Heart Failure

SEATTLE – Patients with heart failure still benefit from spironolactone therapy even when they develop elevated potassium levels, a well-known and potentially life-threatening side effect of the medication, new data suggest.

Investigators led by Orly Vardeny, Pharm.D., conducted a secondary analysis of data from the RALES (Randomized Aldactone Evaluation Study) trial, in which more than 1,500 patients with heart failure were assigned to spironolactone (Aldactone) or placebo.

The spironolactone group had nearly quadruple the risk of hyperkalemia compared with the placebo group, she reported at the annual meeting of the Heart Failure Society of America. And hyperkalemia was indeed associated with a higher mortality rate.

But relative to their placebo-treated counterparts who did not have elevated potassium levels, spironolactone-treated patients who had elevated potassium levels, up to a serum potassium level of at least 5.5 mEq/L, were still less likely to die.

"The benefits of spironolactone are maintained in patients with mild to moderate hyperkalemia, and even in patients with potassium levels approaching 6.0 mEq/L," commented Dr. Vardeny, who is an associate professor of pharmacy at the University of Wisconsin in Madison.

"Our data argue for strategies that maintain spironolactone or aldosterone antagonist therapy even in the setting of mild to moderate hyperkalemia," she maintained.

"How many of these patients were on digoxin, and did you factor that into the analysis?" asked session comoderator Dr. Carl V. Leier of the Ohio State University Medical Center in Columbus.

Dr. Vardeny replied that analyses did not adjust for digoxin use, but they did adjust for age, estimated glomerular filtration rate, baseline potassium level, and diabetes.

"It seems that hypokalemia was more dangerous than hyperkalemia," commented attendee Dr. Edward Gilbert of the University of Utah in Salt Lake City. Might some of the benefit of spironolactone actually be related to reduced hypokalemia, he wondered.

"My personal bias is that there could be an association. This is really difficult to prove, only because potassium will vary so much, so the data will inform multiple categories of potassium," Dr. Vardeny replied. "But yes, we are investigating that as well."

The 1,663 patients in RALES had moderate to severe heart failure with a left ventricular ejection fraction of less than 35%, and were already receiving an angiotensin-converting enzyme inhibitor with or without a diuretic. They were randomized evenly to 25 mg of spironolactone daily, with optional titration up to 50 mg daily or placebo.

Serum potassium levels were monitored regularly. If patients developed hyperkalemia, investigators could reduce the dose of study medication but were encouraged to first adjust doses of other medications.

Main RALES results, previously reported, showed that spironolactone treatment was associated with a 30% reduction in the risk of all-cause mortality and a 35% reduction in the risk of hospitalization for worsening of heart failure (N. Engl. J. Med. 1999;341:709-17).

The new analysis showed that both treatment groups had mean potassium levels of 4.3 mEq/L at baseline. But levels increased within the first month in the spironolactone group and remained persistently higher than those in the placebo group, by 0.25 mEq/L on average, throughout the trial.

Relative to their peers in the placebo group, patients in the spironolactone group were significantly less likely to develop hypokalemia (6.5% vs. 16.2%) and more likely to develop hyperkalemia (14.5% vs. 4.2%), Dr. Vardeny reported. Hypokalemia was defined as a potassium level of less than 3.5 mEq/L; hyperkalemia equalled a potassium level of greater than 5.5 mEq/L.

In the spironolactone group, the rate of death was fairly stable – at about 17 per 100 patient-years – for patients with potassium levels ranging from 3.5 to 6.0 mEq/L. But it was higher among patients with lower levels (about 42 per 100 patient-years) or higher levels (about 25 per 100 patient-years).

In a multivariate analysis, patients were more likely to develop hypokalemia if they were black (hazard ratio, 2.0) or had a higher New York Heart Association functional class (HR, 1.5), whereas they were less likely if they had a higher baseline potassium level (HR, 0.25) or received spironolactone (HR, 0.36).

Patients were more likely to develop hyperkalemia if they received spironolactone (HR, 3.7), had a higher baseline potassium level (HR, 2.4), or had a history of diabetes (HR, 1.9).

Compared with placebo-treated patients having potassium levels of less than 5.0 mEq/L, spironolactone-treated patients with elevated potassium levels still had a significantly lower risk of death with potassium levels up to 5.5 mEq/L, and they had a nonsignificantly lower risk with levels up to about 6.0 mEq/L.

Dr. Vardeny reported having no relevant conflicts of interest. The RALES trial was sponsored by Searle, manufacturer of Aldactone.

SEATTLE – Patients with heart failure still benefit from spironolactone therapy even when they develop elevated potassium levels, a well-known and potentially life-threatening side effect of the medication, new data suggest.

Investigators led by Orly Vardeny, Pharm.D., conducted a secondary analysis of data from the RALES (Randomized Aldactone Evaluation Study) trial, in which more than 1,500 patients with heart failure were assigned to spironolactone (Aldactone) or placebo.

The spironolactone group had nearly quadruple the risk of hyperkalemia compared with the placebo group, she reported at the annual meeting of the Heart Failure Society of America. And hyperkalemia was indeed associated with a higher mortality rate.

But relative to their placebo-treated counterparts who did not have elevated potassium levels, spironolactone-treated patients who had elevated potassium levels, up to a serum potassium level of at least 5.5 mEq/L, were still less likely to die.

"The benefits of spironolactone are maintained in patients with mild to moderate hyperkalemia, and even in patients with potassium levels approaching 6.0 mEq/L," commented Dr. Vardeny, who is an associate professor of pharmacy at the University of Wisconsin in Madison.

"Our data argue for strategies that maintain spironolactone or aldosterone antagonist therapy even in the setting of mild to moderate hyperkalemia," she maintained.

"How many of these patients were on digoxin, and did you factor that into the analysis?" asked session comoderator Dr. Carl V. Leier of the Ohio State University Medical Center in Columbus.

Dr. Vardeny replied that analyses did not adjust for digoxin use, but they did adjust for age, estimated glomerular filtration rate, baseline potassium level, and diabetes.

"It seems that hypokalemia was more dangerous than hyperkalemia," commented attendee Dr. Edward Gilbert of the University of Utah in Salt Lake City. Might some of the benefit of spironolactone actually be related to reduced hypokalemia, he wondered.

"My personal bias is that there could be an association. This is really difficult to prove, only because potassium will vary so much, so the data will inform multiple categories of potassium," Dr. Vardeny replied. "But yes, we are investigating that as well."

The 1,663 patients in RALES had moderate to severe heart failure with a left ventricular ejection fraction of less than 35%, and were already receiving an angiotensin-converting enzyme inhibitor with or without a diuretic. They were randomized evenly to 25 mg of spironolactone daily, with optional titration up to 50 mg daily or placebo.

Serum potassium levels were monitored regularly. If patients developed hyperkalemia, investigators could reduce the dose of study medication but were encouraged to first adjust doses of other medications.

Main RALES results, previously reported, showed that spironolactone treatment was associated with a 30% reduction in the risk of all-cause mortality and a 35% reduction in the risk of hospitalization for worsening of heart failure (N. Engl. J. Med. 1999;341:709-17).

The new analysis showed that both treatment groups had mean potassium levels of 4.3 mEq/L at baseline. But levels increased within the first month in the spironolactone group and remained persistently higher than those in the placebo group, by 0.25 mEq/L on average, throughout the trial.

Relative to their peers in the placebo group, patients in the spironolactone group were significantly less likely to develop hypokalemia (6.5% vs. 16.2%) and more likely to develop hyperkalemia (14.5% vs. 4.2%), Dr. Vardeny reported. Hypokalemia was defined as a potassium level of less than 3.5 mEq/L; hyperkalemia equalled a potassium level of greater than 5.5 mEq/L.

In the spironolactone group, the rate of death was fairly stable – at about 17 per 100 patient-years – for patients with potassium levels ranging from 3.5 to 6.0 mEq/L. But it was higher among patients with lower levels (about 42 per 100 patient-years) or higher levels (about 25 per 100 patient-years).

In a multivariate analysis, patients were more likely to develop hypokalemia if they were black (hazard ratio, 2.0) or had a higher New York Heart Association functional class (HR, 1.5), whereas they were less likely if they had a higher baseline potassium level (HR, 0.25) or received spironolactone (HR, 0.36).

Patients were more likely to develop hyperkalemia if they received spironolactone (HR, 3.7), had a higher baseline potassium level (HR, 2.4), or had a history of diabetes (HR, 1.9).

Compared with placebo-treated patients having potassium levels of less than 5.0 mEq/L, spironolactone-treated patients with elevated potassium levels still had a significantly lower risk of death with potassium levels up to 5.5 mEq/L, and they had a nonsignificantly lower risk with levels up to about 6.0 mEq/L.

Dr. Vardeny reported having no relevant conflicts of interest. The RALES trial was sponsored by Searle, manufacturer of Aldactone.

SEATTLE – Patients with heart failure still benefit from spironolactone therapy even when they develop elevated potassium levels, a well-known and potentially life-threatening side effect of the medication, new data suggest.

Investigators led by Orly Vardeny, Pharm.D., conducted a secondary analysis of data from the RALES (Randomized Aldactone Evaluation Study) trial, in which more than 1,500 patients with heart failure were assigned to spironolactone (Aldactone) or placebo.

The spironolactone group had nearly quadruple the risk of hyperkalemia compared with the placebo group, she reported at the annual meeting of the Heart Failure Society of America. And hyperkalemia was indeed associated with a higher mortality rate.

But relative to their placebo-treated counterparts who did not have elevated potassium levels, spironolactone-treated patients who had elevated potassium levels, up to a serum potassium level of at least 5.5 mEq/L, were still less likely to die.

"The benefits of spironolactone are maintained in patients with mild to moderate hyperkalemia, and even in patients with potassium levels approaching 6.0 mEq/L," commented Dr. Vardeny, who is an associate professor of pharmacy at the University of Wisconsin in Madison.

"Our data argue for strategies that maintain spironolactone or aldosterone antagonist therapy even in the setting of mild to moderate hyperkalemia," she maintained.

"How many of these patients were on digoxin, and did you factor that into the analysis?" asked session comoderator Dr. Carl V. Leier of the Ohio State University Medical Center in Columbus.

Dr. Vardeny replied that analyses did not adjust for digoxin use, but they did adjust for age, estimated glomerular filtration rate, baseline potassium level, and diabetes.

"It seems that hypokalemia was more dangerous than hyperkalemia," commented attendee Dr. Edward Gilbert of the University of Utah in Salt Lake City. Might some of the benefit of spironolactone actually be related to reduced hypokalemia, he wondered.

"My personal bias is that there could be an association. This is really difficult to prove, only because potassium will vary so much, so the data will inform multiple categories of potassium," Dr. Vardeny replied. "But yes, we are investigating that as well."

The 1,663 patients in RALES had moderate to severe heart failure with a left ventricular ejection fraction of less than 35%, and were already receiving an angiotensin-converting enzyme inhibitor with or without a diuretic. They were randomized evenly to 25 mg of spironolactone daily, with optional titration up to 50 mg daily or placebo.

Serum potassium levels were monitored regularly. If patients developed hyperkalemia, investigators could reduce the dose of study medication but were encouraged to first adjust doses of other medications.

