Piazza, a cardiovascular medicine fellow at Beth Israel Deaconess Medical Center, Boston. “Also, I think that because heart failure patients have so many comorbid conditions, VTE prophylaxis might fall lower on the priority list of things physicians have to take care of when they're managing these patients.”

Bringing about improvement in the situation will entail making clinicians more aware of the ACCP guidelines recommending VTE prophylaxis. In addition, cardiologists who consult on heart failure patients need to identify VTE prophylaxis on their list of recommendations.

In an interview, Dr. Piazza said future studies will establish whether it's safe and effective for hospitalized heart failure patients to continue on VTE prophylaxis after being discharged home, as is now routine for 4–6 weeks in orthopedic surgery patients.

This issue of VTE prophylaxis in heart failure patients is not going to go away, the physician stressed. “Some studies show VTE risk increases as left ventricular ejection fraction declines, perhaps suggesting that our very advanced heart failure patients are at even higher risk. And as our treatments for coronary disease and heart failure continue to improve, we're going to have many more patients hanging out in the lower ejection fraction ranges,” Dr. Piazza noted.

This study was sponsored by Sanofi Aventis. Dr. Piazza disclosed he has no financial ties with the company.

The catch-22 is, the conditions that increase heart failure patients' VTE risk also increase their bleeding risk. DR. PIAZZA

ELSEVIER GLOBAL MEDICAL NEWS

CHICAGO — Deep vein thrombosis prophylaxis for hospitalized patients with heart failure is recommended in evidence-based guidelines but is often omitted in practice.

“High medical acuity, an increased prevalence of venous thromboembolism [VTE] risk factors, and a low rate of VTE prophylaxis present a triple threat to heart failure patients,” Dr. Gregory Piazza said at the annual meeting of the American College of Cardiology.

He studied 5,451 consecutive patients with ultrasound-confirmed deep vein thrombosis (DVT) in a prospective registry that included 685 patients with a history of heart failure. The heart failure patients were significantly more likely to have VTE risk factors, including acute infection, chronic obstructive pulmonary disease, and immobilization, and they had more comorbid medical conditions (see table). Moreover, 48% of the heart failure patients had been hospitalized recently. Yet only 46% of them had received any VTE prophylaxis, despite the published recommendations of the American College of Chest Physicians and other groups.

“I think heart failure patients find themselves in a catch-22, where all of the comorbid conditions that give them such high medical acuity and put them at such high risk for VTE also put them at high risk for bleeding. So there's a tendency to shy away from pharmacologic prophylaxis with anticoagulants in these patients,” said Dr. Piazza, a cardiovascular medicine fellow at Beth Israel Deaconess Medical Center, Boston. “Also, I think that because heart failure patients have so many comorbid conditions, VTE prophylaxis might fall lower on the priority list of things physicians have to take care of when they're managing these patients.”

Bringing about improvement in the situation will entail making clinicians more aware of the ACCP guidelines recommending VTE prophylaxis. In addition, cardiologists who consult on heart failure patients need to identify VTE prophylaxis on their list of recommendations.

In an interview, Dr. Piazza said future studies will establish whether it's safe and effective for hospitalized heart failure patients to continue on VTE prophylaxis after being discharged home, as is now routine for 4–6 weeks in orthopedic surgery patients.

This issue of VTE prophylaxis in heart failure patients is not going to go away, the physician stressed. “Some studies show VTE risk increases as left ventricular ejection fraction declines, perhaps suggesting that our very advanced heart failure patients are at even higher risk. And as our treatments for coronary disease and heart failure continue to improve, we're going to have many more patients hanging out in the lower ejection fraction ranges,” Dr. Piazza noted.

This study was sponsored by Sanofi Aventis. Dr. Piazza disclosed he has no financial ties with the company.

The catch-22 is, the conditions that increase heart failure patients' VTE risk also increase their bleeding risk. DR. PIAZZA

ELSEVIER GLOBAL MEDICAL NEWS

The inflammatory markers interleukin-6 and C-reactive protein as well as macroalbuminuria are independently predictive of heart failure, according to a study that followed nearly 7,000 Americans for a median of 4 years.

Each standard deviation increase in serum interleukin-6 or CRP level raised the risk of heart failure (HF) by 50% and 38%, respectively, while the presence of macroalbuminuria increased the risk 4.3-fold (J. Am. Coll. Cardiol. 2008;51:1775–83).

These associations were strong “even after adjustment for established risk factors, LV [left ventricular] dysfunction, and interim MI,” wrote Dr. Hossein Bahrami of Johns Hopkins University, Baltimore, and colleagues.

The community-based Multi-Ethnic Study of Atherosclerosis is a multicenter cohort study of 6,814 whites, blacks, Hispanics, and Chinese Americans with no history of symptomatic cardiovascular disease. Overall, 79 participants developed HF during the study period and 26 of those individuals (33%) had an interim MI. Participants who developed HF were more likely to be older, male, obese, and current smokers and to have hypertension and diabetes.

The presence of metabolic syndrome at baseline (seen in 35% of participants) more than doubled the risk of HF. Specifically, the absolute risk of HF in obese individuals was 16/1,000, compared with 10/1,000 in the nonobese. However, the association between obesity and incident HF was no longer significant after the model was adjusted to include the two inflammatory markers, they reported.

Very few participants (1.3%) had left ventricular ejection fraction (LVEF) below 50%, though 10% of participants had left ventricular hypertrophy (LVH) at baseline by Framingham criteria. Among the individuals who developed HF, rates of LVEF below 50% and LVH were 15% and 32%, respectively.

LVEF was the strongest predictor of incident HF and was therefore incorporated into the multivariate analysis. Among the 60 participants with LV function data at time of HF diagnosis, 87% had LVEF of 30% or greater, 65% had LVEF of 40% or greater, and 55% had LVEF of 50% or greater, the investigators wrote.

The inflammatory markers interleukin-6 and C-reactive protein as well as macroalbuminuria are independently predictive of heart failure, according to a study that followed nearly 7,000 Americans for a median of 4 years.

Each standard deviation increase in serum interleukin-6 or CRP level raised the risk of heart failure (HF) by 50% and 38%, respectively, while the presence of macroalbuminuria increased the risk 4.3-fold (J. Am. Coll. Cardiol. 2008;51:1775–83).

These associations were strong “even after adjustment for established risk factors, LV [left ventricular] dysfunction, and interim MI,” wrote Dr. Hossein Bahrami of Johns Hopkins University, Baltimore, and colleagues.

The community-based Multi-Ethnic Study of Atherosclerosis is a multicenter cohort study of 6,814 whites, blacks, Hispanics, and Chinese Americans with no history of symptomatic cardiovascular disease. Overall, 79 participants developed HF during the study period and 26 of those individuals (33%) had an interim MI. Participants who developed HF were more likely to be older, male, obese, and current smokers and to have hypertension and diabetes.

The presence of metabolic syndrome at baseline (seen in 35% of participants) more than doubled the risk of HF. Specifically, the absolute risk of HF in obese individuals was 16/1,000, compared with 10/1,000 in the nonobese. However, the association between obesity and incident HF was no longer significant after the model was adjusted to include the two inflammatory markers, they reported.

Very few participants (1.3%) had left ventricular ejection fraction (LVEF) below 50%, though 10% of participants had left ventricular hypertrophy (LVH) at baseline by Framingham criteria. Among the individuals who developed HF, rates of LVEF below 50% and LVH were 15% and 32%, respectively.

LVEF was the strongest predictor of incident HF and was therefore incorporated into the multivariate analysis. Among the 60 participants with LV function data at time of HF diagnosis, 87% had LVEF of 30% or greater, 65% had LVEF of 40% or greater, and 55% had LVEF of 50% or greater, the investigators wrote.

The inflammatory markers interleukin-6 and C-reactive protein as well as macroalbuminuria are independently predictive of heart failure, according to a study that followed nearly 7,000 Americans for a median of 4 years.

Each standard deviation increase in serum interleukin-6 or CRP level raised the risk of heart failure (HF) by 50% and 38%, respectively, while the presence of macroalbuminuria increased the risk 4.3-fold (J. Am. Coll. Cardiol. 2008;51:1775–83).

