Heart Failure

BOCA RATON, FLA. — Fixed-dose isosorbide dinitrate and hydralazine significantly reduces left ventricular volume and increases ejection fraction in African American patients with moderate to severe heart failure, according to a subanalysis of the African American Heart Failure Trial.

Decreases in brain natriuretic peptide corresponded with the 6-month improvements in cardiac remodeling.

In the African American Heart Failure Trial (A-HeFT), the drug combination (BiDil, Nitromed Inc.) was associated with a 43% increase in survival for African Americans with moderate to severe heart failure (N. Engl. J. Med. 2004;351:2049–57). The magnitude of this finding surprised some because the A-HeFT patients were already aggressively treated for heart failure: 87% were already taking β-blockers, 78% were on ACE inhibitors, 39% were on aldosterone inhibitors, and 28% were taking angiotensin receptor blockers.

Regarding A-HeFT mortality, “the survival benefit versus placebo became obvious at 6 months or 7 months, and then the curves spread out remarkably after that,” Jay N. Cohn, M.D., said during a late-breaking clinical trial session at the annual meeting of the Heart Failure Society of America. He and his associates performed a subanalysis of the A-HeFT data to determine whether improvements in left ventricular structure and function could explain the improvement in survival. They compared echocardiographic findings and blood levels of brain natriuretic peptide (BNP) taken at baseline and after 6 months of treatment. One cardiologist evaluated all the digitized echocardiograms in blinded fashion.

Of the 1,050 self-identified African Americans enrolled in A-HeFT, 666 had ejection fraction values recorded at baseline and 6 months. Of this group, 329 were treated with combination therapy and 337 with placebo. In addition, there were 678 participants with left ventricular internal diameter in diastole (LVIDd) values taken at baseline and at 6 months. Of this group, 337 were treated with the combination and 341 with placebo.

At 6 months, there was a significant increase in ejection fraction in the combination group versus placebo, said Dr. Cohn, professor of medicine and director, Rasmussen Center for Cardiovascular Disease Prevention, University of Minnesota in Minneapolis. There also was a highly significant difference in LVIDd in the treatment group versus placebo group.

A meeting attendee asked about possible variation with the measurements in the study. “I'm more comfortable with the consistency of the LVIDd measurements, compared with the ejection fraction measurements, which can be interpreted differently,” Dr. Cohn responded.

The mean baseline BNP level was 300 pg/mL. By 6 months, the treatment group had a greater mean decrease, 28 pg/mL, compared with the placebo group, 11 pg/mL. Dr. Cohn called this a “striking difference between groups” that supports the cardiac remodeling improvements.

Another attendee asked how well the BNP values tracked with changes to left ventricular volume. Dr. Cohn said, “We don't know that yet, the tracking between the two is not always perfect. BNP is not always perfect. BNP is a continuum, but the lower the better.”

When asked if remodeling was dose dependent, Dr. Cohn replied, “We haven't looked at that yet.” He and his associates plan to perform subgroup analyses. “I would be surprised if the benefit on remodeling is confined to the African American population,” he said.

“The combination of isosorbide dinitrate and hydralazine induces regression of left ventricular remodeling in patients already treated with neurohormonal inhibitors,” Dr. Cohn said. “These data provide further support for the growing database that favorable effects on outcomes in heart failure can be attributed to favorable effects on left ventricular structural remodeling.”

BOCA RATON, FLA. — Fixed-dose isosorbide dinitrate and hydralazine significantly reduces left ventricular volume and increases ejection fraction in African American patients with moderate to severe heart failure, according to a subanalysis of the African American Heart Failure Trial.

Decreases in brain natriuretic peptide corresponded with the 6-month improvements in cardiac remodeling.

In the African American Heart Failure Trial (A-HeFT), the drug combination (BiDil, Nitromed Inc.) was associated with a 43% increase in survival for African Americans with moderate to severe heart failure (N. Engl. J. Med. 2004;351:2049–57). The magnitude of this finding surprised some because the A-HeFT patients were already aggressively treated for heart failure: 87% were already taking β-blockers, 78% were on ACE inhibitors, 39% were on aldosterone inhibitors, and 28% were taking angiotensin receptor blockers.

Regarding A-HeFT mortality, “the survival benefit versus placebo became obvious at 6 months or 7 months, and then the curves spread out remarkably after that,” Jay N. Cohn, M.D., said during a late-breaking clinical trial session at the annual meeting of the Heart Failure Society of America. He and his associates performed a subanalysis of the A-HeFT data to determine whether improvements in left ventricular structure and function could explain the improvement in survival. They compared echocardiographic findings and blood levels of brain natriuretic peptide (BNP) taken at baseline and after 6 months of treatment. One cardiologist evaluated all the digitized echocardiograms in blinded fashion.

Of the 1,050 self-identified African Americans enrolled in A-HeFT, 666 had ejection fraction values recorded at baseline and 6 months. Of this group, 329 were treated with combination therapy and 337 with placebo. In addition, there were 678 participants with left ventricular internal diameter in diastole (LVIDd) values taken at baseline and at 6 months. Of this group, 337 were treated with the combination and 341 with placebo.

At 6 months, there was a significant increase in ejection fraction in the combination group versus placebo, said Dr. Cohn, professor of medicine and director, Rasmussen Center for Cardiovascular Disease Prevention, University of Minnesota in Minneapolis. There also was a highly significant difference in LVIDd in the treatment group versus placebo group.

A meeting attendee asked about possible variation with the measurements in the study. “I'm more comfortable with the consistency of the LVIDd measurements, compared with the ejection fraction measurements, which can be interpreted differently,” Dr. Cohn responded.

The mean baseline BNP level was 300 pg/mL. By 6 months, the treatment group had a greater mean decrease, 28 pg/mL, compared with the placebo group, 11 pg/mL. Dr. Cohn called this a “striking difference between groups” that supports the cardiac remodeling improvements.

Another attendee asked how well the BNP values tracked with changes to left ventricular volume. Dr. Cohn said, “We don't know that yet, the tracking between the two is not always perfect. BNP is not always perfect. BNP is a continuum, but the lower the better.”

When asked if remodeling was dose dependent, Dr. Cohn replied, “We haven't looked at that yet.” He and his associates plan to perform subgroup analyses. “I would be surprised if the benefit on remodeling is confined to the African American population,” he said.

“The combination of isosorbide dinitrate and hydralazine induces regression of left ventricular remodeling in patients already treated with neurohormonal inhibitors,” Dr. Cohn said. “These data provide further support for the growing database that favorable effects on outcomes in heart failure can be attributed to favorable effects on left ventricular structural remodeling.”

BOCA RATON, FLA. — Fixed-dose isosorbide dinitrate and hydralazine significantly reduces left ventricular volume and increases ejection fraction in African American patients with moderate to severe heart failure, according to a subanalysis of the African American Heart Failure Trial.

Decreases in brain natriuretic peptide corresponded with the 6-month improvements in cardiac remodeling.

In the African American Heart Failure Trial (A-HeFT), the drug combination (BiDil, Nitromed Inc.) was associated with a 43% increase in survival for African Americans with moderate to severe heart failure (N. Engl. J. Med. 2004;351:2049–57). The magnitude of this finding surprised some because the A-HeFT patients were already aggressively treated for heart failure: 87% were already taking β-blockers, 78% were on ACE inhibitors, 39% were on aldosterone inhibitors, and 28% were taking angiotensin receptor blockers.

Regarding A-HeFT mortality, “the survival benefit versus placebo became obvious at 6 months or 7 months, and then the curves spread out remarkably after that,” Jay N. Cohn, M.D., said during a late-breaking clinical trial session at the annual meeting of the Heart Failure Society of America. He and his associates performed a subanalysis of the A-HeFT data to determine whether improvements in left ventricular structure and function could explain the improvement in survival. They compared echocardiographic findings and blood levels of brain natriuretic peptide (BNP) taken at baseline and after 6 months of treatment. One cardiologist evaluated all the digitized echocardiograms in blinded fashion.

Of the 1,050 self-identified African Americans enrolled in A-HeFT, 666 had ejection fraction values recorded at baseline and 6 months. Of this group, 329 were treated with combination therapy and 337 with placebo. In addition, there were 678 participants with left ventricular internal diameter in diastole (LVIDd) values taken at baseline and at 6 months. Of this group, 337 were treated with the combination and 341 with placebo.

At 6 months, there was a significant increase in ejection fraction in the combination group versus placebo, said Dr. Cohn, professor of medicine and director, Rasmussen Center for Cardiovascular Disease Prevention, University of Minnesota in Minneapolis. There also was a highly significant difference in LVIDd in the treatment group versus placebo group.

A meeting attendee asked about possible variation with the measurements in the study. “I'm more comfortable with the consistency of the LVIDd measurements, compared with the ejection fraction measurements, which can be interpreted differently,” Dr. Cohn responded.

The mean baseline BNP level was 300 pg/mL. By 6 months, the treatment group had a greater mean decrease, 28 pg/mL, compared with the placebo group, 11 pg/mL. Dr. Cohn called this a “striking difference between groups” that supports the cardiac remodeling improvements.

Another attendee asked how well the BNP values tracked with changes to left ventricular volume. Dr. Cohn said, “We don't know that yet, the tracking between the two is not always perfect. BNP is not always perfect. BNP is a continuum, but the lower the better.”

When asked if remodeling was dose dependent, Dr. Cohn replied, “We haven't looked at that yet.” He and his associates plan to perform subgroup analyses. “I would be surprised if the benefit on remodeling is confined to the African American population,” he said.

“The combination of isosorbide dinitrate and hydralazine induces regression of left ventricular remodeling in patients already treated with neurohormonal inhibitors,” Dr. Cohn said. “These data provide further support for the growing database that favorable effects on outcomes in heart failure can be attributed to favorable effects on left ventricular structural remodeling.”

STOCKHOLM — An oral inotropic drug was safe but not effective in a pair of studies that together enrolled more than 1,800 patients with advanced heart failure.

Although the Studies of Oral Enoximone Therapy in Advanced Heart Failure (ESSENTIAL) failed to show that enoximone could cut the incidence of death or cardiovascular hospitalization, the fact that the drug was safe means that it is eligible for further testing in very sick heart failure patients, Michael Bristow, M.D., said in an interview at the annual congress of the European Society of Cardiology.