Main RALES results, previously reported, showed that spironolactone treatment was associated with a 30% reduction in the risk of all-cause mortality and a 35% reduction in the risk of hospitalization for worsening of heart failure (N. Engl. J. Med. 1999;341:709-17).

The new analysis showed that both treatment groups had mean potassium levels of 4.3 mEq/L at baseline. But levels increased within the first month in the spironolactone group and remained persistently higher than those in the placebo group, by 0.25 mEq/L on average, throughout the trial.

Relative to their peers in the placebo group, patients in the spironolactone group were significantly less likely to develop hypokalemia (6.5% vs. 16.2%) and more likely to develop hyperkalemia (14.5% vs. 4.2%), Dr. Vardeny reported. Hypokalemia was defined as a potassium level of less than 3.5 mEq/L; hyperkalemia equalled a potassium level of greater than 5.5 mEq/L.

In the spironolactone group, the rate of death was fairly stable – at about 17 per 100 patient-years – for patients with potassium levels ranging from 3.5 to 6.0 mEq/L. But it was higher among patients with lower levels (about 42 per 100 patient-years) or higher levels (about 25 per 100 patient-years).

In a multivariate analysis, patients were more likely to develop hypokalemia if they were black (hazard ratio, 2.0) or had a higher New York Heart Association functional class (HR, 1.5), whereas they were less likely if they had a higher baseline potassium level (HR, 0.25) or received spironolactone (HR, 0.36).

Patients were more likely to develop hyperkalemia if they received spironolactone (HR, 3.7), had a higher baseline potassium level (HR, 2.4), or had a history of diabetes (HR, 1.9).

Compared with placebo-treated patients having potassium levels of less than 5.0 mEq/L, spironolactone-treated patients with elevated potassium levels still had a significantly lower risk of death with potassium levels up to 5.5 mEq/L, and they had a nonsignificantly lower risk with levels up to about 6.0 mEq/L.

Dr. Vardeny reported having no relevant conflicts of interest. The RALES trial was sponsored by Searle, manufacturer of Aldactone.

SEATTLE – A brief cognitive biobehavioral intervention focused on preventing and managing depression reduces adverse outcomes of heart failure, according to results from a randomized trial reported at the annual meeting of the Heart Failure Society of America.

"A 6-week biobehavioral intervention in patients with heart failure really was successful in severing the link between depression and poor outcomes," according to the study’s lead investigator, Debra K. Moser, D.N.Sc., professor and chair of the College of Nursing at the University of Kentucky, Lexington. "These findings provide evidence for the effectiveness of biobehavioral approaches" in this population.

Dr. Moser also noted that more than one-fifth of patients with heart failure have depression, as well as higher depressive symptoms – not necessarily clinical depression. Evidence suggests that in the heart failure population, such symptoms triple the risk of rehospitalization and double the risk of death (J. Am. Coll. Cardiol. 2006;48:1527-37).

Dr. Moser and her colleagues studied 278 patients with heart failure, assigning them to a biobehavioral intervention group (given both cognitive-behavioral therapy and biofeedback-relaxation therapy), an attention control group, or a usual-care control group. At baseline, patients were an average of 60 years old, roughly a third were women, and nearly half had New York Heart Association class III or IV heart failure. Mean depression scores on the 27-point Patient Health Questionnaire-9 were about 5.5; one-fourth of patients were taking antidepressants. Patients with heart failure were eligible for the trial if they had been on stable medication doses for at least 1 month, had not experienced a myocardial infarction or stroke in the previous 3 months, and did not have any cognitive impairment.

At 12 months’ follow-up, the biobehavioral intervention patients were about one-third less likely to have had a cardiac hospitalization or to die (28%) compared with the attention control group (40%) and the usual-care control group (38%).

Patients in the biobehavioral intervention group also had an improvement at 1 year in scores for health-related quality of life, measured with the Minnesota Living with Heart Failure questionnaire, whereas scores worsened in the other groups (P = .005).

Similarly, patients in the biobehavioral intervention group had an improvement at 1 year in scores for depression symptoms, whereas scores worsened in the other groups (P = .001). Some 13% of patients in the biobehavioral intervention group had depression at this time point, compared with 21% of those in the attention control group and 24% of those in the usual-care control group.

The biobehavioral intervention lasted 6 weeks, and consisted of 1-hour weekly sessions conducted by a therapist; it was designed to address depression and comorbid anxiety. "The therapist was a psychiatric nurse practitioner with extensive cardiac experience, and she was well suited to this project because she is from the part of Kentucky where many of the patients come from, so ... there is a lot of concordance between her style and her patients’," Dr. Moser explained.

The attention control condition also lasted 6 weeks, and consisted of 1-hour weekly sessions with the same nurse practitioner present, but entailed only unguided relaxation and the opportunity to speak with her.

Christine Moravec, Ph.D., of the Cleveland Clinic, pointed out that at this point it’s difficult to dissect out whether the benefits seen in the biobehavioral intervention were due to the cognitive-behavioral therapy or the biofeedback.

"That’s our next trial" Dr. Moser noted. "We will be looking at the combination of the two and [each] separately."

Reproducibility is another issue, noted Dr. Javed Butler of Emory University in Atlanta. "Can anybody who does this biobehavioral intervention expect the same results?"

"That’s actually the major question that I have," Dr. Moser acknowledged. The particular nurse practitioner who ran the biobehavioral intervention "is probably the best therapist for these people that I have ever seen, so I really do worry about the reproducibility.

"But also, it sort of speaks to maybe some of the failure of the other clinical trials that we have seen in treating depression for cardiac patients. We have had some colossal failures," she continued. "I don’t think that any therapist can do it. It takes a special therapist who can really connect with patients, and a lot of patients, who can individualize therapy and is concordant with the group. ... The negative impact of depression is so powerful that it bears looking at to try to really define what it is in the therapist-patient relationship that is important and that does need to be reproduced."

Interestingly, depression levels in the biobehavioral intervention group continued to decline over a year, whereas they increased in the control groups, according to Dr. Moser. "We think that that is how cognitive-behavioral therapy should work. It doesn’t of course work for everyone, but if it works, it should give you the skills to manage depressive symptoms in the long term," she said.

"Future research should examine the combined effects of pharmacological and biobehavioral therapy, and ... we need to think about the practicality of this intensive intervention in widespread clinical practice," she added.

Dr. Moser reported having no relevant conflicts of interest.

SEATTLE – A brief cognitive biobehavioral intervention focused on preventing and managing depression reduces adverse outcomes of heart failure, according to results from a randomized trial reported at the annual meeting of the Heart Failure Society of America.

"A 6-week biobehavioral intervention in patients with heart failure really was successful in severing the link between depression and poor outcomes," according to the study’s lead investigator, Debra K. Moser, D.N.Sc., professor and chair of the College of Nursing at the University of Kentucky, Lexington. "These findings provide evidence for the effectiveness of biobehavioral approaches" in this population.

Dr. Moser also noted that more than one-fifth of patients with heart failure have depression, as well as higher depressive symptoms – not necessarily clinical depression. Evidence suggests that in the heart failure population, such symptoms triple the risk of rehospitalization and double the risk of death (J. Am. Coll. Cardiol. 2006;48:1527-37).

Dr. Moser and her colleagues studied 278 patients with heart failure, assigning them to a biobehavioral intervention group (given both cognitive-behavioral therapy and biofeedback-relaxation therapy), an attention control group, or a usual-care control group. At baseline, patients were an average of 60 years old, roughly a third were women, and nearly half had New York Heart Association class III or IV heart failure. Mean depression scores on the 27-point Patient Health Questionnaire-9 were about 5.5; one-fourth of patients were taking antidepressants. Patients with heart failure were eligible for the trial if they had been on stable medication doses for at least 1 month, had not experienced a myocardial infarction or stroke in the previous 3 months, and did not have any cognitive impairment.

At 12 months’ follow-up, the biobehavioral intervention patients were about one-third less likely to have had a cardiac hospitalization or to die (28%) compared with the attention control group (40%) and the usual-care control group (38%).

Patients in the biobehavioral intervention group also had an improvement at 1 year in scores for health-related quality of life, measured with the Minnesota Living with Heart Failure questionnaire, whereas scores worsened in the other groups (P = .005).

Similarly, patients in the biobehavioral intervention group had an improvement at 1 year in scores for depression symptoms, whereas scores worsened in the other groups (P = .001). Some 13% of patients in the biobehavioral intervention group had depression at this time point, compared with 21% of those in the attention control group and 24% of those in the usual-care control group.

The biobehavioral intervention lasted 6 weeks, and consisted of 1-hour weekly sessions conducted by a therapist; it was designed to address depression and comorbid anxiety. "The therapist was a psychiatric nurse practitioner with extensive cardiac experience, and she was well suited to this project because she is from the part of Kentucky where many of the patients come from, so ... there is a lot of concordance between her style and her patients’," Dr. Moser explained.

The attention control condition also lasted 6 weeks, and consisted of 1-hour weekly sessions with the same nurse practitioner present, but entailed only unguided relaxation and the opportunity to speak with her.

Christine Moravec, Ph.D., of the Cleveland Clinic, pointed out that at this point it’s difficult to dissect out whether the benefits seen in the biobehavioral intervention were due to the cognitive-behavioral therapy or the biofeedback.

"That’s our next trial" Dr. Moser noted. "We will be looking at the combination of the two and [each] separately."

Reproducibility is another issue, noted Dr. Javed Butler of Emory University in Atlanta. "Can anybody who does this biobehavioral intervention expect the same results?"

"That’s actually the major question that I have," Dr. Moser acknowledged. The particular nurse practitioner who ran the biobehavioral intervention "is probably the best therapist for these people that I have ever seen, so I really do worry about the reproducibility.

"But also, it sort of speaks to maybe some of the failure of the other clinical trials that we have seen in treating depression for cardiac patients. We have had some colossal failures," she continued. "I don’t think that any therapist can do it. It takes a special therapist who can really connect with patients, and a lot of patients, who can individualize therapy and is concordant with the group. ... The negative impact of depression is so powerful that it bears looking at to try to really define what it is in the therapist-patient relationship that is important and that does need to be reproduced."

Interestingly, depression levels in the biobehavioral intervention group continued to decline over a year, whereas they increased in the control groups, according to Dr. Moser. "We think that that is how cognitive-behavioral therapy should work. It doesn’t of course work for everyone, but if it works, it should give you the skills to manage depressive symptoms in the long term," she said.

"Future research should examine the combined effects of pharmacological and biobehavioral therapy, and ... we need to think about the practicality of this intensive intervention in widespread clinical practice," she added.

Dr. Moser reported having no relevant conflicts of interest.

SEATTLE – A brief cognitive biobehavioral intervention focused on preventing and managing depression reduces adverse outcomes of heart failure, according to results from a randomized trial reported at the annual meeting of the Heart Failure Society of America.

"A 6-week biobehavioral intervention in patients with heart failure really was successful in severing the link between depression and poor outcomes," according to the study’s lead investigator, Debra K. Moser, D.N.Sc., professor and chair of the College of Nursing at the University of Kentucky, Lexington. "These findings provide evidence for the effectiveness of biobehavioral approaches" in this population.