These associations were strong “even after adjustment for established risk factors, LV [left ventricular] dysfunction, and interim MI,” wrote Dr. Hossein Bahrami of Johns Hopkins University, Baltimore, and colleagues.

The community-based Multi-Ethnic Study of Atherosclerosis is a multicenter cohort study of 6,814 whites, blacks, Hispanics, and Chinese Americans with no history of symptomatic cardiovascular disease. Overall, 79 participants developed HF during the study period and 26 of those individuals (33%) had an interim MI. Participants who developed HF were more likely to be older, male, obese, and current smokers and to have hypertension and diabetes.

The presence of metabolic syndrome at baseline (seen in 35% of participants) more than doubled the risk of HF. Specifically, the absolute risk of HF in obese individuals was 16/1,000, compared with 10/1,000 in the nonobese. However, the association between obesity and incident HF was no longer significant after the model was adjusted to include the two inflammatory markers, they reported.

Very few participants (1.3%) had left ventricular ejection fraction (LVEF) below 50%, though 10% of participants had left ventricular hypertrophy (LVH) at baseline by Framingham criteria. Among the individuals who developed HF, rates of LVEF below 50% and LVH were 15% and 32%, respectively.

LVEF was the strongest predictor of incident HF and was therefore incorporated into the multivariate analysis. Among the 60 participants with LV function data at time of HF diagnosis, 87% had LVEF of 30% or greater, 65% had LVEF of 40% or greater, and 55% had LVEF of 50% or greater, the investigators wrote.

BOSTON — Patients with nonischemic cardiomyopathy who received an implantable cardioverter defibrillator did not have a survival benefit while listed as status 2 for a potential heart transplant, compared with patients who did not have an implantable defibrillator, based on records from more than 2,500 U.S. patients who were listed during 2000–2005.

In contrast, patients with ischemic cardiomyopathy who had an implantable cardioverter defibrillator (ICD) while listed as status 2 for a heart transplant during the same period had a significant 6% absolute survival advantage compared with patients without an ICD during the same period, Dr. Katherine Lietz reported at the annual meeting of the International Society for Heart and Lung Transplantation.

The reason for this difference in the impact of ICDs on survival based on whether a patient's cardiomyopathy had an ischemic or nonischemic etiology is not clear, she said. In addition, this finding should not be viewed as a reason to not place ICDs in patients with nonischemic cardiomyopathy, said Dr. Lietz, a transplant cardiologist at Columbia University in New York. Rather, the finding suggests that more research should be done to identify the determinants of survival in patients with nonischemic cardiomyopathy who are awaiting a heart transplant.

Her analysis focused on U.S. patients listed with the United Network for Organ Sharing as status 2 patients, defined as those who meet general criteria for a heart transplant, but are not “high urgency” status 1 patients.

During the period studied, use of ICDs in status 2 patients jumped more than twofold, rising from 37% in 2005 to 77% of listed status 2 patients in 2005, Dr. Lietz said. A total of 6,201 patients were listed as status 2 for a heart transplant in this period: 3,448 patients with ischemic-etiology cardiomyopathy and 2,753 patients with a nonischemic etiology. The vast majority (98%) of these patients who received an ICD had it implanted before they were listed for a heart transplant.

The 3-year survival rate of all patients with ischemic cardiomyopathy who had an ICD was 84%, compared with 76% among patients who did not receive an ICD. The researchers then ran the same analysis only on patients who remained on the list and did not receive a donated heart. In this subgroup, the 3-year survival rate with an ICD was 73.6%, and without an ICD it was 67.4%, a significant difference.

The 6.2% absolute improvement in survival over 3 years linked with ICD use was comparable with the survival benefit seen with ICD use in the Sudden Cardiac Death Heart Failure Trial (SCD-HFT), Dr. Lietz noted.

In contrast, among all patients with nonischemic cardiomyopathy who were listed as status 2, the 3-year survival rate with an ICD was 79.8%, compared with 81.2% among patients without an ICD, a “surprising” finding, said Dr. Lietz. This unexpected disparity remained among those who remained listed without a new heart. The survival rate was 65.7% with an ICD and 74.5% without an ICD, a difference that was not statistically significant, Dr. Lietz said.

Presence of an ICD did not affect the 3-year survival rate in status 2 patients with nonischemic cardiomyopathy. DR. LIETZ

BOSTON — Patients with nonischemic cardiomyopathy who received an implantable cardioverter defibrillator did not have a survival benefit while listed as status 2 for a potential heart transplant, compared with patients who did not have an implantable defibrillator, based on records from more than 2,500 U.S. patients who were listed during 2000–2005.

In contrast, patients with ischemic cardiomyopathy who had an implantable cardioverter defibrillator (ICD) while listed as status 2 for a heart transplant during the same period had a significant 6% absolute survival advantage compared with patients without an ICD during the same period, Dr. Katherine Lietz reported at the annual meeting of the International Society for Heart and Lung Transplantation.

The reason for this difference in the impact of ICDs on survival based on whether a patient's cardiomyopathy had an ischemic or nonischemic etiology is not clear, she said. In addition, this finding should not be viewed as a reason to not place ICDs in patients with nonischemic cardiomyopathy, said Dr. Lietz, a transplant cardiologist at Columbia University in New York. Rather, the finding suggests that more research should be done to identify the determinants of survival in patients with nonischemic cardiomyopathy who are awaiting a heart transplant.

Her analysis focused on U.S. patients listed with the United Network for Organ Sharing as status 2 patients, defined as those who meet general criteria for a heart transplant, but are not “high urgency” status 1 patients.

During the period studied, use of ICDs in status 2 patients jumped more than twofold, rising from 37% in 2005 to 77% of listed status 2 patients in 2005, Dr. Lietz said. A total of 6,201 patients were listed as status 2 for a heart transplant in this period: 3,448 patients with ischemic-etiology cardiomyopathy and 2,753 patients with a nonischemic etiology. The vast majority (98%) of these patients who received an ICD had it implanted before they were listed for a heart transplant.

The 3-year survival rate of all patients with ischemic cardiomyopathy who had an ICD was 84%, compared with 76% among patients who did not receive an ICD. The researchers then ran the same analysis only on patients who remained on the list and did not receive a donated heart. In this subgroup, the 3-year survival rate with an ICD was 73.6%, and without an ICD it was 67.4%, a significant difference.

The 6.2% absolute improvement in survival over 3 years linked with ICD use was comparable with the survival benefit seen with ICD use in the Sudden Cardiac Death Heart Failure Trial (SCD-HFT), Dr. Lietz noted.

In contrast, among all patients with nonischemic cardiomyopathy who were listed as status 2, the 3-year survival rate with an ICD was 79.8%, compared with 81.2% among patients without an ICD, a “surprising” finding, said Dr. Lietz. This unexpected disparity remained among those who remained listed without a new heart. The survival rate was 65.7% with an ICD and 74.5% without an ICD, a difference that was not statistically significant, Dr. Lietz said.

Presence of an ICD did not affect the 3-year survival rate in status 2 patients with nonischemic cardiomyopathy. DR. LIETZ

BOSTON — Patients with nonischemic cardiomyopathy who received an implantable cardioverter defibrillator did not have a survival benefit while listed as status 2 for a potential heart transplant, compared with patients who did not have an implantable defibrillator, based on records from more than 2,500 U.S. patients who were listed during 2000–2005.

In contrast, patients with ischemic cardiomyopathy who had an implantable cardioverter defibrillator (ICD) while listed as status 2 for a heart transplant during the same period had a significant 6% absolute survival advantage compared with patients without an ICD during the same period, Dr. Katherine Lietz reported at the annual meeting of the International Society for Heart and Lung Transplantation.

The reason for this difference in the impact of ICDs on survival based on whether a patient's cardiomyopathy had an ischemic or nonischemic etiology is not clear, she said. In addition, this finding should not be viewed as a reason to not place ICDs in patients with nonischemic cardiomyopathy, said Dr. Lietz, a transplant cardiologist at Columbia University in New York. Rather, the finding suggests that more research should be done to identify the determinants of survival in patients with nonischemic cardiomyopathy who are awaiting a heart transplant.

