Heart Failure

SEATTLE — Blood tests on 507 patients seen in emergency departments for chest pain found resistance to aspirin in 20% of those with a history of heart failure and 12% of patients without heart failure, Dr. Lori B. Daniels reported in a poster presentation at the annual meeting of the Heart Failure Society of America.

“Physicians should be aware of the high rate of aspirin nonresponsiveness in patients with heart failure, since they may be susceptible to thrombotic events” even if treated with aspirin, and may need other antithrombotic therapy, said Dr. Daniels of the University of California, San Diego, and her associates.

Aspirin prevents MI, stroke, or other vascular events by causing platelet dysfunction so that platelets do not aggregate. It irreversibly inhibits platelet cyclooxygenase, a key enzyme in prostaglandin synthesis, so that platelets lose the capacity to synthesize thromboxane A2, an inducer of platelet aggregation with vasoconstrictive properties.

Between 8% and 18% of patients treated with aspirin, however, develop recurrent vascular events within 2 years, a phenomenon described as aspirin resistance “or perhaps more accurately as aspirin nonresponsiveness,” the investigators wrote.

They took blood samples from patients with suspected acute coronary syndromes seen at five medical centers. All were on outpatient aspirin therapy or were given an aspirin when they arrived at the emergency department. The 25% of patients with a history of heart failure were older than those without heart failure (62 vs. 58 years) and were more likely to be taking aspirin as an outpatient (81% vs. 60%), but the two groups did not differ by sex or body mass index.

Blood samples were tested using the Ultegra Rapid Platelet Function Assay on a VerifyNow testing device. The Ultegra assay is a turbidimetric-based optical detection system that measures platelet-induced aggregation as an increase in light transmittance. Aspirin nonresponsiveness was defined as an “aspirin reaction unit” value of at least 550. Results showed a mean of 479 aspirin reaction units in patients with a history of heart failure, compared with 458 units in patients without heart failure.

None of the investigators are associated with Accumetrix, the company that makes the VerifyNow device.

Heart failure patients were more likely to have a history of hypertension, coronary artery disease, MI, diabetes, chronic renal insufficiency, and tobacco use than were non-heart failure patients. Those with heart failure had averaged 4 years of aspirin use, compared with 2 years in patients without prior heart failure, she said.

The high rate of aspirin nonres-ponsiveness in heart failure patients may make them susceptible to thrombotic events. DR. DANIELS

SEATTLE — Blood tests on 507 patients seen in emergency departments for chest pain found resistance to aspirin in 20% of those with a history of heart failure and 12% of patients without heart failure, Dr. Lori B. Daniels reported in a poster presentation at the annual meeting of the Heart Failure Society of America.

“Physicians should be aware of the high rate of aspirin nonresponsiveness in patients with heart failure, since they may be susceptible to thrombotic events” even if treated with aspirin, and may need other antithrombotic therapy, said Dr. Daniels of the University of California, San Diego, and her associates.

Aspirin prevents MI, stroke, or other vascular events by causing platelet dysfunction so that platelets do not aggregate. It irreversibly inhibits platelet cyclooxygenase, a key enzyme in prostaglandin synthesis, so that platelets lose the capacity to synthesize thromboxane A2, an inducer of platelet aggregation with vasoconstrictive properties.

Between 8% and 18% of patients treated with aspirin, however, develop recurrent vascular events within 2 years, a phenomenon described as aspirin resistance “or perhaps more accurately as aspirin nonresponsiveness,” the investigators wrote.

They took blood samples from patients with suspected acute coronary syndromes seen at five medical centers. All were on outpatient aspirin therapy or were given an aspirin when they arrived at the emergency department. The 25% of patients with a history of heart failure were older than those without heart failure (62 vs. 58 years) and were more likely to be taking aspirin as an outpatient (81% vs. 60%), but the two groups did not differ by sex or body mass index.

Blood samples were tested using the Ultegra Rapid Platelet Function Assay on a VerifyNow testing device. The Ultegra assay is a turbidimetric-based optical detection system that measures platelet-induced aggregation as an increase in light transmittance. Aspirin nonresponsiveness was defined as an “aspirin reaction unit” value of at least 550. Results showed a mean of 479 aspirin reaction units in patients with a history of heart failure, compared with 458 units in patients without heart failure.

None of the investigators are associated with Accumetrix, the company that makes the VerifyNow device.

Heart failure patients were more likely to have a history of hypertension, coronary artery disease, MI, diabetes, chronic renal insufficiency, and tobacco use than were non-heart failure patients. Those with heart failure had averaged 4 years of aspirin use, compared with 2 years in patients without prior heart failure, she said.

The high rate of aspirin nonres-ponsiveness in heart failure patients may make them susceptible to thrombotic events. DR. DANIELS

SEATTLE — Blood tests on 507 patients seen in emergency departments for chest pain found resistance to aspirin in 20% of those with a history of heart failure and 12% of patients without heart failure, Dr. Lori B. Daniels reported in a poster presentation at the annual meeting of the Heart Failure Society of America.

“Physicians should be aware of the high rate of aspirin nonresponsiveness in patients with heart failure, since they may be susceptible to thrombotic events” even if treated with aspirin, and may need other antithrombotic therapy, said Dr. Daniels of the University of California, San Diego, and her associates.

Aspirin prevents MI, stroke, or other vascular events by causing platelet dysfunction so that platelets do not aggregate. It irreversibly inhibits platelet cyclooxygenase, a key enzyme in prostaglandin synthesis, so that platelets lose the capacity to synthesize thromboxane A2, an inducer of platelet aggregation with vasoconstrictive properties.

Between 8% and 18% of patients treated with aspirin, however, develop recurrent vascular events within 2 years, a phenomenon described as aspirin resistance “or perhaps more accurately as aspirin nonresponsiveness,” the investigators wrote.

They took blood samples from patients with suspected acute coronary syndromes seen at five medical centers. All were on outpatient aspirin therapy or were given an aspirin when they arrived at the emergency department. The 25% of patients with a history of heart failure were older than those without heart failure (62 vs. 58 years) and were more likely to be taking aspirin as an outpatient (81% vs. 60%), but the two groups did not differ by sex or body mass index.

Blood samples were tested using the Ultegra Rapid Platelet Function Assay on a VerifyNow testing device. The Ultegra assay is a turbidimetric-based optical detection system that measures platelet-induced aggregation as an increase in light transmittance. Aspirin nonresponsiveness was defined as an “aspirin reaction unit” value of at least 550. Results showed a mean of 479 aspirin reaction units in patients with a history of heart failure, compared with 458 units in patients without heart failure.

None of the investigators are associated with Accumetrix, the company that makes the VerifyNow device.

Heart failure patients were more likely to have a history of hypertension, coronary artery disease, MI, diabetes, chronic renal insufficiency, and tobacco use than were non-heart failure patients. Those with heart failure had averaged 4 years of aspirin use, compared with 2 years in patients without prior heart failure, she said.

The high rate of aspirin nonres-ponsiveness in heart failure patients may make them susceptible to thrombotic events. DR. DANIELS

SEATTLE — Low-dose aspirin did not reduce the beneficial effects of ACE inhibitors in patients with atrial fibrillation and a history of heart failure, a subset analysis of 2,031 patients found.

The analysis addressed recurring concerns that aspirin use attenuates the effects of ACE inhibitors in heart failure patients and supported the use of both low-dose aspirin and an ACE inhibitor when indications for both treatments exist, Dr. Akshay S. Desai said at the annual meeting of the Heart Failure Society of America.

Dr. Desai and associates studied data from the Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events (ACTIVE-W). The prospective, open-label study randomized patients with atrial fibrillation to combination antiplatelet therapy with clopidogrel and 75–100 mg/day of aspirin or to oral anticoagulation with warfarin. ACTIVE-W was discontinued early because warfarin clearly reduced the risk of MI, vascular events, or death.

Compared with all ACTIVE-W patients, the 2,031 patients with prior heart failure were more likely to be hypertensive or diabetic; have left ventricular dysfunction, a prior MI, or coronary disease; and be on an ACE inhibitor or angiotensin receptor blocker at baseline. Patients with prior heart failure in ACTIVE-W were twice as likely to develop MI, vascular events, or death, as those with no such history.

Notably, however, the relative benefits of antiplatelet or anticoagulant therapy to prevent thromboembolic events did not differ significantly either in ACTIVE-W patients as a whole or in the subset of patients with heart failure, said Dr. Desai of Brigham and Women's Hospital, Boston. The risk of bleeding complications also did not differ between treatment groups.

Looking at the composite end point of death or hospitalization for heart failure, patients with a history of heart failure carried triple the risk, compared with non-heart failure patients, but again there was no significant difference between the antiplatelet and anticoagulant treatment groups.

The investigators stratified patients with heart failure based on whether they did or did not use an ACE inhibitor at baseline, expecting to see a greater relative benefit in the warfarin group if aspirin attenuated the effects of ACE inhibitors. They found no statistically significant differences between the antiplatelet and anticoagulation groups, suggesting no interaction between aspirin and ACE inhibitors.

Some heart failure patients in the warfarin group also were on ACE inhibitors at baseline, which might have limited the power to detect an aspirin-ACE inhibitor interaction, so they repeated the analyses after excluding patients on an ACE inhibitor at baseline who were randomized to warfarin. Again, they found no significant aspirin-ACE inhibitor interaction.

Concerns about such an interaction began with a 1992 hemodynamic study, later confirmed by others, that showed that coadministration of enalapril and aspirin in 18 patients with severe heart failure attenuated some of the hemodynamic effects of ACE inhibitors on vascular resistance. A retrospective analysis of the SOLVD trial suggested that patients on enalapril were more likely to die if they also took aspirin. A similar finding came from a retrospective analysis of the Scandinavian CONSENSUS II study. A large meta-analysis of ACE inhibitor trials, however, found no significant increase in death or hospitalization for heart failure with concurrent use of aspirin, said Dr. Desai, who has no relationships with the companies that make the drugs he discussed.

SEATTLE — Low-dose aspirin did not reduce the beneficial effects of ACE inhibitors in patients with atrial fibrillation and a history of heart failure, a subset analysis of 2,031 patients found.

The analysis addressed recurring concerns that aspirin use attenuates the effects of ACE inhibitors in heart failure patients and supported the use of both low-dose aspirin and an ACE inhibitor when indications for both treatments exist, Dr. Akshay S. Desai said at the annual meeting of the Heart Failure Society of America.

Dr. Desai and associates studied data from the Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events (ACTIVE-W). The prospective, open-label study randomized patients with atrial fibrillation to combination antiplatelet therapy with clopidogrel and 75–100 mg/day of aspirin or to oral anticoagulation with warfarin. ACTIVE-W was discontinued early because warfarin clearly reduced the risk of MI, vascular events, or death.

Compared with all ACTIVE-W patients, the 2,031 patients with prior heart failure were more likely to be hypertensive or diabetic; have left ventricular dysfunction, a prior MI, or coronary disease; and be on an ACE inhibitor or angiotensin receptor blocker at baseline. Patients with prior heart failure in ACTIVE-W were twice as likely to develop MI, vascular events, or death, as those with no such history.

Notably, however, the relative benefits of antiplatelet or anticoagulant therapy to prevent thromboembolic events did not differ significantly either in ACTIVE-W patients as a whole or in the subset of patients with heart failure, said Dr. Desai of Brigham and Women's Hospital, Boston. The risk of bleeding complications also did not differ between treatment groups.

Looking at the composite end point of death or hospitalization for heart failure, patients with a history of heart failure carried triple the risk, compared with non-heart failure patients, but again there was no significant difference between the antiplatelet and anticoagulant treatment groups.

The investigators stratified patients with heart failure based on whether they did or did not use an ACE inhibitor at baseline, expecting to see a greater relative benefit in the warfarin group if aspirin attenuated the effects of ACE inhibitors. They found no statistically significant differences between the antiplatelet and anticoagulation groups, suggesting no interaction between aspirin and ACE inhibitors.