Dr. Moser also noted that more than one-fifth of patients with heart failure have depression, as well as higher depressive symptoms – not necessarily clinical depression. Evidence suggests that in the heart failure population, such symptoms triple the risk of rehospitalization and double the risk of death (J. Am. Coll. Cardiol. 2006;48:1527-37).

Dr. Moser and her colleagues studied 278 patients with heart failure, assigning them to a biobehavioral intervention group (given both cognitive-behavioral therapy and biofeedback-relaxation therapy), an attention control group, or a usual-care control group. At baseline, patients were an average of 60 years old, roughly a third were women, and nearly half had New York Heart Association class III or IV heart failure. Mean depression scores on the 27-point Patient Health Questionnaire-9 were about 5.5; one-fourth of patients were taking antidepressants. Patients with heart failure were eligible for the trial if they had been on stable medication doses for at least 1 month, had not experienced a myocardial infarction or stroke in the previous 3 months, and did not have any cognitive impairment.

At 12 months’ follow-up, the biobehavioral intervention patients were about one-third less likely to have had a cardiac hospitalization or to die (28%) compared with the attention control group (40%) and the usual-care control group (38%).

Patients in the biobehavioral intervention group also had an improvement at 1 year in scores for health-related quality of life, measured with the Minnesota Living with Heart Failure questionnaire, whereas scores worsened in the other groups (P = .005).

Similarly, patients in the biobehavioral intervention group had an improvement at 1 year in scores for depression symptoms, whereas scores worsened in the other groups (P = .001). Some 13% of patients in the biobehavioral intervention group had depression at this time point, compared with 21% of those in the attention control group and 24% of those in the usual-care control group.

The biobehavioral intervention lasted 6 weeks, and consisted of 1-hour weekly sessions conducted by a therapist; it was designed to address depression and comorbid anxiety. "The therapist was a psychiatric nurse practitioner with extensive cardiac experience, and she was well suited to this project because she is from the part of Kentucky where many of the patients come from, so ... there is a lot of concordance between her style and her patients’," Dr. Moser explained.

The attention control condition also lasted 6 weeks, and consisted of 1-hour weekly sessions with the same nurse practitioner present, but entailed only unguided relaxation and the opportunity to speak with her.

Christine Moravec, Ph.D., of the Cleveland Clinic, pointed out that at this point it’s difficult to dissect out whether the benefits seen in the biobehavioral intervention were due to the cognitive-behavioral therapy or the biofeedback.

"That’s our next trial" Dr. Moser noted. "We will be looking at the combination of the two and [each] separately."

Reproducibility is another issue, noted Dr. Javed Butler of Emory University in Atlanta. "Can anybody who does this biobehavioral intervention expect the same results?"

"That’s actually the major question that I have," Dr. Moser acknowledged. The particular nurse practitioner who ran the biobehavioral intervention "is probably the best therapist for these people that I have ever seen, so I really do worry about the reproducibility.

"But also, it sort of speaks to maybe some of the failure of the other clinical trials that we have seen in treating depression for cardiac patients. We have had some colossal failures," she continued. "I don’t think that any therapist can do it. It takes a special therapist who can really connect with patients, and a lot of patients, who can individualize therapy and is concordant with the group. ... The negative impact of depression is so powerful that it bears looking at to try to really define what it is in the therapist-patient relationship that is important and that does need to be reproduced."

Interestingly, depression levels in the biobehavioral intervention group continued to decline over a year, whereas they increased in the control groups, according to Dr. Moser. "We think that that is how cognitive-behavioral therapy should work. It doesn’t of course work for everyone, but if it works, it should give you the skills to manage depressive symptoms in the long term," she said.

"Future research should examine the combined effects of pharmacological and biobehavioral therapy, and ... we need to think about the practicality of this intensive intervention in widespread clinical practice," she added.

Dr. Moser reported having no relevant conflicts of interest.

MUNICH – Treatment with quinine increased the mortality of heart failure patients who also had ischemic heart disease and received a beta-blocker by a statistically significant 16% in a study of more than 136,000 Danish heart failure patients during 1997-2010.

Although experts suggest that such use of quinine is not commonplace in the United States, the analysis of Danish patient and population registries showed that quinine was used in the treatment of 10% of HF patients. Quinine, an antimalarial drug, is often prescribed off-label to treat leg cramps, a common problem in patients with HF, Dr. Charlotte Andersson said at the annual congress of the European Society of Cardiology.

Mitchel L. Zoler/IMNG Medical Media

"Clinicians should attempt to find a treatment for leg cramps other than prescribing quinine" in patients with chronic HF, especially those with ischemic heart disease, said Dr. Andersson, a cardiologist at Gentofte Hospital in Copenhagen. She also expressed surprise that the dangerous interaction was greatest among patients who also received a beta-blocker drug.

"I would have expected patients on beta-blockers to be protected, but they weren’t, so probably conduction blocks [caused by quinine] are the problem," she said. "We found the highest risk of death during the first week of quinine treatment in patients with ischemic heart disease and on a beta-blocker, but if quinine was used chronically it still increased the risk."

"This is very interesting and important information," commented Dr. Marco Metra, a cardiologist at the University of Brescia, Italy. "The question is, what is the mechanism of the interaction of quinine and beta-blockers? We think that beta-blockers are protective against arrhythmias caused by QT prolongation. In this case, [the problem may be] bradycardia" caused by a beta-blocker that interacts with an effect from quinine, he suggested.

Dr. Andersson and her associates reviewed Danish national patient and population registry records collected during 1997-2010, which included 136,427 patients discharged from a hospital with a diagnosis of heart failure and who were alive at least 30 days following discharge. Their average age was 74 years, 47% were women, and 65% died during a median follow-up of 2.8 years.

The records showed that 14,306 patients (10%) had received at least one course of treatment with quinine, at a dosage of 100 or 200 mg/day. Overall, patients who received quinine had a 3% increased risk of death after adjustment for age and HF severity, which was estimated based on the dosage of loop diuretics they received. This increased risk fell just short of statistical significance.

However, further analysis showed that specific subgroups of HF patients faced a higher mortality threat from quinine treatment. Patients with ischemic heart disease (37% of the HF population) who received treatment with a beta-blocker (60% of the HF patients with ischemic heart disease) had the highest mortality when they received quinine, 16% higher than for similar patients who did not get quinine, after adjustment for age and HF severity. This meant that for every 38 patients with this clinical profile treated with quinine, 1 died.

Among HF patients with ischemic heart disease who did not receive a beta-blocker, the mortality rate was elevated by a statistically significant 8% among quinine users compared with quinine nonusers; 1 death occurred for every 46 patients in this category. And among HF patients who received a beta-blocker but who did not have ischemic heart disease, quinine treatment raised mortality by a statistically significant 9%, or 1 death for every 97 patients treated with quinine who fit this clinical profile.

Dr. Andersson said that she and her associates had no disclosures.

MUNICH – Treatment with quinine increased the mortality of heart failure patients who also had ischemic heart disease and received a beta-blocker by a statistically significant 16% in a study of more than 136,000 Danish heart failure patients during 1997-2010.

Although experts suggest that such use of quinine is not commonplace in the United States, the analysis of Danish patient and population registries showed that quinine was used in the treatment of 10% of HF patients. Quinine, an antimalarial drug, is often prescribed off-label to treat leg cramps, a common problem in patients with HF, Dr. Charlotte Andersson said at the annual congress of the European Society of Cardiology.

Mitchel L. Zoler/IMNG Medical Media

"Clinicians should attempt to find a treatment for leg cramps other than prescribing quinine" in patients with chronic HF, especially those with ischemic heart disease, said Dr. Andersson, a cardiologist at Gentofte Hospital in Copenhagen. She also expressed surprise that the dangerous interaction was greatest among patients who also received a beta-blocker drug.

"I would have expected patients on beta-blockers to be protected, but they weren’t, so probably conduction blocks [caused by quinine] are the problem," she said. "We found the highest risk of death during the first week of quinine treatment in patients with ischemic heart disease and on a beta-blocker, but if quinine was used chronically it still increased the risk."

"This is very interesting and important information," commented Dr. Marco Metra, a cardiologist at the University of Brescia, Italy. "The question is, what is the mechanism of the interaction of quinine and beta-blockers? We think that beta-blockers are protective against arrhythmias caused by QT prolongation. In this case, [the problem may be] bradycardia" caused by a beta-blocker that interacts with an effect from quinine, he suggested.

Dr. Andersson and her associates reviewed Danish national patient and population registry records collected during 1997-2010, which included 136,427 patients discharged from a hospital with a diagnosis of heart failure and who were alive at least 30 days following discharge. Their average age was 74 years, 47% were women, and 65% died during a median follow-up of 2.8 years.

The records showed that 14,306 patients (10%) had received at least one course of treatment with quinine, at a dosage of 100 or 200 mg/day. Overall, patients who received quinine had a 3% increased risk of death after adjustment for age and HF severity, which was estimated based on the dosage of loop diuretics they received. This increased risk fell just short of statistical significance.

However, further analysis showed that specific subgroups of HF patients faced a higher mortality threat from quinine treatment. Patients with ischemic heart disease (37% of the HF population) who received treatment with a beta-blocker (60% of the HF patients with ischemic heart disease) had the highest mortality when they received quinine, 16% higher than for similar patients who did not get quinine, after adjustment for age and HF severity. This meant that for every 38 patients with this clinical profile treated with quinine, 1 died.

Among HF patients with ischemic heart disease who did not receive a beta-blocker, the mortality rate was elevated by a statistically significant 8% among quinine users compared with quinine nonusers; 1 death occurred for every 46 patients in this category. And among HF patients who received a beta-blocker but who did not have ischemic heart disease, quinine treatment raised mortality by a statistically significant 9%, or 1 death for every 97 patients treated with quinine who fit this clinical profile.

Dr. Andersson said that she and her associates had no disclosures.

MUNICH – Treatment with quinine increased the mortality of heart failure patients who also had ischemic heart disease and received a beta-blocker by a statistically significant 16% in a study of more than 136,000 Danish heart failure patients during 1997-2010.

Although experts suggest that such use of quinine is not commonplace in the United States, the analysis of Danish patient and population registries showed that quinine was used in the treatment of 10% of HF patients. Quinine, an antimalarial drug, is often prescribed off-label to treat leg cramps, a common problem in patients with HF, Dr. Charlotte Andersson said at the annual congress of the European Society of Cardiology.

Mitchel L. Zoler/IMNG Medical Media

"Clinicians should attempt to find a treatment for leg cramps other than prescribing quinine" in patients with chronic HF, especially those with ischemic heart disease, said Dr. Andersson, a cardiologist at Gentofte Hospital in Copenhagen. She also expressed surprise that the dangerous interaction was greatest among patients who also received a beta-blocker drug.

"I would have expected patients on beta-blockers to be protected, but they weren’t, so probably conduction blocks [caused by quinine] are the problem," she said. "We found the highest risk of death during the first week of quinine treatment in patients with ischemic heart disease and on a beta-blocker, but if quinine was used chronically it still increased the risk."

"This is very interesting and important information," commented Dr. Marco Metra, a cardiologist at the University of Brescia, Italy. "The question is, what is the mechanism of the interaction of quinine and beta-blockers? We think that beta-blockers are protective against arrhythmias caused by QT prolongation. In this case, [the problem may be] bradycardia" caused by a beta-blocker that interacts with an effect from quinine, he suggested.