Her analysis focused on U.S. patients listed with the United Network for Organ Sharing as status 2 patients, defined as those who meet general criteria for a heart transplant, but are not “high urgency” status 1 patients.

During the period studied, use of ICDs in status 2 patients jumped more than twofold, rising from 37% in 2005 to 77% of listed status 2 patients in 2005, Dr. Lietz said. A total of 6,201 patients were listed as status 2 for a heart transplant in this period: 3,448 patients with ischemic-etiology cardiomyopathy and 2,753 patients with a nonischemic etiology. The vast majority (98%) of these patients who received an ICD had it implanted before they were listed for a heart transplant.

The 3-year survival rate of all patients with ischemic cardiomyopathy who had an ICD was 84%, compared with 76% among patients who did not receive an ICD. The researchers then ran the same analysis only on patients who remained on the list and did not receive a donated heart. In this subgroup, the 3-year survival rate with an ICD was 73.6%, and without an ICD it was 67.4%, a significant difference.

The 6.2% absolute improvement in survival over 3 years linked with ICD use was comparable with the survival benefit seen with ICD use in the Sudden Cardiac Death Heart Failure Trial (SCD-HFT), Dr. Lietz noted.

In contrast, among all patients with nonischemic cardiomyopathy who were listed as status 2, the 3-year survival rate with an ICD was 79.8%, compared with 81.2% among patients without an ICD, a “surprising” finding, said Dr. Lietz. This unexpected disparity remained among those who remained listed without a new heart. The survival rate was 65.7% with an ICD and 74.5% without an ICD, a difference that was not statistically significant, Dr. Lietz said.

Presence of an ICD did not affect the 3-year survival rate in status 2 patients with nonischemic cardiomyopathy. DR. LIETZ

BOSTON – Patients with three or more risk factors who were listed with the highest urgency for a heart transplant—status 1A—on the U.S. waiting list had at least a 30% risk of dying before a donor heart was available, based on actual experience during 2000–2006.

Records from the United Network for Organ Sharing (UNOS) for this period showed that when high-risk patients (defined as those with more than three risk factors for death) received a mechanical circulatory support device, their 90-day survival rate jumped from 50% to 89%, said Dr. Katherine Lietz, who presented an analysis of UNOS data at the annual meeting of the International Society for Heart and Lung Transplantation. When a ventricular assist implant is used this way, it's often called a “bridge-to-transplant” device.

“To bridge or not to bridge is one of the most challenging decisions for medically managed, high-urgency, status 1A patients” who are awaiting a heart transplant, said Dr. Lietz, a transplant cardiologist at Columbia University in New York. Three key factors enter into this decision: the patient's risk for dying while awaiting a donor heart, the chances for successfully receiving a transplanted heart, and the risk of complications from implantation with a mechanical circulatory support device.

To better document the first two factors, Dr. Lietz and her associates analyzed data collected on 1,755 patients who were listed with UNOS as status 1A candidates for a heart transplant during January 2000-December 2006. During their first 30 days on the UNOS list, 14% of the patients died, 49% received a transplanted heart, 33% remained active on the list, and the remaining 4% were removed from the list because their status had improved.

The investigators identified the following six clinical or demographic features that were significantly associated with an elevated risk for death during the first 30 days on the list: blood type O, age older than 60 years, ventilator support, intra-aortic balloon pump, serum creatinine greater than 1.5 mg/dL, and serum albumin less than 3.0 g/dL.

Further analysis showed that the risk of death increased in patients who had higher numbers of these risk factors. Patients with none of these risk factors had an 11% risk of dying while they were maintained on medical treatment during their first 30 days on the list. Mortality risk rates increased as the number of risk factors rose (see box).

A second analysis identified a non-O blood type and a body weight of 89 kg or less as the most important determinants of receiving a heart transplant during the first 30 days on the list. Patients who met both of these criteria had a 66% chance of receiving a heart during this period. Those with either one of these two factors had about a 50% chance, and patients without either factor had about a 23% chance of receiving a donated heart, Dr. Lietz said.

She stressed that patients and their physicians need to determine how these findings can be used to help guide individual decisions about whether to rely on medical treatment alone or opt for implantation of a mechanical circulatory support device while a patient is listed and awaiting a heart. Dr. Lietz suggested that a reasonable cutoff might be a risk for dying of 30% or greater while listed, which corresponds to a patient's having three or more mortality risk factors.

The UNOS data showed that these patients stood to substantially boost their chances for survival if they received a mechanical circulatory support device.

ELSEVIER GLOBAL MEDICAL NEWS

BOSTON – Patients with three or more risk factors who were listed with the highest urgency for a heart transplant—status 1A—on the U.S. waiting list had at least a 30% risk of dying before a donor heart was available, based on actual experience during 2000–2006.

Records from the United Network for Organ Sharing (UNOS) for this period showed that when high-risk patients (defined as those with more than three risk factors for death) received a mechanical circulatory support device, their 90-day survival rate jumped from 50% to 89%, said Dr. Katherine Lietz, who presented an analysis of UNOS data at the annual meeting of the International Society for Heart and Lung Transplantation. When a ventricular assist implant is used this way, it's often called a “bridge-to-transplant” device.

“To bridge or not to bridge is one of the most challenging decisions for medically managed, high-urgency, status 1A patients” who are awaiting a heart transplant, said Dr. Lietz, a transplant cardiologist at Columbia University in New York. Three key factors enter into this decision: the patient's risk for dying while awaiting a donor heart, the chances for successfully receiving a transplanted heart, and the risk of complications from implantation with a mechanical circulatory support device.

To better document the first two factors, Dr. Lietz and her associates analyzed data collected on 1,755 patients who were listed with UNOS as status 1A candidates for a heart transplant during January 2000-December 2006. During their first 30 days on the UNOS list, 14% of the patients died, 49% received a transplanted heart, 33% remained active on the list, and the remaining 4% were removed from the list because their status had improved.

The investigators identified the following six clinical or demographic features that were significantly associated with an elevated risk for death during the first 30 days on the list: blood type O, age older than 60 years, ventilator support, intra-aortic balloon pump, serum creatinine greater than 1.5 mg/dL, and serum albumin less than 3.0 g/dL.

Further analysis showed that the risk of death increased in patients who had higher numbers of these risk factors. Patients with none of these risk factors had an 11% risk of dying while they were maintained on medical treatment during their first 30 days on the list. Mortality risk rates increased as the number of risk factors rose (see box).

A second analysis identified a non-O blood type and a body weight of 89 kg or less as the most important determinants of receiving a heart transplant during the first 30 days on the list. Patients who met both of these criteria had a 66% chance of receiving a heart during this period. Those with either one of these two factors had about a 50% chance, and patients without either factor had about a 23% chance of receiving a donated heart, Dr. Lietz said.

She stressed that patients and their physicians need to determine how these findings can be used to help guide individual decisions about whether to rely on medical treatment alone or opt for implantation of a mechanical circulatory support device while a patient is listed and awaiting a heart. Dr. Lietz suggested that a reasonable cutoff might be a risk for dying of 30% or greater while listed, which corresponds to a patient's having three or more mortality risk factors.

The UNOS data showed that these patients stood to substantially boost their chances for survival if they received a mechanical circulatory support device.

ELSEVIER GLOBAL MEDICAL NEWS

BOSTON – Patients with three or more risk factors who were listed with the highest urgency for a heart transplant—status 1A—on the U.S. waiting list had at least a 30% risk of dying before a donor heart was available, based on actual experience during 2000–2006.

Records from the United Network for Organ Sharing (UNOS) for this period showed that when high-risk patients (defined as those with more than three risk factors for death) received a mechanical circulatory support device, their 90-day survival rate jumped from 50% to 89%, said Dr. Katherine Lietz, who presented an analysis of UNOS data at the annual meeting of the International Society for Heart and Lung Transplantation. When a ventricular assist implant is used this way, it's often called a “bridge-to-transplant” device.

“To bridge or not to bridge is one of the most challenging decisions for medically managed, high-urgency, status 1A patients” who are awaiting a heart transplant, said Dr. Lietz, a transplant cardiologist at Columbia University in New York. Three key factors enter into this decision: the patient's risk for dying while awaiting a donor heart, the chances for successfully receiving a transplanted heart, and the risk of complications from implantation with a mechanical circulatory support device.