“We have a lack of effective medications for very sick patients with decompensated heart failure,” especially those with recurrent episodes of acute decompensation, said Dr. Bristow, codirector of the Cardiovascular Institute at the University of Colorado in Denver. “Enoximone has now been [proved] safe, and we saw a signal of efficacy in the sickest patients.”

The studies enrolled 1,854 patients with New York Heart Association class III or IV heart failure at 211 centers in 16 countries. One study was done in North and South America; the other was done in Europe.

The patients also had a left ventricular ejection fraction (LVEF) of 30% or less and had had at least one hospitalization or two outpatient visits for worsening heart failure during the year before they entered the study. All were already on optimal treatment with both a β-blocker and an ACE inhibitor or an angiotensin-receptor blocker.

The patients were randomized either to placebo or to 25 mg enoximone t.i.d. After 2 weeks, the dosage was raised to 50 mg t.i.d for patients who weighed more than 50 kg and had no adverse effects from the lower dosage. These dosages were substantially lower than were those in previous enoximone studies.

After an average follow-up of 16.4 months, there was no significant difference between the two arms in either all-cause death, the major safety end point, or in all-cause death and cardiovascular hospitalizations, the major efficacy end point, said Marco Metra, M.D., professor of cardiology at the University of Brescia (Italy).

In the American but not the European study, treatment with enoximone was linked with a significant increase in a secondary end point measured by a 6-minute walk test done after 6 months of treatment. The two treatment arms showed no significant difference for the third efficacy end point of the study, patients' self-assessment of symptomatic improvement.

In a prespecified subgroup analysis that assessed efficacy responses in patients with an LVEF below the median for all patients (25%) and in those with an ejection fraction above the median, treatment with enoximone in patients with the worst left ventricular function was associated with a 10% reduction in both all-cause death and in deaths and cardiovascular hospitalizations, compared with placebo.

Enoximone treatment in the subgroup was also linked with a mean gain of 15 m in a 6-minute walk distance, compared with the placebo group. Further analyses of results in the sicker patients also showed enoximone treatment was especially effective for reducing deaths and hospitalizations after the first 16 months of treatment.

Enoximone is in the same inotropic class as milrinone. But enoximone is a pure phosphodiesterase inhibitor, which, along with its use in the setting of β-blocker treatment, may lead to its increased safety, said Dr. Bristow, who is also chief science and medical officer for Myogen, which sponsored ESSENTIAL and markets an intravenous formulation of enoximone (Perfan) in Europe, in an interview.

STOCKHOLM — An oral inotropic drug was safe but not effective in a pair of studies that together enrolled more than 1,800 patients with advanced heart failure.

Although the Studies of Oral Enoximone Therapy in Advanced Heart Failure (ESSENTIAL) failed to show that enoximone could cut the incidence of death or cardiovascular hospitalization, the fact that the drug was safe means that it is eligible for further testing in very sick heart failure patients, Michael Bristow, M.D., said in an interview at the annual congress of the European Society of Cardiology.

“We have a lack of effective medications for very sick patients with decompensated heart failure,” especially those with recurrent episodes of acute decompensation, said Dr. Bristow, codirector of the Cardiovascular Institute at the University of Colorado in Denver. “Enoximone has now been [proved] safe, and we saw a signal of efficacy in the sickest patients.”

The studies enrolled 1,854 patients with New York Heart Association class III or IV heart failure at 211 centers in 16 countries. One study was done in North and South America; the other was done in Europe.

The patients also had a left ventricular ejection fraction (LVEF) of 30% or less and had had at least one hospitalization or two outpatient visits for worsening heart failure during the year before they entered the study. All were already on optimal treatment with both a β-blocker and an ACE inhibitor or an angiotensin-receptor blocker.

The patients were randomized either to placebo or to 25 mg enoximone t.i.d. After 2 weeks, the dosage was raised to 50 mg t.i.d for patients who weighed more than 50 kg and had no adverse effects from the lower dosage. These dosages were substantially lower than were those in previous enoximone studies.

After an average follow-up of 16.4 months, there was no significant difference between the two arms in either all-cause death, the major safety end point, or in all-cause death and cardiovascular hospitalizations, the major efficacy end point, said Marco Metra, M.D., professor of cardiology at the University of Brescia (Italy).

In the American but not the European study, treatment with enoximone was linked with a significant increase in a secondary end point measured by a 6-minute walk test done after 6 months of treatment. The two treatment arms showed no significant difference for the third efficacy end point of the study, patients' self-assessment of symptomatic improvement.

In a prespecified subgroup analysis that assessed efficacy responses in patients with an LVEF below the median for all patients (25%) and in those with an ejection fraction above the median, treatment with enoximone in patients with the worst left ventricular function was associated with a 10% reduction in both all-cause death and in deaths and cardiovascular hospitalizations, compared with placebo.

Enoximone treatment in the subgroup was also linked with a mean gain of 15 m in a 6-minute walk distance, compared with the placebo group. Further analyses of results in the sicker patients also showed enoximone treatment was especially effective for reducing deaths and hospitalizations after the first 16 months of treatment.

Enoximone is in the same inotropic class as milrinone. But enoximone is a pure phosphodiesterase inhibitor, which, along with its use in the setting of β-blocker treatment, may lead to its increased safety, said Dr. Bristow, who is also chief science and medical officer for Myogen, which sponsored ESSENTIAL and markets an intravenous formulation of enoximone (Perfan) in Europe, in an interview.

STOCKHOLM — An oral inotropic drug was safe but not effective in a pair of studies that together enrolled more than 1,800 patients with advanced heart failure.

Although the Studies of Oral Enoximone Therapy in Advanced Heart Failure (ESSENTIAL) failed to show that enoximone could cut the incidence of death or cardiovascular hospitalization, the fact that the drug was safe means that it is eligible for further testing in very sick heart failure patients, Michael Bristow, M.D., said in an interview at the annual congress of the European Society of Cardiology.

“We have a lack of effective medications for very sick patients with decompensated heart failure,” especially those with recurrent episodes of acute decompensation, said Dr. Bristow, codirector of the Cardiovascular Institute at the University of Colorado in Denver. “Enoximone has now been [proved] safe, and we saw a signal of efficacy in the sickest patients.”

The studies enrolled 1,854 patients with New York Heart Association class III or IV heart failure at 211 centers in 16 countries. One study was done in North and South America; the other was done in Europe.

The patients also had a left ventricular ejection fraction (LVEF) of 30% or less and had had at least one hospitalization or two outpatient visits for worsening heart failure during the year before they entered the study. All were already on optimal treatment with both a β-blocker and an ACE inhibitor or an angiotensin-receptor blocker.

The patients were randomized either to placebo or to 25 mg enoximone t.i.d. After 2 weeks, the dosage was raised to 50 mg t.i.d for patients who weighed more than 50 kg and had no adverse effects from the lower dosage. These dosages were substantially lower than were those in previous enoximone studies.

After an average follow-up of 16.4 months, there was no significant difference between the two arms in either all-cause death, the major safety end point, or in all-cause death and cardiovascular hospitalizations, the major efficacy end point, said Marco Metra, M.D., professor of cardiology at the University of Brescia (Italy).

In the American but not the European study, treatment with enoximone was linked with a significant increase in a secondary end point measured by a 6-minute walk test done after 6 months of treatment. The two treatment arms showed no significant difference for the third efficacy end point of the study, patients' self-assessment of symptomatic improvement.

In a prespecified subgroup analysis that assessed efficacy responses in patients with an LVEF below the median for all patients (25%) and in those with an ejection fraction above the median, treatment with enoximone in patients with the worst left ventricular function was associated with a 10% reduction in both all-cause death and in deaths and cardiovascular hospitalizations, compared with placebo.

Enoximone treatment in the subgroup was also linked with a mean gain of 15 m in a 6-minute walk distance, compared with the placebo group. Further analyses of results in the sicker patients also showed enoximone treatment was especially effective for reducing deaths and hospitalizations after the first 16 months of treatment.

Enoximone is in the same inotropic class as milrinone. But enoximone is a pure phosphodiesterase inhibitor, which, along with its use in the setting of β-blocker treatment, may lead to its increased safety, said Dr. Bristow, who is also chief science and medical officer for Myogen, which sponsored ESSENTIAL and markets an intravenous formulation of enoximone (Perfan) in Europe, in an interview.

WASHINGTON — Receipt of a left ventricular assist device at an older age may adversely affect long-term, but not short-term, survival with the device, Evgenij V. Potapov, M.D., reported at the annual conference of the American Society for Artificial Internal Organs.

In a review of 403 patients who have received LVADs at the German Heart Institute, Berlin, since 1987, the 116 patients who were older than 60 years were 2.5 times more likely than younger patients to have a negative long-term outcome, such as no heart transplantation, an inability to wean off the LVAD within 6 months, support for less than 6 months in patients with permanent implants, and failure to continue support for more than 6 months in other patients, said Dr. Potapov, a cardiothoracic surgeon at the institute.

No risk factor significantly predicted a negative long-term outcome in patients older than age 60.

“Postcardiotomy support in older patients should be performed in really selective cases,” he said.

WASHINGTON — Receipt of a left ventricular assist device at an older age may adversely affect long-term, but not short-term, survival with the device, Evgenij V. Potapov, M.D., reported at the annual conference of the American Society for Artificial Internal Organs.

In a review of 403 patients who have received LVADs at the German Heart Institute, Berlin, since 1987, the 116 patients who were older than 60 years were 2.5 times more likely than younger patients to have a negative long-term outcome, such as no heart transplantation, an inability to wean off the LVAD within 6 months, support for less than 6 months in patients with permanent implants, and failure to continue support for more than 6 months in other patients, said Dr. Potapov, a cardiothoracic surgeon at the institute.

No risk factor significantly predicted a negative long-term outcome in patients older than age 60.

“Postcardiotomy support in older patients should be performed in really selective cases,” he said.

WASHINGTON — Receipt of a left ventricular assist device at an older age may adversely affect long-term, but not short-term, survival with the device, Evgenij V. Potapov, M.D., reported at the annual conference of the American Society for Artificial Internal Organs.