Dr. Andersson and her associates reviewed Danish national patient and population registry records collected during 1997-2010, which included 136,427 patients discharged from a hospital with a diagnosis of heart failure and who were alive at least 30 days following discharge. Their average age was 74 years, 47% were women, and 65% died during a median follow-up of 2.8 years.

The records showed that 14,306 patients (10%) had received at least one course of treatment with quinine, at a dosage of 100 or 200 mg/day. Overall, patients who received quinine had a 3% increased risk of death after adjustment for age and HF severity, which was estimated based on the dosage of loop diuretics they received. This increased risk fell just short of statistical significance.

However, further analysis showed that specific subgroups of HF patients faced a higher mortality threat from quinine treatment. Patients with ischemic heart disease (37% of the HF population) who received treatment with a beta-blocker (60% of the HF patients with ischemic heart disease) had the highest mortality when they received quinine, 16% higher than for similar patients who did not get quinine, after adjustment for age and HF severity. This meant that for every 38 patients with this clinical profile treated with quinine, 1 died.

Among HF patients with ischemic heart disease who did not receive a beta-blocker, the mortality rate was elevated by a statistically significant 8% among quinine users compared with quinine nonusers; 1 death occurred for every 46 patients in this category. And among HF patients who received a beta-blocker but who did not have ischemic heart disease, quinine treatment raised mortality by a statistically significant 9%, or 1 death for every 97 patients treated with quinine who fit this clinical profile.

Dr. Andersson said that she and her associates had no disclosures.

Pramipexole, the dopamine agonist approved for treating Parkinson’s disease and restless legs syndrome, may be associated with an increased risk for heart failure, according to a statement issued by the Food and Drug Administration.

"Results of recent studies suggest a potential risk of heart failure that needs further review of available data," but the FDA has not concluded that the drug increases the risk of heart failure, the FDA said in the Sept. 19 statement.

The FDA is currently working with Boehringer Ingelheim, which markets pramipexole as Mirapex, to investigate this association further and will provide an update when more information is available.

The studies include a pooled analysis of randomized clinical trials, which found more cases of heart failure (12 of 4,157 patients) among patients treated with pramipexole than among those on placebo (4 of 2,820). The difference between groups, however, was not statistically significant.

In two epidemiologic studies using European data, though, the increased risk of heart failure associated with pramipexole was statistically significant. In one of the studies, a case control study using a database of patients aged 40-89 years treated with anti-parkinsonian drugs, the risk of heart failure associated with any use of a dopamine agonist compared with no use was increased by almost 60% (relative risk, 1.58). The heart failure risk associated with use of pramipexole (RR, 1.86) and with another dopamine agonist, cabergoline (RR, 2.07), were each higher compared with no use of these drugs.

In the other epidemiologic study, current use of pramipexole was associated with an increased risk of heart failure, compared with levodopa. The risk was increased in the first 3 months of treatment and among patients aged 80 years and older, but was no higher among people who had been treated with pramipexole for more than 3 months.

This last finding is "difficult to explain," since heart failure is a chronic condition, and the studies had limitations, which "make it difficult to determine whether excess heart failure was related to Mirapex use or other influencing factors," the FDA statement said.

The agency advises that health care professionals continue following recommendations in the pramipexole label and that patients continue to take the medication as directed.

Pramipexole was approved in July 1997.

The full FDA notice is available here. Serious adverse events associated with pramipexole should be reported to the FDA’s MedWatch program by clicking here or by calling 800-332-1088.

Pramipexole, the dopamine agonist approved for treating Parkinson’s disease and restless legs syndrome, may be associated with an increased risk for heart failure, according to a statement issued by the Food and Drug Administration.

"Results of recent studies suggest a potential risk of heart failure that needs further review of available data," but the FDA has not concluded that the drug increases the risk of heart failure, the FDA said in the Sept. 19 statement.

The FDA is currently working with Boehringer Ingelheim, which markets pramipexole as Mirapex, to investigate this association further and will provide an update when more information is available.

The studies include a pooled analysis of randomized clinical trials, which found more cases of heart failure (12 of 4,157 patients) among patients treated with pramipexole than among those on placebo (4 of 2,820). The difference between groups, however, was not statistically significant.

In two epidemiologic studies using European data, though, the increased risk of heart failure associated with pramipexole was statistically significant. In one of the studies, a case control study using a database of patients aged 40-89 years treated with anti-parkinsonian drugs, the risk of heart failure associated with any use of a dopamine agonist compared with no use was increased by almost 60% (relative risk, 1.58). The heart failure risk associated with use of pramipexole (RR, 1.86) and with another dopamine agonist, cabergoline (RR, 2.07), were each higher compared with no use of these drugs.

In the other epidemiologic study, current use of pramipexole was associated with an increased risk of heart failure, compared with levodopa. The risk was increased in the first 3 months of treatment and among patients aged 80 years and older, but was no higher among people who had been treated with pramipexole for more than 3 months.

This last finding is "difficult to explain," since heart failure is a chronic condition, and the studies had limitations, which "make it difficult to determine whether excess heart failure was related to Mirapex use or other influencing factors," the FDA statement said.

The agency advises that health care professionals continue following recommendations in the pramipexole label and that patients continue to take the medication as directed.

Pramipexole was approved in July 1997.

The full FDA notice is available here. Serious adverse events associated with pramipexole should be reported to the FDA’s MedWatch program by clicking here or by calling 800-332-1088.

Pramipexole, the dopamine agonist approved for treating Parkinson’s disease and restless legs syndrome, may be associated with an increased risk for heart failure, according to a statement issued by the Food and Drug Administration.

"Results of recent studies suggest a potential risk of heart failure that needs further review of available data," but the FDA has not concluded that the drug increases the risk of heart failure, the FDA said in the Sept. 19 statement.

The FDA is currently working with Boehringer Ingelheim, which markets pramipexole as Mirapex, to investigate this association further and will provide an update when more information is available.

The studies include a pooled analysis of randomized clinical trials, which found more cases of heart failure (12 of 4,157 patients) among patients treated with pramipexole than among those on placebo (4 of 2,820). The difference between groups, however, was not statistically significant.

In two epidemiologic studies using European data, though, the increased risk of heart failure associated with pramipexole was statistically significant. In one of the studies, a case control study using a database of patients aged 40-89 years treated with anti-parkinsonian drugs, the risk of heart failure associated with any use of a dopamine agonist compared with no use was increased by almost 60% (relative risk, 1.58). The heart failure risk associated with use of pramipexole (RR, 1.86) and with another dopamine agonist, cabergoline (RR, 2.07), were each higher compared with no use of these drugs.

In the other epidemiologic study, current use of pramipexole was associated with an increased risk of heart failure, compared with levodopa. The risk was increased in the first 3 months of treatment and among patients aged 80 years and older, but was no higher among people who had been treated with pramipexole for more than 3 months.

This last finding is "difficult to explain," since heart failure is a chronic condition, and the studies had limitations, which "make it difficult to determine whether excess heart failure was related to Mirapex use or other influencing factors," the FDA statement said.

The agency advises that health care professionals continue following recommendations in the pramipexole label and that patients continue to take the medication as directed.

Pramipexole was approved in July 1997.

The full FDA notice is available here. Serious adverse events associated with pramipexole should be reported to the FDA’s MedWatch program by clicking here or by calling 800-332-1088.

SILVER SPRING, MD. – A Food and Drug Administration advisory panel has recommended against the approval of lixivaptan, an orally administered vasopressin-2 receptor antagonist, for treating hyponatremia in two groups of adult patients at a meeting on Sept. 13.

The manufacturer, Cardiokine Biopharma, has proposed that lixivaptan be approved for the treatment of hypervolemic hyponatremia associated with heart failure, and for the treatment of euvolemic hyponatremia associated with syndrome of inappropriate antidiuretic hormone (SIADH). The company submitted the results of three phase III placebo-controlled trials that evaluated the changes from baseline in serum sodium at day 7 of treatment, the primary efficacy end point. The company proposed that for the SIADH indication, treatment could be initiated in an outpatient setting, which would be a potential benefit over existing treatments, including the only approved orally administered vasopressin-2 receptor antagonist that is approved for hyponatremia, tolvaptan (Samsca). Tolvaptan is approved for inpatients with diagnoses that include SIADH, heart failure, and cirrhosis, and is initiated in the hospital. The other approved "vaptan" – zomivaptan (Vaprisol), approved in 2005 – is administered intravenously.

Lixivaptan acts specifically on the vasopressin-2 receptor in the kidneys, "causing water to be excreted while sparing sodium without affecting other electrolytes," according to Cardiokine. While the changes in serum sodium from baseline to day 7 among treated patients over placebo were statistically significant, the improvements were modest and were not associated with improved cognitive function, the FDA reviewers pointed out.

In the study of patients with hypervolemic hyponatremia hospitalized with New York Heart Association (NYHA) class III or IV heart failure (652 patients), the increase in serum sodium at day 7 was 1.2 mEq/L greater among treated patients, compared with those on placebo. The mortality rate was 17.7% among those who had at least one dose of lixivaptan, compared with 14.3% on placebo; most deaths were related to heart failure, according to Cardiokine, which was recently acquired by Cornerstone Therapeutics.

In the two other studies, comprising a total of 312 patients with SIADH, the increases in serum sodium at day 7 over placebo were 2.2 mEq/L and 2.4 mEq/L.

But at the meeting of the FDA’s Cardiovascular and Renal Drugs Advisory Committee, the panel unanimously voted against approval of lixivaptan for the heart failure indication, because its members were not convinced that the modest effect of treatment on hyponatremia observed in the study of heart failure patients provided evidence that it benefited patients. The panel also agreed that more data on how improvements in serum sodium translated to clinical benefits, such as quality of life improvements, were needed. Another concern was that mortality was higher among the patients treated with lixivaptan than in those on placebo, particularly early in treatment.

The panel voted 5 to 3 against approval for treatment of hyponatremia in patients with SIADH, with clinicians voting on both sides of this question.

Dr. Linda Fried, professor of medicine at the VA Health Care System in Pittsburgh, voted in favor of approval because she said she believed that the vaptans directly affect pathophysiology in SIADH, and because she did not see a safety signal.

But Dr. Mori Krantz, associate professor of cardiology at the University of Colorado, Denver, voted against approval, because there were not enough data to show whether the improvements with treatment were clinically meaningful. He said that a larger study evaluating the effects of improvements in serum sodium with treatment on quality of life and other measures was needed, "to at least give clinicians some sense of security that they are helping patients."

Most panelists questioned the feasibility of initiating treatment as an outpatient, in most clinical settings.

The FDA is expected to make a decision on approval by Oct. 29.

Panelists have been cleared of potential conflicts of interest related to the topic of the meeting. Occasionally, a panelist may be given a waiver, but not at this meeting.

SILVER SPRING, MD. – A Food and Drug Administration advisory panel has recommended against the approval of lixivaptan, an orally administered vasopressin-2 receptor antagonist, for treating hyponatremia in two groups of adult patients at a meeting on Sept. 13.

