Heart Failure

ELSEVIER GLOBAL MEDICAL NEWS

ELSEVIER GLOBAL MEDICAL NEWS

ELSEVIER GLOBAL MEDICAL NEWS

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

ELSEVIER GLOBAL MEDICAL NEWS

ELSEVIER GLOBAL MEDICAL NEWS

ELSEVIER GLOBAL MEDICAL NEWS

VIENNA — The dopamine agonist bromocriptine shows considerable promise for the treatment of peripartum cardiomyopathy, Dr. Olaf Forster said at the annual congress of the European Society of Cardiology.

“The results obtained by the addition of bromocriptine to standard heart failure treatment in this study are encouraging. Bromocriptine may represent a novel therapeutic approach in the treatment of peripartum cardiomyopathy, but the data need to be considered as preliminary,” according to Dr. Forster of the University of the Witwatersrand, Johannesburg, South Africa.

The hallmark of peripartum cardiomyopathy (PPCM) is onset of left ventricular failure between 1 month before and 5 months after delivery. The highest rates of PPCM in the world are reported in South Africa. “We get two or three new patients per week in Soweto,” said Dr. Forster, who is with the university's cardiovascular research unit at the Chris Hani Baragwanath Hospital, Soweto.

Treatment of PPCM involves standard heart failure medications and firm advice to avoid further pregnancies. A subsequent pregnancy can be fatal; half of women who become pregnant again after a first episode of PPCM experience long-term worsening of heart failure, whereas the other half return to their normal prepregnancy left ventricular systolic function.

Dr. Forster reported on 16 indigenous black women ages 26–39 with PPCM who presented with a subsequent pregnancy 1–6 years following their index PPCM pregnancy. The first six women—the control group—didn't receive bromocriptine because their pregnancies occurred before the South African team learned of evidence from German studies in knockout mice suggesting that the drug might be beneficial in PPCM. The next 10 patients received bromocriptine at 2.5 mg b.i.d. for 2 months beginning 4 hours post delivery. This was the first study of the drug in human PPCM.

All 16 patients were on a diuretic and β-blocker during pregnancy, with an ACE inhibitor added post partum.

The mean left ventricular ejection fraction in controls was 44% at baseline, declining to 36% at 1 month post partum and to 25% 3 months post partum. In contrast, the baseline ejection fraction was 51% in the bromocriptine-treated group, dropping to 43% 1 month post partum, and rebounding to 55% by 3 months post partum.

At 3 months post partum, 2 of 6 controls were dead of heart failure, compared with none of the 10 women who received bromocriptine.

Bromocriptine had no side effects, but some women on the prolactin inhibitor were quite disturbed that they couldn't breast feed, according to Dr. Forster.

In the STAT3 female knockout mouse model of PPCM, enhanced postpartum oxidative stress results in cathepsin D-facilitated cleavage of the 23-kd form of prolactin into its 16-kd form, which is proapoptotic and antiangiogenic. This short-form prolactin disrupts endothelial cell function and promotes vasoconstriction, resulting in impaired cardiac microcirculation, increased cardiac apoptosis, and reduced postpartum survival. Bromocriptine prevents PPCM in this model.

Session cochair Dr. Robert Califf, vice-chancellor for clinical research, director of the Translational Medicine Institute, and professor of medicine at Duke University, Durham, N.C., called the clinical results encouraging, but wondered why the investigators hadn't mounted a randomized trial. Dr. Forster replied that the risks posed by subsequent pregnancy in women with PPCM are so great that he and his coworkers believe it would be unethical to deny them bromocriptine. “The risk is simply too high—and we can see that it works,” he explained.

However, a randomized trial is ongoing in women experiencing a first episode of PPCM, Dr. Forster added.

VIENNA — The dopamine agonist bromocriptine shows considerable promise for the treatment of peripartum cardiomyopathy, Dr. Olaf Forster said at the annual congress of the European Society of Cardiology.

“The results obtained by the addition of bromocriptine to standard heart failure treatment in this study are encouraging. Bromocriptine may represent a novel therapeutic approach in the treatment of peripartum cardiomyopathy, but the data need to be considered as preliminary,” according to Dr. Forster of the University of the Witwatersrand, Johannesburg, South Africa.

The hallmark of peripartum cardiomyopathy (PPCM) is onset of left ventricular failure between 1 month before and 5 months after delivery. The highest rates of PPCM in the world are reported in South Africa. “We get two or three new patients per week in Soweto,” said Dr. Forster, who is with the university's cardiovascular research unit at the Chris Hani Baragwanath Hospital, Soweto.

Treatment of PPCM involves standard heart failure medications and firm advice to avoid further pregnancies. A subsequent pregnancy can be fatal; half of women who become pregnant again after a first episode of PPCM experience long-term worsening of heart failure, whereas the other half return to their normal prepregnancy left ventricular systolic function.

Dr. Forster reported on 16 indigenous black women ages 26–39 with PPCM who presented with a subsequent pregnancy 1–6 years following their index PPCM pregnancy. The first six women—the control group—didn't receive bromocriptine because their pregnancies occurred before the South African team learned of evidence from German studies in knockout mice suggesting that the drug might be beneficial in PPCM. The next 10 patients received bromocriptine at 2.5 mg b.i.d. for 2 months beginning 4 hours post delivery. This was the first study of the drug in human PPCM.

All 16 patients were on a diuretic and β-blocker during pregnancy, with an ACE inhibitor added post partum.

The mean left ventricular ejection fraction in controls was 44% at baseline, declining to 36% at 1 month post partum and to 25% 3 months post partum. In contrast, the baseline ejection fraction was 51% in the bromocriptine-treated group, dropping to 43% 1 month post partum, and rebounding to 55% by 3 months post partum.

At 3 months post partum, 2 of 6 controls were dead of heart failure, compared with none of the 10 women who received bromocriptine.

Bromocriptine had no side effects, but some women on the prolactin inhibitor were quite disturbed that they couldn't breast feed, according to Dr. Forster.

In the STAT3 female knockout mouse model of PPCM, enhanced postpartum oxidative stress results in cathepsin D-facilitated cleavage of the 23-kd form of prolactin into its 16-kd form, which is proapoptotic and antiangiogenic. This short-form prolactin disrupts endothelial cell function and promotes vasoconstriction, resulting in impaired cardiac microcirculation, increased cardiac apoptosis, and reduced postpartum survival. Bromocriptine prevents PPCM in this model.

Session cochair Dr. Robert Califf, vice-chancellor for clinical research, director of the Translational Medicine Institute, and professor of medicine at Duke University, Durham, N.C., called the clinical results encouraging, but wondered why the investigators hadn't mounted a randomized trial. Dr. Forster replied that the risks posed by subsequent pregnancy in women with PPCM are so great that he and his coworkers believe it would be unethical to deny them bromocriptine. “The risk is simply too high—and we can see that it works,” he explained.