In a review of 403 patients who have received LVADs at the German Heart Institute, Berlin, since 1987, the 116 patients who were older than 60 years were 2.5 times more likely than younger patients to have a negative long-term outcome, such as no heart transplantation, an inability to wean off the LVAD within 6 months, support for less than 6 months in patients with permanent implants, and failure to continue support for more than 6 months in other patients, said Dr. Potapov, a cardiothoracic surgeon at the institute.

No risk factor significantly predicted a negative long-term outcome in patients older than age 60.

“Postcardiotomy support in older patients should be performed in really selective cases,” he said.

VANCOUVER, B.C. — The latest Cochrane systematic review of digoxin for treatment of heart failure patients in sinus rhythm paints a picture of a more than 200-year-old drug that's still clinically useful, although it has no effect on mortality, William B. Hood Jr., M.D., said at a meeting sponsored by the International Academy of Cardiology.

“It's probably not first-line therapy. It's not very powerful. But it's available for patients who are not fully responsive to other agents that have become first-line treatments—the ACE inhibitors, β-blockers, spironolactone, and the angiotensin receptor blockers,” added Dr. Hood, lead author of the recent Cochrane review and a cardiologist at the University of Washington, Seattle.

The metaanalysis was restricted to randomized, double-blind, placebo-controlled trials involving adults followed for at least 7 weeks. Thirteen trials totaling nearly 7,900 patients qualified, including the largest of all digoxin studies: the 6,800-patient, 3-year Digitalis Investigation Group (DIG) trial (N. Engl. J. Med. 1997;336:525–33).

Why even bother doing a metaanalysis when one trial is so dominant? Dr. Hood explained that the smaller trials are helpful in that each consistently reached the same conclusion as DIG regarding the effect of digoxin on mortality—namely, there is none. The drug didn't lessen mortality, nor did it significantly worsen it.

In the DIG trial, however, there was a nonsignificant trend for fewer deaths from heart failure in digoxin-treated patients and a hint that the inotrope may have caused more arrhythmia deaths, although this wasn't a prespecified study end point.

Digoxin's effect on deterioration in clinical status was much more clearcut in the metaanalysis. The odds ratio for that end point was 0.31, meaning patients randomized to digoxin were 69% less likely to show significant clinical deterioration than were control patients.

Digoxin patients were 32% less likely to experience the end point of hospitalization for worsening heart failure.

Two studies included in the metaanalysis showed that patients on an ACE inhibitor plus digoxin did better than those on an ACE inhibitor plus placebo. However, the effects of digoxin in patients on other agents that have become first-line therapies in heart failure more recently than the ACE inhibitors, including β-blockers and aldosterone antagonists, haven't been systematically studied. For ethical reasons it's highly unlikely such trials will ever be done, Dr. Hood said.

VANCOUVER, B.C. — The latest Cochrane systematic review of digoxin for treatment of heart failure patients in sinus rhythm paints a picture of a more than 200-year-old drug that's still clinically useful, although it has no effect on mortality, William B. Hood Jr., M.D., said at a meeting sponsored by the International Academy of Cardiology.

“It's probably not first-line therapy. It's not very powerful. But it's available for patients who are not fully responsive to other agents that have become first-line treatments—the ACE inhibitors, β-blockers, spironolactone, and the angiotensin receptor blockers,” added Dr. Hood, lead author of the recent Cochrane review and a cardiologist at the University of Washington, Seattle.

The metaanalysis was restricted to randomized, double-blind, placebo-controlled trials involving adults followed for at least 7 weeks. Thirteen trials totaling nearly 7,900 patients qualified, including the largest of all digoxin studies: the 6,800-patient, 3-year Digitalis Investigation Group (DIG) trial (N. Engl. J. Med. 1997;336:525–33).

Why even bother doing a metaanalysis when one trial is so dominant? Dr. Hood explained that the smaller trials are helpful in that each consistently reached the same conclusion as DIG regarding the effect of digoxin on mortality—namely, there is none. The drug didn't lessen mortality, nor did it significantly worsen it.

In the DIG trial, however, there was a nonsignificant trend for fewer deaths from heart failure in digoxin-treated patients and a hint that the inotrope may have caused more arrhythmia deaths, although this wasn't a prespecified study end point.

Digoxin's effect on deterioration in clinical status was much more clearcut in the metaanalysis. The odds ratio for that end point was 0.31, meaning patients randomized to digoxin were 69% less likely to show significant clinical deterioration than were control patients.

Digoxin patients were 32% less likely to experience the end point of hospitalization for worsening heart failure.

Two studies included in the metaanalysis showed that patients on an ACE inhibitor plus digoxin did better than those on an ACE inhibitor plus placebo. However, the effects of digoxin in patients on other agents that have become first-line therapies in heart failure more recently than the ACE inhibitors, including β-blockers and aldosterone antagonists, haven't been systematically studied. For ethical reasons it's highly unlikely such trials will ever be done, Dr. Hood said.

VANCOUVER, B.C. — The latest Cochrane systematic review of digoxin for treatment of heart failure patients in sinus rhythm paints a picture of a more than 200-year-old drug that's still clinically useful, although it has no effect on mortality, William B. Hood Jr., M.D., said at a meeting sponsored by the International Academy of Cardiology.

“It's probably not first-line therapy. It's not very powerful. But it's available for patients who are not fully responsive to other agents that have become first-line treatments—the ACE inhibitors, β-blockers, spironolactone, and the angiotensin receptor blockers,” added Dr. Hood, lead author of the recent Cochrane review and a cardiologist at the University of Washington, Seattle.

The metaanalysis was restricted to randomized, double-blind, placebo-controlled trials involving adults followed for at least 7 weeks. Thirteen trials totaling nearly 7,900 patients qualified, including the largest of all digoxin studies: the 6,800-patient, 3-year Digitalis Investigation Group (DIG) trial (N. Engl. J. Med. 1997;336:525–33).

Why even bother doing a metaanalysis when one trial is so dominant? Dr. Hood explained that the smaller trials are helpful in that each consistently reached the same conclusion as DIG regarding the effect of digoxin on mortality—namely, there is none. The drug didn't lessen mortality, nor did it significantly worsen it.

In the DIG trial, however, there was a nonsignificant trend for fewer deaths from heart failure in digoxin-treated patients and a hint that the inotrope may have caused more arrhythmia deaths, although this wasn't a prespecified study end point.

Digoxin's effect on deterioration in clinical status was much more clearcut in the metaanalysis. The odds ratio for that end point was 0.31, meaning patients randomized to digoxin were 69% less likely to show significant clinical deterioration than were control patients.

Digoxin patients were 32% less likely to experience the end point of hospitalization for worsening heart failure.

Two studies included in the metaanalysis showed that patients on an ACE inhibitor plus digoxin did better than those on an ACE inhibitor plus placebo. However, the effects of digoxin in patients on other agents that have become first-line therapies in heart failure more recently than the ACE inhibitors, including β-blockers and aldosterone antagonists, haven't been systematically studied. For ethical reasons it's highly unlikely such trials will ever be done, Dr. Hood said.

VANCOUVER, B.C. — The recent big therapeutic successes in heart failure have come from implantable electrophysiologic devices—cardiac resynchronization therapy, implantable cardioverter defibrillators—and surgical advances, such as ventricular reduction procedures.

Although attempts to develop new drugs have proved largely disappointing of late, that may be about to change, Robert E. Hobbs, M.D., said at a meeting sponsored by the International Academy of Cardiology.

Many heart failure drugs are working their way through the developmental process. Dr. Hobbs chose to highlight half a dozen, each having a different and novel mechanism of action.

Each of these drugs has shown promise in clinical trials, and each addresses a different hypothesis about the nature of worsening heart failure. And these six interesting drugs constitute only a portion of what's in the pipeline, added Dr. Hobbs of the Cleveland Clinic Foundation.

▸ A xanthine oxidase inhibitor. Oxypurinol, an analogue of allopurinol, inhibits xanthine oxidase, the enzyme that produces uric acid, as well as harmful oxygen free radicals. Xanthine oxidase is upregulated in heart failure. By inhibiting this enzyme, oxypurinol has been shown to improve myocardial energetics and endothelial function.

The Oxypurinol Therapy for Congestive Heart Failure (OPT-CHF) trial is a recently completed 400-patient phase II/III randomized double-blind trial. The data are now being analyzed and are due to be presented this fall at the annual meeting of the American Heart Association.

▸ A unique inotropic agent. Levosimendan's mechanism of action differs from that of other inotropes, such as dobutamine and milrinone. It binds to cardiac troponin C. Levosimendan is categorized as a calcium-sensitizing agent because it enhances myocardial contractility without increasing intracellular calcium concentrations. The drug also acts as a vasodilator through activation of potassium channels. Moreover, it's a weak phosphodiesterase inhibitor as well.

Levosimendan's hemodynamic effects include an increase in cardiac index along with systemic and coronary vasodilation. In heart failure patients, levosimendan reduces elevated intracardiac pressures without increasing myocardial oxygen consumption. Unlike other inotropes, it has low arrhythmic potential, Dr. Hobbs stressed. The drug is approved for use in more than 30 countries as a treatment for patients with decompensated heart failure in need of inotropic support. But not in the United States.

“In the United States, they're reinventing the wheel and taking the drug through repeats of the clinical trials,” the cardiologist said. “I can't believe I'm still talking about levosimendan 10 years later. I was involved in clinical trials of the oral formulation a decade ago.”

What's under study today, however, is the intravenous version of levosimendan. The 800-patient phase-III Randomized Multicenter Evaluation of Intravenous Levosimendan Efficacy (REVIVE) trial is due to be presented in November at the AHA meeting.

▸ A thyroid hormone analogue. Roughly 30% of patients with advanced heart failure have low T₃ and normal TSH. Giving T₃ to patients with heart failure confers multiple cardiovascular benefits, including positive inotropic effects, improved diastolic relaxation, and stimulation of alpha-myosin heavy chain gene expression. But it also causes tachycardia, largely negating the improved cardiac performance.

Treatment with 3,5-diiodothyropropionic acid (DITPA), a T₃ analogue, offers similar cardiovascular benefits—but without the tachycardia. A 40-center, 34-week randomized trial is underway in 150 patients with class III/IV heart failure, low ejection fraction, low T₃, and normal TSH. Participants are assigned to one of two doses of DITPA or placebo.