The manufacturer, Cardiokine Biopharma, has proposed that lixivaptan be approved for the treatment of hypervolemic hyponatremia associated with heart failure, and for the treatment of euvolemic hyponatremia associated with syndrome of inappropriate antidiuretic hormone (SIADH). The company submitted the results of three phase III placebo-controlled trials that evaluated the changes from baseline in serum sodium at day 7 of treatment, the primary efficacy end point. The company proposed that for the SIADH indication, treatment could be initiated in an outpatient setting, which would be a potential benefit over existing treatments, including the only approved orally administered vasopressin-2 receptor antagonist that is approved for hyponatremia, tolvaptan (Samsca). Tolvaptan is approved for inpatients with diagnoses that include SIADH, heart failure, and cirrhosis, and is initiated in the hospital. The other approved "vaptan" – zomivaptan (Vaprisol), approved in 2005 – is administered intravenously.

Lixivaptan acts specifically on the vasopressin-2 receptor in the kidneys, "causing water to be excreted while sparing sodium without affecting other electrolytes," according to Cardiokine. While the changes in serum sodium from baseline to day 7 among treated patients over placebo were statistically significant, the improvements were modest and were not associated with improved cognitive function, the FDA reviewers pointed out.

In the study of patients with hypervolemic hyponatremia hospitalized with New York Heart Association (NYHA) class III or IV heart failure (652 patients), the increase in serum sodium at day 7 was 1.2 mEq/L greater among treated patients, compared with those on placebo. The mortality rate was 17.7% among those who had at least one dose of lixivaptan, compared with 14.3% on placebo; most deaths were related to heart failure, according to Cardiokine, which was recently acquired by Cornerstone Therapeutics.

In the two other studies, comprising a total of 312 patients with SIADH, the increases in serum sodium at day 7 over placebo were 2.2 mEq/L and 2.4 mEq/L.

But at the meeting of the FDA’s Cardiovascular and Renal Drugs Advisory Committee, the panel unanimously voted against approval of lixivaptan for the heart failure indication, because its members were not convinced that the modest effect of treatment on hyponatremia observed in the study of heart failure patients provided evidence that it benefited patients. The panel also agreed that more data on how improvements in serum sodium translated to clinical benefits, such as quality of life improvements, were needed. Another concern was that mortality was higher among the patients treated with lixivaptan than in those on placebo, particularly early in treatment.

The panel voted 5 to 3 against approval for treatment of hyponatremia in patients with SIADH, with clinicians voting on both sides of this question.

Dr. Linda Fried, professor of medicine at the VA Health Care System in Pittsburgh, voted in favor of approval because she said she believed that the vaptans directly affect pathophysiology in SIADH, and because she did not see a safety signal.

But Dr. Mori Krantz, associate professor of cardiology at the University of Colorado, Denver, voted against approval, because there were not enough data to show whether the improvements with treatment were clinically meaningful. He said that a larger study evaluating the effects of improvements in serum sodium with treatment on quality of life and other measures was needed, "to at least give clinicians some sense of security that they are helping patients."

Most panelists questioned the feasibility of initiating treatment as an outpatient, in most clinical settings.

The FDA is expected to make a decision on approval by Oct. 29.

Panelists have been cleared of potential conflicts of interest related to the topic of the meeting. Occasionally, a panelist may be given a waiver, but not at this meeting.

SILVER SPRING, MD. – A Food and Drug Administration advisory panel has recommended against the approval of lixivaptan, an orally administered vasopressin-2 receptor antagonist, for treating hyponatremia in two groups of adult patients at a meeting on Sept. 13.

The manufacturer, Cardiokine Biopharma, has proposed that lixivaptan be approved for the treatment of hypervolemic hyponatremia associated with heart failure, and for the treatment of euvolemic hyponatremia associated with syndrome of inappropriate antidiuretic hormone (SIADH). The company submitted the results of three phase III placebo-controlled trials that evaluated the changes from baseline in serum sodium at day 7 of treatment, the primary efficacy end point. The company proposed that for the SIADH indication, treatment could be initiated in an outpatient setting, which would be a potential benefit over existing treatments, including the only approved orally administered vasopressin-2 receptor antagonist that is approved for hyponatremia, tolvaptan (Samsca). Tolvaptan is approved for inpatients with diagnoses that include SIADH, heart failure, and cirrhosis, and is initiated in the hospital. The other approved "vaptan" – zomivaptan (Vaprisol), approved in 2005 – is administered intravenously.

Lixivaptan acts specifically on the vasopressin-2 receptor in the kidneys, "causing water to be excreted while sparing sodium without affecting other electrolytes," according to Cardiokine. While the changes in serum sodium from baseline to day 7 among treated patients over placebo were statistically significant, the improvements were modest and were not associated with improved cognitive function, the FDA reviewers pointed out.

In the study of patients with hypervolemic hyponatremia hospitalized with New York Heart Association (NYHA) class III or IV heart failure (652 patients), the increase in serum sodium at day 7 was 1.2 mEq/L greater among treated patients, compared with those on placebo. The mortality rate was 17.7% among those who had at least one dose of lixivaptan, compared with 14.3% on placebo; most deaths were related to heart failure, according to Cardiokine, which was recently acquired by Cornerstone Therapeutics.

In the two other studies, comprising a total of 312 patients with SIADH, the increases in serum sodium at day 7 over placebo were 2.2 mEq/L and 2.4 mEq/L.

But at the meeting of the FDA’s Cardiovascular and Renal Drugs Advisory Committee, the panel unanimously voted against approval of lixivaptan for the heart failure indication, because its members were not convinced that the modest effect of treatment on hyponatremia observed in the study of heart failure patients provided evidence that it benefited patients. The panel also agreed that more data on how improvements in serum sodium translated to clinical benefits, such as quality of life improvements, were needed. Another concern was that mortality was higher among the patients treated with lixivaptan than in those on placebo, particularly early in treatment.

The panel voted 5 to 3 against approval for treatment of hyponatremia in patients with SIADH, with clinicians voting on both sides of this question.

Dr. Linda Fried, professor of medicine at the VA Health Care System in Pittsburgh, voted in favor of approval because she said she believed that the vaptans directly affect pathophysiology in SIADH, and because she did not see a safety signal.

But Dr. Mori Krantz, associate professor of cardiology at the University of Colorado, Denver, voted against approval, because there were not enough data to show whether the improvements with treatment were clinically meaningful. He said that a larger study evaluating the effects of improvements in serum sodium with treatment on quality of life and other measures was needed, "to at least give clinicians some sense of security that they are helping patients."

Most panelists questioned the feasibility of initiating treatment as an outpatient, in most clinical settings.

The FDA is expected to make a decision on approval by Oct. 29.

Panelists have been cleared of potential conflicts of interest related to the topic of the meeting. Occasionally, a panelist may be given a waiver, but not at this meeting.

For patients discharged after hospitalization for heart failure, case-management interventions led by a specialist nurse reduce HF-related readmissions, HF-related mortality, and all-cause mortality, according to an update published online Sept. 11 in the Cochrane Database of Systematic Reviews.

© Dron/Fotolia.com

The initial Cochrane Review that addressed the effectiveness of three different types of follow-up care (case-management, clinic-based, and multidisciplinary) after hospitalization for HF was published in 2005, and found mixed and inconclusive results for all three (Cochrane Database Syst. Rev. 2005 8;(2):CD002752).

Since then, several new clinical trials have been performed, and "there is now strong evidence that case-management interventions are associated with a substantial, statistically significant reduction in all-cause mortality" as well as HF mortality and rehospitalization, said Dr. Andrea Takeda of Queen Mary University, London, and her associates in the Cochrane Collaboration.

In contrast, the evidence doesn’t support interventions in which the major component is follow-up in a hospital HF clinic. And the evidence for multidisciplinary interventions is too sparse to be conclusive because only two high-quality studies have examined these approaches, the investigators wrote (Cochrane Database of Systematic Reviews 2012 [doi:101002/14651858.CD002752.pub3]).

Case-management programs led by personnel other than nurses specializing in HF, such as hospital-based or community pharmacists, nonspecialist nurses, or interdisciplinary teams, were not as successful as those led by specialist nurses, they added.

Dr. Takeda and her colleagues reviewed 25 randomized clinical trials of at least 6 months’ duration that compared the three types of interventions against usual care in 5,942 adults who had been hospitalized for HF. They excluded interventions that focused on patient education only, exercise only, telemedicine (which was examined in a separate Cochrane Review), or cardiac rehabilitation.

Most of the clinical trials had 100-350 study subjects, but some had fewer than 100 and one had over 1,000 subjects. They were conducted in Europe, the United States, Canada, Australia, and China.

Seventeen studies assessed case-management interventions. Pooling the results demonstrated that these interventions produced a substantial and highly significant reduction in all-cause mortality, HF-related mortality, and HF-related rehospitalization at 12 months. Although the overall impact of the interventions on inpatient days was "not clear," the researchers wrote, there was "a strong suggestion" that these interventions decreased hospital length of stay.

However, case-management interventions did not appear to improve event-free survival. They also did not appear to improve health-related quality of life, but few studies examined this outcome and those that did suffered from high dropout rates, so the data were inconclusive.

Only six clinical trials involving 1,486 patients assessed clinic-based interventions. They showed no reduction in readmissions, mortality, inpatient days, event-free survival, or health-related quality of life.

Only two clinical trials involving 403 patients assessed multidisciplinary programs. The data were inadequate to establish conclusive results, Dr. Takeda and her associates wrote.

In a post hoc analysis, the intensity of various interventions did not appear to influence their effectiveness. Studies of the most intensive, moderately intensive, and low-intensity interventions all showed some reductions in mortality and rehospitalization, the researchers added.

No financial conflicts of interest were reported.

For patients discharged after hospitalization for heart failure, case-management interventions led by a specialist nurse reduce HF-related readmissions, HF-related mortality, and all-cause mortality, according to an update published online Sept. 11 in the Cochrane Database of Systematic Reviews.

© Dron/Fotolia.com

The initial Cochrane Review that addressed the effectiveness of three different types of follow-up care (case-management, clinic-based, and multidisciplinary) after hospitalization for HF was published in 2005, and found mixed and inconclusive results for all three (Cochrane Database Syst. Rev. 2005 8;(2):CD002752).

Since then, several new clinical trials have been performed, and "there is now strong evidence that case-management interventions are associated with a substantial, statistically significant reduction in all-cause mortality" as well as HF mortality and rehospitalization, said Dr. Andrea Takeda of Queen Mary University, London, and her associates in the Cochrane Collaboration.

In contrast, the evidence doesn’t support interventions in which the major component is follow-up in a hospital HF clinic. And the evidence for multidisciplinary interventions is too sparse to be conclusive because only two high-quality studies have examined these approaches, the investigators wrote (Cochrane Database of Systematic Reviews 2012 [doi:101002/14651858.CD002752.pub3]).

Case-management programs led by personnel other than nurses specializing in HF, such as hospital-based or community pharmacists, nonspecialist nurses, or interdisciplinary teams, were not as successful as those led by specialist nurses, they added.

Dr. Takeda and her colleagues reviewed 25 randomized clinical trials of at least 6 months’ duration that compared the three types of interventions against usual care in 5,942 adults who had been hospitalized for HF. They excluded interventions that focused on patient education only, exercise only, telemedicine (which was examined in a separate Cochrane Review), or cardiac rehabilitation.