Some heart failure patients in the warfarin group also were on ACE inhibitors at baseline, which might have limited the power to detect an aspirin-ACE inhibitor interaction, so they repeated the analyses after excluding patients on an ACE inhibitor at baseline who were randomized to warfarin. Again, they found no significant aspirin-ACE inhibitor interaction.

Concerns about such an interaction began with a 1992 hemodynamic study, later confirmed by others, that showed that coadministration of enalapril and aspirin in 18 patients with severe heart failure attenuated some of the hemodynamic effects of ACE inhibitors on vascular resistance. A retrospective analysis of the SOLVD trial suggested that patients on enalapril were more likely to die if they also took aspirin. A similar finding came from a retrospective analysis of the Scandinavian CONSENSUS II study. A large meta-analysis of ACE inhibitor trials, however, found no significant increase in death or hospitalization for heart failure with concurrent use of aspirin, said Dr. Desai, who has no relationships with the companies that make the drugs he discussed.

SEATTLE — Low-dose aspirin did not reduce the beneficial effects of ACE inhibitors in patients with atrial fibrillation and a history of heart failure, a subset analysis of 2,031 patients found.

The analysis addressed recurring concerns that aspirin use attenuates the effects of ACE inhibitors in heart failure patients and supported the use of both low-dose aspirin and an ACE inhibitor when indications for both treatments exist, Dr. Akshay S. Desai said at the annual meeting of the Heart Failure Society of America.

Dr. Desai and associates studied data from the Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events (ACTIVE-W). The prospective, open-label study randomized patients with atrial fibrillation to combination antiplatelet therapy with clopidogrel and 75–100 mg/day of aspirin or to oral anticoagulation with warfarin. ACTIVE-W was discontinued early because warfarin clearly reduced the risk of MI, vascular events, or death.

Compared with all ACTIVE-W patients, the 2,031 patients with prior heart failure were more likely to be hypertensive or diabetic; have left ventricular dysfunction, a prior MI, or coronary disease; and be on an ACE inhibitor or angiotensin receptor blocker at baseline. Patients with prior heart failure in ACTIVE-W were twice as likely to develop MI, vascular events, or death, as those with no such history.

Notably, however, the relative benefits of antiplatelet or anticoagulant therapy to prevent thromboembolic events did not differ significantly either in ACTIVE-W patients as a whole or in the subset of patients with heart failure, said Dr. Desai of Brigham and Women's Hospital, Boston. The risk of bleeding complications also did not differ between treatment groups.

Looking at the composite end point of death or hospitalization for heart failure, patients with a history of heart failure carried triple the risk, compared with non-heart failure patients, but again there was no significant difference between the antiplatelet and anticoagulant treatment groups.

The investigators stratified patients with heart failure based on whether they did or did not use an ACE inhibitor at baseline, expecting to see a greater relative benefit in the warfarin group if aspirin attenuated the effects of ACE inhibitors. They found no statistically significant differences between the antiplatelet and anticoagulation groups, suggesting no interaction between aspirin and ACE inhibitors.

Some heart failure patients in the warfarin group also were on ACE inhibitors at baseline, which might have limited the power to detect an aspirin-ACE inhibitor interaction, so they repeated the analyses after excluding patients on an ACE inhibitor at baseline who were randomized to warfarin. Again, they found no significant aspirin-ACE inhibitor interaction.

Concerns about such an interaction began with a 1992 hemodynamic study, later confirmed by others, that showed that coadministration of enalapril and aspirin in 18 patients with severe heart failure attenuated some of the hemodynamic effects of ACE inhibitors on vascular resistance. A retrospective analysis of the SOLVD trial suggested that patients on enalapril were more likely to die if they also took aspirin. A similar finding came from a retrospective analysis of the Scandinavian CONSENSUS II study. A large meta-analysis of ACE inhibitor trials, however, found no significant increase in death or hospitalization for heart failure with concurrent use of aspirin, said Dr. Desai, who has no relationships with the companies that make the drugs he discussed.

SAN FRANCISCO — Patients with end-stage heart failure who received cardiac injections of autologous endothelial progenitor cells showed significant improvements in function and ejection fraction 3 months later, Dr. Kitipan V. Arom reported.

The stem cell therapy treated 32 patients with ischemic cardiomyopathy and 21 with nonischemic dilated cardiomyopathy. Forty-three patients received the cell injections alone, eight underwent coronary artery bypass grafting with the cell injections, and two had a redo CABG with the cell injections, he said at the annual meeting of the International Society for Minimally Invasive Cardiothoracic Surgery.

One patient died 3 days after treatment, most likely from pulmonary emboli. The rest of the patients improved their New York Heart Association functional class from an average of class III to less than class II, said Dr. Arom of Bangkok Heart Hospital, Thailand, and associates.

The NYHA class improved in patients with ischemic cardiomyopathy from an average of 2.7 before cell injections to 1.4 at the 3-month follow-up. In the dilated cardiomyopathy group, the average improved from class III before treatment to II at the 3-month follow-up. Preoperative left ventricular ejection fractions averaged 26% in the ischemic cardiomyopathy group and 23% in the dilated cardiomyopathy group. Cell injection therapy improved ejection fractions significantly by an absolute 10% and 11%, respectively, he said.

Perfusion defects were seen in 19 patients before treatment and 11 patients at follow-up. Patients were able to walk farther in the 6-minute walk test after treatment, and scores on quality-of-life measures improved. Improvements in regional wall motion after therapy could be seen on cardiac MRI and four-chamber echocardiography.

The results are short term, and no one yet has data on outcomes longer than 2 years after stem cell transplants, Dr. Arom noted. So far, however, results are encouraging. “Hopefully, some time in the future, cell therapy can replace heart transplantation for end-stage heart failure,” he said.

Stem cells can come from many sources; this study used peripheral blood, which has the capacity to self-renew and differentiate into one or more cell types, Dr. Arom said. A week before surgery, patients donated 250 cc of blood that was sent for cell separation and growing. The stem cells produced were returned in 15-cc vials, each containing 1.5 million cells. All patients underwent cardiac MRI, echocardiography, and coronary angiography to help plan the injections.

In the dilated cardiomyopathy group, surgeons made 30 injections into multiple areas of the left ventricular wall using 0.5 cc per injection. Patients with ischemic cardiomyopathy received injections directly into the scar area and surrounding tissue.

The treatment was the last hope for these patients, who were much sicker than the average patient undergoing CABG is, he said. They had run the course of medical and surgical therapies. They suffered from mitral or tricuspid regurgitation, renal insufficiency, or other problems, and had been turned down for redo CABGs, valve replacements, or other surgeries.

The use of autologous progenitor cells avoids rejection concerns, and so far, there has been no evidence with these cells of the arrhythmogenic side effects seen with bone marrow cell transplant, he said.

SAN FRANCISCO — Patients with end-stage heart failure who received cardiac injections of autologous endothelial progenitor cells showed significant improvements in function and ejection fraction 3 months later, Dr. Kitipan V. Arom reported.

The stem cell therapy treated 32 patients with ischemic cardiomyopathy and 21 with nonischemic dilated cardiomyopathy. Forty-three patients received the cell injections alone, eight underwent coronary artery bypass grafting with the cell injections, and two had a redo CABG with the cell injections, he said at the annual meeting of the International Society for Minimally Invasive Cardiothoracic Surgery.

One patient died 3 days after treatment, most likely from pulmonary emboli. The rest of the patients improved their New York Heart Association functional class from an average of class III to less than class II, said Dr. Arom of Bangkok Heart Hospital, Thailand, and associates.

The NYHA class improved in patients with ischemic cardiomyopathy from an average of 2.7 before cell injections to 1.4 at the 3-month follow-up. In the dilated cardiomyopathy group, the average improved from class III before treatment to II at the 3-month follow-up. Preoperative left ventricular ejection fractions averaged 26% in the ischemic cardiomyopathy group and 23% in the dilated cardiomyopathy group. Cell injection therapy improved ejection fractions significantly by an absolute 10% and 11%, respectively, he said.

Perfusion defects were seen in 19 patients before treatment and 11 patients at follow-up. Patients were able to walk farther in the 6-minute walk test after treatment, and scores on quality-of-life measures improved. Improvements in regional wall motion after therapy could be seen on cardiac MRI and four-chamber echocardiography.

The results are short term, and no one yet has data on outcomes longer than 2 years after stem cell transplants, Dr. Arom noted. So far, however, results are encouraging. “Hopefully, some time in the future, cell therapy can replace heart transplantation for end-stage heart failure,” he said.

Stem cells can come from many sources; this study used peripheral blood, which has the capacity to self-renew and differentiate into one or more cell types, Dr. Arom said. A week before surgery, patients donated 250 cc of blood that was sent for cell separation and growing. The stem cells produced were returned in 15-cc vials, each containing 1.5 million cells. All patients underwent cardiac MRI, echocardiography, and coronary angiography to help plan the injections.

In the dilated cardiomyopathy group, surgeons made 30 injections into multiple areas of the left ventricular wall using 0.5 cc per injection. Patients with ischemic cardiomyopathy received injections directly into the scar area and surrounding tissue.

The treatment was the last hope for these patients, who were much sicker than the average patient undergoing CABG is, he said. They had run the course of medical and surgical therapies. They suffered from mitral or tricuspid regurgitation, renal insufficiency, or other problems, and had been turned down for redo CABGs, valve replacements, or other surgeries.

The use of autologous progenitor cells avoids rejection concerns, and so far, there has been no evidence with these cells of the arrhythmogenic side effects seen with bone marrow cell transplant, he said.

SAN FRANCISCO — Patients with end-stage heart failure who received cardiac injections of autologous endothelial progenitor cells showed significant improvements in function and ejection fraction 3 months later, Dr. Kitipan V. Arom reported.

The stem cell therapy treated 32 patients with ischemic cardiomyopathy and 21 with nonischemic dilated cardiomyopathy. Forty-three patients received the cell injections alone, eight underwent coronary artery bypass grafting with the cell injections, and two had a redo CABG with the cell injections, he said at the annual meeting of the International Society for Minimally Invasive Cardiothoracic Surgery.

One patient died 3 days after treatment, most likely from pulmonary emboli. The rest of the patients improved their New York Heart Association functional class from an average of class III to less than class II, said Dr. Arom of Bangkok Heart Hospital, Thailand, and associates.

The NYHA class improved in patients with ischemic cardiomyopathy from an average of 2.7 before cell injections to 1.4 at the 3-month follow-up. In the dilated cardiomyopathy group, the average improved from class III before treatment to II at the 3-month follow-up. Preoperative left ventricular ejection fractions averaged 26% in the ischemic cardiomyopathy group and 23% in the dilated cardiomyopathy group. Cell injection therapy improved ejection fractions significantly by an absolute 10% and 11%, respectively, he said.

Perfusion defects were seen in 19 patients before treatment and 11 patients at follow-up. Patients were able to walk farther in the 6-minute walk test after treatment, and scores on quality-of-life measures improved. Improvements in regional wall motion after therapy could be seen on cardiac MRI and four-chamber echocardiography.

The results are short term, and no one yet has data on outcomes longer than 2 years after stem cell transplants, Dr. Arom noted. So far, however, results are encouraging. “Hopefully, some time in the future, cell therapy can replace heart transplantation for end-stage heart failure,” he said.

Stem cells can come from many sources; this study used peripheral blood, which has the capacity to self-renew and differentiate into one or more cell types, Dr. Arom said. A week before surgery, patients donated 250 cc of blood that was sent for cell separation and growing. The stem cells produced were returned in 15-cc vials, each containing 1.5 million cells. All patients underwent cardiac MRI, echocardiography, and coronary angiography to help plan the injections.

In the dilated cardiomyopathy group, surgeons made 30 injections into multiple areas of the left ventricular wall using 0.5 cc per injection. Patients with ischemic cardiomyopathy received injections directly into the scar area and surrounding tissue.