▸ An atrial natriuretic peptide. Carperitide, a synthetic atrial natriuretic peptide, is an intravenous vasodilator approved for use in acutely decompensated heart failure in Japan for a decade. Its multiple effects are similar to those of nesiritide (Natrecor), recombinant brain natriuretic peptide.

An ongoing U.S. clinical trial is aimed at determining the safety and efficacy of seven different doses of carperitide in 158 patients.

▸ Adenosine receptor antagonists. These agents cause afferent arteriolar dilatation. They promote diuresis while preserving renal function and maintaining glomerular filtration rate. One agent—known at this point only as KW-3902—is the subject of an ongoing clinical trial in 200 hospitalized heart failure patients with impaired renal function. It's a 4-day treatment study with 30-day follow-up. “These agents look promising, but it's early,” Dr. Hobbs commented.

▸ Vasopressin antagonists. Nicknamed “super diuretics,” these drugs cause profound diuresis without disrupting electrolytes. The target of these drugs—vasopressin—is synthesized by the hypothalamus in response to baroreceptor and osmotic stimuli. It causes vasoconstriction and sodium and water retention.

Two vasopressin antagonists, or “vaptans,” have been tested in clinical trials: conivaptan and tolvaptan. Ongoing is the large multinational phase III Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan (EVEREST). Results are probably several years off, according to Dr. Hobbs.

Udho Thadani, M.D., commented that heart failure patients already have a rather full plate just with today's standard medications, which include a b-blocker, an ACE inhibitor or angiotensin receptor blocker, an aldosterone blocker such as spironolactone, and digoxin.

If even a few of the drugs with novel mechanisms of action that are in the developmental pipeline eventually find their way into routine clinical practice on top of today's standard therapy, compliance issues will become a much more prominent concern, predicted Dr. Thadani, professor emeritus of medicine at the University of Oklahoma, Oklahoma City.

VANCOUVER, B.C. — The recent big therapeutic successes in heart failure have come from implantable electrophysiologic devices—cardiac resynchronization therapy, implantable cardioverter defibrillators—and surgical advances, such as ventricular reduction procedures.

Although attempts to develop new drugs have proved largely disappointing of late, that may be about to change, Robert E. Hobbs, M.D., said at a meeting sponsored by the International Academy of Cardiology.

Many heart failure drugs are working their way through the developmental process. Dr. Hobbs chose to highlight half a dozen, each having a different and novel mechanism of action.

Each of these drugs has shown promise in clinical trials, and each addresses a different hypothesis about the nature of worsening heart failure. And these six interesting drugs constitute only a portion of what's in the pipeline, added Dr. Hobbs of the Cleveland Clinic Foundation.

▸ A xanthine oxidase inhibitor. Oxypurinol, an analogue of allopurinol, inhibits xanthine oxidase, the enzyme that produces uric acid, as well as harmful oxygen free radicals. Xanthine oxidase is upregulated in heart failure. By inhibiting this enzyme, oxypurinol has been shown to improve myocardial energetics and endothelial function.

The Oxypurinol Therapy for Congestive Heart Failure (OPT-CHF) trial is a recently completed 400-patient phase II/III randomized double-blind trial. The data are now being analyzed and are due to be presented this fall at the annual meeting of the American Heart Association.

▸ A unique inotropic agent. Levosimendan's mechanism of action differs from that of other inotropes, such as dobutamine and milrinone. It binds to cardiac troponin C. Levosimendan is categorized as a calcium-sensitizing agent because it enhances myocardial contractility without increasing intracellular calcium concentrations. The drug also acts as a vasodilator through activation of potassium channels. Moreover, it's a weak phosphodiesterase inhibitor as well.

Levosimendan's hemodynamic effects include an increase in cardiac index along with systemic and coronary vasodilation. In heart failure patients, levosimendan reduces elevated intracardiac pressures without increasing myocardial oxygen consumption. Unlike other inotropes, it has low arrhythmic potential, Dr. Hobbs stressed. The drug is approved for use in more than 30 countries as a treatment for patients with decompensated heart failure in need of inotropic support. But not in the United States.

“In the United States, they're reinventing the wheel and taking the drug through repeats of the clinical trials,” the cardiologist said. “I can't believe I'm still talking about levosimendan 10 years later. I was involved in clinical trials of the oral formulation a decade ago.”

What's under study today, however, is the intravenous version of levosimendan. The 800-patient phase-III Randomized Multicenter Evaluation of Intravenous Levosimendan Efficacy (REVIVE) trial is due to be presented in November at the AHA meeting.

▸ A thyroid hormone analogue. Roughly 30% of patients with advanced heart failure have low T₃ and normal TSH. Giving T₃ to patients with heart failure confers multiple cardiovascular benefits, including positive inotropic effects, improved diastolic relaxation, and stimulation of alpha-myosin heavy chain gene expression. But it also causes tachycardia, largely negating the improved cardiac performance.

Treatment with 3,5-diiodothyropropionic acid (DITPA), a T₃ analogue, offers similar cardiovascular benefits—but without the tachycardia. A 40-center, 34-week randomized trial is underway in 150 patients with class III/IV heart failure, low ejection fraction, low T₃, and normal TSH. Participants are assigned to one of two doses of DITPA or placebo.

▸ An atrial natriuretic peptide. Carperitide, a synthetic atrial natriuretic peptide, is an intravenous vasodilator approved for use in acutely decompensated heart failure in Japan for a decade. Its multiple effects are similar to those of nesiritide (Natrecor), recombinant brain natriuretic peptide.

An ongoing U.S. clinical trial is aimed at determining the safety and efficacy of seven different doses of carperitide in 158 patients.

▸ Adenosine receptor antagonists. These agents cause afferent arteriolar dilatation. They promote diuresis while preserving renal function and maintaining glomerular filtration rate. One agent—known at this point only as KW-3902—is the subject of an ongoing clinical trial in 200 hospitalized heart failure patients with impaired renal function. It's a 4-day treatment study with 30-day follow-up. “These agents look promising, but it's early,” Dr. Hobbs commented.

▸ Vasopressin antagonists. Nicknamed “super diuretics,” these drugs cause profound diuresis without disrupting electrolytes. The target of these drugs—vasopressin—is synthesized by the hypothalamus in response to baroreceptor and osmotic stimuli. It causes vasoconstriction and sodium and water retention.

Two vasopressin antagonists, or “vaptans,” have been tested in clinical trials: conivaptan and tolvaptan. Ongoing is the large multinational phase III Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan (EVEREST). Results are probably several years off, according to Dr. Hobbs.

Udho Thadani, M.D., commented that heart failure patients already have a rather full plate just with today's standard medications, which include a b-blocker, an ACE inhibitor or angiotensin receptor blocker, an aldosterone blocker such as spironolactone, and digoxin.

If even a few of the drugs with novel mechanisms of action that are in the developmental pipeline eventually find their way into routine clinical practice on top of today's standard therapy, compliance issues will become a much more prominent concern, predicted Dr. Thadani, professor emeritus of medicine at the University of Oklahoma, Oklahoma City.

VANCOUVER, B.C. — The recent big therapeutic successes in heart failure have come from implantable electrophysiologic devices—cardiac resynchronization therapy, implantable cardioverter defibrillators—and surgical advances, such as ventricular reduction procedures.

Although attempts to develop new drugs have proved largely disappointing of late, that may be about to change, Robert E. Hobbs, M.D., said at a meeting sponsored by the International Academy of Cardiology.

Many heart failure drugs are working their way through the developmental process. Dr. Hobbs chose to highlight half a dozen, each having a different and novel mechanism of action.

Each of these drugs has shown promise in clinical trials, and each addresses a different hypothesis about the nature of worsening heart failure. And these six interesting drugs constitute only a portion of what's in the pipeline, added Dr. Hobbs of the Cleveland Clinic Foundation.

▸ A xanthine oxidase inhibitor. Oxypurinol, an analogue of allopurinol, inhibits xanthine oxidase, the enzyme that produces uric acid, as well as harmful oxygen free radicals. Xanthine oxidase is upregulated in heart failure. By inhibiting this enzyme, oxypurinol has been shown to improve myocardial energetics and endothelial function.

The Oxypurinol Therapy for Congestive Heart Failure (OPT-CHF) trial is a recently completed 400-patient phase II/III randomized double-blind trial. The data are now being analyzed and are due to be presented this fall at the annual meeting of the American Heart Association.

▸ A unique inotropic agent. Levosimendan's mechanism of action differs from that of other inotropes, such as dobutamine and milrinone. It binds to cardiac troponin C. Levosimendan is categorized as a calcium-sensitizing agent because it enhances myocardial contractility without increasing intracellular calcium concentrations. The drug also acts as a vasodilator through activation of potassium channels. Moreover, it's a weak phosphodiesterase inhibitor as well.

Levosimendan's hemodynamic effects include an increase in cardiac index along with systemic and coronary vasodilation. In heart failure patients, levosimendan reduces elevated intracardiac pressures without increasing myocardial oxygen consumption. Unlike other inotropes, it has low arrhythmic potential, Dr. Hobbs stressed. The drug is approved for use in more than 30 countries as a treatment for patients with decompensated heart failure in need of inotropic support. But not in the United States.

“In the United States, they're reinventing the wheel and taking the drug through repeats of the clinical trials,” the cardiologist said. “I can't believe I'm still talking about levosimendan 10 years later. I was involved in clinical trials of the oral formulation a decade ago.”

What's under study today, however, is the intravenous version of levosimendan. The 800-patient phase-III Randomized Multicenter Evaluation of Intravenous Levosimendan Efficacy (REVIVE) trial is due to be presented in November at the AHA meeting.

▸ A thyroid hormone analogue. Roughly 30% of patients with advanced heart failure have low T₃ and normal TSH. Giving T₃ to patients with heart failure confers multiple cardiovascular benefits, including positive inotropic effects, improved diastolic relaxation, and stimulation of alpha-myosin heavy chain gene expression. But it also causes tachycardia, largely negating the improved cardiac performance.