Most of the clinical trials had 100-350 study subjects, but some had fewer than 100 and one had over 1,000 subjects. They were conducted in Europe, the United States, Canada, Australia, and China.

Seventeen studies assessed case-management interventions. Pooling the results demonstrated that these interventions produced a substantial and highly significant reduction in all-cause mortality, HF-related mortality, and HF-related rehospitalization at 12 months. Although the overall impact of the interventions on inpatient days was "not clear," the researchers wrote, there was "a strong suggestion" that these interventions decreased hospital length of stay.

However, case-management interventions did not appear to improve event-free survival. They also did not appear to improve health-related quality of life, but few studies examined this outcome and those that did suffered from high dropout rates, so the data were inconclusive.

Only six clinical trials involving 1,486 patients assessed clinic-based interventions. They showed no reduction in readmissions, mortality, inpatient days, event-free survival, or health-related quality of life.

Only two clinical trials involving 403 patients assessed multidisciplinary programs. The data were inadequate to establish conclusive results, Dr. Takeda and her associates wrote.

In a post hoc analysis, the intensity of various interventions did not appear to influence their effectiveness. Studies of the most intensive, moderately intensive, and low-intensity interventions all showed some reductions in mortality and rehospitalization, the researchers added.

No financial conflicts of interest were reported.

For patients discharged after hospitalization for heart failure, case-management interventions led by a specialist nurse reduce HF-related readmissions, HF-related mortality, and all-cause mortality, according to an update published online Sept. 11 in the Cochrane Database of Systematic Reviews.

© Dron/Fotolia.com

The initial Cochrane Review that addressed the effectiveness of three different types of follow-up care (case-management, clinic-based, and multidisciplinary) after hospitalization for HF was published in 2005, and found mixed and inconclusive results for all three (Cochrane Database Syst. Rev. 2005 8;(2):CD002752).

Since then, several new clinical trials have been performed, and "there is now strong evidence that case-management interventions are associated with a substantial, statistically significant reduction in all-cause mortality" as well as HF mortality and rehospitalization, said Dr. Andrea Takeda of Queen Mary University, London, and her associates in the Cochrane Collaboration.

In contrast, the evidence doesn’t support interventions in which the major component is follow-up in a hospital HF clinic. And the evidence for multidisciplinary interventions is too sparse to be conclusive because only two high-quality studies have examined these approaches, the investigators wrote (Cochrane Database of Systematic Reviews 2012 [doi:101002/14651858.CD002752.pub3]).

Case-management programs led by personnel other than nurses specializing in HF, such as hospital-based or community pharmacists, nonspecialist nurses, or interdisciplinary teams, were not as successful as those led by specialist nurses, they added.

Dr. Takeda and her colleagues reviewed 25 randomized clinical trials of at least 6 months’ duration that compared the three types of interventions against usual care in 5,942 adults who had been hospitalized for HF. They excluded interventions that focused on patient education only, exercise only, telemedicine (which was examined in a separate Cochrane Review), or cardiac rehabilitation.

Most of the clinical trials had 100-350 study subjects, but some had fewer than 100 and one had over 1,000 subjects. They were conducted in Europe, the United States, Canada, Australia, and China.

Seventeen studies assessed case-management interventions. Pooling the results demonstrated that these interventions produced a substantial and highly significant reduction in all-cause mortality, HF-related mortality, and HF-related rehospitalization at 12 months. Although the overall impact of the interventions on inpatient days was "not clear," the researchers wrote, there was "a strong suggestion" that these interventions decreased hospital length of stay.

However, case-management interventions did not appear to improve event-free survival. They also did not appear to improve health-related quality of life, but few studies examined this outcome and those that did suffered from high dropout rates, so the data were inconclusive.

Only six clinical trials involving 1,486 patients assessed clinic-based interventions. They showed no reduction in readmissions, mortality, inpatient days, event-free survival, or health-related quality of life.

Only two clinical trials involving 403 patients assessed multidisciplinary programs. The data were inadequate to establish conclusive results, Dr. Takeda and her associates wrote.

In a post hoc analysis, the intensity of various interventions did not appear to influence their effectiveness. Studies of the most intensive, moderately intensive, and low-intensity interventions all showed some reductions in mortality and rehospitalization, the researchers added.

No financial conflicts of interest were reported.

Trastuzumab, whether given with or without anthracyline-based chemotherapy, was associated with significant increases in heart failure and cardiomyopathy in a large population-based, retrospective cohort study of women treated for breast cancer.

In the "real world" study, which used data from the health maintenance organization Cancer Research Network, the adjusted risk of heart failure (HF) and/or cardiomyopathy increased fourfold among women who received trastuzumab (Herceptin) alone and sevenfold in those who received anthracycline plus trastuzumab, compared with women who received no chemotherapy.

In all, the risk of anthracycline-associated HF/cardiomyopathy among women younger than 65 years was similar to results from randomized clinical trials, while the trastuzumab-associated HF/cardiomyopathy risk – whether administered alone or following an anthracycline – was greater than that previously reported.

"Our results highlight the importance of generalizability in applying clinical trial findings to community settings; although similar to clinical trial results, these population-based results cannot be attributed to any single patient in clinical practice," wrote Erin J. Aiello Bowles of Group Health Research Institute, Seattle, and her associates.

Randomized trials have typically excluded older women and those with major comorbidities, and therefore the association between the two agents and HF/cardiomyopathy in this population is not well understood, Ms. Bowles and her associates noted (J. Natl. Cancer Inst. 2012 Aug. 30 [doi:10.1093/jnci/djs317]).

The current study population comprised 12,500 women diagnosed with incident, invasive breast cancer from Jan. 1, 1999, through Dec. 31, 2007, at eight integrated Cancer Research Network health systems. Women diagnosed with HF/cardiomyopathy prior to breast cancer diagnosis or initiation of chemotherapy were excluded. They had a mean age of 60 years (range, 22-99), and 85.8% were white.

In a median follow-up of 4.4 years, nearly half (46.5%) had received no chemotherapy. Just under a third, 29.6%, had received anthracycline-based chemotherapy alone, 0.9% received trastuzumab-based therapy without anthracycline, 3.5% received anthracycline plus trastuzumab, and 19.5% received other chemotherapy.

Compared with the women who received other chemotherapy or no chemotherapy, the women who received anthracycline alone or anthracycline plus trastuzumab were younger, diagnosed at later stages, had fewer comorbidities, and were slightly more likely to receive radiation therapy. These findings "suggest substantial individualization of adjuvant chemotherapy administration by age and comorbidity in community practice," Ms. Bowles and her associates wrote.

The incidence of HF/cardiomyopathy increased with increasing follow-up time for all of the chemotherapy types, but to a greater degree with trastuzumab. The cumulative HF/cardiomyopathy incidence increased from 1.2% at year 1 to 4.3% at year 5 for the anthracycline recipients, which was similar to the increase from 1.3% to 4.5% for those on other chemotherapies. For those with no chemotherapy, the cumulative incidence rose from 0.9% to 3.1%.

In contrast, the cumulative HF/cardiomyopathy incidence among recipients of anthracycline plus trastuzumab was 6.2% after 1 year of follow-up and continued to increase to 20.1% by 5 years.

Compared with no chemotherapy, the risk of incident HF/cardiomyopathy among all women was statistically significantly increased for anthracycline alone (adjusted hazard ratio, 1.40), trastuzumab without anthracycline (HR, 4.12), anthracycline plus trastuzumab (HR, 7.19), and other chemotherapy (HR, 1.49), the investigators said.

The 5-year cumulative incidence for HF/cardiomyopathy associated with each of the chemotherapies was greater in the older age groups, but the hazard ratios for HF/cardiomyopathy associated with chemotherapy use decreased with increasing age. For example, the hazard ratio for HF/cardiomyopathy associated with anthracycline use alone was statistically significant among women younger than 55 years (HR, 2.52) but not among women 55-64 years (HR, 1.61) or older.

According to Ms. Bowles and her associates, this study demonstrates the importance of observational comparative safety and effectiveness studies in providing complementary data to those obtained in clinical trials. "Observational studies allow for estimation of risks and benefits in community practice, which includes patients who may not be eligible for clinical trials. Clinical trials may provide more relevant estimates for patients who are eligible candidates, but many people are not and still receive these treatments in community practice," they wrote.

This work was supported by the National Cancer Institute through an administrative supplement to the Cancer Research Network. Ms. Bowles did not report any financial disclosures, but one of her coauthors, Dr. Larry A. Allen, has received consulting fees from Amgen, Janssen Scientific Affairs, and the Robert Wood Johnson Foundation.

Trastuzumab, whether given with or without anthracyline-based chemotherapy, was associated with significant increases in heart failure and cardiomyopathy in a large population-based, retrospective cohort study of women treated for breast cancer.

In the "real world" study, which used data from the health maintenance organization Cancer Research Network, the adjusted risk of heart failure (HF) and/or cardiomyopathy increased fourfold among women who received trastuzumab (Herceptin) alone and sevenfold in those who received anthracycline plus trastuzumab, compared with women who received no chemotherapy.

In all, the risk of anthracycline-associated HF/cardiomyopathy among women younger than 65 years was similar to results from randomized clinical trials, while the trastuzumab-associated HF/cardiomyopathy risk – whether administered alone or following an anthracycline – was greater than that previously reported.

"Our results highlight the importance of generalizability in applying clinical trial findings to community settings; although similar to clinical trial results, these population-based results cannot be attributed to any single patient in clinical practice," wrote Erin J. Aiello Bowles of Group Health Research Institute, Seattle, and her associates.

Randomized trials have typically excluded older women and those with major comorbidities, and therefore the association between the two agents and HF/cardiomyopathy in this population is not well understood, Ms. Bowles and her associates noted (J. Natl. Cancer Inst. 2012 Aug. 30 [doi:10.1093/jnci/djs317]).

The current study population comprised 12,500 women diagnosed with incident, invasive breast cancer from Jan. 1, 1999, through Dec. 31, 2007, at eight integrated Cancer Research Network health systems. Women diagnosed with HF/cardiomyopathy prior to breast cancer diagnosis or initiation of chemotherapy were excluded. They had a mean age of 60 years (range, 22-99), and 85.8% were white.

In a median follow-up of 4.4 years, nearly half (46.5%) had received no chemotherapy. Just under a third, 29.6%, had received anthracycline-based chemotherapy alone, 0.9% received trastuzumab-based therapy without anthracycline, 3.5% received anthracycline plus trastuzumab, and 19.5% received other chemotherapy.

Compared with the women who received other chemotherapy or no chemotherapy, the women who received anthracycline alone or anthracycline plus trastuzumab were younger, diagnosed at later stages, had fewer comorbidities, and were slightly more likely to receive radiation therapy. These findings "suggest substantial individualization of adjuvant chemotherapy administration by age and comorbidity in community practice," Ms. Bowles and her associates wrote.