The treatment was the last hope for these patients, who were much sicker than the average patient undergoing CABG is, he said. They had run the course of medical and surgical therapies. They suffered from mitral or tricuspid regurgitation, renal insufficiency, or other problems, and had been turned down for redo CABGs, valve replacements, or other surgeries.

The use of autologous progenitor cells avoids rejection concerns, and so far, there has been no evidence with these cells of the arrhythmogenic side effects seen with bone marrow cell transplant, he said.

The discovery of a common polymorphism in the gene for β₁-adrenergic-receptor blocker that predicts response to the β-blocker bucindolol has resurrected interest in the discarded drug.

Bucindolol could be the first genetically targeted cardiovascular drug, said Dr. Michael Bristow, codirector of the Cardiovascular Institute at the University of Colorado. His company, ARCA Discovery Inc. of Denver, intends to file a new drug and diagnostic test application with the Food and Drug Administration. If approved, the drug would be marketed along with a genetic test to identify potential responders.

Subjects with heart failure who were homozygous for the arginine variant of the β₁ AR-389 gene (Arg-389 variant) and who took bucindolol had a 38% reduction in mortality, compared with such patients who were treated with placebo, Dr. Bristow and his colleagues have reported. They also had a 34% reduction in the combined end point of hospitalizations and mortality (PNAS 2006;doi/10.1073/pnas.0509937103).

“This is where the field of pharmacogenetic therapy needs to go in cardiovascular medicine,” Dr. Bristow said in an interview. “Developing therapies that are specifically effective on pharmacogenetic subsets, so patients unlikely to respond to therapy aren't exposed to the risks and costs of treatment.”

The drug could be especially important for blacks, who are twice as likely as whites to develop heart failure, but who also have a poorer response to drugs, he said. The DNA test would target blacks who could benefit from bucindolol. “We wouldn't have to rely on skin color to assign therapy. We could assign therapy based on much better criteria: biology as predicted by a genetic profile.”

The bucindolol study is an exciting one, said Dr. Sidney Goldstein, head, emeritus, of the division of cardiovascular medicine at Henry Ford Hospital in Detroit. “Previous studies trying to link genotypes to β-blocker efficacy have shown some association. This study, which is the largest randomized population that has been looked at, certainly lends further credibility to the thought.”

But it will take more than one DNA study to bring bucindolol to market, he predicted. “It's very intriguing, but in order to get approval we'd need a lot more clinical evidence in this particular population,” said Dr. Goldstein, medical editor of CARDIOLOGY NEWS.

Mainstream research abandoned bucindolol in 1999, when the Beta-Blocker Evaluation of Survival Time study (BEST) was halted for ethical reasons. After a median of 2 years, bucindolol offered no significant survival advantage over placebo, while other β-blockers had long been confirmed as beneficial.

But as the study was further analyzed, substudies using its database emerged, including one using DNA collected from 1,040 BEST subjects. In 1998, Dr. Steve Liggett, BEST's lead investigator, identified several genetic variants of the β₁-adrenergic receptor—the target of β-blocker therapy. In a DNA substudy submitted before BEST ended, Dr. Liggett and Dr. Bristow hypothesized that the Arg-389 variant would predict bucindolol response.

Dr. Bristow and his colleagues reexamined the BEST response data, stratifying survival of placebo and bucindolol-treated patients according to genetic type. Only homozygous Arg-389 variant patients treated with bucindolol showed a significant survival advantage: a hazard ratio of 0.62 for mortality, compared with Arg-389 variant placebo-treated patients.

The polymorphism occurred more frequently in whites than in blacks (51% vs. 35%), Dr. Bristow said—an intriguing finding that probably speaks to bucindolol's better performance among whites in the original BEST study (N. Engl. J. Med. 2001;344:1659–67). “We need more research on this point, but it may be possible that this genetic variant has a great deal to do with why black patients have more heart failure, and worse outcomes, than white patients.”

Bucindolol has a unique pharmacologic profile among β-blockers, not only blocking adrenergic receptors but lowering norepinephrine as well. “It appears that those with the Arg/Arg polymorphism can tolerate the loss of norepinephrine signalling better than those who don't have it,” Dr. Bristow said. “In them, the combination of actions produces a supertherapeutic response.”

It's impossible to extrapolate bucindolol's positive effect on patients with the arginine variant to any other β-blocker, however. One study has already addressed this issue, finding no association between β₁-AR genetic subtype and survival in patients taking metoprolol (Eur. J. Heart Fail. 2003;5:463–78). There are no data available on carvedilol or bisoprolol.

If bucindolol and its accompanying genetic screen are eventually approved, physicians and patients will have to decide if the additional time and expense of genetic testing will be worth the drug's benefit, Dr. Goldstein said. “Metoprolol and carvedilol will probably both be coming out in generic forms pretty quickly. In all probability they will be substantially less expensive than bucindolol, and it's hard to believe bucindolol would be better than those drugs, although it does appear to be just as good for these particular patients.”

The discovery of a common polymorphism in the gene for β₁-adrenergic-receptor blocker that predicts response to the β-blocker bucindolol has resurrected interest in the discarded drug.

Bucindolol could be the first genetically targeted cardiovascular drug, said Dr. Michael Bristow, codirector of the Cardiovascular Institute at the University of Colorado. His company, ARCA Discovery Inc. of Denver, intends to file a new drug and diagnostic test application with the Food and Drug Administration. If approved, the drug would be marketed along with a genetic test to identify potential responders.

Subjects with heart failure who were homozygous for the arginine variant of the β₁ AR-389 gene (Arg-389 variant) and who took bucindolol had a 38% reduction in mortality, compared with such patients who were treated with placebo, Dr. Bristow and his colleagues have reported. They also had a 34% reduction in the combined end point of hospitalizations and mortality (PNAS 2006;doi/10.1073/pnas.0509937103).

“This is where the field of pharmacogenetic therapy needs to go in cardiovascular medicine,” Dr. Bristow said in an interview. “Developing therapies that are specifically effective on pharmacogenetic subsets, so patients unlikely to respond to therapy aren't exposed to the risks and costs of treatment.”

The drug could be especially important for blacks, who are twice as likely as whites to develop heart failure, but who also have a poorer response to drugs, he said. The DNA test would target blacks who could benefit from bucindolol. “We wouldn't have to rely on skin color to assign therapy. We could assign therapy based on much better criteria: biology as predicted by a genetic profile.”

The bucindolol study is an exciting one, said Dr. Sidney Goldstein, head, emeritus, of the division of cardiovascular medicine at Henry Ford Hospital in Detroit. “Previous studies trying to link genotypes to β-blocker efficacy have shown some association. This study, which is the largest randomized population that has been looked at, certainly lends further credibility to the thought.”

But it will take more than one DNA study to bring bucindolol to market, he predicted. “It's very intriguing, but in order to get approval we'd need a lot more clinical evidence in this particular population,” said Dr. Goldstein, medical editor of CARDIOLOGY NEWS.

Mainstream research abandoned bucindolol in 1999, when the Beta-Blocker Evaluation of Survival Time study (BEST) was halted for ethical reasons. After a median of 2 years, bucindolol offered no significant survival advantage over placebo, while other β-blockers had long been confirmed as beneficial.

But as the study was further analyzed, substudies using its database emerged, including one using DNA collected from 1,040 BEST subjects. In 1998, Dr. Steve Liggett, BEST's lead investigator, identified several genetic variants of the β₁-adrenergic receptor—the target of β-blocker therapy. In a DNA substudy submitted before BEST ended, Dr. Liggett and Dr. Bristow hypothesized that the Arg-389 variant would predict bucindolol response.

Dr. Bristow and his colleagues reexamined the BEST response data, stratifying survival of placebo and bucindolol-treated patients according to genetic type. Only homozygous Arg-389 variant patients treated with bucindolol showed a significant survival advantage: a hazard ratio of 0.62 for mortality, compared with Arg-389 variant placebo-treated patients.

The polymorphism occurred more frequently in whites than in blacks (51% vs. 35%), Dr. Bristow said—an intriguing finding that probably speaks to bucindolol's better performance among whites in the original BEST study (N. Engl. J. Med. 2001;344:1659–67). “We need more research on this point, but it may be possible that this genetic variant has a great deal to do with why black patients have more heart failure, and worse outcomes, than white patients.”

Bucindolol has a unique pharmacologic profile among β-blockers, not only blocking adrenergic receptors but lowering norepinephrine as well. “It appears that those with the Arg/Arg polymorphism can tolerate the loss of norepinephrine signalling better than those who don't have it,” Dr. Bristow said. “In them, the combination of actions produces a supertherapeutic response.”

It's impossible to extrapolate bucindolol's positive effect on patients with the arginine variant to any other β-blocker, however. One study has already addressed this issue, finding no association between β₁-AR genetic subtype and survival in patients taking metoprolol (Eur. J. Heart Fail. 2003;5:463–78). There are no data available on carvedilol or bisoprolol.

If bucindolol and its accompanying genetic screen are eventually approved, physicians and patients will have to decide if the additional time and expense of genetic testing will be worth the drug's benefit, Dr. Goldstein said. “Metoprolol and carvedilol will probably both be coming out in generic forms pretty quickly. In all probability they will be substantially less expensive than bucindolol, and it's hard to believe bucindolol would be better than those drugs, although it does appear to be just as good for these particular patients.”

The discovery of a common polymorphism in the gene for β₁-adrenergic-receptor blocker that predicts response to the β-blocker bucindolol has resurrected interest in the discarded drug.

Bucindolol could be the first genetically targeted cardiovascular drug, said Dr. Michael Bristow, codirector of the Cardiovascular Institute at the University of Colorado. His company, ARCA Discovery Inc. of Denver, intends to file a new drug and diagnostic test application with the Food and Drug Administration. If approved, the drug would be marketed along with a genetic test to identify potential responders.

Subjects with heart failure who were homozygous for the arginine variant of the β₁ AR-389 gene (Arg-389 variant) and who took bucindolol had a 38% reduction in mortality, compared with such patients who were treated with placebo, Dr. Bristow and his colleagues have reported. They also had a 34% reduction in the combined end point of hospitalizations and mortality (PNAS 2006;doi/10.1073/pnas.0509937103).

“This is where the field of pharmacogenetic therapy needs to go in cardiovascular medicine,” Dr. Bristow said in an interview. “Developing therapies that are specifically effective on pharmacogenetic subsets, so patients unlikely to respond to therapy aren't exposed to the risks and costs of treatment.”

The drug could be especially important for blacks, who are twice as likely as whites to develop heart failure, but who also have a poorer response to drugs, he said. The DNA test would target blacks who could benefit from bucindolol. “We wouldn't have to rely on skin color to assign therapy. We could assign therapy based on much better criteria: biology as predicted by a genetic profile.”

The bucindolol study is an exciting one, said Dr. Sidney Goldstein, head, emeritus, of the division of cardiovascular medicine at Henry Ford Hospital in Detroit. “Previous studies trying to link genotypes to β-blocker efficacy have shown some association. This study, which is the largest randomized population that has been looked at, certainly lends further credibility to the thought.”

But it will take more than one DNA study to bring bucindolol to market, he predicted. “It's very intriguing, but in order to get approval we'd need a lot more clinical evidence in this particular population,” said Dr. Goldstein, medical editor of CARDIOLOGY NEWS.

Mainstream research abandoned bucindolol in 1999, when the Beta-Blocker Evaluation of Survival Time study (BEST) was halted for ethical reasons. After a median of 2 years, bucindolol offered no significant survival advantage over placebo, while other β-blockers had long been confirmed as beneficial.

But as the study was further analyzed, substudies using its database emerged, including one using DNA collected from 1,040 BEST subjects. In 1998, Dr. Steve Liggett, BEST's lead investigator, identified several genetic variants of the β₁-adrenergic receptor—the target of β-blocker therapy. In a DNA substudy submitted before BEST ended, Dr. Liggett and Dr. Bristow hypothesized that the Arg-389 variant would predict bucindolol response.