Treatment with 3,5-diiodothyropropionic acid (DITPA), a T₃ analogue, offers similar cardiovascular benefits—but without the tachycardia. A 40-center, 34-week randomized trial is underway in 150 patients with class III/IV heart failure, low ejection fraction, low T₃, and normal TSH. Participants are assigned to one of two doses of DITPA or placebo.

▸ An atrial natriuretic peptide. Carperitide, a synthetic atrial natriuretic peptide, is an intravenous vasodilator approved for use in acutely decompensated heart failure in Japan for a decade. Its multiple effects are similar to those of nesiritide (Natrecor), recombinant brain natriuretic peptide.

An ongoing U.S. clinical trial is aimed at determining the safety and efficacy of seven different doses of carperitide in 158 patients.

▸ Adenosine receptor antagonists. These agents cause afferent arteriolar dilatation. They promote diuresis while preserving renal function and maintaining glomerular filtration rate. One agent—known at this point only as KW-3902—is the subject of an ongoing clinical trial in 200 hospitalized heart failure patients with impaired renal function. It's a 4-day treatment study with 30-day follow-up. “These agents look promising, but it's early,” Dr. Hobbs commented.

▸ Vasopressin antagonists. Nicknamed “super diuretics,” these drugs cause profound diuresis without disrupting electrolytes. The target of these drugs—vasopressin—is synthesized by the hypothalamus in response to baroreceptor and osmotic stimuli. It causes vasoconstriction and sodium and water retention.

Two vasopressin antagonists, or “vaptans,” have been tested in clinical trials: conivaptan and tolvaptan. Ongoing is the large multinational phase III Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan (EVEREST). Results are probably several years off, according to Dr. Hobbs.

Udho Thadani, M.D., commented that heart failure patients already have a rather full plate just with today's standard medications, which include a b-blocker, an ACE inhibitor or angiotensin receptor blocker, an aldosterone blocker such as spironolactone, and digoxin.

If even a few of the drugs with novel mechanisms of action that are in the developmental pipeline eventually find their way into routine clinical practice on top of today's standard therapy, compliance issues will become a much more prominent concern, predicted Dr. Thadani, professor emeritus of medicine at the University of Oklahoma, Oklahoma City.

VANCOUVER, B.C. — Baseline echocardiographic evidence of mechanical ventricular dyssynchrony is a powerful predictor of the long-term clinical benefit of cardiac resynchronization therapy in patients with severe heart failure, Maria Vittoria Pitzalis, M.D., said at a meeting sponsored by the International Academy of Cardiology.

Indeed, echocardiographic ventricular dyssynchrony is such a strong predictor that it ought to replace ECG evidence of prolonged QRS duration as a major screening criterion for cardiac resynchronization therapy (CRT) patient eligibility, added Dr. Pitzalis, who did her groundbreaking work in this field while at the University of Bari (Italy).

In the past few years, CRT has emerged as a major therapeutic advance for patients with severe heart failure despite optimal medical management. Studies have shown CRT results in reverse left ventricular remodeling as reflected in increased left ventricular ejection fraction, improved exercise tolerance and New York Heart Association functional class, enhanced quality of life, fewer hospitalizations, and, most recently, in the Cardiac Resynchronization in Heart Failure (CARE-HF) trial, a 36% reduction in all-cause mortality.

However, about one-quarter of treated patients do not benefit from CRT. There is great interest in developing ways to identify them in advance so as to spare them the expense of the device therapy as well as the risks associated with the at-times technically challenging transvenous lead placement.

A prolonged QRS interval has been a requirement for participation in all of the major CRT trials and is routinely used as a screening criterion for CRT eligibility in clinical practice. A long QRS is an ECG marker for ventricular dyssynchrony. But there is increasing dissatisfaction with its use as a screening tool in light of clear evidence that some patients with a normal QRS duration have echocardiographic evidence of mechanical ventricular dyssynchrony while others with a long QRS do not.

Dr. Pitzalis and her Italian coworkers have developed an echocardiographic method of assessing patients for ventricular dyssynchrony using a standard two-dimensional Doppler short-axis view at the papillary muscle level. It is obtained by calculating the shortest interval between the greatest posterior displacement of the septum and the maximum displacement of the left posterior ventricular wall. They call it the septal-to-posterior wall motion delay (SPWMD). It's simple, reproducible, widely available, and doesn't require specialized techniques and equipment, unlike tissue Doppler imaging, an alternative echocardiographic means of assessment for ventricular dyssynchrony.

The cardiologist presented a prospective study involving 60 patients, with severe heart failure and left bundle branch block, who underwent CRT. All had a baseline QRS greater than 130 milliseconds, and all underwent baseline measurement of SPWMD.

During a median 14-month follow-up, 4 patients died of heart failure and 12 others were hospitalized for worsening heart failure. In a multivariate analysis, only baseline SPWMD was significantly associated with subsequent heart failure progression or improvement. A long septal-to-posterior wall motion delay—that is, at least 130 milliseconds—was present in 79% of patients who experienced clinical improvement as defined by an increase in left ventricular ejection fraction along with at least a one-class improvement in New York Heart Association functional class. Only 9% of patients with an SPWMD of less than 130 milliseconds experienced such improvement. Change in QRS duration in response to therapy was unrelated to these outcomes.

“If you think about this result, it's not illogical, because in those patients with a long baseline delay, you're correcting the delay with CRT and therefore you are modifying prognosis. If a delay doesn't exist at baseline, you're not improving anything,” she said.

The investigators also compared the SPWMD results with those of tissue Doppler imaging and found no significant difference between the two echocardiographic techniques in terms of the end point of improved ejection fraction at 6 months.

Audience members inquired how they should manage patients who meet the now-standard prolonged QRS criterion for CRT implantation but have a short SPWMD.

“You can find very different things at the echocardiographic and ECG levels. There is dissociation between the two,” Dr. Pitzalis said. “In my opinion, based on our results, if you don't have any ventricular mechanical dyssynchrony, the possibility that your patient will improve with CRT is very low—just 9%. I'm wondering if the QRS duration criterion could be eliminated in the next few years, because we know there are patients with a narrow QRS that have mechanical dyssynchrony, and if an echo evaluation shows a rather large dyssynchrony, we have to implant them with CRT because they will benefit in clinical and functional terms.”

VANCOUVER, B.C. — Baseline echocardiographic evidence of mechanical ventricular dyssynchrony is a powerful predictor of the long-term clinical benefit of cardiac resynchronization therapy in patients with severe heart failure, Maria Vittoria Pitzalis, M.D., said at a meeting sponsored by the International Academy of Cardiology.

Indeed, echocardiographic ventricular dyssynchrony is such a strong predictor that it ought to replace ECG evidence of prolonged QRS duration as a major screening criterion for cardiac resynchronization therapy (CRT) patient eligibility, added Dr. Pitzalis, who did her groundbreaking work in this field while at the University of Bari (Italy).

In the past few years, CRT has emerged as a major therapeutic advance for patients with severe heart failure despite optimal medical management. Studies have shown CRT results in reverse left ventricular remodeling as reflected in increased left ventricular ejection fraction, improved exercise tolerance and New York Heart Association functional class, enhanced quality of life, fewer hospitalizations, and, most recently, in the Cardiac Resynchronization in Heart Failure (CARE-HF) trial, a 36% reduction in all-cause mortality.

However, about one-quarter of treated patients do not benefit from CRT. There is great interest in developing ways to identify them in advance so as to spare them the expense of the device therapy as well as the risks associated with the at-times technically challenging transvenous lead placement.

A prolonged QRS interval has been a requirement for participation in all of the major CRT trials and is routinely used as a screening criterion for CRT eligibility in clinical practice. A long QRS is an ECG marker for ventricular dyssynchrony. But there is increasing dissatisfaction with its use as a screening tool in light of clear evidence that some patients with a normal QRS duration have echocardiographic evidence of mechanical ventricular dyssynchrony while others with a long QRS do not.

Dr. Pitzalis and her Italian coworkers have developed an echocardiographic method of assessing patients for ventricular dyssynchrony using a standard two-dimensional Doppler short-axis view at the papillary muscle level. It is obtained by calculating the shortest interval between the greatest posterior displacement of the septum and the maximum displacement of the left posterior ventricular wall. They call it the septal-to-posterior wall motion delay (SPWMD). It's simple, reproducible, widely available, and doesn't require specialized techniques and equipment, unlike tissue Doppler imaging, an alternative echocardiographic means of assessment for ventricular dyssynchrony.

The cardiologist presented a prospective study involving 60 patients, with severe heart failure and left bundle branch block, who underwent CRT. All had a baseline QRS greater than 130 milliseconds, and all underwent baseline measurement of SPWMD.

During a median 14-month follow-up, 4 patients died of heart failure and 12 others were hospitalized for worsening heart failure. In a multivariate analysis, only baseline SPWMD was significantly associated with subsequent heart failure progression or improvement. A long septal-to-posterior wall motion delay—that is, at least 130 milliseconds—was present in 79% of patients who experienced clinical improvement as defined by an increase in left ventricular ejection fraction along with at least a one-class improvement in New York Heart Association functional class. Only 9% of patients with an SPWMD of less than 130 milliseconds experienced such improvement. Change in QRS duration in response to therapy was unrelated to these outcomes.

“If you think about this result, it's not illogical, because in those patients with a long baseline delay, you're correcting the delay with CRT and therefore you are modifying prognosis. If a delay doesn't exist at baseline, you're not improving anything,” she said.

The investigators also compared the SPWMD results with those of tissue Doppler imaging and found no significant difference between the two echocardiographic techniques in terms of the end point of improved ejection fraction at 6 months.

Audience members inquired how they should manage patients who meet the now-standard prolonged QRS criterion for CRT implantation but have a short SPWMD.

“You can find very different things at the echocardiographic and ECG levels. There is dissociation between the two,” Dr. Pitzalis said. “In my opinion, based on our results, if you don't have any ventricular mechanical dyssynchrony, the possibility that your patient will improve with CRT is very low—just 9%. I'm wondering if the QRS duration criterion could be eliminated in the next few years, because we know there are patients with a narrow QRS that have mechanical dyssynchrony, and if an echo evaluation shows a rather large dyssynchrony, we have to implant them with CRT because they will benefit in clinical and functional terms.”