The incidence of HF/cardiomyopathy increased with increasing follow-up time for all of the chemotherapy types, but to a greater degree with trastuzumab. The cumulative HF/cardiomyopathy incidence increased from 1.2% at year 1 to 4.3% at year 5 for the anthracycline recipients, which was similar to the increase from 1.3% to 4.5% for those on other chemotherapies. For those with no chemotherapy, the cumulative incidence rose from 0.9% to 3.1%.

In contrast, the cumulative HF/cardiomyopathy incidence among recipients of anthracycline plus trastuzumab was 6.2% after 1 year of follow-up and continued to increase to 20.1% by 5 years.

Compared with no chemotherapy, the risk of incident HF/cardiomyopathy among all women was statistically significantly increased for anthracycline alone (adjusted hazard ratio, 1.40), trastuzumab without anthracycline (HR, 4.12), anthracycline plus trastuzumab (HR, 7.19), and other chemotherapy (HR, 1.49), the investigators said.

The 5-year cumulative incidence for HF/cardiomyopathy associated with each of the chemotherapies was greater in the older age groups, but the hazard ratios for HF/cardiomyopathy associated with chemotherapy use decreased with increasing age. For example, the hazard ratio for HF/cardiomyopathy associated with anthracycline use alone was statistically significant among women younger than 55 years (HR, 2.52) but not among women 55-64 years (HR, 1.61) or older.

According to Ms. Bowles and her associates, this study demonstrates the importance of observational comparative safety and effectiveness studies in providing complementary data to those obtained in clinical trials. "Observational studies allow for estimation of risks and benefits in community practice, which includes patients who may not be eligible for clinical trials. Clinical trials may provide more relevant estimates for patients who are eligible candidates, but many people are not and still receive these treatments in community practice," they wrote.

This work was supported by the National Cancer Institute through an administrative supplement to the Cancer Research Network. Ms. Bowles did not report any financial disclosures, but one of her coauthors, Dr. Larry A. Allen, has received consulting fees from Amgen, Janssen Scientific Affairs, and the Robert Wood Johnson Foundation.

Trastuzumab, whether given with or without anthracyline-based chemotherapy, was associated with significant increases in heart failure and cardiomyopathy in a large population-based, retrospective cohort study of women treated for breast cancer.

In the "real world" study, which used data from the health maintenance organization Cancer Research Network, the adjusted risk of heart failure (HF) and/or cardiomyopathy increased fourfold among women who received trastuzumab (Herceptin) alone and sevenfold in those who received anthracycline plus trastuzumab, compared with women who received no chemotherapy.

In all, the risk of anthracycline-associated HF/cardiomyopathy among women younger than 65 years was similar to results from randomized clinical trials, while the trastuzumab-associated HF/cardiomyopathy risk – whether administered alone or following an anthracycline – was greater than that previously reported.

"Our results highlight the importance of generalizability in applying clinical trial findings to community settings; although similar to clinical trial results, these population-based results cannot be attributed to any single patient in clinical practice," wrote Erin J. Aiello Bowles of Group Health Research Institute, Seattle, and her associates.

Randomized trials have typically excluded older women and those with major comorbidities, and therefore the association between the two agents and HF/cardiomyopathy in this population is not well understood, Ms. Bowles and her associates noted (J. Natl. Cancer Inst. 2012 Aug. 30 [doi:10.1093/jnci/djs317]).

The current study population comprised 12,500 women diagnosed with incident, invasive breast cancer from Jan. 1, 1999, through Dec. 31, 2007, at eight integrated Cancer Research Network health systems. Women diagnosed with HF/cardiomyopathy prior to breast cancer diagnosis or initiation of chemotherapy were excluded. They had a mean age of 60 years (range, 22-99), and 85.8% were white.

In a median follow-up of 4.4 years, nearly half (46.5%) had received no chemotherapy. Just under a third, 29.6%, had received anthracycline-based chemotherapy alone, 0.9% received trastuzumab-based therapy without anthracycline, 3.5% received anthracycline plus trastuzumab, and 19.5% received other chemotherapy.

Compared with the women who received other chemotherapy or no chemotherapy, the women who received anthracycline alone or anthracycline plus trastuzumab were younger, diagnosed at later stages, had fewer comorbidities, and were slightly more likely to receive radiation therapy. These findings "suggest substantial individualization of adjuvant chemotherapy administration by age and comorbidity in community practice," Ms. Bowles and her associates wrote.

The incidence of HF/cardiomyopathy increased with increasing follow-up time for all of the chemotherapy types, but to a greater degree with trastuzumab. The cumulative HF/cardiomyopathy incidence increased from 1.2% at year 1 to 4.3% at year 5 for the anthracycline recipients, which was similar to the increase from 1.3% to 4.5% for those on other chemotherapies. For those with no chemotherapy, the cumulative incidence rose from 0.9% to 3.1%.

In contrast, the cumulative HF/cardiomyopathy incidence among recipients of anthracycline plus trastuzumab was 6.2% after 1 year of follow-up and continued to increase to 20.1% by 5 years.

Compared with no chemotherapy, the risk of incident HF/cardiomyopathy among all women was statistically significantly increased for anthracycline alone (adjusted hazard ratio, 1.40), trastuzumab without anthracycline (HR, 4.12), anthracycline plus trastuzumab (HR, 7.19), and other chemotherapy (HR, 1.49), the investigators said.

The 5-year cumulative incidence for HF/cardiomyopathy associated with each of the chemotherapies was greater in the older age groups, but the hazard ratios for HF/cardiomyopathy associated with chemotherapy use decreased with increasing age. For example, the hazard ratio for HF/cardiomyopathy associated with anthracycline use alone was statistically significant among women younger than 55 years (HR, 2.52) but not among women 55-64 years (HR, 1.61) or older.

According to Ms. Bowles and her associates, this study demonstrates the importance of observational comparative safety and effectiveness studies in providing complementary data to those obtained in clinical trials. "Observational studies allow for estimation of risks and benefits in community practice, which includes patients who may not be eligible for clinical trials. Clinical trials may provide more relevant estimates for patients who are eligible candidates, but many people are not and still receive these treatments in community practice," they wrote.

This work was supported by the National Cancer Institute through an administrative supplement to the Cancer Research Network. Ms. Bowles did not report any financial disclosures, but one of her coauthors, Dr. Larry A. Allen, has received consulting fees from Amgen, Janssen Scientific Affairs, and the Robert Wood Johnson Foundation.

MUNICH – A new universal definition of myocardial infarction has been unveiled, sparked by the development of ever more sensitive cardiac biomarker assays and imaging techniques.

These assays, including the new high-sensitivity cardiac troponin (cTn) assays available throughout Europe and awaiting approval in the United States, have created confusion in the diagnosis of myocardial infarction because they detect small cTn elevations associated with many other clinical conditions such as heart failure, arrhythmias, and pulmonary embolism that are not MIs, but rather myocardial injury with necrosis.

Patrice Wendling/IMNG Medical Media

"I think there has been a little bit of a problem in the past where we’ve had too many infarctions [diagnosed] ... where there is some damage or injury to the myocardial cells," said document task force cochair Dr. Kristian Thygeysen, who presented the third universal MI definition at the annual meeting of the European Society of Cardiology (ESC).

The expert consensus document, developed by the ESC, American College of Cardiology (ACC), American Heart Association (AHA), and World Heart Federation (WHF), maintains the pathological definition of acute MI as myocardial cell death due to prolonged myocardial ischemia, but goes on to refine the definition of MI in five settings, including the controversial area of MIs associated with revascularization procedures.

Patrice Wendling/IMNG Medical Media

MI in the PCI Setting

An MI related to percutaneous coronary intervention (PCI) is defined as an elevation of cTn values more than five times the 99th percentile upper reference limit (URL) in the first 48 hours after a procedure in patients with normal baseline troponin values, or a rise of cTn values of more than 20% in patients with elevated baseline levels that are stable or falling.

It also requires one of the following events: symptoms suggestive of myocardial ischemia, new ischemic ECG changes, angiographic findings consistent with a procedural complication, or imaging evidence of new loss of viable myocardium or new regional wall motion abnormality.

In the previous 2007 document, the troponin threshold had been more than three times the 99th percentile, and was raised based on new prognostic information from long-term follow-up of patients undergoing PCI showing that there is unavoidable injury associated with the procedure, document task force codirector Dr. Joseph Alpert said during the presentation.

CABG-Related MI

Similarly, the 2012 version raises the troponin threshold for MI related to coronary artery bypass graft surgery from five times the 99th percentile URL in the 2007 document to 10 times the 99th percentile in patients with normal cTn baseline values.

It also requires one of the following: new pathological Q waves or new left bundle branch block (LBBB), angiographically documented new graft or new native coronary artery occlusion, or imaging evidence of new loss of viable myocardium or new regional wall motion abnormality.

Once again, the decision to raise the troponin threshold was made because there is unavoidable injury to the heart during CABG from needle sticks, handling of the heart, and the myocardial preservation procedure, said Dr. Alpert, a professor of medicine at the University of Arizona, Tucson.

Many Sources of Heart Injury

"The problem that every clinician – not just cardiologists, but internists and surgeons – is having with these troponin tests, and particularly with the high-sensitivity test, is that it turns out we’re finding that there are lots and lots of people having heart injuries," he said in an interview. "We’ve known for decades that it’s not uncommon for a very sick patient to have liver injuries, but now we’re saying, ‘My goodness, they’re having heart injuries, and these injuries are not MIs, or at least we have no evidence there is ischemia.’ "

The updated guideline points out that novel procedures such as transcatheter aortic valve implantation or mitral clip may also cause myocardial injury with necrosis, and that "it is likely that, similarly to CABG, the more marked the elevation of the biomarker values, the worse the prognosis – but data on that are not available.&qu

Although high-sensitivity troponin assays are not yet approved in the United States, it is only a matter of time before they are and the financial battle heats up over the distinction between myocardial injury and MI, according to Dr. Alpert. The reason is that there is currently no reimbursement code for patients with myocardial injury, who require substantial time and resources that currently are not being reimbursed.

"We’re pushing to get that code, because when you have an elevated troponin it means something, and it always means something not good," he said in the interview.

Cardiac troponin (I or T) is the preferred biomarker for the definition of acute MI, although less sensitive biomarkers such as the creatine kinase-MB (CKMB) mass can still be used when cardiac troponin is not available, said Dr. Thygesen, with the department of cardiological medicine, Aarhus (Denmark) University.

The criteria for an acute MI include detection of a rise and/or fall of cardiac biomarker values exceeding the 99th percentile URL, plus at least one of the following:

• Symptoms of ischemia.

• New or presumably new significant ST-segment/T wave changes or new LBBB.

• Development of pathological Q waves in the ECG.

• Imaging evidence of new loss of viable myocardium or new regional wall motion abnormality.

• Identification of an intracoronary thrombus by angiography or autopsy.

The new MI definition is expected to become the gold standard for diagnosis and to be adopted by the U.S. Food and Drug Administration for use in clinical trial protocols accepted by the agency. This is significant because it will help standardize the way MI is defined in clinical trials, making comparisons between studies more meaningful, Dr. Thygesen observed.

The expert consensus document, as well as pocket versions, are available on the websites of the ESC, ACC, AHA, and World Heart Federation.

The document is also being copublished in five journals: the Journal of the American College of Cardiology, European Heart Journal, Circulation, Global Heart, and Nature Reviews of Cardiology.