Dr. Bristow and his colleagues reexamined the BEST response data, stratifying survival of placebo and bucindolol-treated patients according to genetic type. Only homozygous Arg-389 variant patients treated with bucindolol showed a significant survival advantage: a hazard ratio of 0.62 for mortality, compared with Arg-389 variant placebo-treated patients.

The polymorphism occurred more frequently in whites than in blacks (51% vs. 35%), Dr. Bristow said—an intriguing finding that probably speaks to bucindolol's better performance among whites in the original BEST study (N. Engl. J. Med. 2001;344:1659–67). “We need more research on this point, but it may be possible that this genetic variant has a great deal to do with why black patients have more heart failure, and worse outcomes, than white patients.”

Bucindolol has a unique pharmacologic profile among β-blockers, not only blocking adrenergic receptors but lowering norepinephrine as well. “It appears that those with the Arg/Arg polymorphism can tolerate the loss of norepinephrine signalling better than those who don't have it,” Dr. Bristow said. “In them, the combination of actions produces a supertherapeutic response.”

It's impossible to extrapolate bucindolol's positive effect on patients with the arginine variant to any other β-blocker, however. One study has already addressed this issue, finding no association between β₁-AR genetic subtype and survival in patients taking metoprolol (Eur. J. Heart Fail. 2003;5:463–78). There are no data available on carvedilol or bisoprolol.

If bucindolol and its accompanying genetic screen are eventually approved, physicians and patients will have to decide if the additional time and expense of genetic testing will be worth the drug's benefit, Dr. Goldstein said. “Metoprolol and carvedilol will probably both be coming out in generic forms pretty quickly. In all probability they will be substantially less expensive than bucindolol, and it's hard to believe bucindolol would be better than those drugs, although it does appear to be just as good for these particular patients.”

ATLANTA — Carvedilol proved no better than placebo in the first-ever randomized trial of any therapy for chronic heart failure in children, Dr. Robert E. Shaddy said at the annual meeting of the American College of Cardiology.

Until now, treatment of pediatric heart failure has been based largely on the findings of the landmark heart failure trials in adults, with anecdotal best-guess extrapolation in regard to dosing in children. β-Blocker therapy is standard in adult heart failure. But the results of this first multicenter study emphasize that heart failure in children and adults are in some ways very different conditions, added Dr. Shaddy, professor of pediatric cardiology at the University of Utah, Salt Lake City.

He reported on 161 children with symptomatic systolic heart failure who participated in a 26-center double-blind trial in which they were randomized to one of the following regimens: twice-daily placebo, carvedilol at 0.2 mg/kg b.i.d. to a maximum of 12.5 mg per dose in children weighing more than 62.5 kg, or carvedilol at 0.4 mg/kg b.i.d. to a maximum of 25 mg per dose.

The participants had dilated cardiomyopathy or congenital heart disease. Their median age was 3 years, with a range of 3 months to 17 years. All were on an ACE inhibitor unless they were intolerant. Of the total, 71% had New York Heart Association class II heart failure and 27% had class III disease at baseline, with a median left ventricular ejection fraction of 26%.

The primary study end point was heart failure outcome at 8 months as defined by a composite including death, cardiovascular hospitalization, and change in NYHA class, Ross classification of heart failure, and/or physician global assessment score. The results proved similar in the placebo and combined carvedilol groups because of an unexpectedly robust improvement in the placebo group. (See box.)

In hindsight, this might have been predicted because many think that spontaneous improvement is more frequent in younger children with heart failure—and 45% of the trial participants in this trial were younger than 2 years.

A prespecified secondary analysis showed differential results for β-blocker therapy based on ventricular anatomy. In patients with a systemic left ventricle, the rate of improvement was 51% with placebo and 64% with carvedilol. By contrast, the 41 patients with a systemic ventricle other than the left ventricle had a 64% rate of improvement with placebo, compared with 35% with carvedilol.

But it would be difficult to pursue this finding through further controlled trials restricted to children with a systemic left ventricle. Many parents, physicians, and institutional review boards have reservations about randomizing children with heart failure to placebo, said Dr. Shaddy, who is a consultant to GlaxoSmithKline, which sponsored the trial.

Discussant Dr. JoAnn Lindenfeld said that although this was a negative study, she was impressed with the trends for reduction in the objective end points of death and cardiovascular hospitalization with carvedilol, even though the trends didn't reach statistical significance. Dr. Lindenfeld is professor of medicine at the University of Colorado, Denver.

ELSEVIER GLOBAL MEDICAL NEWS

ATLANTA — Carvedilol proved no better than placebo in the first-ever randomized trial of any therapy for chronic heart failure in children, Dr. Robert E. Shaddy said at the annual meeting of the American College of Cardiology.

Until now, treatment of pediatric heart failure has been based largely on the findings of the landmark heart failure trials in adults, with anecdotal best-guess extrapolation in regard to dosing in children. β-Blocker therapy is standard in adult heart failure. But the results of this first multicenter study emphasize that heart failure in children and adults are in some ways very different conditions, added Dr. Shaddy, professor of pediatric cardiology at the University of Utah, Salt Lake City.

He reported on 161 children with symptomatic systolic heart failure who participated in a 26-center double-blind trial in which they were randomized to one of the following regimens: twice-daily placebo, carvedilol at 0.2 mg/kg b.i.d. to a maximum of 12.5 mg per dose in children weighing more than 62.5 kg, or carvedilol at 0.4 mg/kg b.i.d. to a maximum of 25 mg per dose.

The participants had dilated cardiomyopathy or congenital heart disease. Their median age was 3 years, with a range of 3 months to 17 years. All were on an ACE inhibitor unless they were intolerant. Of the total, 71% had New York Heart Association class II heart failure and 27% had class III disease at baseline, with a median left ventricular ejection fraction of 26%.

The primary study end point was heart failure outcome at 8 months as defined by a composite including death, cardiovascular hospitalization, and change in NYHA class, Ross classification of heart failure, and/or physician global assessment score. The results proved similar in the placebo and combined carvedilol groups because of an unexpectedly robust improvement in the placebo group. (See box.)

In hindsight, this might have been predicted because many think that spontaneous improvement is more frequent in younger children with heart failure—and 45% of the trial participants in this trial were younger than 2 years.

A prespecified secondary analysis showed differential results for β-blocker therapy based on ventricular anatomy. In patients with a systemic left ventricle, the rate of improvement was 51% with placebo and 64% with carvedilol. By contrast, the 41 patients with a systemic ventricle other than the left ventricle had a 64% rate of improvement with placebo, compared with 35% with carvedilol.

But it would be difficult to pursue this finding through further controlled trials restricted to children with a systemic left ventricle. Many parents, physicians, and institutional review boards have reservations about randomizing children with heart failure to placebo, said Dr. Shaddy, who is a consultant to GlaxoSmithKline, which sponsored the trial.

Discussant Dr. JoAnn Lindenfeld said that although this was a negative study, she was impressed with the trends for reduction in the objective end points of death and cardiovascular hospitalization with carvedilol, even though the trends didn't reach statistical significance. Dr. Lindenfeld is professor of medicine at the University of Colorado, Denver.

ELSEVIER GLOBAL MEDICAL NEWS

ATLANTA — Carvedilol proved no better than placebo in the first-ever randomized trial of any therapy for chronic heart failure in children, Dr. Robert E. Shaddy said at the annual meeting of the American College of Cardiology.

Until now, treatment of pediatric heart failure has been based largely on the findings of the landmark heart failure trials in adults, with anecdotal best-guess extrapolation in regard to dosing in children. β-Blocker therapy is standard in adult heart failure. But the results of this first multicenter study emphasize that heart failure in children and adults are in some ways very different conditions, added Dr. Shaddy, professor of pediatric cardiology at the University of Utah, Salt Lake City.

He reported on 161 children with symptomatic systolic heart failure who participated in a 26-center double-blind trial in which they were randomized to one of the following regimens: twice-daily placebo, carvedilol at 0.2 mg/kg b.i.d. to a maximum of 12.5 mg per dose in children weighing more than 62.5 kg, or carvedilol at 0.4 mg/kg b.i.d. to a maximum of 25 mg per dose.

The participants had dilated cardiomyopathy or congenital heart disease. Their median age was 3 years, with a range of 3 months to 17 years. All were on an ACE inhibitor unless they were intolerant. Of the total, 71% had New York Heart Association class II heart failure and 27% had class III disease at baseline, with a median left ventricular ejection fraction of 26%.

The primary study end point was heart failure outcome at 8 months as defined by a composite including death, cardiovascular hospitalization, and change in NYHA class, Ross classification of heart failure, and/or physician global assessment score. The results proved similar in the placebo and combined carvedilol groups because of an unexpectedly robust improvement in the placebo group. (See box.)

In hindsight, this might have been predicted because many think that spontaneous improvement is more frequent in younger children with heart failure—and 45% of the trial participants in this trial were younger than 2 years.

A prespecified secondary analysis showed differential results for β-blocker therapy based on ventricular anatomy. In patients with a systemic left ventricle, the rate of improvement was 51% with placebo and 64% with carvedilol. By contrast, the 41 patients with a systemic ventricle other than the left ventricle had a 64% rate of improvement with placebo, compared with 35% with carvedilol.

But it would be difficult to pursue this finding through further controlled trials restricted to children with a systemic left ventricle. Many parents, physicians, and institutional review boards have reservations about randomizing children with heart failure to placebo, said Dr. Shaddy, who is a consultant to GlaxoSmithKline, which sponsored the trial.

Discussant Dr. JoAnn Lindenfeld said that although this was a negative study, she was impressed with the trends for reduction in the objective end points of death and cardiovascular hospitalization with carvedilol, even though the trends didn't reach statistical significance. Dr. Lindenfeld is professor of medicine at the University of Colorado, Denver.

ELSEVIER GLOBAL MEDICAL NEWS

MADRID — Patients with acute decompensated heart failure who were treated with nesiritide had an in-hospital mortality rate that appeared to be no worse than that of patients who were treated intravenously with either nitroglycerin or a diuretic, according to data from a registry with more than 100,000 patients.

The findings “warrant prospective confirmation of the mortality risk associated with different therapies for acute decompensated heart failure,” Dr. Maria Rosa Costanzo said at the annual meeting of the International Society for Heart and Lung Transplantation.

“We did not find any signal of increased [in-hospital] mortality in patients treated with either nesiritide or nitroglycerin,” said Dr. Costanzo in an interview. The results of her analysis “confirm the appropriateness of nesiritide treatment in patients for whom it's approved,” specifically single-dose treatment of patients with acute decompensated heart failure and symptoms that lead to hospitalization for heart failure, said Dr. Costanzo, medical director of the Edward Hospital Center for Advanced Heart Failure in Naperville, Ill.

Nesiritide's safety for treating patients with heart failure has been under a cloud since a pair of metaanalyses were published last year that suggested that patients who were treated with a single dose of the drug had an excess rate of worsening renal function and death during the subsequent 30 days.

At least one expert who reviewed the new report found limited reassurance in the findings. “The analyses appear to be well done, and they provide some comfort about the short-term safety of nesiritide,” said Dr. Barry M. Massie in an interview. But the results “are not very helpful because they were only able to examine the in-hospital phase,” and there was no information on renal function or length of hospital stay. The results from other studies with nesiritide have indicated that the excess of worsening renal failure occurred primarily after 7 days, and the trends toward increased mortality were most apparent after 30 days, said Dr. Massie, professor of medicine at the University of California, San Francisco, and chief of cardiology at the San Francisco Veterans Affairs Medical Center.

The new analysis used data from the Acute Decompensated Heart Failure National Registry (ADHERE), which collected data from more than 180,000 patients who were hospitalized at any of 263 participating hospitals in the United States during October 2001 to March 2006, when the registry closed. The analysis by Dr. Costanzo and her associates used data collected from nearly 135,000 patients who were enrolled through August 2004.

The ADHERE registry was sponsored by Scios Inc., the division of Johnson & Johnson that markets nesiritide (Natrecor). Dr. Costanzo serves on the scientific advisory board of Scios.