VANCOUVER, B.C. — Baseline echocardiographic evidence of mechanical ventricular dyssynchrony is a powerful predictor of the long-term clinical benefit of cardiac resynchronization therapy in patients with severe heart failure, Maria Vittoria Pitzalis, M.D., said at a meeting sponsored by the International Academy of Cardiology.

Indeed, echocardiographic ventricular dyssynchrony is such a strong predictor that it ought to replace ECG evidence of prolonged QRS duration as a major screening criterion for cardiac resynchronization therapy (CRT) patient eligibility, added Dr. Pitzalis, who did her groundbreaking work in this field while at the University of Bari (Italy).

In the past few years, CRT has emerged as a major therapeutic advance for patients with severe heart failure despite optimal medical management. Studies have shown CRT results in reverse left ventricular remodeling as reflected in increased left ventricular ejection fraction, improved exercise tolerance and New York Heart Association functional class, enhanced quality of life, fewer hospitalizations, and, most recently, in the Cardiac Resynchronization in Heart Failure (CARE-HF) trial, a 36% reduction in all-cause mortality.

However, about one-quarter of treated patients do not benefit from CRT. There is great interest in developing ways to identify them in advance so as to spare them the expense of the device therapy as well as the risks associated with the at-times technically challenging transvenous lead placement.

A prolonged QRS interval has been a requirement for participation in all of the major CRT trials and is routinely used as a screening criterion for CRT eligibility in clinical practice. A long QRS is an ECG marker for ventricular dyssynchrony. But there is increasing dissatisfaction with its use as a screening tool in light of clear evidence that some patients with a normal QRS duration have echocardiographic evidence of mechanical ventricular dyssynchrony while others with a long QRS do not.

Dr. Pitzalis and her Italian coworkers have developed an echocardiographic method of assessing patients for ventricular dyssynchrony using a standard two-dimensional Doppler short-axis view at the papillary muscle level. It is obtained by calculating the shortest interval between the greatest posterior displacement of the septum and the maximum displacement of the left posterior ventricular wall. They call it the septal-to-posterior wall motion delay (SPWMD). It's simple, reproducible, widely available, and doesn't require specialized techniques and equipment, unlike tissue Doppler imaging, an alternative echocardiographic means of assessment for ventricular dyssynchrony.

The cardiologist presented a prospective study involving 60 patients, with severe heart failure and left bundle branch block, who underwent CRT. All had a baseline QRS greater than 130 milliseconds, and all underwent baseline measurement of SPWMD.

During a median 14-month follow-up, 4 patients died of heart failure and 12 others were hospitalized for worsening heart failure. In a multivariate analysis, only baseline SPWMD was significantly associated with subsequent heart failure progression or improvement. A long septal-to-posterior wall motion delay—that is, at least 130 milliseconds—was present in 79% of patients who experienced clinical improvement as defined by an increase in left ventricular ejection fraction along with at least a one-class improvement in New York Heart Association functional class. Only 9% of patients with an SPWMD of less than 130 milliseconds experienced such improvement. Change in QRS duration in response to therapy was unrelated to these outcomes.

“If you think about this result, it's not illogical, because in those patients with a long baseline delay, you're correcting the delay with CRT and therefore you are modifying prognosis. If a delay doesn't exist at baseline, you're not improving anything,” she said.

The investigators also compared the SPWMD results with those of tissue Doppler imaging and found no significant difference between the two echocardiographic techniques in terms of the end point of improved ejection fraction at 6 months.

Audience members inquired how they should manage patients who meet the now-standard prolonged QRS criterion for CRT implantation but have a short SPWMD.

“You can find very different things at the echocardiographic and ECG levels. There is dissociation between the two,” Dr. Pitzalis said. “In my opinion, based on our results, if you don't have any ventricular mechanical dyssynchrony, the possibility that your patient will improve with CRT is very low—just 9%. I'm wondering if the QRS duration criterion could be eliminated in the next few years, because we know there are patients with a narrow QRS that have mechanical dyssynchrony, and if an echo evaluation shows a rather large dyssynchrony, we have to implant them with CRT because they will benefit in clinical and functional terms.”

WASHINGTON — Measuring markers of inflammation and neurohumoral activation in candidates for implantation with a left ventricular assist device may help predict the probability of right ventricular failure, Evgenij V. Potapov, M.D., reported at the annual conference of the American Society for Artificial Internal Organs.

“The problem is that up to 20% of patients receiving a left ventricular assist device [LVAD] develop right heart failure,” Dr. Potapov, a cardiothoracic surgeon at the Deutsches Herzzentrum Berlin, said in an interview.

Dr. Potapov and his colleagues reviewed the records of patients with chronic end-stage heart failure who received an LVAD during 2002-2004.

They found no differences in preoperative echocardiographic findings or laboratory or hemodynamic parameters between the 102 patients who had normal right ventricular function after LVAD implantation and the 9 patients with right ventricular failure, defined as having at least two of the following within 24 hours of LVAD implantation: mean arterial pressure less than 55 mm Hg, central venous pressure less than 16 mm Hg, mixed venous oxygen saturation less than 55%, cardiac index less than 2 L/min per square meter, and more than 20 inotropic equivalents of inotropic support.

But a subsequent prospective study of 40 patients found that people with normal right ventricular function after left ventricular assist device implantation had significantly lower levels of markers of inflammation (procalcitonin and neopterin) and neurohumoral activation (N-terminal pro-B-type natriuretic peptide and big endothelin-1) than did those who would later develop right ventricular failure, he said in a poster session at the conference.

Patients who are identified as having a high probability of right ventricular failure after implantation of a left ventricular assist device could instead undergo implantation of a biventricular support device or a total artificial heart, Dr. Potapov suggested.

None of the patients who were in either study required a left ventricular assist device for postcardiotomy heart failure.

WASHINGTON — Measuring markers of inflammation and neurohumoral activation in candidates for implantation with a left ventricular assist device may help predict the probability of right ventricular failure, Evgenij V. Potapov, M.D., reported at the annual conference of the American Society for Artificial Internal Organs.

“The problem is that up to 20% of patients receiving a left ventricular assist device [LVAD] develop right heart failure,” Dr. Potapov, a cardiothoracic surgeon at the Deutsches Herzzentrum Berlin, said in an interview.

Dr. Potapov and his colleagues reviewed the records of patients with chronic end-stage heart failure who received an LVAD during 2002-2004.

They found no differences in preoperative echocardiographic findings or laboratory or hemodynamic parameters between the 102 patients who had normal right ventricular function after LVAD implantation and the 9 patients with right ventricular failure, defined as having at least two of the following within 24 hours of LVAD implantation: mean arterial pressure less than 55 mm Hg, central venous pressure less than 16 mm Hg, mixed venous oxygen saturation less than 55%, cardiac index less than 2 L/min per square meter, and more than 20 inotropic equivalents of inotropic support.

But a subsequent prospective study of 40 patients found that people with normal right ventricular function after left ventricular assist device implantation had significantly lower levels of markers of inflammation (procalcitonin and neopterin) and neurohumoral activation (N-terminal pro-B-type natriuretic peptide and big endothelin-1) than did those who would later develop right ventricular failure, he said in a poster session at the conference.

Patients who are identified as having a high probability of right ventricular failure after implantation of a left ventricular assist device could instead undergo implantation of a biventricular support device or a total artificial heart, Dr. Potapov suggested.

None of the patients who were in either study required a left ventricular assist device for postcardiotomy heart failure.

WASHINGTON — Measuring markers of inflammation and neurohumoral activation in candidates for implantation with a left ventricular assist device may help predict the probability of right ventricular failure, Evgenij V. Potapov, M.D., reported at the annual conference of the American Society for Artificial Internal Organs.

“The problem is that up to 20% of patients receiving a left ventricular assist device [LVAD] develop right heart failure,” Dr. Potapov, a cardiothoracic surgeon at the Deutsches Herzzentrum Berlin, said in an interview.

Dr. Potapov and his colleagues reviewed the records of patients with chronic end-stage heart failure who received an LVAD during 2002-2004.

They found no differences in preoperative echocardiographic findings or laboratory or hemodynamic parameters between the 102 patients who had normal right ventricular function after LVAD implantation and the 9 patients with right ventricular failure, defined as having at least two of the following within 24 hours of LVAD implantation: mean arterial pressure less than 55 mm Hg, central venous pressure less than 16 mm Hg, mixed venous oxygen saturation less than 55%, cardiac index less than 2 L/min per square meter, and more than 20 inotropic equivalents of inotropic support.

But a subsequent prospective study of 40 patients found that people with normal right ventricular function after left ventricular assist device implantation had significantly lower levels of markers of inflammation (procalcitonin and neopterin) and neurohumoral activation (N-terminal pro-B-type natriuretic peptide and big endothelin-1) than did those who would later develop right ventricular failure, he said in a poster session at the conference.

Patients who are identified as having a high probability of right ventricular failure after implantation of a left ventricular assist device could instead undergo implantation of a biventricular support device or a total artificial heart, Dr. Potapov suggested.

None of the patients who were in either study required a left ventricular assist device for postcardiotomy heart failure.

WASHINGTON — Short-term use of a percutaneous ventricular assist device during high-risk surgery or in cases of near-death heart failure can help support patients long enough for them to recover or receive additional treatment, Reynolds M. Delgado III, M.D., said at the annual conference of the American Society for Artificial Internal Organs.

Dr. Delgado and his colleagues at the Texas Heart Institute have used the TandemHeart in four different scenarios as:

▸ A supportive device during high-risk percutaneous transluminal coronary angioplasty in nine patients.

▸ A bridge to recovery in two patients with acute cardiogenic shock.

▸ Circulatory support in five patients during high-risk cardiac surgery (coronary artery bypass and/or mitral valve surgery).

▸ A bridge to an implanted left ventricular assist device (LVAD) in seven patients.

Blood flow in the TandemHeart, made by CardiacAssist Inc., follows a path from a cannula in the femoral vein that pierces the intraatrial septum and takes oxygenated blood from the left atrium back to a continuously flowing extracorporeal pump (attached to the patient's leg), which distributes the blood through a cannula in one or both femoral arteries.

“The tricky part of this procedure is the transseptal cannulation; putting this venous catheter across the septum requires some special skill. A subset of cardiologists are able to do this—perhaps 10% or less,” said Dr. Delgado, medical director of mechanical assist devices in heart failure at the institute, located at St. Luke's Episcopal Hospital, Houston.