To better document the first two factors, Dr. Lietz and her associates analyzed data collected on 1,755 patients who were listed with UNOS as status 1A candidates for a heart transplant during January 2000-December 2006. During their first 30 days on the UNOS list, 14% of the patients died, 49% received a transplanted heart, 33% remained active on the list, and the remaining 4% were removed from the list because their status had improved.

The investigators identified the following six clinical or demographic features that were significantly associated with an elevated risk for death during the first 30 days on the list: blood type O, age older than 60 years, ventilator support, intra-aortic balloon pump, serum creatinine greater than 1.5 mg/dL, and serum albumin less than 3.0 g/dL.

Further analysis showed that the risk of death increased in patients who had higher numbers of these risk factors. Patients with none of these risk factors had an 11% risk of dying while they were maintained on medical treatment during their first 30 days on the list. Mortality risk rates increased as the number of risk factors rose (see box).

A second analysis identified a non-O blood type and a body weight of 89 kg or less as the most important determinants of receiving a heart transplant during the first 30 days on the list. Patients who met both of these criteria had a 66% chance of receiving a heart during this period. Those with either one of these two factors had about a 50% chance, and patients without either factor had about a 23% chance of receiving a donated heart, Dr. Lietz said.

She stressed that patients and their physicians need to determine how these findings can be used to help guide individual decisions about whether to rely on medical treatment alone or opt for implantation of a mechanical circulatory support device while a patient is listed and awaiting a heart. Dr. Lietz suggested that a reasonable cutoff might be a risk for dying of 30% or greater while listed, which corresponds to a patient's having three or more mortality risk factors.

The UNOS data showed that these patients stood to substantially boost their chances for survival if they received a mechanical circulatory support device.

ELSEVIER GLOBAL MEDICAL NEWS

NEW YORK — Subclinical hypothyroidism with a thyroid-stimulating hormone level of 10–20 mU/L was associated with an almost twofold risk of clinical heart failure in a study of more than 3,000 older adults.

The findings, presented by Dr. Douglas Bauer at the annual meeting of the American Thyroid Association, come from an analysis of participants in the prospective Cardiovascular Health Study, which includes persons from Medicare population-based listings at four university hospitals in the United States and is funded by the National Institutes of Health.

Dr. Bauer and his colleagues recruited 3,065 participants who were free of heart failure at baseline and not taking any medication known to affect thyroid function. Any participants who initiated T4 replacement during the study were removed from the analysis, and 21 were excluded because of insufficient serum for testing. Participants were followed for 12 years and were contacted every 6 months for assessment of outcomes, said Dr. Bauer of the University of California, San Francisco.

Of the 495 persons (16%) with hypothyroidism, 448 had a TSH level between 4.5 mU/L and 9.9 mU/L and 47 had a TSH level of 10–20 mU/L. Hyperthyroidism (TSH level below 0.45 mU/L and normal T4 value) was found in 44 persons. All hypothyroidism and hyperthyroidism in the study was subclinical.

Echocardiograms were obtained for all participants at baseline and at 5 years' follow-up and read by blinded clinicians (including cardiologists). Some participants experienced heart failure before the 5-year follow-up, and their clinical echocardiograms were also included.

At 12 years' follow-up, 660 persons (22%) had heart failure. In the 47 participants with a TSH level of 10–20 mU/L, there were 45 heart failure events per 1,000 person-years, compared with 22 events per 1,000 person-years in euthyroid participants. Multivariate analysis showed an unadjusted hazard ratio of 2.03 for those with a TSH level of 10–20 mU/L, versus euthyroid participants—a significant difference. (Adjusted for confounding factors, the hazard ratio was 1.88.) No increase in heart failure risk was seen in the hypothyroid participants with TSH levels of 4.5–9.9 mU/L or in euthyroid persons, versus those with TSH levels below that range. There was no difference in the heart failure rate between men and women.

Moreover, at 12 years, impaired cardiac function was associated with TSH levels of 10–20 mU/L: The percentage of participants who had an abnormal left ventricular ejection fraction at time of incident heart failure was 80% in the high-TSH hypothyroid group, compared with 39% in the lower-TSH hypothyroid group, 44% in the euthyroid group, and 33% in the hyperthyroid group.

Dr. Bauer and colleagues concluded that “subclinical hypothyroidism is associated with a moderately increased risk of clinical events of congestive heart failure among older individuals with a TSH greater than 10 [mU/L].”

He acknowledged that the study was limited by a shorter follow-up period for the echocardiography data than for the heart failure data (5 years vs. 12 years), as well as missing follow-up echocardiograms for some participants.

Several studies have established an association between subclinical hypothyroid and hyperthyroid disease and cardiac dysfunction, Dr. Bauer said. But most studies have looked at subtle abnormalities in contractility, rather than at more clinically important measures, such as left ventricular ejection fraction. Also, most of those studies have been limited by small sample sizes and lack of randomization.

NEW YORK — Subclinical hypothyroidism with a thyroid-stimulating hormone level of 10–20 mU/L was associated with an almost twofold risk of clinical heart failure in a study of more than 3,000 older adults.

The findings, presented by Dr. Douglas Bauer at the annual meeting of the American Thyroid Association, come from an analysis of participants in the prospective Cardiovascular Health Study, which includes persons from Medicare population-based listings at four university hospitals in the United States and is funded by the National Institutes of Health.

Dr. Bauer and his colleagues recruited 3,065 participants who were free of heart failure at baseline and not taking any medication known to affect thyroid function. Any participants who initiated T4 replacement during the study were removed from the analysis, and 21 were excluded because of insufficient serum for testing. Participants were followed for 12 years and were contacted every 6 months for assessment of outcomes, said Dr. Bauer of the University of California, San Francisco.

Of the 495 persons (16%) with hypothyroidism, 448 had a TSH level between 4.5 mU/L and 9.9 mU/L and 47 had a TSH level of 10–20 mU/L. Hyperthyroidism (TSH level below 0.45 mU/L and normal T4 value) was found in 44 persons. All hypothyroidism and hyperthyroidism in the study was subclinical.

Echocardiograms were obtained for all participants at baseline and at 5 years' follow-up and read by blinded clinicians (including cardiologists). Some participants experienced heart failure before the 5-year follow-up, and their clinical echocardiograms were also included.

At 12 years' follow-up, 660 persons (22%) had heart failure. In the 47 participants with a TSH level of 10–20 mU/L, there were 45 heart failure events per 1,000 person-years, compared with 22 events per 1,000 person-years in euthyroid participants. Multivariate analysis showed an unadjusted hazard ratio of 2.03 for those with a TSH level of 10–20 mU/L, versus euthyroid participants—a significant difference. (Adjusted for confounding factors, the hazard ratio was 1.88.) No increase in heart failure risk was seen in the hypothyroid participants with TSH levels of 4.5–9.9 mU/L or in euthyroid persons, versus those with TSH levels below that range. There was no difference in the heart failure rate between men and women.

Moreover, at 12 years, impaired cardiac function was associated with TSH levels of 10–20 mU/L: The percentage of participants who had an abnormal left ventricular ejection fraction at time of incident heart failure was 80% in the high-TSH hypothyroid group, compared with 39% in the lower-TSH hypothyroid group, 44% in the euthyroid group, and 33% in the hyperthyroid group.

Dr. Bauer and colleagues concluded that “subclinical hypothyroidism is associated with a moderately increased risk of clinical events of congestive heart failure among older individuals with a TSH greater than 10 [mU/L].”

He acknowledged that the study was limited by a shorter follow-up period for the echocardiography data than for the heart failure data (5 years vs. 12 years), as well as missing follow-up echocardiograms for some participants.

Several studies have established an association between subclinical hypothyroid and hyperthyroid disease and cardiac dysfunction, Dr. Bauer said. But most studies have looked at subtle abnormalities in contractility, rather than at more clinically important measures, such as left ventricular ejection fraction. Also, most of those studies have been limited by small sample sizes and lack of randomization.