The analysis excluded about 35,000 patients from the registry who turned out not to have heart failure, had a delayed diagnosis, or had complicating conditions such as a respiratory infection or MI.

Data collected on the remaining 99,963 patients were further refined using two analytic tools aimed at simulating a prospective, controlled study.

The first tool categorized patients by their “intended primary treatment (IPT),” a method used to “simulate an intention-to-treat analysis,” said Dr. Costanzo in an interview. The IPT was whichever drug or drugs a patient received during the first 2 hours of treatment. By this criterion, the vast majority of patients, more than 74,000, received an intravenous diuretic alone as their IPT. Monotherapy with nesiritide as the IPT occurred in 1,855 patients, intravenous nitroglycerin monotherapy was the IPT in 1,590 patients, and 2,465 patients received an inotrope (dobutamine, dopamine, or milrinone) as monotherapy IPT. The remaining patients received at least two drugs during their first 2 hours of treatment.

Comparisons of the IPT groups were then made using a propensity analysis, a method that matches patients from two unrandomized groups by a variety of demographic and clinical characteristics. In this case, the propensity analysis used more than 55 variables, said Dr. Costanzo. Patients who could not be matched with patients from the comparator group were excluded from the analysis.

“The problem with observational data sets is that most physician-determined interventions are not random and reflect something about the judgment of risk and therefore are confounded by the resulting biases. Propensity-score matching is the favored approach to deal with confounding but is limited by only being able to deal with measured variables,” commented Dr. Massie.

The two main analyses that Dr. Costanzo presented compared the in-hospital mortality rates of patients treated with nesiritide or a diuretic, and those of patients treated with nitroglycerin or a diuretic.

In the first comparison, the mortality rate was 3.6% among 1,701 patients treated with nesiritide and 4.8% among 8,505 patients treated with a diuretic, a statistically significant difference. In the second comparison, in-hospital mortality occurred in 2.7% of 1,488 patients treated with nitroglycerin compared with a 3.0% mortality rate among 7,440 patients treated with a diuretic, a difference that was not statistically significant.

Another analysis focused on patients who received either nesiritide or nitroglycerin as a second drug sometime after the initial 2-hour window that was used to define the IPT. The 1,028 patients who received nesiritide as a second drug (following initial treatment with a diuretic, nitroglycerin, or an inotrope) had an in-hospital mortality rate of 3.4%. By comparison, 1,028 patients who received nitroglycerin as a second drug had a mortality rate of 6.2%, a statistically significant difference.

Data like these are useful, Dr. Costanzo said in an interview, because following publication of the two metaanalyses a year ago, physicians have become more reluctant to prescribe nesiritide to patients with acute decompensated heart failure. “Many physicians have reverted back to using more inotropes, which I'm pretty confident are associated with increased mortality,” she said.

MADRID — Patients with acute decompensated heart failure who were treated with nesiritide had an in-hospital mortality rate that appeared to be no worse than that of patients who were treated intravenously with either nitroglycerin or a diuretic, according to data from a registry with more than 100,000 patients.

The findings “warrant prospective confirmation of the mortality risk associated with different therapies for acute decompensated heart failure,” Dr. Maria Rosa Costanzo said at the annual meeting of the International Society for Heart and Lung Transplantation.

“We did not find any signal of increased [in-hospital] mortality in patients treated with either nesiritide or nitroglycerin,” said Dr. Costanzo in an interview. The results of her analysis “confirm the appropriateness of nesiritide treatment in patients for whom it's approved,” specifically single-dose treatment of patients with acute decompensated heart failure and symptoms that lead to hospitalization for heart failure, said Dr. Costanzo, medical director of the Edward Hospital Center for Advanced Heart Failure in Naperville, Ill.

Nesiritide's safety for treating patients with heart failure has been under a cloud since a pair of metaanalyses were published last year that suggested that patients who were treated with a single dose of the drug had an excess rate of worsening renal function and death during the subsequent 30 days.

At least one expert who reviewed the new report found limited reassurance in the findings. “The analyses appear to be well done, and they provide some comfort about the short-term safety of nesiritide,” said Dr. Barry M. Massie in an interview. But the results “are not very helpful because they were only able to examine the in-hospital phase,” and there was no information on renal function or length of hospital stay. The results from other studies with nesiritide have indicated that the excess of worsening renal failure occurred primarily after 7 days, and the trends toward increased mortality were most apparent after 30 days, said Dr. Massie, professor of medicine at the University of California, San Francisco, and chief of cardiology at the San Francisco Veterans Affairs Medical Center.

The new analysis used data from the Acute Decompensated Heart Failure National Registry (ADHERE), which collected data from more than 180,000 patients who were hospitalized at any of 263 participating hospitals in the United States during October 2001 to March 2006, when the registry closed. The analysis by Dr. Costanzo and her associates used data collected from nearly 135,000 patients who were enrolled through August 2004.

The ADHERE registry was sponsored by Scios Inc., the division of Johnson & Johnson that markets nesiritide (Natrecor). Dr. Costanzo serves on the scientific advisory board of Scios.

The analysis excluded about 35,000 patients from the registry who turned out not to have heart failure, had a delayed diagnosis, or had complicating conditions such as a respiratory infection or MI.

Data collected on the remaining 99,963 patients were further refined using two analytic tools aimed at simulating a prospective, controlled study.

The first tool categorized patients by their “intended primary treatment (IPT),” a method used to “simulate an intention-to-treat analysis,” said Dr. Costanzo in an interview. The IPT was whichever drug or drugs a patient received during the first 2 hours of treatment. By this criterion, the vast majority of patients, more than 74,000, received an intravenous diuretic alone as their IPT. Monotherapy with nesiritide as the IPT occurred in 1,855 patients, intravenous nitroglycerin monotherapy was the IPT in 1,590 patients, and 2,465 patients received an inotrope (dobutamine, dopamine, or milrinone) as monotherapy IPT. The remaining patients received at least two drugs during their first 2 hours of treatment.

Comparisons of the IPT groups were then made using a propensity analysis, a method that matches patients from two unrandomized groups by a variety of demographic and clinical characteristics. In this case, the propensity analysis used more than 55 variables, said Dr. Costanzo. Patients who could not be matched with patients from the comparator group were excluded from the analysis.

“The problem with observational data sets is that most physician-determined interventions are not random and reflect something about the judgment of risk and therefore are confounded by the resulting biases. Propensity-score matching is the favored approach to deal with confounding but is limited by only being able to deal with measured variables,” commented Dr. Massie.

The two main analyses that Dr. Costanzo presented compared the in-hospital mortality rates of patients treated with nesiritide or a diuretic, and those of patients treated with nitroglycerin or a diuretic.

In the first comparison, the mortality rate was 3.6% among 1,701 patients treated with nesiritide and 4.8% among 8,505 patients treated with a diuretic, a statistically significant difference. In the second comparison, in-hospital mortality occurred in 2.7% of 1,488 patients treated with nitroglycerin compared with a 3.0% mortality rate among 7,440 patients treated with a diuretic, a difference that was not statistically significant.

Another analysis focused on patients who received either nesiritide or nitroglycerin as a second drug sometime after the initial 2-hour window that was used to define the IPT. The 1,028 patients who received nesiritide as a second drug (following initial treatment with a diuretic, nitroglycerin, or an inotrope) had an in-hospital mortality rate of 3.4%. By comparison, 1,028 patients who received nitroglycerin as a second drug had a mortality rate of 6.2%, a statistically significant difference.

Data like these are useful, Dr. Costanzo said in an interview, because following publication of the two metaanalyses a year ago, physicians have become more reluctant to prescribe nesiritide to patients with acute decompensated heart failure. “Many physicians have reverted back to using more inotropes, which I'm pretty confident are associated with increased mortality,” she said.

MADRID — Patients with acute decompensated heart failure who were treated with nesiritide had an in-hospital mortality rate that appeared to be no worse than that of patients who were treated intravenously with either nitroglycerin or a diuretic, according to data from a registry with more than 100,000 patients.

The findings “warrant prospective confirmation of the mortality risk associated with different therapies for acute decompensated heart failure,” Dr. Maria Rosa Costanzo said at the annual meeting of the International Society for Heart and Lung Transplantation.

“We did not find any signal of increased [in-hospital] mortality in patients treated with either nesiritide or nitroglycerin,” said Dr. Costanzo in an interview. The results of her analysis “confirm the appropriateness of nesiritide treatment in patients for whom it's approved,” specifically single-dose treatment of patients with acute decompensated heart failure and symptoms that lead to hospitalization for heart failure, said Dr. Costanzo, medical director of the Edward Hospital Center for Advanced Heart Failure in Naperville, Ill.

Nesiritide's safety for treating patients with heart failure has been under a cloud since a pair of metaanalyses were published last year that suggested that patients who were treated with a single dose of the drug had an excess rate of worsening renal function and death during the subsequent 30 days.

At least one expert who reviewed the new report found limited reassurance in the findings. “The analyses appear to be well done, and they provide some comfort about the short-term safety of nesiritide,” said Dr. Barry M. Massie in an interview. But the results “are not very helpful because they were only able to examine the in-hospital phase,” and there was no information on renal function or length of hospital stay. The results from other studies with nesiritide have indicated that the excess of worsening renal failure occurred primarily after 7 days, and the trends toward increased mortality were most apparent after 30 days, said Dr. Massie, professor of medicine at the University of California, San Francisco, and chief of cardiology at the San Francisco Veterans Affairs Medical Center.

The new analysis used data from the Acute Decompensated Heart Failure National Registry (ADHERE), which collected data from more than 180,000 patients who were hospitalized at any of 263 participating hospitals in the United States during October 2001 to March 2006, when the registry closed. The analysis by Dr. Costanzo and her associates used data collected from nearly 135,000 patients who were enrolled through August 2004.

The ADHERE registry was sponsored by Scios Inc., the division of Johnson & Johnson that markets nesiritide (Natrecor). Dr. Costanzo serves on the scientific advisory board of Scios.

The analysis excluded about 35,000 patients from the registry who turned out not to have heart failure, had a delayed diagnosis, or had complicating conditions such as a respiratory infection or MI.

Data collected on the remaining 99,963 patients were further refined using two analytic tools aimed at simulating a prospective, controlled study.

The first tool categorized patients by their “intended primary treatment (IPT),” a method used to “simulate an intention-to-treat analysis,” said Dr. Costanzo in an interview. The IPT was whichever drug or drugs a patient received during the first 2 hours of treatment. By this criterion, the vast majority of patients, more than 74,000, received an intravenous diuretic alone as their IPT. Monotherapy with nesiritide as the IPT occurred in 1,855 patients, intravenous nitroglycerin monotherapy was the IPT in 1,590 patients, and 2,465 patients received an inotrope (dobutamine, dopamine, or milrinone) as monotherapy IPT. The remaining patients received at least two drugs during their first 2 hours of treatment.

Comparisons of the IPT groups were then made using a propensity analysis, a method that matches patients from two unrandomized groups by a variety of demographic and clinical characteristics. In this case, the propensity analysis used more than 55 variables, said Dr. Costanzo. Patients who could not be matched with patients from the comparator group were excluded from the analysis.

“The problem with observational data sets is that most physician-determined interventions are not random and reflect something about the judgment of risk and therefore are confounded by the resulting biases. Propensity-score matching is the favored approach to deal with confounding but is limited by only being able to deal with measured variables,” commented Dr. Massie.

The two main analyses that Dr. Costanzo presented compared the in-hospital mortality rates of patients treated with nesiritide or a diuretic, and those of patients treated with nitroglycerin or a diuretic.

In the first comparison, the mortality rate was 3.6% among 1,701 patients treated with nesiritide and 4.8% among 8,505 patients treated with a diuretic, a statistically significant difference. In the second comparison, in-hospital mortality occurred in 2.7% of 1,488 patients treated with nitroglycerin compared with a 3.0% mortality rate among 7,440 patients treated with a diuretic, a difference that was not statistically significant.