However, a randomized trial is ongoing in women experiencing a first episode of PPCM, Dr. Forster added.

VIENNA — The dopamine agonist bromocriptine shows considerable promise for the treatment of peripartum cardiomyopathy, Dr. Olaf Forster said at the annual congress of the European Society of Cardiology.

“The results obtained by the addition of bromocriptine to standard heart failure treatment in this study are encouraging. Bromocriptine may represent a novel therapeutic approach in the treatment of peripartum cardiomyopathy, but the data need to be considered as preliminary,” according to Dr. Forster of the University of the Witwatersrand, Johannesburg, South Africa.

The hallmark of peripartum cardiomyopathy (PPCM) is onset of left ventricular failure between 1 month before and 5 months after delivery. The highest rates of PPCM in the world are reported in South Africa. “We get two or three new patients per week in Soweto,” said Dr. Forster, who is with the university's cardiovascular research unit at the Chris Hani Baragwanath Hospital, Soweto.

Treatment of PPCM involves standard heart failure medications and firm advice to avoid further pregnancies. A subsequent pregnancy can be fatal; half of women who become pregnant again after a first episode of PPCM experience long-term worsening of heart failure, whereas the other half return to their normal prepregnancy left ventricular systolic function.

Dr. Forster reported on 16 indigenous black women ages 26–39 with PPCM who presented with a subsequent pregnancy 1–6 years following their index PPCM pregnancy. The first six women—the control group—didn't receive bromocriptine because their pregnancies occurred before the South African team learned of evidence from German studies in knockout mice suggesting that the drug might be beneficial in PPCM. The next 10 patients received bromocriptine at 2.5 mg b.i.d. for 2 months beginning 4 hours post delivery. This was the first study of the drug in human PPCM.

All 16 patients were on a diuretic and β-blocker during pregnancy, with an ACE inhibitor added post partum.

The mean left ventricular ejection fraction in controls was 44% at baseline, declining to 36% at 1 month post partum and to 25% 3 months post partum. In contrast, the baseline ejection fraction was 51% in the bromocriptine-treated group, dropping to 43% 1 month post partum, and rebounding to 55% by 3 months post partum.

At 3 months post partum, 2 of 6 controls were dead of heart failure, compared with none of the 10 women who received bromocriptine.

Bromocriptine had no side effects, but some women on the prolactin inhibitor were quite disturbed that they couldn't breast feed, according to Dr. Forster.

In the STAT3 female knockout mouse model of PPCM, enhanced postpartum oxidative stress results in cathepsin D-facilitated cleavage of the 23-kd form of prolactin into its 16-kd form, which is proapoptotic and antiangiogenic. This short-form prolactin disrupts endothelial cell function and promotes vasoconstriction, resulting in impaired cardiac microcirculation, increased cardiac apoptosis, and reduced postpartum survival. Bromocriptine prevents PPCM in this model.

Session cochair Dr. Robert Califf, vice-chancellor for clinical research, director of the Translational Medicine Institute, and professor of medicine at Duke University, Durham, N.C., called the clinical results encouraging, but wondered why the investigators hadn't mounted a randomized trial. Dr. Forster replied that the risks posed by subsequent pregnancy in women with PPCM are so great that he and his coworkers believe it would be unethical to deny them bromocriptine. “The risk is simply too high—and we can see that it works,” he explained.

However, a randomized trial is ongoing in women experiencing a first episode of PPCM, Dr. Forster added.

Updated clinical practice guidelines for the medical management of pulmonary arterial hypertension from the American College of Chest Physicians reflect findings from several recent clinical trials as well as the additional drugs that have been approved since the previous guidelines were issued in 2004.

The guidelines include an evidence-based, updated treatment algorithm intended to assist physicians in decision making (Chest 2007;131:1917–28).

Providing new data were two “important” studies that demonstrated survival benefits in patients treated with bosentan, which binds to both endothelin receptors (ETA and ETB), according to lead author Dr. David B. Badesch of the University of Colorado Health Sciences Center, Denver.

In the first study, 169 patients (aged 13–80 years) with class III or IV PAH were treated with bosentan as first-line therapy. Survival was 96% at 12 months and 89% at 24 months, in contrast to predicted survival rates from the earlier National Institutes of Health registry of 69% and 57%, respectively (Eur. Respir. J. 2005;25:244–9).

In the second study, survival in 139 patients treated with bosentan was compared with historical data from 346 patients who had been treated with epoprostenol. Survival estimates after 1 and 2 years were 97% and 91%, respectively, in the bosentan-treated group, and 91% and 84% in the epoprostenol-treated group (Thorax 2005;60:1025–30).

Baseline characteristics of the patients suggested that the epoprostenol patients had more severe disease. But Cox regression analyses adjusting for baseline factors showed a greater risk of death in the epoprostenol group (hazard ratio 2.2).

Bosentan also has now been evaluated in children with PAH associated with congenital heart disease or connective tissue disease. In a retrospective study, 86 children were treated with bosentan with or without concomitant epoprostenol or treprostinil. WHO functional class improved in 46% of patients and was unchanged in 44%, and survival estimates at 1 and 2 years were 98% and 91% (J. Am. Coll. Cardiol. 2005;46:697–704).

Another recent study included 245 patients (ranging in age from 12 years to 78 years) who received bosentan, placebo, or one of two doses of a selective ETA endothelin receptor antagonist, sitaxsentan. At week 18, patients receiving the higher dose of sitaxsentan (100 mg/day) had significant improvements on a 6-minute walk test, compared with those receiving placebo. The incidence of elevated transaminases was 6% in the placebo group, 5% in the sitaxsentan low-dose (50 mg/day) group, 3% in the high-dose sitaxsentan group, and 11% in the bosentan group (J. Am. Coll. Cardiol. 2006;47:2049–56).

Sitaxsentan remains investigational in the United States, but has been approved for use in Europe and Canada.

A second selective ETA endothelin receptor antagonist, ambrisentan, was evaluated in a double-blind, dose-ranging study that included 64 adult patients with PAH. They were randomized to receive 1 mg, 2.5 mg, 5 mg, or 10 mg of ambrisentan orally once daily for 12 weeks. The 6-minute walk test improved significantly for all groups, with a mean increase from baseline of 36.1 meters. Improvements also were seen in WHO functional class, Borg dyspnea index, and cardiac index (J. Am. Coll. Cardiol. 2005;46:529–35).

Adverse events were mild, with elevated serum aminotransferase exceeding three times the upper limit of normal seen in 3.1% of patients. This drug was recently approved for class II and class III PAH in the United States.