NEW YORK — Subclinical hypothyroidism with a thyroid-stimulating hormone level of 10–20 mU/L was associated with an almost twofold risk of clinical heart failure in a study of more than 3,000 older adults.

The findings, presented by Dr. Douglas Bauer at the annual meeting of the American Thyroid Association, come from an analysis of participants in the prospective Cardiovascular Health Study, which includes persons from Medicare population-based listings at four university hospitals in the United States and is funded by the National Institutes of Health.

Dr. Bauer and his colleagues recruited 3,065 participants who were free of heart failure at baseline and not taking any medication known to affect thyroid function. Any participants who initiated T4 replacement during the study were removed from the analysis, and 21 were excluded because of insufficient serum for testing. Participants were followed for 12 years and were contacted every 6 months for assessment of outcomes, said Dr. Bauer of the University of California, San Francisco.

Of the 495 persons (16%) with hypothyroidism, 448 had a TSH level between 4.5 mU/L and 9.9 mU/L and 47 had a TSH level of 10–20 mU/L. Hyperthyroidism (TSH level below 0.45 mU/L and normal T4 value) was found in 44 persons. All hypothyroidism and hyperthyroidism in the study was subclinical.

Echocardiograms were obtained for all participants at baseline and at 5 years' follow-up and read by blinded clinicians (including cardiologists). Some participants experienced heart failure before the 5-year follow-up, and their clinical echocardiograms were also included.

At 12 years' follow-up, 660 persons (22%) had heart failure. In the 47 participants with a TSH level of 10–20 mU/L, there were 45 heart failure events per 1,000 person-years, compared with 22 events per 1,000 person-years in euthyroid participants. Multivariate analysis showed an unadjusted hazard ratio of 2.03 for those with a TSH level of 10–20 mU/L, versus euthyroid participants—a significant difference. (Adjusted for confounding factors, the hazard ratio was 1.88.) No increase in heart failure risk was seen in the hypothyroid participants with TSH levels of 4.5–9.9 mU/L or in euthyroid persons, versus those with TSH levels below that range. There was no difference in the heart failure rate between men and women.

Moreover, at 12 years, impaired cardiac function was associated with TSH levels of 10–20 mU/L: The percentage of participants who had an abnormal left ventricular ejection fraction at time of incident heart failure was 80% in the high-TSH hypothyroid group, compared with 39% in the lower-TSH hypothyroid group, 44% in the euthyroid group, and 33% in the hyperthyroid group.

Dr. Bauer and colleagues concluded that “subclinical hypothyroidism is associated with a moderately increased risk of clinical events of congestive heart failure among older individuals with a TSH greater than 10 [mU/L].”

He acknowledged that the study was limited by a shorter follow-up period for the echocardiography data than for the heart failure data (5 years vs. 12 years), as well as missing follow-up echocardiograms for some participants.

Several studies have established an association between subclinical hypothyroid and hyperthyroid disease and cardiac dysfunction, Dr. Bauer said. But most studies have looked at subtle abnormalities in contractility, rather than at more clinically important measures, such as left ventricular ejection fraction. Also, most of those studies have been limited by small sample sizes and lack of randomization.

ELSEVIER GLOBAL MEDICAL NEWS

ELSEVIER GLOBAL MEDICAL NEWS

ELSEVIER GLOBAL MEDICAL NEWS

SNOWMASS, COLO. — Administering an ACE inhibitor or carvedilol in cancer patients prior to high-dose chemotherapy is an excellent strategy for preventing chemotherapy-induced cardiomyopathy.

Chemotherapy-induced cardiomyopathy (CIC) is a far more common problem than most nononcologists appreciate, occurring in at least a quarter of patients on some widely prescribed regimens. Affected patients are not only exposed to the morbidity and mortality of heart failure, but their cancer therapy often has to be curtailed because of their cardiac impairment.

So rather than waiting for CIC to occur and then scrambling treat it, why not prevent it?, asked Dr. John S. Schroeder, professor of medicine at Stanford (Calif.) University, asked at a conference sponsored by the Society for Cardiovascular Angiography and Interventions.

He cited two randomized trials that have paved the way. In one, Dr. Nihat Kalay and colleagues at Erciyes University, Kayseri, Turkey, randomized 50 cancer patients slated to start notoriously cardiotoxic anthracycline chemotherapy to carvedilol (Coreg) at 12.5 mg once daily or placebo. At 6 months' follow-up, the mean left ventricular ejection fraction (EF) in the carvedilol group was essentially unchanged from the 70% baseline figure, while in the control group it fell from 69% to 52%.

One patient in the carvedilol arm and five on placebo had an EF below 50% at 6 months. There was one death in the carvedilol arm and four among controls (J. Am. Coll. Cardiol. 2006;48:2258–62).

Oxidative stress and mitochondrial dysfunction are believed to figure prominently in the pathophysiology of anthracycline-induced cardiomyopathy. The Turkish cardiologists pointed to carvedilol's antioxidant effects—considered the most potent of any β-blocker—as the most likely mechanism for the drug's ability to prevent cardiotoxicity. They selected a relatively low dosage because patients had normal baseline ventricular function and carvedilol's antioxidant properties are manifest even at lower doses.

Dr. Schroeder agreed that carvedilol's strong antioxidant effects make it the β-blocker of choice for prevention of CIC. He added, however, that the prolonged-release formulation probably makes more sense.

The other key clinical trial in the prevention of chemotherapy-induced cardiomyopathy was conducted by Dr. Daniela Cardinale and colleagues at the European Institute of Oncology in Milan.

Among 473 cancer patients with a normal baseline EF undergoing high-dose chemotherapy, they identified 24% as being at particularly high risk for CIC on the basis of a troponin I level greater than 0.07 ng/mL obtained within several days after completing any chemo cycle. The investigators randomized these 114 patients to 1 year of enalapril or to no enalapril beginning 1 month after the end of the final cycle of chemo. The ACE inhibitor was slowly titrated to 20 mg once daily.

The primary end point—a greater than absolute 10% drop in EF to a value below 50% at 1 year as assessed by blinded echocardiographers—occurred in 43% of controls and 0% of the ACE inhibitor recipients. In the control group there were 30 cases of the secondary combined end point of cardiac death, acute pulmonary edema, overt heart failure, or life-threatening arrhythmia, compared to just one in the enalapril group (Circulation 2006;114:2474–81).

The Italians surmised that the observed benefits involved a class effect and any ACE inhibitor would probably be effective. Dr. Schroeder agreed, adding that there are few data regarding the use of angiotensin II receptor blockers for this purpose.

In an earlier study Dr. Cardinale and colleagues showed that an increased troponin I level shortly after a cycle of high-dose chemotherapy was a strong predictor of cardiotoxicity, while patients with a normal troponin I didn't develop ventricular dysfunction. The highest risk was seen in patients whose troponin I was elevated early and again 1 month later (Circulation 2004;109:2749–54).

Thus, serial troponin I monitoring allows for a selective approach to the use of drugs aimed at preventing cardiotoxicity.

But Dr. Schroeder indicated he did not like the idea of waiting to treat until the troponin elevation indicated the disease process was underway. His preference is to prevent the troponin rise by starting prophylaxis before chemotherapy.

It's worthwhile to get an EF measurement in the middle and at the end of each cycle of chemotherapy and hold the chemo should the EF fall by more than 10% from baseline, he advised at the meeting, also sponsored by the American College of Cardiology.

Dr. Schroeder is on the speakers bureau for several pharmaceutical companies, including GlaxoSmithKline, which markets carvedilol.

Carvedilol's strong antioxidant effects make it the β-blocker of choice for prevention of CIC. DR. SCHROEDER

SNOWMASS, COLO. — Administering an ACE inhibitor or carvedilol in cancer patients prior to high-dose chemotherapy is an excellent strategy for preventing chemotherapy-induced cardiomyopathy.

Chemotherapy-induced cardiomyopathy (CIC) is a far more common problem than most nononcologists appreciate, occurring in at least a quarter of patients on some widely prescribed regimens. Affected patients are not only exposed to the morbidity and mortality of heart failure, but their cancer therapy often has to be curtailed because of their cardiac impairment.