Another analysis focused on patients who received either nesiritide or nitroglycerin as a second drug sometime after the initial 2-hour window that was used to define the IPT. The 1,028 patients who received nesiritide as a second drug (following initial treatment with a diuretic, nitroglycerin, or an inotrope) had an in-hospital mortality rate of 3.4%. By comparison, 1,028 patients who received nitroglycerin as a second drug had a mortality rate of 6.2%, a statistically significant difference.

Data like these are useful, Dr. Costanzo said in an interview, because following publication of the two metaanalyses a year ago, physicians have become more reluctant to prescribe nesiritide to patients with acute decompensated heart failure. “Many physicians have reverted back to using more inotropes, which I'm pretty confident are associated with increased mortality,” she said.

MADRID — The four criteria now used to measure hospitals' performance in treating patients with heart failure also have a significant impact on patient survival, based on a review of more than 2,000 patients.

In 2002, the Joint Commission on Accreditation of Healthcare Organizations (JCAHO) set four core measures for the assessment of the quality of heart failure management.

“To our knowledge, this is the first report showing that adherence to the JCAHO heart failure core measures improves 1-year survival following hospitalization for heart failure,” Dr. A.G. Kfoury said at the annual meeting of the International Society for Heart and Lung Transplantation.

“The data show that these four cheap interventions can have an impact on patient outcomes,” said Dr. Kfoury, who is the medical director of the Utah Transplantation Affiliated Hospitals cardiac transplant program, and associate director of the heart failure prevention and treatment program at LDS Hospital in Salt Lake City.

The four performance measures are: discharge instructions to patients on heart failure management, including medications, diet, and weight control; assessment of left ventricular function or scheduling an assessment at discharge; treatment with an ACE inhibitor or angiotensin receptor blocker (ARB) at discharge; and instructions on smoking cessation at discharge.

To determine how the application of these four measures correlated with patient survival, Dr. Kfoury and his associates reviewed the records of 2,144 patients who were discharged with a primary diagnosis of heart failure and left ventricular dysfunction from 20 hospitals within the Intermountain Healthcare system from January 2003 to May 2005. The primary end point of the analysis was death during the 12 months following hospital discharge.

Because 90% of the patients were nonsmokers, one analysis excluded the smoking cessation measure and focused on the application of the other three criteria.

About 43% of patients received all three interventions, and another 39% of the patients received two of the interventions. Some 3% of patients received none of the interventions. When only one intervention was used, it was most often prescription of an ACE inhibitor or ARB.

The second most commonly used intervention was assessment of left ventricular function. Patient education was applied less often.

According to an analysis that adjusted for patients' age, gender, and severity of illness, patients who received none of these three interventions had about a 25% mortality rate during the 12 months following hospital discharge. Patients who received one or two interventions had about a 15% mortality rate, and patients who received all three interventions had about a 10% mortality rate.

When differences between these subgroups were analyzed statistically, patients who received two or three of the JCAHO-prescribed interventions had a significantly improved 12-month survival, compared with the patients who did not, Dr. Kfoury said.

A second analysis looked at the impact of all four interventions, including counseling on smoking cessation. The pattern was quite similar to the previous analysis: Patients who received all four interventions at discharge had a 5% mortality rate over the next 12 months. Those who received none of the interventions had a 25% mortality rate.

“These results should be an impetus to implement these simple but effective measures,” said Dr. Kfoury.

“Most patients get one or more of the interventions, but patients do not always get all of them.”

Treatment with an ACE inhibitor or ARB at discharge has become standard practice, but patient education at discharge is a strategy that's been used only for a few years and needs to become more widely used, he added.

MADRID — The four criteria now used to measure hospitals' performance in treating patients with heart failure also have a significant impact on patient survival, based on a review of more than 2,000 patients.

In 2002, the Joint Commission on Accreditation of Healthcare Organizations (JCAHO) set four core measures for the assessment of the quality of heart failure management.

“To our knowledge, this is the first report showing that adherence to the JCAHO heart failure core measures improves 1-year survival following hospitalization for heart failure,” Dr. A.G. Kfoury said at the annual meeting of the International Society for Heart and Lung Transplantation.

“The data show that these four cheap interventions can have an impact on patient outcomes,” said Dr. Kfoury, who is the medical director of the Utah Transplantation Affiliated Hospitals cardiac transplant program, and associate director of the heart failure prevention and treatment program at LDS Hospital in Salt Lake City.

The four performance measures are: discharge instructions to patients on heart failure management, including medications, diet, and weight control; assessment of left ventricular function or scheduling an assessment at discharge; treatment with an ACE inhibitor or angiotensin receptor blocker (ARB) at discharge; and instructions on smoking cessation at discharge.

To determine how the application of these four measures correlated with patient survival, Dr. Kfoury and his associates reviewed the records of 2,144 patients who were discharged with a primary diagnosis of heart failure and left ventricular dysfunction from 20 hospitals within the Intermountain Healthcare system from January 2003 to May 2005. The primary end point of the analysis was death during the 12 months following hospital discharge.

Because 90% of the patients were nonsmokers, one analysis excluded the smoking cessation measure and focused on the application of the other three criteria.

About 43% of patients received all three interventions, and another 39% of the patients received two of the interventions. Some 3% of patients received none of the interventions. When only one intervention was used, it was most often prescription of an ACE inhibitor or ARB.

The second most commonly used intervention was assessment of left ventricular function. Patient education was applied less often.

According to an analysis that adjusted for patients' age, gender, and severity of illness, patients who received none of these three interventions had about a 25% mortality rate during the 12 months following hospital discharge. Patients who received one or two interventions had about a 15% mortality rate, and patients who received all three interventions had about a 10% mortality rate.

When differences between these subgroups were analyzed statistically, patients who received two or three of the JCAHO-prescribed interventions had a significantly improved 12-month survival, compared with the patients who did not, Dr. Kfoury said.

A second analysis looked at the impact of all four interventions, including counseling on smoking cessation. The pattern was quite similar to the previous analysis: Patients who received all four interventions at discharge had a 5% mortality rate over the next 12 months. Those who received none of the interventions had a 25% mortality rate.

“These results should be an impetus to implement these simple but effective measures,” said Dr. Kfoury.

“Most patients get one or more of the interventions, but patients do not always get all of them.”

Treatment with an ACE inhibitor or ARB at discharge has become standard practice, but patient education at discharge is a strategy that's been used only for a few years and needs to become more widely used, he added.

MADRID — The four criteria now used to measure hospitals' performance in treating patients with heart failure also have a significant impact on patient survival, based on a review of more than 2,000 patients.

In 2002, the Joint Commission on Accreditation of Healthcare Organizations (JCAHO) set four core measures for the assessment of the quality of heart failure management.

“To our knowledge, this is the first report showing that adherence to the JCAHO heart failure core measures improves 1-year survival following hospitalization for heart failure,” Dr. A.G. Kfoury said at the annual meeting of the International Society for Heart and Lung Transplantation.

“The data show that these four cheap interventions can have an impact on patient outcomes,” said Dr. Kfoury, who is the medical director of the Utah Transplantation Affiliated Hospitals cardiac transplant program, and associate director of the heart failure prevention and treatment program at LDS Hospital in Salt Lake City.

The four performance measures are: discharge instructions to patients on heart failure management, including medications, diet, and weight control; assessment of left ventricular function or scheduling an assessment at discharge; treatment with an ACE inhibitor or angiotensin receptor blocker (ARB) at discharge; and instructions on smoking cessation at discharge.

To determine how the application of these four measures correlated with patient survival, Dr. Kfoury and his associates reviewed the records of 2,144 patients who were discharged with a primary diagnosis of heart failure and left ventricular dysfunction from 20 hospitals within the Intermountain Healthcare system from January 2003 to May 2005. The primary end point of the analysis was death during the 12 months following hospital discharge.

Because 90% of the patients were nonsmokers, one analysis excluded the smoking cessation measure and focused on the application of the other three criteria.

About 43% of patients received all three interventions, and another 39% of the patients received two of the interventions. Some 3% of patients received none of the interventions. When only one intervention was used, it was most often prescription of an ACE inhibitor or ARB.

The second most commonly used intervention was assessment of left ventricular function. Patient education was applied less often.

According to an analysis that adjusted for patients' age, gender, and severity of illness, patients who received none of these three interventions had about a 25% mortality rate during the 12 months following hospital discharge. Patients who received one or two interventions had about a 15% mortality rate, and patients who received all three interventions had about a 10% mortality rate.

When differences between these subgroups were analyzed statistically, patients who received two or three of the JCAHO-prescribed interventions had a significantly improved 12-month survival, compared with the patients who did not, Dr. Kfoury said.

A second analysis looked at the impact of all four interventions, including counseling on smoking cessation. The pattern was quite similar to the previous analysis: Patients who received all four interventions at discharge had a 5% mortality rate over the next 12 months. Those who received none of the interventions had a 25% mortality rate.

“These results should be an impetus to implement these simple but effective measures,” said Dr. Kfoury.

“Most patients get one or more of the interventions, but patients do not always get all of them.”

Treatment with an ACE inhibitor or ARB at discharge has become standard practice, but patient education at discharge is a strategy that's been used only for a few years and needs to become more widely used, he added.

ATLANTA — Predischarge initiation of β-blocker therapy in patients with heart failure and left ventricular systolic dysfunction halved mortality during the next 60–90 days among 5,791 patients in a registry, Dr. Gregg C. Fonarow reported at the annual meeting of the American College of Cardiology.

Inpatient initiation of β-blocker therapy ought to be considered a standard of care in heart failure management, according to Dr. Fonarow, professor of medicine at the University of California, Los Angeles, and director of the Ahmanson-UCLA Cardiomyopathy Center.

The treatment has all the elements of an ideal clinical performance measure for use in quality improvement and pay-for-performance programs.

And yet it was not included among the five inpatient performance measures for adults with chronic heart failure that were recently published by an ACC/American Heart Association (AHA) task force. That is an oversight, and the issue deserves to be revisited, Dr. Fonarow said.

He reported on 5,791 heart failure patients in 91 U.S. hospitals who comprised a prespecified subgroup with prospective follow-up among enrollees in the Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure (OPTIMIZE-HF) registry.

Of the 53% who had left ventricular systolic dysfunction, 90% were deemed eligible for β-blocker therapy at discharge. And of those eligible, 84% were actually discharged on a β-blocker, and 93% of those remained on the drug at 60- to 90-day follow-up.

Postdischarge 60- to 90-day all-cause mortality in patients eligible for β-blocker therapy who weren't discharged on it was 11.1%, with a combined rate of death or rehospitalization of 42%.

A risk-adjusted multivariate analysis showed that discharge on a β-blocker was associated with a highly significant 49% reduction in all-cause mortality and a 28% reduction in death or rehospitalization, compared with rates in the eligible-but-untreated group.

Dr. Fonarow stressed that when he and his coinvestigators applied the five recently published ACC/AHA performance measures to the OPTIMIZE-HF cohort of nearly 6,000 patients, none of the five predicted 60- to 90-day mortality, and only one—discharge on an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker (ARB)—was associated with a significant reduction in the combined death or rehospitalization end point.

In addition to discharge on an ACE inhibitor or ARB, the other current ACC/AHA inpatient performance indicators are the evaluation of left ventricular systolic function, the issuance of discharge instructions, smoking cessation advice/counseling, and discharge anticoagulation for heart failure patients with atrial fibrillation.

The ACC/AHA task force considered including β-blockade as an inpatient performance measure but elected not to on the grounds that “the complexities of establishing the right conditions under which stable HF patients would be included in the measure minus the exclusions would result in so small a denominator that the measure would not be meaningful at this time” (J. Am. Coll. Cardiol. 2005;46:1144–78). But this was an assumption not based on data—and the OPTIMIZE-HF experience undercuts the task force's rationale, Dr. Fonarow said in an interview.

“Here in OPTIMIZE-HF are the actual prospective data showing that a large number of patients qualify for β-blocker therapy, the tolerability is phenomenal, and it's the most important measure with respect to outcome prediction in terms of death and rehospitalization.