The phosphodiesterase inhibitor sildenafil also is now approved for the treatment of all classes of PAH in a dosage of 20 mg three times daily. The drug was evaluated in a double-blind study that randomized 278 patients (mean age 50 years) to placebo or 20, 40, or 80 mg three times daily for 12 weeks.

Improvements were seen in the 6-minute walk test in all groups, with placebo-corrected treatment effects being +13%, +13.3%, and +14.7% in the 20-, 40-, and 80-mg groups, respectively. The incidence of clinical worsening did not differ significantly between the placebo and sildenafil groups. Side effects included flushing, dyspepsia, and diarrhea.

In summarizing the treatment options, the authors noted that for patients in functional class II, the only current recommended drugs are sildenafil and subcutaneous and intravenous treprostinil, and suggested that sildenafil may be the first choice for most patients because of ease of administration and relative efficacy.

For patients in functional class III, five drugs are available: bosentan, sildenafil, intravenous epoprostenol, inhaled iloprost, and subcutaneous or intravenous treprostinil. For those with early class III disease, oral bosentan or sildenafil may be used, with the choice reflecting relative toxicities. For patients with more advanced disease, prostanoid therapy may be needed.

All the available agents are approved for patients with class IV PAH. However, the authors wrote, “[we] strongly encourage IV epoprostenol as the treatment of choice for these most critically ill patients. IV epoprostenol has a rapid and predictable onset of action, and most experts are familiar with how to titrate this drug in the acute setting.”

Updated clinical practice guidelines for the medical management of pulmonary arterial hypertension from the American College of Chest Physicians reflect findings from several recent clinical trials as well as the additional drugs that have been approved since the previous guidelines were issued in 2004.

The guidelines include an evidence-based, updated treatment algorithm intended to assist physicians in decision making (Chest 2007;131:1917–28).

Providing new data were two “important” studies that demonstrated survival benefits in patients treated with bosentan, which binds to both endothelin receptors (ETA and ETB), according to lead author Dr. David B. Badesch of the University of Colorado Health Sciences Center, Denver.

In the first study, 169 patients (aged 13–80 years) with class III or IV PAH were treated with bosentan as first-line therapy. Survival was 96% at 12 months and 89% at 24 months, in contrast to predicted survival rates from the earlier National Institutes of Health registry of 69% and 57%, respectively (Eur. Respir. J. 2005;25:244–9).

In the second study, survival in 139 patients treated with bosentan was compared with historical data from 346 patients who had been treated with epoprostenol. Survival estimates after 1 and 2 years were 97% and 91%, respectively, in the bosentan-treated group, and 91% and 84% in the epoprostenol-treated group (Thorax 2005;60:1025–30).

Baseline characteristics of the patients suggested that the epoprostenol patients had more severe disease. But Cox regression analyses adjusting for baseline factors showed a greater risk of death in the epoprostenol group (hazard ratio 2.2).

Bosentan also has now been evaluated in children with PAH associated with congenital heart disease or connective tissue disease. In a retrospective study, 86 children were treated with bosentan with or without concomitant epoprostenol or treprostinil. WHO functional class improved in 46% of patients and was unchanged in 44%, and survival estimates at 1 and 2 years were 98% and 91% (J. Am. Coll. Cardiol. 2005;46:697–704).

Another recent study included 245 patients (ranging in age from 12 years to 78 years) who received bosentan, placebo, or one of two doses of a selective ETA endothelin receptor antagonist, sitaxsentan. At week 18, patients receiving the higher dose of sitaxsentan (100 mg/day) had significant improvements on a 6-minute walk test, compared with those receiving placebo. The incidence of elevated transaminases was 6% in the placebo group, 5% in the sitaxsentan low-dose (50 mg/day) group, 3% in the high-dose sitaxsentan group, and 11% in the bosentan group (J. Am. Coll. Cardiol. 2006;47:2049–56).

Sitaxsentan remains investigational in the United States, but has been approved for use in Europe and Canada.

A second selective ETA endothelin receptor antagonist, ambrisentan, was evaluated in a double-blind, dose-ranging study that included 64 adult patients with PAH. They were randomized to receive 1 mg, 2.5 mg, 5 mg, or 10 mg of ambrisentan orally once daily for 12 weeks. The 6-minute walk test improved significantly for all groups, with a mean increase from baseline of 36.1 meters. Improvements also were seen in WHO functional class, Borg dyspnea index, and cardiac index (J. Am. Coll. Cardiol. 2005;46:529–35).

Adverse events were mild, with elevated serum aminotransferase exceeding three times the upper limit of normal seen in 3.1% of patients. This drug was recently approved for class II and class III PAH in the United States.

The phosphodiesterase inhibitor sildenafil also is now approved for the treatment of all classes of PAH in a dosage of 20 mg three times daily. The drug was evaluated in a double-blind study that randomized 278 patients (mean age 50 years) to placebo or 20, 40, or 80 mg three times daily for 12 weeks.

Improvements were seen in the 6-minute walk test in all groups, with placebo-corrected treatment effects being +13%, +13.3%, and +14.7% in the 20-, 40-, and 80-mg groups, respectively. The incidence of clinical worsening did not differ significantly between the placebo and sildenafil groups. Side effects included flushing, dyspepsia, and diarrhea.

In summarizing the treatment options, the authors noted that for patients in functional class II, the only current recommended drugs are sildenafil and subcutaneous and intravenous treprostinil, and suggested that sildenafil may be the first choice for most patients because of ease of administration and relative efficacy.

For patients in functional class III, five drugs are available: bosentan, sildenafil, intravenous epoprostenol, inhaled iloprost, and subcutaneous or intravenous treprostinil. For those with early class III disease, oral bosentan or sildenafil may be used, with the choice reflecting relative toxicities. For patients with more advanced disease, prostanoid therapy may be needed.

All the available agents are approved for patients with class IV PAH. However, the authors wrote, “[we] strongly encourage IV epoprostenol as the treatment of choice for these most critically ill patients. IV epoprostenol has a rapid and predictable onset of action, and most experts are familiar with how to titrate this drug in the acute setting.”

Updated clinical practice guidelines for the medical management of pulmonary arterial hypertension from the American College of Chest Physicians reflect findings from several recent clinical trials as well as the additional drugs that have been approved since the previous guidelines were issued in 2004.

The guidelines include an evidence-based, updated treatment algorithm intended to assist physicians in decision making (Chest 2007;131:1917–28).

Providing new data were two “important” studies that demonstrated survival benefits in patients treated with bosentan, which binds to both endothelin receptors (ETA and ETB), according to lead author Dr. David B. Badesch of the University of Colorado Health Sciences Center, Denver.

In the first study, 169 patients (aged 13–80 years) with class III or IV PAH were treated with bosentan as first-line therapy. Survival was 96% at 12 months and 89% at 24 months, in contrast to predicted survival rates from the earlier National Institutes of Health registry of 69% and 57%, respectively (Eur. Respir. J. 2005;25:244–9).