So rather than waiting for CIC to occur and then scrambling treat it, why not prevent it?, asked Dr. John S. Schroeder, professor of medicine at Stanford (Calif.) University, asked at a conference sponsored by the Society for Cardiovascular Angiography and Interventions.

He cited two randomized trials that have paved the way. In one, Dr. Nihat Kalay and colleagues at Erciyes University, Kayseri, Turkey, randomized 50 cancer patients slated to start notoriously cardiotoxic anthracycline chemotherapy to carvedilol (Coreg) at 12.5 mg once daily or placebo. At 6 months' follow-up, the mean left ventricular ejection fraction (EF) in the carvedilol group was essentially unchanged from the 70% baseline figure, while in the control group it fell from 69% to 52%.

One patient in the carvedilol arm and five on placebo had an EF below 50% at 6 months. There was one death in the carvedilol arm and four among controls (J. Am. Coll. Cardiol. 2006;48:2258–62).

Oxidative stress and mitochondrial dysfunction are believed to figure prominently in the pathophysiology of anthracycline-induced cardiomyopathy. The Turkish cardiologists pointed to carvedilol's antioxidant effects—considered the most potent of any β-blocker—as the most likely mechanism for the drug's ability to prevent cardiotoxicity. They selected a relatively low dosage because patients had normal baseline ventricular function and carvedilol's antioxidant properties are manifest even at lower doses.

Dr. Schroeder agreed that carvedilol's strong antioxidant effects make it the β-blocker of choice for prevention of CIC. He added, however, that the prolonged-release formulation probably makes more sense.

The other key clinical trial in the prevention of chemotherapy-induced cardiomyopathy was conducted by Dr. Daniela Cardinale and colleagues at the European Institute of Oncology in Milan.

Among 473 cancer patients with a normal baseline EF undergoing high-dose chemotherapy, they identified 24% as being at particularly high risk for CIC on the basis of a troponin I level greater than 0.07 ng/mL obtained within several days after completing any chemo cycle. The investigators randomized these 114 patients to 1 year of enalapril or to no enalapril beginning 1 month after the end of the final cycle of chemo. The ACE inhibitor was slowly titrated to 20 mg once daily.

The primary end point—a greater than absolute 10% drop in EF to a value below 50% at 1 year as assessed by blinded echocardiographers—occurred in 43% of controls and 0% of the ACE inhibitor recipients. In the control group there were 30 cases of the secondary combined end point of cardiac death, acute pulmonary edema, overt heart failure, or life-threatening arrhythmia, compared to just one in the enalapril group (Circulation 2006;114:2474–81).

The Italians surmised that the observed benefits involved a class effect and any ACE inhibitor would probably be effective. Dr. Schroeder agreed, adding that there are few data regarding the use of angiotensin II receptor blockers for this purpose.

In an earlier study Dr. Cardinale and colleagues showed that an increased troponin I level shortly after a cycle of high-dose chemotherapy was a strong predictor of cardiotoxicity, while patients with a normal troponin I didn't develop ventricular dysfunction. The highest risk was seen in patients whose troponin I was elevated early and again 1 month later (Circulation 2004;109:2749–54).

Thus, serial troponin I monitoring allows for a selective approach to the use of drugs aimed at preventing cardiotoxicity.

But Dr. Schroeder indicated he did not like the idea of waiting to treat until the troponin elevation indicated the disease process was underway. His preference is to prevent the troponin rise by starting prophylaxis before chemotherapy.

It's worthwhile to get an EF measurement in the middle and at the end of each cycle of chemotherapy and hold the chemo should the EF fall by more than 10% from baseline, he advised at the meeting, also sponsored by the American College of Cardiology.

Dr. Schroeder is on the speakers bureau for several pharmaceutical companies, including GlaxoSmithKline, which markets carvedilol.

Carvedilol's strong antioxidant effects make it the β-blocker of choice for prevention of CIC. DR. SCHROEDER

SNOWMASS, COLO. — Administering an ACE inhibitor or carvedilol in cancer patients prior to high-dose chemotherapy is an excellent strategy for preventing chemotherapy-induced cardiomyopathy.

Chemotherapy-induced cardiomyopathy (CIC) is a far more common problem than most nononcologists appreciate, occurring in at least a quarter of patients on some widely prescribed regimens. Affected patients are not only exposed to the morbidity and mortality of heart failure, but their cancer therapy often has to be curtailed because of their cardiac impairment.

So rather than waiting for CIC to occur and then scrambling treat it, why not prevent it?, asked Dr. John S. Schroeder, professor of medicine at Stanford (Calif.) University, asked at a conference sponsored by the Society for Cardiovascular Angiography and Interventions.

He cited two randomized trials that have paved the way. In one, Dr. Nihat Kalay and colleagues at Erciyes University, Kayseri, Turkey, randomized 50 cancer patients slated to start notoriously cardiotoxic anthracycline chemotherapy to carvedilol (Coreg) at 12.5 mg once daily or placebo. At 6 months' follow-up, the mean left ventricular ejection fraction (EF) in the carvedilol group was essentially unchanged from the 70% baseline figure, while in the control group it fell from 69% to 52%.

One patient in the carvedilol arm and five on placebo had an EF below 50% at 6 months. There was one death in the carvedilol arm and four among controls (J. Am. Coll. Cardiol. 2006;48:2258–62).

Oxidative stress and mitochondrial dysfunction are believed to figure prominently in the pathophysiology of anthracycline-induced cardiomyopathy. The Turkish cardiologists pointed to carvedilol's antioxidant effects—considered the most potent of any β-blocker—as the most likely mechanism for the drug's ability to prevent cardiotoxicity. They selected a relatively low dosage because patients had normal baseline ventricular function and carvedilol's antioxidant properties are manifest even at lower doses.

Dr. Schroeder agreed that carvedilol's strong antioxidant effects make it the β-blocker of choice for prevention of CIC. He added, however, that the prolonged-release formulation probably makes more sense.

The other key clinical trial in the prevention of chemotherapy-induced cardiomyopathy was conducted by Dr. Daniela Cardinale and colleagues at the European Institute of Oncology in Milan.

Among 473 cancer patients with a normal baseline EF undergoing high-dose chemotherapy, they identified 24% as being at particularly high risk for CIC on the basis of a troponin I level greater than 0.07 ng/mL obtained within several days after completing any chemo cycle. The investigators randomized these 114 patients to 1 year of enalapril or to no enalapril beginning 1 month after the end of the final cycle of chemo. The ACE inhibitor was slowly titrated to 20 mg once daily.

The primary end point—a greater than absolute 10% drop in EF to a value below 50% at 1 year as assessed by blinded echocardiographers—occurred in 43% of controls and 0% of the ACE inhibitor recipients. In the control group there were 30 cases of the secondary combined end point of cardiac death, acute pulmonary edema, overt heart failure, or life-threatening arrhythmia, compared to just one in the enalapril group (Circulation 2006;114:2474–81).

The Italians surmised that the observed benefits involved a class effect and any ACE inhibitor would probably be effective. Dr. Schroeder agreed, adding that there are few data regarding the use of angiotensin II receptor blockers for this purpose.

In an earlier study Dr. Cardinale and colleagues showed that an increased troponin I level shortly after a cycle of high-dose chemotherapy was a strong predictor of cardiotoxicity, while patients with a normal troponin I didn't develop ventricular dysfunction. The highest risk was seen in patients whose troponin I was elevated early and again 1 month later (Circulation 2004;109:2749–54).

Thus, serial troponin I monitoring allows for a selective approach to the use of drugs aimed at preventing cardiotoxicity.

But Dr. Schroeder indicated he did not like the idea of waiting to treat until the troponin elevation indicated the disease process was underway. His preference is to prevent the troponin rise by starting prophylaxis before chemotherapy.

It's worthwhile to get an EF measurement in the middle and at the end of each cycle of chemotherapy and hold the chemo should the EF fall by more than 10% from baseline, he advised at the meeting, also sponsored by the American College of Cardiology.

Dr. Schroeder is on the speakers bureau for several pharmaceutical companies, including GlaxoSmithKline, which markets carvedilol.