None of the high-risk percutaneous transluminal coronary angioplasty patients were candidates for surgery. They had high-risk coronary anatomy and were at risk for imminent death without intervention. The investigators successfully performed the procedure without complications in eight of these nine patients; one patient had a perforated left atrium. Overall, eight patients were discharged from the hospital with good long-term outcomes while one patient died of multiorgan failure after surgery, said Dr. Delgado, a cardiologist. Dr. Delgado reported that he was an investigator on a previous trial sponsored by CardiacAssist but has no financial conflicts of interest with the company.

Both cardiogenic shock patients successfully underwent the implantation procedure. After 7 days, one patient successfully recovered from heart failure due to acute myocarditis. The other patient initially suffered an acute MI and then cardiac arrest just prior to implantation of the TandemHeart; the patient died despite successful implantation.

Of five patients who underwent high-risk cardiac surgery, all had successful implantation, but one patient with coagulopathy and multiorgan failure died of major intraoperative bleeding.

Seven patients were successfully bridged from the TandemHeart to an LVAD. However, four of these patients did not survive long term with an LVAD, primarily because of multiorgan failure that existed prior to the implantation of the TandemHeart.

On average, the 23 patients in the study were aged 68 years and were on percutaneous ventricular assist device support for 2.8 days; 20 patients were male.

WASHINGTON — Short-term use of a percutaneous ventricular assist device during high-risk surgery or in cases of near-death heart failure can help support patients long enough for them to recover or receive additional treatment, Reynolds M. Delgado III, M.D., said at the annual conference of the American Society for Artificial Internal Organs.

Dr. Delgado and his colleagues at the Texas Heart Institute have used the TandemHeart in four different scenarios as:

▸ A supportive device during high-risk percutaneous transluminal coronary angioplasty in nine patients.

▸ A bridge to recovery in two patients with acute cardiogenic shock.

▸ Circulatory support in five patients during high-risk cardiac surgery (coronary artery bypass and/or mitral valve surgery).

▸ A bridge to an implanted left ventricular assist device (LVAD) in seven patients.

Blood flow in the TandemHeart, made by CardiacAssist Inc., follows a path from a cannula in the femoral vein that pierces the intraatrial septum and takes oxygenated blood from the left atrium back to a continuously flowing extracorporeal pump (attached to the patient's leg), which distributes the blood through a cannula in one or both femoral arteries.

“The tricky part of this procedure is the transseptal cannulation; putting this venous catheter across the septum requires some special skill. A subset of cardiologists are able to do this—perhaps 10% or less,” said Dr. Delgado, medical director of mechanical assist devices in heart failure at the institute, located at St. Luke's Episcopal Hospital, Houston.

None of the high-risk percutaneous transluminal coronary angioplasty patients were candidates for surgery. They had high-risk coronary anatomy and were at risk for imminent death without intervention. The investigators successfully performed the procedure without complications in eight of these nine patients; one patient had a perforated left atrium. Overall, eight patients were discharged from the hospital with good long-term outcomes while one patient died of multiorgan failure after surgery, said Dr. Delgado, a cardiologist. Dr. Delgado reported that he was an investigator on a previous trial sponsored by CardiacAssist but has no financial conflicts of interest with the company.

Both cardiogenic shock patients successfully underwent the implantation procedure. After 7 days, one patient successfully recovered from heart failure due to acute myocarditis. The other patient initially suffered an acute MI and then cardiac arrest just prior to implantation of the TandemHeart; the patient died despite successful implantation.

Of five patients who underwent high-risk cardiac surgery, all had successful implantation, but one patient with coagulopathy and multiorgan failure died of major intraoperative bleeding.

Seven patients were successfully bridged from the TandemHeart to an LVAD. However, four of these patients did not survive long term with an LVAD, primarily because of multiorgan failure that existed prior to the implantation of the TandemHeart.

On average, the 23 patients in the study were aged 68 years and were on percutaneous ventricular assist device support for 2.8 days; 20 patients were male.

WASHINGTON — Short-term use of a percutaneous ventricular assist device during high-risk surgery or in cases of near-death heart failure can help support patients long enough for them to recover or receive additional treatment, Reynolds M. Delgado III, M.D., said at the annual conference of the American Society for Artificial Internal Organs.

Dr. Delgado and his colleagues at the Texas Heart Institute have used the TandemHeart in four different scenarios as:

▸ A supportive device during high-risk percutaneous transluminal coronary angioplasty in nine patients.

▸ A bridge to recovery in two patients with acute cardiogenic shock.

▸ Circulatory support in five patients during high-risk cardiac surgery (coronary artery bypass and/or mitral valve surgery).

▸ A bridge to an implanted left ventricular assist device (LVAD) in seven patients.

Blood flow in the TandemHeart, made by CardiacAssist Inc., follows a path from a cannula in the femoral vein that pierces the intraatrial septum and takes oxygenated blood from the left atrium back to a continuously flowing extracorporeal pump (attached to the patient's leg), which distributes the blood through a cannula in one or both femoral arteries.

“The tricky part of this procedure is the transseptal cannulation; putting this venous catheter across the septum requires some special skill. A subset of cardiologists are able to do this—perhaps 10% or less,” said Dr. Delgado, medical director of mechanical assist devices in heart failure at the institute, located at St. Luke's Episcopal Hospital, Houston.

None of the high-risk percutaneous transluminal coronary angioplasty patients were candidates for surgery. They had high-risk coronary anatomy and were at risk for imminent death without intervention. The investigators successfully performed the procedure without complications in eight of these nine patients; one patient had a perforated left atrium. Overall, eight patients were discharged from the hospital with good long-term outcomes while one patient died of multiorgan failure after surgery, said Dr. Delgado, a cardiologist. Dr. Delgado reported that he was an investigator on a previous trial sponsored by CardiacAssist but has no financial conflicts of interest with the company.

Both cardiogenic shock patients successfully underwent the implantation procedure. After 7 days, one patient successfully recovered from heart failure due to acute myocarditis. The other patient initially suffered an acute MI and then cardiac arrest just prior to implantation of the TandemHeart; the patient died despite successful implantation.

Of five patients who underwent high-risk cardiac surgery, all had successful implantation, but one patient with coagulopathy and multiorgan failure died of major intraoperative bleeding.

Seven patients were successfully bridged from the TandemHeart to an LVAD. However, four of these patients did not survive long term with an LVAD, primarily because of multiorgan failure that existed prior to the implantation of the TandemHeart.

On average, the 23 patients in the study were aged 68 years and were on percutaneous ventricular assist device support for 2.8 days; 20 patients were male.

ORLANDO, FLA. — A standard 7-week course of enhanced external counterpulsation therapy in patients with heart failure who are on optimal pharmacotherapy improves their exercise duration, quality of life, and New York Heart Association class for at least 6 months afterward, according to the results of a randomized trial presented at the annual meeting of the American College of Cardiology.

“We believe these results suggest that EECP provides adjunctive therapy in patients with New York Heart Association [NYHA] class II-III heart failure receiving optimal pharmacologic therapy,” said Arthur M. Feldman, M.D., chairman of the steering committee for the Prospective Evaluation of EECP in Congestive Heart failure (PEECH) trial.

PEECH involved 187 patients with systolic heart failure (HF) and a mean ejection fraction of 26% who were randomized at 29 medical centers to optimal drug therapy alone or in combination with 35 hour-long EECP sessions over 7 weeks. Patients were unblinded as to their treatment allocation, as were their treating physicians; however, a separate group of blinded investigators performed all patient evaluations, explained Dr. Feldman, professor and chairman of the department of medicine at Thomas Jefferson University, Philadelphia.

The primary end point of the study was at least a 60-second improvement in exercise duration at follow-up 6 months after the last EECP session. This was achieved in 35% of the EECP group and 25% of the control patients, a significant difference. However, there was no between-group difference in a predefined alternative primary end point, which was the percentage of patients achieving at least a 1.25-mL/kg per minute increase in peak oxygen consumption (VO₂).

Exercise duration improved by a mean of 25 seconds in the EECP group, whereas it declined by 10 seconds in controls. To put this 35-second difference into perspective, Dr. Feldman said that randomized trials of cardiac resynchronization therapy show it typically results in roughly a 50-second differential in exercise duration, compared with sham therapy.

Improvement in NYHA class was a secondary PEECH end point. At 6 months, 31% of the EECP patients, and only 14% of control patients showed at least a one-class improvement.

Another secondary end point was quality of life as measured in terms of change from baseline in scores on the Minnesota Living with Heart Failure questionnaire. One month after completion of the EECP sessions, treated patients had a mean 8.9-point improvement, compared with a 3.4-point gain in control patients. The quality of life advantage favoring the EECP group remained significant at 3 months, but not at 6 months.

EECP treatment was well tolerated, although one patient developed a pulmonary embolism that investigators believed was therapy related.

Discussant Andrew D. Michaels, M.D., characterized the PEECH results as “mixed.”

“The trial met one of two primary end points. It's somewhat concerning that the end points that were met—namely increased exercise duration, improved quality of life, and improvement in [NYHA] class—are all subject to the placebo effect,” added Dr. Michaels of the University of California, San Francisco.

Dr. Feldman said that although EECP resulted in a significant gain in VO₂ in an earlier pilot study, the PEECH population may have been biased against realizing a similar benefit because they were predominantly NYHA class II and hence did not have a long way to go to reach an essentially normal response.

EECP utilizes a series of ECG-synchronized inflatable cuffs wrapped around the legs. The cuffs swiftly inflate at onset of diastole and rapidly deflate at onset of systole, providing hemodynamic effects similar to intraaortic balloon counterpulsation, including increased coronary artery blood flow along with afterload reduction.

Enhanced external counterpulsation therapy is approved for the treatment of stable angina. The average payment to physicians under Medicare is $138.34 per session.

Both Dr. Feldman and Dr. Michaels are consultants to Vasomedical Inc., which markets EECP systems and sponsored the PEECH trial.

ORLANDO, FLA. — A standard 7-week course of enhanced external counterpulsation therapy in patients with heart failure who are on optimal pharmacotherapy improves their exercise duration, quality of life, and New York Heart Association class for at least 6 months afterward, according to the results of a randomized trial presented at the annual meeting of the American College of Cardiology.