In the second study, survival in 139 patients treated with bosentan was compared with historical data from 346 patients who had been treated with epoprostenol. Survival estimates after 1 and 2 years were 97% and 91%, respectively, in the bosentan-treated group, and 91% and 84% in the epoprostenol-treated group (Thorax 2005;60:1025–30).

Baseline characteristics of the patients suggested that the epoprostenol patients had more severe disease. But Cox regression analyses adjusting for baseline factors showed a greater risk of death in the epoprostenol group (hazard ratio 2.2).

Bosentan also has now been evaluated in children with PAH associated with congenital heart disease or connective tissue disease. In a retrospective study, 86 children were treated with bosentan with or without concomitant epoprostenol or treprostinil. WHO functional class improved in 46% of patients and was unchanged in 44%, and survival estimates at 1 and 2 years were 98% and 91% (J. Am. Coll. Cardiol. 2005;46:697–704).

Another recent study included 245 patients (ranging in age from 12 years to 78 years) who received bosentan, placebo, or one of two doses of a selective ETA endothelin receptor antagonist, sitaxsentan. At week 18, patients receiving the higher dose of sitaxsentan (100 mg/day) had significant improvements on a 6-minute walk test, compared with those receiving placebo. The incidence of elevated transaminases was 6% in the placebo group, 5% in the sitaxsentan low-dose (50 mg/day) group, 3% in the high-dose sitaxsentan group, and 11% in the bosentan group (J. Am. Coll. Cardiol. 2006;47:2049–56).

Sitaxsentan remains investigational in the United States, but has been approved for use in Europe and Canada.

A second selective ETA endothelin receptor antagonist, ambrisentan, was evaluated in a double-blind, dose-ranging study that included 64 adult patients with PAH. They were randomized to receive 1 mg, 2.5 mg, 5 mg, or 10 mg of ambrisentan orally once daily for 12 weeks. The 6-minute walk test improved significantly for all groups, with a mean increase from baseline of 36.1 meters. Improvements also were seen in WHO functional class, Borg dyspnea index, and cardiac index (J. Am. Coll. Cardiol. 2005;46:529–35).

Adverse events were mild, with elevated serum aminotransferase exceeding three times the upper limit of normal seen in 3.1% of patients. This drug was recently approved for class II and class III PAH in the United States.

The phosphodiesterase inhibitor sildenafil also is now approved for the treatment of all classes of PAH in a dosage of 20 mg three times daily. The drug was evaluated in a double-blind study that randomized 278 patients (mean age 50 years) to placebo or 20, 40, or 80 mg three times daily for 12 weeks.

Improvements were seen in the 6-minute walk test in all groups, with placebo-corrected treatment effects being +13%, +13.3%, and +14.7% in the 20-, 40-, and 80-mg groups, respectively. The incidence of clinical worsening did not differ significantly between the placebo and sildenafil groups. Side effects included flushing, dyspepsia, and diarrhea.

In summarizing the treatment options, the authors noted that for patients in functional class II, the only current recommended drugs are sildenafil and subcutaneous and intravenous treprostinil, and suggested that sildenafil may be the first choice for most patients because of ease of administration and relative efficacy.

For patients in functional class III, five drugs are available: bosentan, sildenafil, intravenous epoprostenol, inhaled iloprost, and subcutaneous or intravenous treprostinil. For those with early class III disease, oral bosentan or sildenafil may be used, with the choice reflecting relative toxicities. For patients with more advanced disease, prostanoid therapy may be needed.

All the available agents are approved for patients with class IV PAH. However, the authors wrote, “[we] strongly encourage IV epoprostenol as the treatment of choice for these most critically ill patients. IV epoprostenol has a rapid and predictable onset of action, and most experts are familiar with how to titrate this drug in the acute setting.”

SAN FRANCISCO — Some patients awaiting heart transplantation are as likely to remain alive for 2 years as are those who get transplanted hearts, an outcome that raises the question of whether better risk-stratification methods would keep some patients from being wait-listed in the first place, Dr. Katherine Lietz said at the annual meeting of the International Society for Heart and Lung Transplantation.

In a retrospective study of newly wait-listed patients in the U.S. from 1990 to 2005, Dr. Lietz and her colleague found that the odds of being alive 1 year later or having received a heart transplant jumped from 49% to 69% for patients classified as United Network for Organ Sharing (UNOS) status 1, and improved from 81% to 89% for UNOS status 2 patients.

The probability of wait-listed patients undergoing heart transplantation within 1 year barely changed during that time span. For status 2 patients, the odds of being transplanted within 1 year decreased from 53% in 1990–1994 to 49% in 2000–2005. For status 1 patients, the odds of being transplanted within 1 year crept from 85% to 87%, and the probability of remaining alive on the waiting list for 1 year increased from 17% in 1990–1994 to 40% in 2000–2005.

The improvements seem to be attributable to better medical and device therapies for advanced heart failure, which are keeping patients alive longer on transplant waiting lists, Dr. Lietz said. UNOS status 1 includes the sickest patients who are on device or mechanical support or continuous infusion with IV inotropes. The number of status 1 patients on heart transplant waiting lists increased from 836 in 1990 to 1,159 in 2005, while the number of status 2 patients on a waiting list decreased from 2,612 in 1992 to 1,147 in 2005. Today, the two groups are nearly equally represented on the waiting lists, reported the investigators, of Georgetown University, Washington.

For status 2 patients, the chances of being alive after 2 years on the waiting list increased from 65% in 1990–1994 to 81% in 2000–2005. That 81% survival rate approaches the current 85% survival rate for patients undergoing heart transplantation. Statistical modeling suggests that 2-year survival for patients added to waiting lists today as status 2 would be equivalent to that of patients undergoing heart transplantation, Dr. Lietz observed.

“That raises the question of whether early listing is justified in some of these patients,” she said.

Status 2 patients are a heterogeneous group, however. In the study, 20% died within 2 years of wait-listing, and another 20% were upgraded to status 1. On the other hand, 1,701 status 2 patients were alive more than 5 years after being wait-listed, and 261 patients were alive after 10 years on the list.

“We need better methods of risk-stratifying them, as early listing may not be justified in all these patients,” Dr. Lietz said.

A physician in the audience suggested that what might help more than better risk stratification at the time of wait-listing is better recognition of “triggers” that should prompt reclassification of patients on the list. These might include status 2 patients whose tolerance to β-blocker therapy decreases, or those who develop a creatinine level greater than 1 mg/dL, she said.