“So if you were to ask in terms of actual data what would be the most important performance measure for heart failure at the time of discharge, it would be β-blocker therapy, followed by ACE inhibitor/ARBs,” he said.

Although the other current performance measures may be important in terms of long-term care, the finding that they do not improve 60- to 90-day mortality or rehospitalization means they do not address the highest priority issues, Dr. Fonarow continued.

Task force member Dr. Kim A. Eagle, the clinical director of the University of Michigan Cardiovascular Center, Ann Arbor, said in an interview that it is unclear whether the group will reconsider adding inpatient β-blocker therapy as a heart failure performance indicator.

There is a concern that starting the therapy too early—before a patient is stabilized—can have adverse consequences, he added.

The OPTIMIZE-HF registry is funded by GlaxoSmithKline. Last year, the registry was incorporated into AHA's ongoing Get With The Guidelines-Heart Failure project.

ATLANTA — Predischarge initiation of β-blocker therapy in patients with heart failure and left ventricular systolic dysfunction halved mortality during the next 60–90 days among 5,791 patients in a registry, Dr. Gregg C. Fonarow reported at the annual meeting of the American College of Cardiology.

Inpatient initiation of β-blocker therapy ought to be considered a standard of care in heart failure management, according to Dr. Fonarow, professor of medicine at the University of California, Los Angeles, and director of the Ahmanson-UCLA Cardiomyopathy Center.

The treatment has all the elements of an ideal clinical performance measure for use in quality improvement and pay-for-performance programs.

And yet it was not included among the five inpatient performance measures for adults with chronic heart failure that were recently published by an ACC/American Heart Association (AHA) task force. That is an oversight, and the issue deserves to be revisited, Dr. Fonarow said.

He reported on 5,791 heart failure patients in 91 U.S. hospitals who comprised a prespecified subgroup with prospective follow-up among enrollees in the Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure (OPTIMIZE-HF) registry.

Of the 53% who had left ventricular systolic dysfunction, 90% were deemed eligible for β-blocker therapy at discharge. And of those eligible, 84% were actually discharged on a β-blocker, and 93% of those remained on the drug at 60- to 90-day follow-up.

Postdischarge 60- to 90-day all-cause mortality in patients eligible for β-blocker therapy who weren't discharged on it was 11.1%, with a combined rate of death or rehospitalization of 42%.

A risk-adjusted multivariate analysis showed that discharge on a β-blocker was associated with a highly significant 49% reduction in all-cause mortality and a 28% reduction in death or rehospitalization, compared with rates in the eligible-but-untreated group.

Dr. Fonarow stressed that when he and his coinvestigators applied the five recently published ACC/AHA performance measures to the OPTIMIZE-HF cohort of nearly 6,000 patients, none of the five predicted 60- to 90-day mortality, and only one—discharge on an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker (ARB)—was associated with a significant reduction in the combined death or rehospitalization end point.

In addition to discharge on an ACE inhibitor or ARB, the other current ACC/AHA inpatient performance indicators are the evaluation of left ventricular systolic function, the issuance of discharge instructions, smoking cessation advice/counseling, and discharge anticoagulation for heart failure patients with atrial fibrillation.

The ACC/AHA task force considered including β-blockade as an inpatient performance measure but elected not to on the grounds that “the complexities of establishing the right conditions under which stable HF patients would be included in the measure minus the exclusions would result in so small a denominator that the measure would not be meaningful at this time” (J. Am. Coll. Cardiol. 2005;46:1144–78). But this was an assumption not based on data—and the OPTIMIZE-HF experience undercuts the task force's rationale, Dr. Fonarow said in an interview.

“Here in OPTIMIZE-HF are the actual prospective data showing that a large number of patients qualify for β-blocker therapy, the tolerability is phenomenal, and it's the most important measure with respect to outcome prediction in terms of death and rehospitalization.

“So if you were to ask in terms of actual data what would be the most important performance measure for heart failure at the time of discharge, it would be β-blocker therapy, followed by ACE inhibitor/ARBs,” he said.

Although the other current performance measures may be important in terms of long-term care, the finding that they do not improve 60- to 90-day mortality or rehospitalization means they do not address the highest priority issues, Dr. Fonarow continued.

Task force member Dr. Kim A. Eagle, the clinical director of the University of Michigan Cardiovascular Center, Ann Arbor, said in an interview that it is unclear whether the group will reconsider adding inpatient β-blocker therapy as a heart failure performance indicator.

There is a concern that starting the therapy too early—before a patient is stabilized—can have adverse consequences, he added.

The OPTIMIZE-HF registry is funded by GlaxoSmithKline. Last year, the registry was incorporated into AHA's ongoing Get With The Guidelines-Heart Failure project.

ATLANTA — Predischarge initiation of β-blocker therapy in patients with heart failure and left ventricular systolic dysfunction halved mortality during the next 60–90 days among 5,791 patients in a registry, Dr. Gregg C. Fonarow reported at the annual meeting of the American College of Cardiology.

Inpatient initiation of β-blocker therapy ought to be considered a standard of care in heart failure management, according to Dr. Fonarow, professor of medicine at the University of California, Los Angeles, and director of the Ahmanson-UCLA Cardiomyopathy Center.

The treatment has all the elements of an ideal clinical performance measure for use in quality improvement and pay-for-performance programs.

And yet it was not included among the five inpatient performance measures for adults with chronic heart failure that were recently published by an ACC/American Heart Association (AHA) task force. That is an oversight, and the issue deserves to be revisited, Dr. Fonarow said.

He reported on 5,791 heart failure patients in 91 U.S. hospitals who comprised a prespecified subgroup with prospective follow-up among enrollees in the Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure (OPTIMIZE-HF) registry.

Of the 53% who had left ventricular systolic dysfunction, 90% were deemed eligible for β-blocker therapy at discharge. And of those eligible, 84% were actually discharged on a β-blocker, and 93% of those remained on the drug at 60- to 90-day follow-up.

Postdischarge 60- to 90-day all-cause mortality in patients eligible for β-blocker therapy who weren't discharged on it was 11.1%, with a combined rate of death or rehospitalization of 42%.

A risk-adjusted multivariate analysis showed that discharge on a β-blocker was associated with a highly significant 49% reduction in all-cause mortality and a 28% reduction in death or rehospitalization, compared with rates in the eligible-but-untreated group.

Dr. Fonarow stressed that when he and his coinvestigators applied the five recently published ACC/AHA performance measures to the OPTIMIZE-HF cohort of nearly 6,000 patients, none of the five predicted 60- to 90-day mortality, and only one—discharge on an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker (ARB)—was associated with a significant reduction in the combined death or rehospitalization end point.

In addition to discharge on an ACE inhibitor or ARB, the other current ACC/AHA inpatient performance indicators are the evaluation of left ventricular systolic function, the issuance of discharge instructions, smoking cessation advice/counseling, and discharge anticoagulation for heart failure patients with atrial fibrillation.

The ACC/AHA task force considered including β-blockade as an inpatient performance measure but elected not to on the grounds that “the complexities of establishing the right conditions under which stable HF patients would be included in the measure minus the exclusions would result in so small a denominator that the measure would not be meaningful at this time” (J. Am. Coll. Cardiol. 2005;46:1144–78). But this was an assumption not based on data—and the OPTIMIZE-HF experience undercuts the task force's rationale, Dr. Fonarow said in an interview.

“Here in OPTIMIZE-HF are the actual prospective data showing that a large number of patients qualify for β-blocker therapy, the tolerability is phenomenal, and it's the most important measure with respect to outcome prediction in terms of death and rehospitalization.

“So if you were to ask in terms of actual data what would be the most important performance measure for heart failure at the time of discharge, it would be β-blocker therapy, followed by ACE inhibitor/ARBs,” he said.

Although the other current performance measures may be important in terms of long-term care, the finding that they do not improve 60- to 90-day mortality or rehospitalization means they do not address the highest priority issues, Dr. Fonarow continued.

Task force member Dr. Kim A. Eagle, the clinical director of the University of Michigan Cardiovascular Center, Ann Arbor, said in an interview that it is unclear whether the group will reconsider adding inpatient β-blocker therapy as a heart failure performance indicator.

There is a concern that starting the therapy too early—before a patient is stabilized—can have adverse consequences, he added.

The OPTIMIZE-HF registry is funded by GlaxoSmithKline. Last year, the registry was incorporated into AHA's ongoing Get With The Guidelines-Heart Failure project.

ATLANTA — Treatment with an antidepressant drug relieved the mild to moderate depression that often occurs in patients with heart failure in a controlled study with 26 patients.

But the reduction of depression symptoms using a selective serotonin reuptake inhibitor generally did not improve quality of life measures in these patients, Dr. Mark R. Vesely and his associates reported in a poster at the annual meeting of the American College of Cardiology.

The findings suggest physicians should screen for depression in patients with heart failure, then treat when depression is diagnosed, he said in an interview. Treatment with an SSRI is safe and effective. Next would be to examine whether treating depression can produce any reductions in hospitalization rates or death in heart failure patients, said Dr. Vesely, a cardiologist at the University of Maryland in Baltimore.

Results from previous studies have shown that depression occurs in 24%–48% of patients with heart failure. Despite this high prevalence, “heart failure patients usually don't get treated” for depression, said Dr. Stephen S. Gottlieb, professor of medicine and director of the heart failure service at the University of Maryland and a coinvestigator for the study.

An SSRI is the logical, first-line agent to use to treat depression in a patient with heart failure because of its presumed safety in these patients. By contrast, treatment with a tricyclic antidepressant involves the risk of producing neurohormonal activation that might exacerbate the heart failure, Dr. Vesely said.

The study included patients with New York Heart Association class II or III heart failure who were diagnosed with mild or moderate depression by a score of 10 or more on the Beck Depression Index (BDI). The average BDI score of the patients enrolled was about 21, and they were all placed on an optimal panel of heart failure medications.

The patients were randomized to treatment with either paroxetine-CR (Paxil CR) 12.5 mg daily or placebo for 12 weeks. During follow-up, three patients dropped out of the study. After 12 weeks, the BDI score fell by an average of 12 points in the 12 patients treated with paroxetine-CR for the full study, compared with an average 0.5 point rise in 11 placebo patients, a significant difference.

Quality of life was measured with several scales: the Minnesota Living With Heart Failure emotional and physical scales, and the mental and physical scales of the Short Form-36. There were no significant improvements for most of these measures in the paroxetine-treated patients compared with the controls. The sole exception was the mental score on the Short Form-36, which rose by 9 points in the actively treated patients and by 1 point in the placebo-treated patients, a significant difference.

GlaxoSmithKline, which markets Paxil CR, supplied the drug in this study. The study and investigators received no other industry support.

ATLANTA — Treatment with an antidepressant drug relieved the mild to moderate depression that often occurs in patients with heart failure in a controlled study with 26 patients.

But the reduction of depression symptoms using a selective serotonin reuptake inhibitor generally did not improve quality of life measures in these patients, Dr. Mark R. Vesely and his associates reported in a poster at the annual meeting of the American College of Cardiology.

The findings suggest physicians should screen for depression in patients with heart failure, then treat when depression is diagnosed, he said in an interview. Treatment with an SSRI is safe and effective. Next would be to examine whether treating depression can produce any reductions in hospitalization rates or death in heart failure patients, said Dr. Vesely, a cardiologist at the University of Maryland in Baltimore.

Results from previous studies have shown that depression occurs in 24%–48% of patients with heart failure. Despite this high prevalence, “heart failure patients usually don't get treated” for depression, said Dr. Stephen S. Gottlieb, professor of medicine and director of the heart failure service at the University of Maryland and a coinvestigator for the study.

An SSRI is the logical, first-line agent to use to treat depression in a patient with heart failure because of its presumed safety in these patients. By contrast, treatment with a tricyclic antidepressant involves the risk of producing neurohormonal activation that might exacerbate the heart failure, Dr. Vesely said.