“We believe these results suggest that EECP provides adjunctive therapy in patients with New York Heart Association [NYHA] class II-III heart failure receiving optimal pharmacologic therapy,” said Arthur M. Feldman, M.D., chairman of the steering committee for the Prospective Evaluation of EECP in Congestive Heart failure (PEECH) trial.

PEECH involved 187 patients with systolic heart failure (HF) and a mean ejection fraction of 26% who were randomized at 29 medical centers to optimal drug therapy alone or in combination with 35 hour-long EECP sessions over 7 weeks. Patients were unblinded as to their treatment allocation, as were their treating physicians; however, a separate group of blinded investigators performed all patient evaluations, explained Dr. Feldman, professor and chairman of the department of medicine at Thomas Jefferson University, Philadelphia.

The primary end point of the study was at least a 60-second improvement in exercise duration at follow-up 6 months after the last EECP session. This was achieved in 35% of the EECP group and 25% of the control patients, a significant difference. However, there was no between-group difference in a predefined alternative primary end point, which was the percentage of patients achieving at least a 1.25-mL/kg per minute increase in peak oxygen consumption (VO₂).

Exercise duration improved by a mean of 25 seconds in the EECP group, whereas it declined by 10 seconds in controls. To put this 35-second difference into perspective, Dr. Feldman said that randomized trials of cardiac resynchronization therapy show it typically results in roughly a 50-second differential in exercise duration, compared with sham therapy.

Improvement in NYHA class was a secondary PEECH end point. At 6 months, 31% of the EECP patients, and only 14% of control patients showed at least a one-class improvement.

Another secondary end point was quality of life as measured in terms of change from baseline in scores on the Minnesota Living with Heart Failure questionnaire. One month after completion of the EECP sessions, treated patients had a mean 8.9-point improvement, compared with a 3.4-point gain in control patients. The quality of life advantage favoring the EECP group remained significant at 3 months, but not at 6 months.

EECP treatment was well tolerated, although one patient developed a pulmonary embolism that investigators believed was therapy related.

Discussant Andrew D. Michaels, M.D., characterized the PEECH results as “mixed.”

“The trial met one of two primary end points. It's somewhat concerning that the end points that were met—namely increased exercise duration, improved quality of life, and improvement in [NYHA] class—are all subject to the placebo effect,” added Dr. Michaels of the University of California, San Francisco.

Dr. Feldman said that although EECP resulted in a significant gain in VO₂ in an earlier pilot study, the PEECH population may have been biased against realizing a similar benefit because they were predominantly NYHA class II and hence did not have a long way to go to reach an essentially normal response.

EECP utilizes a series of ECG-synchronized inflatable cuffs wrapped around the legs. The cuffs swiftly inflate at onset of diastole and rapidly deflate at onset of systole, providing hemodynamic effects similar to intraaortic balloon counterpulsation, including increased coronary artery blood flow along with afterload reduction.

Enhanced external counterpulsation therapy is approved for the treatment of stable angina. The average payment to physicians under Medicare is $138.34 per session.

Both Dr. Feldman and Dr. Michaels are consultants to Vasomedical Inc., which markets EECP systems and sponsored the PEECH trial.

ORLANDO, FLA. — A standard 7-week course of enhanced external counterpulsation therapy in patients with heart failure who are on optimal pharmacotherapy improves their exercise duration, quality of life, and New York Heart Association class for at least 6 months afterward, according to the results of a randomized trial presented at the annual meeting of the American College of Cardiology.

“We believe these results suggest that EECP provides adjunctive therapy in patients with New York Heart Association [NYHA] class II-III heart failure receiving optimal pharmacologic therapy,” said Arthur M. Feldman, M.D., chairman of the steering committee for the Prospective Evaluation of EECP in Congestive Heart failure (PEECH) trial.

PEECH involved 187 patients with systolic heart failure (HF) and a mean ejection fraction of 26% who were randomized at 29 medical centers to optimal drug therapy alone or in combination with 35 hour-long EECP sessions over 7 weeks. Patients were unblinded as to their treatment allocation, as were their treating physicians; however, a separate group of blinded investigators performed all patient evaluations, explained Dr. Feldman, professor and chairman of the department of medicine at Thomas Jefferson University, Philadelphia.

The primary end point of the study was at least a 60-second improvement in exercise duration at follow-up 6 months after the last EECP session. This was achieved in 35% of the EECP group and 25% of the control patients, a significant difference. However, there was no between-group difference in a predefined alternative primary end point, which was the percentage of patients achieving at least a 1.25-mL/kg per minute increase in peak oxygen consumption (VO₂).

Exercise duration improved by a mean of 25 seconds in the EECP group, whereas it declined by 10 seconds in controls. To put this 35-second difference into perspective, Dr. Feldman said that randomized trials of cardiac resynchronization therapy show it typically results in roughly a 50-second differential in exercise duration, compared with sham therapy.

Improvement in NYHA class was a secondary PEECH end point. At 6 months, 31% of the EECP patients, and only 14% of control patients showed at least a one-class improvement.

Another secondary end point was quality of life as measured in terms of change from baseline in scores on the Minnesota Living with Heart Failure questionnaire. One month after completion of the EECP sessions, treated patients had a mean 8.9-point improvement, compared with a 3.4-point gain in control patients. The quality of life advantage favoring the EECP group remained significant at 3 months, but not at 6 months.

EECP treatment was well tolerated, although one patient developed a pulmonary embolism that investigators believed was therapy related.

Discussant Andrew D. Michaels, M.D., characterized the PEECH results as “mixed.”

“The trial met one of two primary end points. It's somewhat concerning that the end points that were met—namely increased exercise duration, improved quality of life, and improvement in [NYHA] class—are all subject to the placebo effect,” added Dr. Michaels of the University of California, San Francisco.

Dr. Feldman said that although EECP resulted in a significant gain in VO₂ in an earlier pilot study, the PEECH population may have been biased against realizing a similar benefit because they were predominantly NYHA class II and hence did not have a long way to go to reach an essentially normal response.

EECP utilizes a series of ECG-synchronized inflatable cuffs wrapped around the legs. The cuffs swiftly inflate at onset of diastole and rapidly deflate at onset of systole, providing hemodynamic effects similar to intraaortic balloon counterpulsation, including increased coronary artery blood flow along with afterload reduction.

Enhanced external counterpulsation therapy is approved for the treatment of stable angina. The average payment to physicians under Medicare is $138.34 per session.

Both Dr. Feldman and Dr. Michaels are consultants to Vasomedical Inc., which markets EECP systems and sponsored the PEECH trial.

WASHINGTON — Body temperature below 36° C at hospital admission was independently associated with a lower survival rate in a study of 56,659 patients with advanced heart failure.

Disordered thermoregulation is common in patients with advanced heart failure, and body temperature measurements may improve risk assessment in these patients, Brahmajee K. Nallamothu, M.D., wrote in a poster presented at the Clinical Research 2005 meeting sponsored by the American Federation for Medical Research.

Dr. Nallamothu, a cardiologist at the University of Michigan, Ann Arbor, and his associates reviewed data on patients aged 65 years and older who were participating in the National Heart Care Project.

The mean body temperature upon hospital admission was 36.5° C, and most of the patients' admission temperatures were between 36° C and 38° C. However, 10,754 (18.5%) of the patients had body temperatures below 36° C and 1,145 (1.9%) had body temperatures above 38° C.

After multivariate analysis, patients with body temperatures below 36° C had significantly higher mortality, both in hospital (adjusted risk ratio, 1.28) and at 1 year after their hospitalizations (adjusted risk ratio, 1.14). Body temperatures above 38° C were not significantly associated with in-hospital mortality, but they were significantly associated with lower mortality after 1 year (adjusted risk ratio, 0.80).

WASHINGTON — Body temperature below 36° C at hospital admission was independently associated with a lower survival rate in a study of 56,659 patients with advanced heart failure.

Disordered thermoregulation is common in patients with advanced heart failure, and body temperature measurements may improve risk assessment in these patients, Brahmajee K. Nallamothu, M.D., wrote in a poster presented at the Clinical Research 2005 meeting sponsored by the American Federation for Medical Research.

Dr. Nallamothu, a cardiologist at the University of Michigan, Ann Arbor, and his associates reviewed data on patients aged 65 years and older who were participating in the National Heart Care Project.

The mean body temperature upon hospital admission was 36.5° C, and most of the patients' admission temperatures were between 36° C and 38° C. However, 10,754 (18.5%) of the patients had body temperatures below 36° C and 1,145 (1.9%) had body temperatures above 38° C.

After multivariate analysis, patients with body temperatures below 36° C had significantly higher mortality, both in hospital (adjusted risk ratio, 1.28) and at 1 year after their hospitalizations (adjusted risk ratio, 1.14). Body temperatures above 38° C were not significantly associated with in-hospital mortality, but they were significantly associated with lower mortality after 1 year (adjusted risk ratio, 0.80).

WASHINGTON — Body temperature below 36° C at hospital admission was independently associated with a lower survival rate in a study of 56,659 patients with advanced heart failure.

Disordered thermoregulation is common in patients with advanced heart failure, and body temperature measurements may improve risk assessment in these patients, Brahmajee K. Nallamothu, M.D., wrote in a poster presented at the Clinical Research 2005 meeting sponsored by the American Federation for Medical Research.

Dr. Nallamothu, a cardiologist at the University of Michigan, Ann Arbor, and his associates reviewed data on patients aged 65 years and older who were participating in the National Heart Care Project.

The mean body temperature upon hospital admission was 36.5° C, and most of the patients' admission temperatures were between 36° C and 38° C. However, 10,754 (18.5%) of the patients had body temperatures below 36° C and 1,145 (1.9%) had body temperatures above 38° C.

After multivariate analysis, patients with body temperatures below 36° C had significantly higher mortality, both in hospital (adjusted risk ratio, 1.28) and at 1 year after their hospitalizations (adjusted risk ratio, 1.14). Body temperatures above 38° C were not significantly associated with in-hospital mortality, but they were significantly associated with lower mortality after 1 year (adjusted risk ratio, 0.80).