Among the wait-listed status 1 patients, 39% died within 2 months. In this very high-risk group, few patients were supported with mechanical devices. The lack of an implantable cardioverter defibrillator (ICD) was significantly associated with poorer outcomes, “perhaps confirming the role of ICD as a bridge to transplantation in these patients,” Dr. Lietz said. “For [status 1] patients who are very sick with signs of severe pump failure, use of mechanical circulatory support should be considered,” especially if the anticipated wait before transplantation exceeds 2 months because of the patient's blood type, body size, or other factors.

SAN FRANCISCO — Some patients awaiting heart transplantation are as likely to remain alive for 2 years as are those who get transplanted hearts, an outcome that raises the question of whether better risk-stratification methods would keep some patients from being wait-listed in the first place, Dr. Katherine Lietz said at the annual meeting of the International Society for Heart and Lung Transplantation.

In a retrospective study of newly wait-listed patients in the U.S. from 1990 to 2005, Dr. Lietz and her colleague found that the odds of being alive 1 year later or having received a heart transplant jumped from 49% to 69% for patients classified as United Network for Organ Sharing (UNOS) status 1, and improved from 81% to 89% for UNOS status 2 patients.

The probability of wait-listed patients undergoing heart transplantation within 1 year barely changed during that time span. For status 2 patients, the odds of being transplanted within 1 year decreased from 53% in 1990–1994 to 49% in 2000–2005. For status 1 patients, the odds of being transplanted within 1 year crept from 85% to 87%, and the probability of remaining alive on the waiting list for 1 year increased from 17% in 1990–1994 to 40% in 2000–2005.

The improvements seem to be attributable to better medical and device therapies for advanced heart failure, which are keeping patients alive longer on transplant waiting lists, Dr. Lietz said. UNOS status 1 includes the sickest patients who are on device or mechanical support or continuous infusion with IV inotropes. The number of status 1 patients on heart transplant waiting lists increased from 836 in 1990 to 1,159 in 2005, while the number of status 2 patients on a waiting list decreased from 2,612 in 1992 to 1,147 in 2005. Today, the two groups are nearly equally represented on the waiting lists, reported the investigators, of Georgetown University, Washington.

For status 2 patients, the chances of being alive after 2 years on the waiting list increased from 65% in 1990–1994 to 81% in 2000–2005. That 81% survival rate approaches the current 85% survival rate for patients undergoing heart transplantation. Statistical modeling suggests that 2-year survival for patients added to waiting lists today as status 2 would be equivalent to that of patients undergoing heart transplantation, Dr. Lietz observed.

“That raises the question of whether early listing is justified in some of these patients,” she said.

Status 2 patients are a heterogeneous group, however. In the study, 20% died within 2 years of wait-listing, and another 20% were upgraded to status 1. On the other hand, 1,701 status 2 patients were alive more than 5 years after being wait-listed, and 261 patients were alive after 10 years on the list.

“We need better methods of risk-stratifying them, as early listing may not be justified in all these patients,” Dr. Lietz said.

A physician in the audience suggested that what might help more than better risk stratification at the time of wait-listing is better recognition of “triggers” that should prompt reclassification of patients on the list. These might include status 2 patients whose tolerance to β-blocker therapy decreases, or those who develop a creatinine level greater than 1 mg/dL, she said.

Among the wait-listed status 1 patients, 39% died within 2 months. In this very high-risk group, few patients were supported with mechanical devices. The lack of an implantable cardioverter defibrillator (ICD) was significantly associated with poorer outcomes, “perhaps confirming the role of ICD as a bridge to transplantation in these patients,” Dr. Lietz said. “For [status 1] patients who are very sick with signs of severe pump failure, use of mechanical circulatory support should be considered,” especially if the anticipated wait before transplantation exceeds 2 months because of the patient's blood type, body size, or other factors.

SAN FRANCISCO — Some patients awaiting heart transplantation are as likely to remain alive for 2 years as are those who get transplanted hearts, an outcome that raises the question of whether better risk-stratification methods would keep some patients from being wait-listed in the first place, Dr. Katherine Lietz said at the annual meeting of the International Society for Heart and Lung Transplantation.

In a retrospective study of newly wait-listed patients in the U.S. from 1990 to 2005, Dr. Lietz and her colleague found that the odds of being alive 1 year later or having received a heart transplant jumped from 49% to 69% for patients classified as United Network for Organ Sharing (UNOS) status 1, and improved from 81% to 89% for UNOS status 2 patients.

The probability of wait-listed patients undergoing heart transplantation within 1 year barely changed during that time span. For status 2 patients, the odds of being transplanted within 1 year decreased from 53% in 1990–1994 to 49% in 2000–2005. For status 1 patients, the odds of being transplanted within 1 year crept from 85% to 87%, and the probability of remaining alive on the waiting list for 1 year increased from 17% in 1990–1994 to 40% in 2000–2005.

The improvements seem to be attributable to better medical and device therapies for advanced heart failure, which are keeping patients alive longer on transplant waiting lists, Dr. Lietz said. UNOS status 1 includes the sickest patients who are on device or mechanical support or continuous infusion with IV inotropes. The number of status 1 patients on heart transplant waiting lists increased from 836 in 1990 to 1,159 in 2005, while the number of status 2 patients on a waiting list decreased from 2,612 in 1992 to 1,147 in 2005. Today, the two groups are nearly equally represented on the waiting lists, reported the investigators, of Georgetown University, Washington.

For status 2 patients, the chances of being alive after 2 years on the waiting list increased from 65% in 1990–1994 to 81% in 2000–2005. That 81% survival rate approaches the current 85% survival rate for patients undergoing heart transplantation. Statistical modeling suggests that 2-year survival for patients added to waiting lists today as status 2 would be equivalent to that of patients undergoing heart transplantation, Dr. Lietz observed.

“That raises the question of whether early listing is justified in some of these patients,” she said.

Status 2 patients are a heterogeneous group, however. In the study, 20% died within 2 years of wait-listing, and another 20% were upgraded to status 1. On the other hand, 1,701 status 2 patients were alive more than 5 years after being wait-listed, and 261 patients were alive after 10 years on the list.

“We need better methods of risk-stratifying them, as early listing may not be justified in all these patients,” Dr. Lietz said.

A physician in the audience suggested that what might help more than better risk stratification at the time of wait-listing is better recognition of “triggers” that should prompt reclassification of patients on the list. These might include status 2 patients whose tolerance to β-blocker therapy decreases, or those who develop a creatinine level greater than 1 mg/dL, she said.

Among the wait-listed status 1 patients, 39% died within 2 months. In this very high-risk group, few patients were supported with mechanical devices. The lack of an implantable cardioverter defibrillator (ICD) was significantly associated with poorer outcomes, “perhaps confirming the role of ICD as a bridge to transplantation in these patients,” Dr. Lietz said. “For [status 1] patients who are very sick with signs of severe pump failure, use of mechanical circulatory support should be considered,” especially if the anticipated wait before transplantation exceeds 2 months because of the patient's blood type, body size, or other factors.