Carvedilol's strong antioxidant effects make it the β-blocker of choice for prevention of CIC. DR. SCHROEDER

VIENNA — Patients with functional class II pulmonary arterial hypertension had significantly slower disease progression when treated with bosentan in a study with 185 patients, a finding that may shift the time to diagnose and start treatment of this disease.

The results support starting treatment of pulmonary arterial hypertension (PAH) “as soon as possible after the diagnosis is made because the majority of patients with PAH are in functional class II or III; the majority of PAH patients need treatment [with bosentan] according to these data,” Dr. Nazzareno Galiè said at the annual congress of the European Society of Cardiology. “In PAH it's very important to prevent deterioration, and that's what treatment with bosentan does. The results show that PAH is a progressive disease, even in class II, highlighting the need for early diagnosis and treatment.”

The Endothelin Antagonist Trial in Mildly Symptomatic PAH Patients (EARLY) study “is the only study to focus on class II patients,” and it included a strict definition of class II, said Dr. Galiè, professor of cardiology and head of the Pulmonary Hypertension Centre at the University of Bologna, Italy.

Based on these and other findings, applications have been filed with the Food and Drug Administration and similar agencies in other countries to expand bosentan treatment to patients with class II PAH. Bosentan (Tracleer) is already marketed for treating classes III and IV PAH by Actelion. The new study was sponsored by Actelion, and Dr. Galiè is a speaker for and consultant to Actelion.

“The EARLY study results, and the results from [five] other studies that included class II PAH patients, support the benefit of treating patients with less-severe PAH. The added strength of the data from EARLY is that they demonstrated in a pure cohort of class II patients that early treatment may delay progression of the disease,” commented Dr. Lewis J. Rubin, a coauthor of the study and professor of medicine and director of pulmonary and critical care medicine at the University of California, San Diego. Dr. Rubin is a consultant to Actelion.

The study enrolled patients aged 12 years and older, mean age 44, with PAH rated as functional class II by World Health Organization criteria. The disease could have been idiopathic (as it was in about 60% of patients), or caused by congenital heart disease (in about 17%), connective tissue disease (in about 18%), or HIV infection (in about 5%). The average duration of PAH was about 3 years. Patients were randomized to treatment with either 62.5 mg bosentan b.i.d. for 4 weeks, followed by 125 mg b.i.d. for 5 months, or placebo.

After 6 months of treatment, the change from baseline in pulmonary vascular resistance, one of two primary end points, was increased by about 7% among 88 evaluable patients in the placebo group, and was decreased by about 16% in 80 patients in the bosentan group. The overall effect of bosentan treatment was to lower pulmonary vascular resistance by 23%, compared with placebo, a statistically significant effect.

The second primary end point was change in exercise capacity, measured by distance walked in 6 minutes. By this measure, bosentan was linked to a significant, 19-meter boost in distance walked, compared with placebo, Dr. Galiè reported.

Bosentan treatment also led to significant improvements in time to clinical worsening, and a reduction in the percentage of patients whose condition worsened. Symptomatic progression of PAH occurred in 10% of patients on placebo, compared with 1% of the patients treated with bosentan. “With bosentan, there is more preservation of functional class,” said Dr. Galiè. Bosentan also led to significant improvements in self-rated quality of life, and a significant reduction in serum levels of NT-probrain natriuretic peptide (NT-proBNP). The drug was well tolerated, with an adverse event profile similar to the placebo group.

To boost the number of patients with PAH who start treatment early, Dr. Galiè suggested screening for PAH in groups that are known to have a relatively high prevalence of PAH. This includes patients with connective tissue diseases, such scleroderma, patients infected with HIV, and patients with congenital heart disease.

Three other reports at the meeting dealt with using bosentan to treat PAH; all three studies also were sponsored by Actelion.

One study enrolled 157 patients who had a specific, relatively common form of PAH, chronic thromboembolic pulmonary hypertension (CTEPH), which was inoperable or recurrent. The results showed that treatment with bosentan was safe and led to improvements in pulmonary vascular resistance and other measures, Dr. Irene Lang, professor of vascular biology at the Medical University of Vienna, reported at the meeting.

The Bosentan Effects in Inoperable Forms of CTEPH (BENEFIT) study randomized patients to treatment with 62.5 mg bosentan b.i.d for 4 weeks, followed by 125 mg b.i.d. for 12 weeks or placebo. Their average age was 63 years. Bosentan was linked with a significant, 24% reduction in peripheral vascular resistance in 66 evaluable patients, compared with 71 placebo patients. Treatment also significantly boosted cardiac index, and cut NT-proBNP levels and dyspnea scores. Bosentan treatment had no significant effect on 6-minute walk distance.

Another study assessed the acute hemodynamic effect of a single, 25-mg dose of sildenafil in 44 patients with PAH already on chronic bosentan treatment. The results showed that the single sildenafil dose was safe, and after 60 minutes led to a significant drop in pulmonary vascular resistance, total pulmonary resistance, pulmonary artery pressure, and cardiac output.

The third study examined the pharmacokinetics of a new formulation of bosentan designed for use in children. Results from 35 patients aged 2–11 years showed that the formulation led to reasonable serum levels and a good safety profile.

“New drugs such as bosentan have dramatically improved outcomes for patients with pulmonary arterial hypertension. It is gratifying to see extension of the research into patients with early disease and in children,” commented Dr. Daniel Jones, professor of medicine and dean of the medical school at the University of Mississippi, Jackson, and president of the American Heart Association.

EARLY showed that in a pure cohort of class II patients, early treatment may delay PAH progression. DR. RUBIN

VIENNA — Patients with functional class II pulmonary arterial hypertension had significantly slower disease progression when treated with bosentan in a study with 185 patients, a finding that may shift the time to diagnose and start treatment of this disease.

The results support starting treatment of pulmonary arterial hypertension (PAH) “as soon as possible after the diagnosis is made because the majority of patients with PAH are in functional class II or III; the majority of PAH patients need treatment [with bosentan] according to these data,” Dr. Nazzareno Galiè said at the annual congress of the European Society of Cardiology. “In PAH it's very important to prevent deterioration, and that's what treatment with bosentan does. The results show that PAH is a progressive disease, even in class II, highlighting the need for early diagnosis and treatment.”

The Endothelin Antagonist Trial in Mildly Symptomatic PAH Patients (EARLY) study “is the only study to focus on class II patients,” and it included a strict definition of class II, said Dr. Galiè, professor of cardiology and head of the Pulmonary Hypertension Centre at the University of Bologna, Italy.

Based on these and other findings, applications have been filed with the Food and Drug Administration and similar agencies in other countries to expand bosentan treatment to patients with class II PAH. Bosentan (Tracleer) is already marketed for treating classes III and IV PAH by Actelion. The new study was sponsored by Actelion, and Dr. Galiè is a speaker for and consultant to Actelion.

“The EARLY study results, and the results from [five] other studies that included class II PAH patients, support the benefit of treating patients with less-severe PAH. The added strength of the data from EARLY is that they demonstrated in a pure cohort of class II patients that early treatment may delay progression of the disease,” commented Dr. Lewis J. Rubin, a coauthor of the study and professor of medicine and director of pulmonary and critical care medicine at the University of California, San Diego. Dr. Rubin is a consultant to Actelion.

The study enrolled patients aged 12 years and older, mean age 44, with PAH rated as functional class II by World Health Organization criteria. The disease could have been idiopathic (as it was in about 60% of patients), or caused by congenital heart disease (in about 17%), connective tissue disease (in about 18%), or HIV infection (in about 5%). The average duration of PAH was about 3 years. Patients were randomized to treatment with either 62.5 mg bosentan b.i.d. for 4 weeks, followed by 125 mg b.i.d. for 5 months, or placebo.

After 6 months of treatment, the change from baseline in pulmonary vascular resistance, one of two primary end points, was increased by about 7% among 88 evaluable patients in the placebo group, and was decreased by about 16% in 80 patients in the bosentan group. The overall effect of bosentan treatment was to lower pulmonary vascular resistance by 23%, compared with placebo, a statistically significant effect.

The second primary end point was change in exercise capacity, measured by distance walked in 6 minutes. By this measure, bosentan was linked to a significant, 19-meter boost in distance walked, compared with placebo, Dr. Galiè reported.