The study included patients with New York Heart Association class II or III heart failure who were diagnosed with mild or moderate depression by a score of 10 or more on the Beck Depression Index (BDI). The average BDI score of the patients enrolled was about 21, and they were all placed on an optimal panel of heart failure medications.

The patients were randomized to treatment with either paroxetine-CR (Paxil CR) 12.5 mg daily or placebo for 12 weeks. During follow-up, three patients dropped out of the study. After 12 weeks, the BDI score fell by an average of 12 points in the 12 patients treated with paroxetine-CR for the full study, compared with an average 0.5 point rise in 11 placebo patients, a significant difference.

Quality of life was measured with several scales: the Minnesota Living With Heart Failure emotional and physical scales, and the mental and physical scales of the Short Form-36. There were no significant improvements for most of these measures in the paroxetine-treated patients compared with the controls. The sole exception was the mental score on the Short Form-36, which rose by 9 points in the actively treated patients and by 1 point in the placebo-treated patients, a significant difference.

GlaxoSmithKline, which markets Paxil CR, supplied the drug in this study. The study and investigators received no other industry support.

ATLANTA — Treatment with an antidepressant drug relieved the mild to moderate depression that often occurs in patients with heart failure in a controlled study with 26 patients.

But the reduction of depression symptoms using a selective serotonin reuptake inhibitor generally did not improve quality of life measures in these patients, Dr. Mark R. Vesely and his associates reported in a poster at the annual meeting of the American College of Cardiology.

The findings suggest physicians should screen for depression in patients with heart failure, then treat when depression is diagnosed, he said in an interview. Treatment with an SSRI is safe and effective. Next would be to examine whether treating depression can produce any reductions in hospitalization rates or death in heart failure patients, said Dr. Vesely, a cardiologist at the University of Maryland in Baltimore.

Results from previous studies have shown that depression occurs in 24%–48% of patients with heart failure. Despite this high prevalence, “heart failure patients usually don't get treated” for depression, said Dr. Stephen S. Gottlieb, professor of medicine and director of the heart failure service at the University of Maryland and a coinvestigator for the study.

An SSRI is the logical, first-line agent to use to treat depression in a patient with heart failure because of its presumed safety in these patients. By contrast, treatment with a tricyclic antidepressant involves the risk of producing neurohormonal activation that might exacerbate the heart failure, Dr. Vesely said.

The study included patients with New York Heart Association class II or III heart failure who were diagnosed with mild or moderate depression by a score of 10 or more on the Beck Depression Index (BDI). The average BDI score of the patients enrolled was about 21, and they were all placed on an optimal panel of heart failure medications.

The patients were randomized to treatment with either paroxetine-CR (Paxil CR) 12.5 mg daily or placebo for 12 weeks. During follow-up, three patients dropped out of the study. After 12 weeks, the BDI score fell by an average of 12 points in the 12 patients treated with paroxetine-CR for the full study, compared with an average 0.5 point rise in 11 placebo patients, a significant difference.

Quality of life was measured with several scales: the Minnesota Living With Heart Failure emotional and physical scales, and the mental and physical scales of the Short Form-36. There were no significant improvements for most of these measures in the paroxetine-treated patients compared with the controls. The sole exception was the mental score on the Short Form-36, which rose by 9 points in the actively treated patients and by 1 point in the placebo-treated patients, a significant difference.

GlaxoSmithKline, which markets Paxil CR, supplied the drug in this study. The study and investigators received no other industry support.

ATLANTA — Candesartan therapy triples the already significant background risk of potentially serious hyperkalemia in patients with heart failure, according to a new secondary analysis of the Candesartan in Heart Failure—Assessment of Reduction in Mortality and Morbidity (CHARM) program.

Periodic monitoring of serum potassium is therefore “critical” in heart failure patients—and not just those on candesartan, Dr. Akshay Desai said at the annual meeting of the American College of Cardiology.

“The estimate from our study is that one would expect roughly 34 excess hyperkalemic events per 1,000 candesartan-treated patients over 3 years. But with careful surveillance of serum potassium, this risk can be substantially reduced. In the trial, seven excess serious events per 1,000 patients were noted over the 3-year duration of follow-up with careful monitoring by study investigators. We feel that this represents the unavoidable risk of candesartan therapy in this population of patients,” said Dr. Desai of Brigham and Women's Hospital, Boston.

To place this risk in perspective, he added, candesartan also prevented 43 cardiovascular death or hospitalization events per 1,000 patients.

The CHARM program involved 7,599 heart failure patients on standard therapy who were randomized in double-blind fashion to candesartan or placebo and followed for just over 3 years with regular monitoring of serum potassium. Candesartan resulted in a significant 16% reduction in the relative risk of the primary end point of cardiovascular death or heart failure hospitalization.

Hyperkalemia is well recognized to be a common and potentially life-threatening complication of treatment with renin-angiotensin-aldosterone system inhibitors. CHARM investigators categorized hyperkalemic events as “serious” if they posed a risk of death or hospitalization, and “concerning” if events were serious or would have become so if not detected early through the monitoring program, with subsequent dose adjustment or drug discontinuation.

The incidence of concerning hyperkalemia during the study was 1.8% in the placebo arm and 5.2% in the candesartan group. Serious hyperkalemic events occurred in 1.1% of the placebo group and 1.8% on candesartan. Of particular clinical relevance was the finding that hyperkalemic events were not confined to the period of candesartan dose titration; they occurred throughout follow-up, although the incidence was greater during titration, said Dr. Desai.

Several predictors of increased background risk of concerning hyperkalemia were identified. Age greater than 75 years, being on an ACE inhibitor or spironolactone, or a history of diabetes was associated with roughly a twofold increased risk. Baseline renal insufficiency or hyperkalemia conferred a fivefold spike in risk. Candesartan therapy was associated with a threefold increase in risk of hyperkalemia, compared with placebo—but the drug's therapeutic benefit was also consistent across all patient subgroups, including those at high baseline risk for hyperkalemia.

Dr. Gary S. Francis, director of the coronary intensive care unit at the Cleveland Clinic Foundation, called the new results “very important data that have practical implications.” He asked how often potassium should be monitored.

“I would suggest, particularly in patients at high baseline risk, be quite careful to measure serum potassium within a 2- to 3-week period after every dose titration, and again intermittently—even randomly—over the course of follow-up,” he said.

ATLANTA — Candesartan therapy triples the already significant background risk of potentially serious hyperkalemia in patients with heart failure, according to a new secondary analysis of the Candesartan in Heart Failure—Assessment of Reduction in Mortality and Morbidity (CHARM) program.

Periodic monitoring of serum potassium is therefore “critical” in heart failure patients—and not just those on candesartan, Dr. Akshay Desai said at the annual meeting of the American College of Cardiology.

“The estimate from our study is that one would expect roughly 34 excess hyperkalemic events per 1,000 candesartan-treated patients over 3 years. But with careful surveillance of serum potassium, this risk can be substantially reduced. In the trial, seven excess serious events per 1,000 patients were noted over the 3-year duration of follow-up with careful monitoring by study investigators. We feel that this represents the unavoidable risk of candesartan therapy in this population of patients,” said Dr. Desai of Brigham and Women's Hospital, Boston.

To place this risk in perspective, he added, candesartan also prevented 43 cardiovascular death or hospitalization events per 1,000 patients.

The CHARM program involved 7,599 heart failure patients on standard therapy who were randomized in double-blind fashion to candesartan or placebo and followed for just over 3 years with regular monitoring of serum potassium. Candesartan resulted in a significant 16% reduction in the relative risk of the primary end point of cardiovascular death or heart failure hospitalization.

Hyperkalemia is well recognized to be a common and potentially life-threatening complication of treatment with renin-angiotensin-aldosterone system inhibitors. CHARM investigators categorized hyperkalemic events as “serious” if they posed a risk of death or hospitalization, and “concerning” if events were serious or would have become so if not detected early through the monitoring program, with subsequent dose adjustment or drug discontinuation.

The incidence of concerning hyperkalemia during the study was 1.8% in the placebo arm and 5.2% in the candesartan group. Serious hyperkalemic events occurred in 1.1% of the placebo group and 1.8% on candesartan. Of particular clinical relevance was the finding that hyperkalemic events were not confined to the period of candesartan dose titration; they occurred throughout follow-up, although the incidence was greater during titration, said Dr. Desai.

Several predictors of increased background risk of concerning hyperkalemia were identified. Age greater than 75 years, being on an ACE inhibitor or spironolactone, or a history of diabetes was associated with roughly a twofold increased risk. Baseline renal insufficiency or hyperkalemia conferred a fivefold spike in risk. Candesartan therapy was associated with a threefold increase in risk of hyperkalemia, compared with placebo—but the drug's therapeutic benefit was also consistent across all patient subgroups, including those at high baseline risk for hyperkalemia.

Dr. Gary S. Francis, director of the coronary intensive care unit at the Cleveland Clinic Foundation, called the new results “very important data that have practical implications.” He asked how often potassium should be monitored.

“I would suggest, particularly in patients at high baseline risk, be quite careful to measure serum potassium within a 2- to 3-week period after every dose titration, and again intermittently—even randomly—over the course of follow-up,” he said.

ATLANTA — Candesartan therapy triples the already significant background risk of potentially serious hyperkalemia in patients with heart failure, according to a new secondary analysis of the Candesartan in Heart Failure—Assessment of Reduction in Mortality and Morbidity (CHARM) program.

Periodic monitoring of serum potassium is therefore “critical” in heart failure patients—and not just those on candesartan, Dr. Akshay Desai said at the annual meeting of the American College of Cardiology.

“The estimate from our study is that one would expect roughly 34 excess hyperkalemic events per 1,000 candesartan-treated patients over 3 years. But with careful surveillance of serum potassium, this risk can be substantially reduced. In the trial, seven excess serious events per 1,000 patients were noted over the 3-year duration of follow-up with careful monitoring by study investigators. We feel that this represents the unavoidable risk of candesartan therapy in this population of patients,” said Dr. Desai of Brigham and Women's Hospital, Boston.

To place this risk in perspective, he added, candesartan also prevented 43 cardiovascular death or hospitalization events per 1,000 patients.

The CHARM program involved 7,599 heart failure patients on standard therapy who were randomized in double-blind fashion to candesartan or placebo and followed for just over 3 years with regular monitoring of serum potassium. Candesartan resulted in a significant 16% reduction in the relative risk of the primary end point of cardiovascular death or heart failure hospitalization.

Hyperkalemia is well recognized to be a common and potentially life-threatening complication of treatment with renin-angiotensin-aldosterone system inhibitors. CHARM investigators categorized hyperkalemic events as “serious” if they posed a risk of death or hospitalization, and “concerning” if events were serious or would have become so if not detected early through the monitoring program, with subsequent dose adjustment or drug discontinuation.

The incidence of concerning hyperkalemia during the study was 1.8% in the placebo arm and 5.2% in the candesartan group. Serious hyperkalemic events occurred in 1.1% of the placebo group and 1.8% on candesartan. Of particular clinical relevance was the finding that hyperkalemic events were not confined to the period of candesartan dose titration; they occurred throughout follow-up, although the incidence was greater during titration, said Dr. Desai.

Several predictors of increased background risk of concerning hyperkalemia were identified. Age greater than 75 years, being on an ACE inhibitor or spironolactone, or a history of diabetes was associated with roughly a twofold increased risk. Baseline renal insufficiency or hyperkalemia conferred a fivefold spike in risk. Candesartan therapy was associated with a threefold increase in risk of hyperkalemia, compared with placebo—but the drug's therapeutic benefit was also consistent across all patient subgroups, including those at high baseline risk for hyperkalemia.

Dr. Gary S. Francis, director of the coronary intensive care unit at the Cleveland Clinic Foundation, called the new results “very important data that have practical implications.” He asked how often potassium should be monitored.

“I would suggest, particularly in patients at high baseline risk, be quite careful to measure serum potassium within a 2- to 3-week period after every dose titration, and again intermittently—even randomly—over the course of follow-up,” he said.