SAN FRANCISCO — Patients over the age of 70 do almost as well after heart transplants as younger recipients, unless they are infected with hepatitis C, according to a poster presentation by Dr. Jignesh K. Patel at the American Transplant Congress.

In a retrospective analysis, Dr. Patel and colleagues from the University of California, Los Angeles, compared 25 heart recipients aged 70-75 years (mean of 72 years) with 246 younger patients (mean of 56 years).

There were no differences between the groups in early cardiac allograft vasculopathy or in the percentage of patients being treated for rejection during the first year.

The younger patients did have a significantly higher 5-year survival rate than did the older patients–80% vs. 64%. However, when the investigators excluded from the analysis all patients with hepatitis C at the time of transplant and those receiving organs from hepatitis C-positive donors, the difference in 5-year survival failed to reach statistical significance. Three of the nine patients who died in the older age group had hepatitis C prior to transplantation.

Since all the older patients were classified as status 2, indicating relatively low-risk patients who did not require intravenous medications, the investigators selected only status 2 recipients for the control group.

SAN FRANCISCO — Patients over the age of 70 do almost as well after heart transplants as younger recipients, unless they are infected with hepatitis C, according to a poster presentation by Dr. Jignesh K. Patel at the American Transplant Congress.

In a retrospective analysis, Dr. Patel and colleagues from the University of California, Los Angeles, compared 25 heart recipients aged 70-75 years (mean of 72 years) with 246 younger patients (mean of 56 years).

There were no differences between the groups in early cardiac allograft vasculopathy or in the percentage of patients being treated for rejection during the first year.

The younger patients did have a significantly higher 5-year survival rate than did the older patients–80% vs. 64%. However, when the investigators excluded from the analysis all patients with hepatitis C at the time of transplant and those receiving organs from hepatitis C-positive donors, the difference in 5-year survival failed to reach statistical significance. Three of the nine patients who died in the older age group had hepatitis C prior to transplantation.

Since all the older patients were classified as status 2, indicating relatively low-risk patients who did not require intravenous medications, the investigators selected only status 2 recipients for the control group.

SAN FRANCISCO — Patients over the age of 70 do almost as well after heart transplants as younger recipients, unless they are infected with hepatitis C, according to a poster presentation by Dr. Jignesh K. Patel at the American Transplant Congress.

In a retrospective analysis, Dr. Patel and colleagues from the University of California, Los Angeles, compared 25 heart recipients aged 70-75 years (mean of 72 years) with 246 younger patients (mean of 56 years).

There were no differences between the groups in early cardiac allograft vasculopathy or in the percentage of patients being treated for rejection during the first year.

The younger patients did have a significantly higher 5-year survival rate than did the older patients–80% vs. 64%. However, when the investigators excluded from the analysis all patients with hepatitis C at the time of transplant and those receiving organs from hepatitis C-positive donors, the difference in 5-year survival failed to reach statistical significance. Three of the nine patients who died in the older age group had hepatitis C prior to transplantation.

Since all the older patients were classified as status 2, indicating relatively low-risk patients who did not require intravenous medications, the investigators selected only status 2 recipients for the control group.

NEW ORLEANS — Angiotensin receptor blockers were associated with significantly greater risk of worsening renal function than were angiotentin-converting enzyme inhibitors in patients with systolic heart failure in a meta-analysis of all seven head-to-head comparative randomized, controlled, clinical trials, Dr. Rachid Lakhdar reported at the annual meeting of the American College of Cardiology.

“The ARBs are trying to make it as first-line drugs. The most recent guidelines put them as a class IIa indication, allowing them as first-line therapy in patients with mild to moderate heart failure and reduced left ventricular function,” he said in an interview.

“Our conclusion from the meta-analysis is maybe that's not such a good idea, and ARBs should continue to be second line, to be used when ACE inhibitors are contraindicated,” he continued.

The meta-analysis involved 20,143 systolic dysfunction heart failure patients who were randomized to an ACE inhibitor or ARB. Among the studies they were drawn from were the Valsartan in Acute Myocardial Infarction Trial (VALIANT), the first and second Evaluation of Losartan in the Elderly (ELITE I and II), the Optimal Therapy in Myocardial Infarction With the Angiotensin II Antagonist Losartan (OPTIMAAL) trial, and the Randomized Evaluation of Strategies for Left Ventricular Dysfunction (RESOLVD) study.

Carried out without commercial support, the meta-analysis clearly showed that overall side effects were significantly less frequent with ARBs. Indeed, the combined incidence of cough, angioedema, hyperkalemia, hypotension, and worsening renal function was 42% less with ARB therapy than with ACE inhibitor therapy in patients with systolic heart failure. However, the relative risk of worsening renal function was 60% greater with angiotensin receptor blockers, according to Dr. Lakhdar, a third-year resident at the Henry Ford Hospital System, Detroit.

The ARB and ACE inhibitor arms were evenly matched in terms of diuretic therapy and other potential confounders.

“This is a new observation that certainly needs more research, including a prospective study to pinpoint the pathophysiology as to why ARBs are more likely to worsen renal function,” the physician added.

Discussant Dr. Lynne E. Wagoner predicted that guideline-writing committees are going to have to pay attention to the new meta-analysis.

“Cough is the major reason ACE inhibitors are discontinued. Often that cough is not severe and certainly is not life threatening,” said Dr. Wagoner, medical director of the cardiac transplantation division at the University of Cincinnati.

“However, the risk of worsening renal function is potentially life threatening and therefore should be stressed in guideline recommendations. ARBs should remain second-line therapy behind ACE inhibitors as a result of these findings,” he continued.

NEW ORLEANS — Angiotensin receptor blockers were associated with significantly greater risk of worsening renal function than were angiotentin-converting enzyme inhibitors in patients with systolic heart failure in a meta-analysis of all seven head-to-head comparative randomized, controlled, clinical trials, Dr. Rachid Lakhdar reported at the annual meeting of the American College of Cardiology.

“The ARBs are trying to make it as first-line drugs. The most recent guidelines put them as a class IIa indication, allowing them as first-line therapy in patients with mild to moderate heart failure and reduced left ventricular function,” he said in an interview.

“Our conclusion from the meta-analysis is maybe that's not such a good idea, and ARBs should continue to be second line, to be used when ACE inhibitors are contraindicated,” he continued.

The meta-analysis involved 20,143 systolic dysfunction heart failure patients who were randomized to an ACE inhibitor or ARB. Among the studies they were drawn from were the Valsartan in Acute Myocardial Infarction Trial (VALIANT), the first and second Evaluation of Losartan in the Elderly (ELITE I and II), the Optimal Therapy in Myocardial Infarction With the Angiotensin II Antagonist Losartan (OPTIMAAL) trial, and the Randomized Evaluation of Strategies for Left Ventricular Dysfunction (RESOLVD) study.