Bosentan treatment also led to significant improvements in time to clinical worsening, and a reduction in the percentage of patients whose condition worsened. Symptomatic progression of PAH occurred in 10% of patients on placebo, compared with 1% of the patients treated with bosentan. “With bosentan, there is more preservation of functional class,” said Dr. Galiè. Bosentan also led to significant improvements in self-rated quality of life, and a significant reduction in serum levels of NT-probrain natriuretic peptide (NT-proBNP). The drug was well tolerated, with an adverse event profile similar to the placebo group.

To boost the number of patients with PAH who start treatment early, Dr. Galiè suggested screening for PAH in groups that are known to have a relatively high prevalence of PAH. This includes patients with connective tissue diseases, such scleroderma, patients infected with HIV, and patients with congenital heart disease.

Three other reports at the meeting dealt with using bosentan to treat PAH; all three studies also were sponsored by Actelion.

One study enrolled 157 patients who had a specific, relatively common form of PAH, chronic thromboembolic pulmonary hypertension (CTEPH), which was inoperable or recurrent. The results showed that treatment with bosentan was safe and led to improvements in pulmonary vascular resistance and other measures, Dr. Irene Lang, professor of vascular biology at the Medical University of Vienna, reported at the meeting.

The Bosentan Effects in Inoperable Forms of CTEPH (BENEFIT) study randomized patients to treatment with 62.5 mg bosentan b.i.d for 4 weeks, followed by 125 mg b.i.d. for 12 weeks or placebo. Their average age was 63 years. Bosentan was linked with a significant, 24% reduction in peripheral vascular resistance in 66 evaluable patients, compared with 71 placebo patients. Treatment also significantly boosted cardiac index, and cut NT-proBNP levels and dyspnea scores. Bosentan treatment had no significant effect on 6-minute walk distance.

Another study assessed the acute hemodynamic effect of a single, 25-mg dose of sildenafil in 44 patients with PAH already on chronic bosentan treatment. The results showed that the single sildenafil dose was safe, and after 60 minutes led to a significant drop in pulmonary vascular resistance, total pulmonary resistance, pulmonary artery pressure, and cardiac output.

The third study examined the pharmacokinetics of a new formulation of bosentan designed for use in children. Results from 35 patients aged 2–11 years showed that the formulation led to reasonable serum levels and a good safety profile.

“New drugs such as bosentan have dramatically improved outcomes for patients with pulmonary arterial hypertension. It is gratifying to see extension of the research into patients with early disease and in children,” commented Dr. Daniel Jones, professor of medicine and dean of the medical school at the University of Mississippi, Jackson, and president of the American Heart Association.

EARLY showed that in a pure cohort of class II patients, early treatment may delay PAH progression. DR. RUBIN

VIENNA — Patients with functional class II pulmonary arterial hypertension had significantly slower disease progression when treated with bosentan in a study with 185 patients, a finding that may shift the time to diagnose and start treatment of this disease.

The results support starting treatment of pulmonary arterial hypertension (PAH) “as soon as possible after the diagnosis is made because the majority of patients with PAH are in functional class II or III; the majority of PAH patients need treatment [with bosentan] according to these data,” Dr. Nazzareno Galiè said at the annual congress of the European Society of Cardiology. “In PAH it's very important to prevent deterioration, and that's what treatment with bosentan does. The results show that PAH is a progressive disease, even in class II, highlighting the need for early diagnosis and treatment.”

The Endothelin Antagonist Trial in Mildly Symptomatic PAH Patients (EARLY) study “is the only study to focus on class II patients,” and it included a strict definition of class II, said Dr. Galiè, professor of cardiology and head of the Pulmonary Hypertension Centre at the University of Bologna, Italy.

Based on these and other findings, applications have been filed with the Food and Drug Administration and similar agencies in other countries to expand bosentan treatment to patients with class II PAH. Bosentan (Tracleer) is already marketed for treating classes III and IV PAH by Actelion. The new study was sponsored by Actelion, and Dr. Galiè is a speaker for and consultant to Actelion.

“The EARLY study results, and the results from [five] other studies that included class II PAH patients, support the benefit of treating patients with less-severe PAH. The added strength of the data from EARLY is that they demonstrated in a pure cohort of class II patients that early treatment may delay progression of the disease,” commented Dr. Lewis J. Rubin, a coauthor of the study and professor of medicine and director of pulmonary and critical care medicine at the University of California, San Diego. Dr. Rubin is a consultant to Actelion.

The study enrolled patients aged 12 years and older, mean age 44, with PAH rated as functional class II by World Health Organization criteria. The disease could have been idiopathic (as it was in about 60% of patients), or caused by congenital heart disease (in about 17%), connective tissue disease (in about 18%), or HIV infection (in about 5%). The average duration of PAH was about 3 years. Patients were randomized to treatment with either 62.5 mg bosentan b.i.d. for 4 weeks, followed by 125 mg b.i.d. for 5 months, or placebo.

After 6 months of treatment, the change from baseline in pulmonary vascular resistance, one of two primary end points, was increased by about 7% among 88 evaluable patients in the placebo group, and was decreased by about 16% in 80 patients in the bosentan group. The overall effect of bosentan treatment was to lower pulmonary vascular resistance by 23%, compared with placebo, a statistically significant effect.

The second primary end point was change in exercise capacity, measured by distance walked in 6 minutes. By this measure, bosentan was linked to a significant, 19-meter boost in distance walked, compared with placebo, Dr. Galiè reported.

Bosentan treatment also led to significant improvements in time to clinical worsening, and a reduction in the percentage of patients whose condition worsened. Symptomatic progression of PAH occurred in 10% of patients on placebo, compared with 1% of the patients treated with bosentan. “With bosentan, there is more preservation of functional class,” said Dr. Galiè. Bosentan also led to significant improvements in self-rated quality of life, and a significant reduction in serum levels of NT-probrain natriuretic peptide (NT-proBNP). The drug was well tolerated, with an adverse event profile similar to the placebo group.

To boost the number of patients with PAH who start treatment early, Dr. Galiè suggested screening for PAH in groups that are known to have a relatively high prevalence of PAH. This includes patients with connective tissue diseases, such scleroderma, patients infected with HIV, and patients with congenital heart disease.

Three other reports at the meeting dealt with using bosentan to treat PAH; all three studies also were sponsored by Actelion.

One study enrolled 157 patients who had a specific, relatively common form of PAH, chronic thromboembolic pulmonary hypertension (CTEPH), which was inoperable or recurrent. The results showed that treatment with bosentan was safe and led to improvements in pulmonary vascular resistance and other measures, Dr. Irene Lang, professor of vascular biology at the Medical University of Vienna, reported at the meeting.

The Bosentan Effects in Inoperable Forms of CTEPH (BENEFIT) study randomized patients to treatment with 62.5 mg bosentan b.i.d for 4 weeks, followed by 125 mg b.i.d. for 12 weeks or placebo. Their average age was 63 years. Bosentan was linked with a significant, 24% reduction in peripheral vascular resistance in 66 evaluable patients, compared with 71 placebo patients. Treatment also significantly boosted cardiac index, and cut NT-proBNP levels and dyspnea scores. Bosentan treatment had no significant effect on 6-minute walk distance.

Another study assessed the acute hemodynamic effect of a single, 25-mg dose of sildenafil in 44 patients with PAH already on chronic bosentan treatment. The results showed that the single sildenafil dose was safe, and after 60 minutes led to a significant drop in pulmonary vascular resistance, total pulmonary resistance, pulmonary artery pressure, and cardiac output.

The third study examined the pharmacokinetics of a new formulation of bosentan designed for use in children. Results from 35 patients aged 2–11 years showed that the formulation led to reasonable serum levels and a good safety profile.

“New drugs such as bosentan have dramatically improved outcomes for patients with pulmonary arterial hypertension. It is gratifying to see extension of the research into patients with early disease and in children,” commented Dr. Daniel Jones, professor of medicine and dean of the medical school at the University of Mississippi, Jackson, and president of the American Heart Association.

EARLY showed that in a pure cohort of class II patients, early treatment may delay PAH progression. DR. RUBIN