Carried out without commercial support, the meta-analysis clearly showed that overall side effects were significantly less frequent with ARBs. Indeed, the combined incidence of cough, angioedema, hyperkalemia, hypotension, and worsening renal function was 42% less with ARB therapy than with ACE inhibitor therapy in patients with systolic heart failure. However, the relative risk of worsening renal function was 60% greater with angiotensin receptor blockers, according to Dr. Lakhdar, a third-year resident at the Henry Ford Hospital System, Detroit.

The ARB and ACE inhibitor arms were evenly matched in terms of diuretic therapy and other potential confounders.

“This is a new observation that certainly needs more research, including a prospective study to pinpoint the pathophysiology as to why ARBs are more likely to worsen renal function,” the physician added.

Discussant Dr. Lynne E. Wagoner predicted that guideline-writing committees are going to have to pay attention to the new meta-analysis.

“Cough is the major reason ACE inhibitors are discontinued. Often that cough is not severe and certainly is not life threatening,” said Dr. Wagoner, medical director of the cardiac transplantation division at the University of Cincinnati.

“However, the risk of worsening renal function is potentially life threatening and therefore should be stressed in guideline recommendations. ARBs should remain second-line therapy behind ACE inhibitors as a result of these findings,” he continued.

NEW ORLEANS — Angiotensin receptor blockers were associated with significantly greater risk of worsening renal function than were angiotentin-converting enzyme inhibitors in patients with systolic heart failure in a meta-analysis of all seven head-to-head comparative randomized, controlled, clinical trials, Dr. Rachid Lakhdar reported at the annual meeting of the American College of Cardiology.

“The ARBs are trying to make it as first-line drugs. The most recent guidelines put them as a class IIa indication, allowing them as first-line therapy in patients with mild to moderate heart failure and reduced left ventricular function,” he said in an interview.

“Our conclusion from the meta-analysis is maybe that's not such a good idea, and ARBs should continue to be second line, to be used when ACE inhibitors are contraindicated,” he continued.

The meta-analysis involved 20,143 systolic dysfunction heart failure patients who were randomized to an ACE inhibitor or ARB. Among the studies they were drawn from were the Valsartan in Acute Myocardial Infarction Trial (VALIANT), the first and second Evaluation of Losartan in the Elderly (ELITE I and II), the Optimal Therapy in Myocardial Infarction With the Angiotensin II Antagonist Losartan (OPTIMAAL) trial, and the Randomized Evaluation of Strategies for Left Ventricular Dysfunction (RESOLVD) study.

Carried out without commercial support, the meta-analysis clearly showed that overall side effects were significantly less frequent with ARBs. Indeed, the combined incidence of cough, angioedema, hyperkalemia, hypotension, and worsening renal function was 42% less with ARB therapy than with ACE inhibitor therapy in patients with systolic heart failure. However, the relative risk of worsening renal function was 60% greater with angiotensin receptor blockers, according to Dr. Lakhdar, a third-year resident at the Henry Ford Hospital System, Detroit.

The ARB and ACE inhibitor arms were evenly matched in terms of diuretic therapy and other potential confounders.

“This is a new observation that certainly needs more research, including a prospective study to pinpoint the pathophysiology as to why ARBs are more likely to worsen renal function,” the physician added.

Discussant Dr. Lynne E. Wagoner predicted that guideline-writing committees are going to have to pay attention to the new meta-analysis.

“Cough is the major reason ACE inhibitors are discontinued. Often that cough is not severe and certainly is not life threatening,” said Dr. Wagoner, medical director of the cardiac transplantation division at the University of Cincinnati.

“However, the risk of worsening renal function is potentially life threatening and therefore should be stressed in guideline recommendations. ARBs should remain second-line therapy behind ACE inhibitors as a result of these findings,” he continued.

NEW ORLEANS — Depression is common among patients with heart failure and is independently associated with poor outcomes, Dr. Aldo P. Maggioni said at the annual meeting of the American College of Cardiology.

He presented a retrospective study involving 18,623 patients with heart failure over age 60 identified in an administrative health care database covering two regions of Italy. At entry, 13% were being treated for depression.

In a multivariate logistic regression analysis, comorbid depression was independently associated with a highly significant 28% increased risk of all-cause mortality at 1 year, compared with the risk in heart failure patients not treated for depression.

Depression also was associated with an adjusted 36% increased risk of a 1-year composite end point consisting of MI, stroke, or transient ischemic attack, along with an 18% increase in all-cause hospitalization. However, the risk of rehospitalization for heart failure was no greater in patients treated for depression than in those who weren't, according to Dr. Maggioni, a cardiologist at the Mario Negri Research Consortium South, Santa Maria Imbaro, Italy.

He noted that while the adverse effect of comorbid depression on outcomes in patients with coronary artery disease is well established, there is much less evidence regarding the mood disorder's effect in patients with heart failure. Most previous studies have been quite small.

The strength of the new Italian study is its very large numbers. Its weakness is that there was no systematic screening for depression, so it's entirely possible the “nondepressed” comparator group included a fair number of heart failure patients with undiagnosed and untreated depression. Regardless, Dr. Maggioni said, the study conclusion was essentially the same as in the much smaller studies in which heart failure patients were screened for depression by questionnaire or interview: Depression is associated with poor outcomes in heart failure.

The mean age of participants in this study was 78 years. Patients treated for comorbid depression were significantly older than those who weren't. Sixty-nine percent were women, compared with 58% of heart failure patients not treated for depression.

Patients with depression also were significantly more likely to have a baseline history of stroke, transient ischemic attack, cancer, and chronic obstructive pulmonary disease.

Dr. Maggioni offered three potential explanations for the worse clinical outcomes in heart failure patients treated for depression. One possibility is that some antidepressant medications might have adverse effects in this population. Another is that depression exacerbates the underlying pathophysiology of heart failure, which is plausible in light of the fact that both conditions involve increased sympathetic nervous system activity, platelet activation, and systemic inflammation. But the most likely explanation for the association, in Dr. Maggioni's view, is that depressed patients have less social support and are less adherent to their cardiovascular therapy.

The big unanswered question is whether treatment of depression improves heart failure outcomes, he said. There are no data, and a definitive randomized clinical trial would need to be very large.

“You need the numbers. If you're testing a new drug, just to see a 15% relative difference in mortality, you need perhaps 7,000 patients,” Dr. Maggioni noted in an interview.

Session Chair Douglas P. Zipes called the Italian report linking depression to worse outcomes in heart failure “a very important observation” regarding an issue that doesn't receive sufficient attention from nonpsychiatrists.

“I think we tend to focus on more tangible issues, such as which coronary artery is occluded [and] the warfarin dose. My impression is that issues such as depression, sexual activity, and support groups aren't discussed at length–and they should be,” said Dr. Zipes, Distinguished Professor of Medicine, Pharmacology, and Toxicology at Indiana University, Indianapolis.

Depressed patients have less social support and are less adherent to their cardiovascular therapy. DR. MAGGIONI

NEW ORLEANS — Depression is common among patients with heart failure and is independently associated with poor outcomes, Dr. Aldo P. Maggioni said at the annual meeting of the American College of Cardiology.

He presented a retrospective study involving 18,623 patients with heart failure over age 60 identified in an administrative health care database covering two regions of Italy. At entry, 13% were being treated for depression.

In a multivariate logistic regression analysis, comorbid depression was independently associated with a highly significant 28% increased risk of all-cause mortality at 1 year, compared with the risk in heart failure patients not treated for depression.

Depression also was associated with an adjusted 36% increased risk of a 1-year composite end point consisting of MI, stroke, or transient ischemic attack, along with an 18% increase in all-cause hospitalization. However, the risk of rehospitalization for heart failure was no greater in patients treated for depression than in those who weren't, according to Dr. Maggioni, a cardiologist at the Mario Negri Research Consortium South, Santa Maria Imbaro, Italy.

He noted that while the adverse effect of comorbid depression on outcomes in patients with coronary artery disease is well established, there is much less evidence regarding the mood disorder's effect in patients with heart failure. Most previous studies have been quite small.

The strength of the new Italian study is its very large numbers. Its weakness is that there was no systematic screening for depression, so it's entirely possible the “nondepressed” comparator group included a fair number of heart failure patients with undiagnosed and untreated depression. Regardless, Dr. Maggioni said, the study conclusion was essentially the same as in the much smaller studies in which heart failure patients were screened for depression by questionnaire or interview: Depression is associated with poor outcomes in heart failure.

The mean age of participants in this study was 78 years. Patients treated for comorbid depression were significantly older than those who weren't. Sixty-nine percent were women, compared with 58% of heart failure patients not treated for depression.

Patients with depression also were significantly more likely to have a baseline history of stroke, transient ischemic attack, cancer, and chronic obstructive pulmonary disease.

Dr. Maggioni offered three potential explanations for the worse clinical outcomes in heart failure patients treated for depression. One possibility is that some antidepressant medications might have adverse effects in this population. Another is that depression exacerbates the underlying pathophysiology of heart failure, which is plausible in light of the fact that both conditions involve increased sympathetic nervous system activity, platelet activation, and systemic inflammation. But the most likely explanation for the association, in Dr. Maggioni's view, is that depressed patients have less social support and are less adherent to their cardiovascular therapy.

The big unanswered question is whether treatment of depression improves heart failure outcomes, he said. There are no data, and a definitive randomized clinical trial would need to be very large.

“You need the numbers. If you're testing a new drug, just to see a 15% relative difference in mortality, you need perhaps 7,000 patients,” Dr. Maggioni noted in an interview.

Session Chair Douglas P. Zipes called the Italian report linking depression to worse outcomes in heart failure “a very important observation” regarding an issue that doesn't receive sufficient attention from nonpsychiatrists.

“I think we tend to focus on more tangible issues, such as which coronary artery is occluded [and] the warfarin dose. My impression is that issues such as depression, sexual activity, and support groups aren't discussed at length–and they should be,” said Dr. Zipes, Distinguished Professor of Medicine, Pharmacology, and Toxicology at Indiana University, Indianapolis.

Depressed patients have less social support and are less adherent to their cardiovascular therapy. DR. MAGGIONI

NEW ORLEANS — Depression is common among patients with heart failure and is independently associated with poor outcomes, Dr. Aldo P. Maggioni said at the annual meeting of the American College of Cardiology.

He presented a retrospective study involving 18,623 patients with heart failure over age 60 identified in an administrative health care database covering two regions of Italy. At entry, 13% were being treated for depression.

In a multivariate logistic regression analysis, comorbid depression was independently associated with a highly significant 28% increased risk of all-cause mortality at 1 year, compared with the risk in heart failure patients not treated for depression.

Depression also was associated with an adjusted 36% increased risk of a 1-year composite end point consisting of MI, stroke, or transient ischemic attack, along with an 18% increase in all-cause hospitalization. However, the risk of rehospitalization for heart failure was no greater in patients treated for depression than in those who weren't, according to Dr. Maggioni, a cardiologist at the Mario Negri Research Consortium South, Santa Maria Imbaro, Italy.

He noted that while the adverse effect of comorbid depression on outcomes in patients with coronary artery disease is well established, there is much less evidence regarding the mood disorder's effect in patients with heart failure. Most previous studies have been quite small.

The strength of the new Italian study is its very large numbers. Its weakness is that there was no systematic screening for depression, so it's entirely possible the “nondepressed” comparator group included a fair number of heart failure patients with undiagnosed and untreated depression. Regardless, Dr. Maggioni said, the study conclusion was essentially the same as in the much smaller studies in which heart failure patients were screened for depression by questionnaire or interview: Depression is associated with poor outcomes in heart failure.

The mean age of participants in this study was 78 years. Patients treated for comorbid depression were significantly older than those who weren't. Sixty-nine percent were women, compared with 58% of heart failure patients not treated for depression.

Patients with depression also were significantly more likely to have a baseline history of stroke, transient ischemic attack, cancer, and chronic obstructive pulmonary disease.

Dr. Maggioni offered three potential explanations for the worse clinical outcomes in heart failure patients treated for depression. One possibility is that some antidepressant medications might have adverse effects in this population. Another is that depression exacerbates the underlying pathophysiology of heart failure, which is plausible in light of the fact that both conditions involve increased sympathetic nervous system activity, platelet activation, and systemic inflammation. But the most likely explanation for the association, in Dr. Maggioni's view, is that depressed patients have less social support and are less adherent to their cardiovascular therapy.

The big unanswered question is whether treatment of depression improves heart failure outcomes, he said. There are no data, and a definitive randomized clinical trial would need to be very large.

“You need the numbers. If you're testing a new drug, just to see a 15% relative difference in mortality, you need perhaps 7,000 patients,” Dr. Maggioni noted in an interview.

Session Chair Douglas P. Zipes called the Italian report linking depression to worse outcomes in heart failure “a very important observation” regarding an issue that doesn't receive sufficient attention from nonpsychiatrists.

“I think we tend to focus on more tangible issues, such as which coronary artery is occluded [and] the warfarin dose. My impression is that issues such as depression, sexual activity, and support groups aren't discussed at length–and they should be,” said Dr. Zipes, Distinguished Professor of Medicine, Pharmacology, and Toxicology at Indiana University, Indianapolis.

Depressed patients have less social support and are less adherent to their cardiovascular therapy. DR. MAGGIONI