Dr. Thygesen reported no conflicts of interest. Dr. Alpert reported consulting for several pharmaceutical firms as well as the North American Center for Continuing Medical Education.

MUNICH – A new universal definition of myocardial infarction has been unveiled, sparked by the development of ever more sensitive cardiac biomarker assays and imaging techniques.

These assays, including the new high-sensitivity cardiac troponin (cTn) assays available throughout Europe and awaiting approval in the United States, have created confusion in the diagnosis of myocardial infarction because they detect small cTn elevations associated with many other clinical conditions such as heart failure, arrhythmias, and pulmonary embolism that are not MIs, but rather myocardial injury with necrosis.

Patrice Wendling/IMNG Medical Media

"I think there has been a little bit of a problem in the past where we’ve had too many infarctions [diagnosed] ... where there is some damage or injury to the myocardial cells," said document task force cochair Dr. Kristian Thygeysen, who presented the third universal MI definition at the annual meeting of the European Society of Cardiology (ESC).

The expert consensus document, developed by the ESC, American College of Cardiology (ACC), American Heart Association (AHA), and World Heart Federation (WHF), maintains the pathological definition of acute MI as myocardial cell death due to prolonged myocardial ischemia, but goes on to refine the definition of MI in five settings, including the controversial area of MIs associated with revascularization procedures.

Patrice Wendling/IMNG Medical Media

MI in the PCI Setting

An MI related to percutaneous coronary intervention (PCI) is defined as an elevation of cTn values more than five times the 99th percentile upper reference limit (URL) in the first 48 hours after a procedure in patients with normal baseline troponin values, or a rise of cTn values of more than 20% in patients with elevated baseline levels that are stable or falling.

It also requires one of the following events: symptoms suggestive of myocardial ischemia, new ischemic ECG changes, angiographic findings consistent with a procedural complication, or imaging evidence of new loss of viable myocardium or new regional wall motion abnormality.

In the previous 2007 document, the troponin threshold had been more than three times the 99th percentile, and was raised based on new prognostic information from long-term follow-up of patients undergoing PCI showing that there is unavoidable injury associated with the procedure, document task force codirector Dr. Joseph Alpert said during the presentation.

CABG-Related MI

Similarly, the 2012 version raises the troponin threshold for MI related to coronary artery bypass graft surgery from five times the 99th percentile URL in the 2007 document to 10 times the 99th percentile in patients with normal cTn baseline values.

It also requires one of the following: new pathological Q waves or new left bundle branch block (LBBB), angiographically documented new graft or new native coronary artery occlusion, or imaging evidence of new loss of viable myocardium or new regional wall motion abnormality.

Once again, the decision to raise the troponin threshold was made because there is unavoidable injury to the heart during CABG from needle sticks, handling of the heart, and the myocardial preservation procedure, said Dr. Alpert, a professor of medicine at the University of Arizona, Tucson.

Many Sources of Heart Injury

"The problem that every clinician – not just cardiologists, but internists and surgeons – is having with these troponin tests, and particularly with the high-sensitivity test, is that it turns out we’re finding that there are lots and lots of people having heart injuries," he said in an interview. "We’ve known for decades that it’s not uncommon for a very sick patient to have liver injuries, but now we’re saying, ‘My goodness, they’re having heart injuries, and these injuries are not MIs, or at least we have no evidence there is ischemia.’ "

The updated guideline points out that novel procedures such as transcatheter aortic valve implantation or mitral clip may also cause myocardial injury with necrosis, and that "it is likely that, similarly to CABG, the more marked the elevation of the biomarker values, the worse the prognosis – but data on that are not available.&qu

Although high-sensitivity troponin assays are not yet approved in the United States, it is only a matter of time before they are and the financial battle heats up over the distinction between myocardial injury and MI, according to Dr. Alpert. The reason is that there is currently no reimbursement code for patients with myocardial injury, who require substantial time and resources that currently are not being reimbursed.

"We’re pushing to get that code, because when you have an elevated troponin it means something, and it always means something not good," he said in the interview.

Cardiac troponin (I or T) is the preferred biomarker for the definition of acute MI, although less sensitive biomarkers such as the creatine kinase-MB (CKMB) mass can still be used when cardiac troponin is not available, said Dr. Thygesen, with the department of cardiological medicine, Aarhus (Denmark) University.

The criteria for an acute MI include detection of a rise and/or fall of cardiac biomarker values exceeding the 99th percentile URL, plus at least one of the following:

• Symptoms of ischemia.

• New or presumably new significant ST-segment/T wave changes or new LBBB.

• Development of pathological Q waves in the ECG.

• Imaging evidence of new loss of viable myocardium or new regional wall motion abnormality.

• Identification of an intracoronary thrombus by angiography or autopsy.

The new MI definition is expected to become the gold standard for diagnosis and to be adopted by the U.S. Food and Drug Administration for use in clinical trial protocols accepted by the agency. This is significant because it will help standardize the way MI is defined in clinical trials, making comparisons between studies more meaningful, Dr. Thygesen observed.

The expert consensus document, as well as pocket versions, are available on the websites of the ESC, ACC, AHA, and World Heart Federation.

The document is also being copublished in five journals: the Journal of the American College of Cardiology, European Heart Journal, Circulation, Global Heart, and Nature Reviews of Cardiology.

Dr. Thygesen reported no conflicts of interest. Dr. Alpert reported consulting for several pharmaceutical firms as well as the North American Center for Continuing Medical Education.

MUNICH – A new universal definition of myocardial infarction has been unveiled, sparked by the development of ever more sensitive cardiac biomarker assays and imaging techniques.

These assays, including the new high-sensitivity cardiac troponin (cTn) assays available throughout Europe and awaiting approval in the United States, have created confusion in the diagnosis of myocardial infarction because they detect small cTn elevations associated with many other clinical conditions such as heart failure, arrhythmias, and pulmonary embolism that are not MIs, but rather myocardial injury with necrosis.

Patrice Wendling/IMNG Medical Media

"I think there has been a little bit of a problem in the past where we’ve had too many infarctions [diagnosed] ... where there is some damage or injury to the myocardial cells," said document task force cochair Dr. Kristian Thygeysen, who presented the third universal MI definition at the annual meeting of the European Society of Cardiology (ESC).

The expert consensus document, developed by the ESC, American College of Cardiology (ACC), American Heart Association (AHA), and World Heart Federation (WHF), maintains the pathological definition of acute MI as myocardial cell death due to prolonged myocardial ischemia, but goes on to refine the definition of MI in five settings, including the controversial area of MIs associated with revascularization procedures.

Patrice Wendling/IMNG Medical Media

MI in the PCI Setting

An MI related to percutaneous coronary intervention (PCI) is defined as an elevation of cTn values more than five times the 99th percentile upper reference limit (URL) in the first 48 hours after a procedure in patients with normal baseline troponin values, or a rise of cTn values of more than 20% in patients with elevated baseline levels that are stable or falling.

It also requires one of the following events: symptoms suggestive of myocardial ischemia, new ischemic ECG changes, angiographic findings consistent with a procedural complication, or imaging evidence of new loss of viable myocardium or new regional wall motion abnormality.

In the previous 2007 document, the troponin threshold had been more than three times the 99th percentile, and was raised based on new prognostic information from long-term follow-up of patients undergoing PCI showing that there is unavoidable injury associated with the procedure, document task force codirector Dr. Joseph Alpert said during the presentation.

CABG-Related MI

Similarly, the 2012 version raises the troponin threshold for MI related to coronary artery bypass graft surgery from five times the 99th percentile URL in the 2007 document to 10 times the 99th percentile in patients with normal cTn baseline values.

It also requires one of the following: new pathological Q waves or new left bundle branch block (LBBB), angiographically documented new graft or new native coronary artery occlusion, or imaging evidence of new loss of viable myocardium or new regional wall motion abnormality.

Once again, the decision to raise the troponin threshold was made because there is unavoidable injury to the heart during CABG from needle sticks, handling of the heart, and the myocardial preservation procedure, said Dr. Alpert, a professor of medicine at the University of Arizona, Tucson.

Many Sources of Heart Injury

"The problem that every clinician – not just cardiologists, but internists and surgeons – is having with these troponin tests, and particularly with the high-sensitivity test, is that it turns out we’re finding that there are lots and lots of people having heart injuries," he said in an interview. "We’ve known for decades that it’s not uncommon for a very sick patient to have liver injuries, but now we’re saying, ‘My goodness, they’re having heart injuries, and these injuries are not MIs, or at least we have no evidence there is ischemia.’ "

The updated guideline points out that novel procedures such as transcatheter aortic valve implantation or mitral clip may also cause myocardial injury with necrosis, and that "it is likely that, similarly to CABG, the more marked the elevation of the biomarker values, the worse the prognosis – but data on that are not available.&qu

Although high-sensitivity troponin assays are not yet approved in the United States, it is only a matter of time before they are and the financial battle heats up over the distinction between myocardial injury and MI, according to Dr. Alpert. The reason is that there is currently no reimbursement code for patients with myocardial injury, who require substantial time and resources that currently are not being reimbursed.

"We’re pushing to get that code, because when you have an elevated troponin it means something, and it always means something not good," he said in the interview.

Cardiac troponin (I or T) is the preferred biomarker for the definition of acute MI, although less sensitive biomarkers such as the creatine kinase-MB (CKMB) mass can still be used when cardiac troponin is not available, said Dr. Thygesen, with the department of cardiological medicine, Aarhus (Denmark) University.

The criteria for an acute MI include detection of a rise and/or fall of cardiac biomarker values exceeding the 99th percentile URL, plus at least one of the following:

• Symptoms of ischemia.

• New or presumably new significant ST-segment/T wave changes or new LBBB.

• Development of pathological Q waves in the ECG.

• Imaging evidence of new loss of viable myocardium or new regional wall motion abnormality.

• Identification of an intracoronary thrombus by angiography or autopsy.

The new MI definition is expected to become the gold standard for diagnosis and to be adopted by the U.S. Food and Drug Administration for use in clinical trial protocols accepted by the agency. This is significant because it will help standardize the way MI is defined in clinical trials, making comparisons between studies more meaningful, Dr. Thygesen observed.

The expert consensus document, as well as pocket versions, are available on the websites of the ESC, ACC, AHA, and World Heart Federation.

The document is also being copublished in five journals: the Journal of the American College of Cardiology, European Heart Journal, Circulation, Global Heart, and Nature Reviews of Cardiology.

Dr. Thygesen reported no conflicts of interest. Dr. Alpert reported consulting for several pharmaceutical firms as well as the North American Center for Continuing Medical Education.

Heart failure patients with preserved ejection who received an investigational agent LCA696 experienced a significant reduction of NT-proBNP at 12 weeks, compared with those who received valsartan, a randomized, multicenter, phase II trial demonstrated.

In addition, a reduction in left atrial size at 36 weeks was observed in patients in the LCA696 group, compared with those who received the angiotensin receptor blocker, researchers led by Dr. Scott Solomon of the cardiovascular division at Brigham and Women’s Hospital, Boston, reported in a study published online Aug. 26, 2012, in the Lancet. The study was simultaneously presented at the annual congress of the European Society of Cardiology.

"Present treatment of heart failure with preserved ejection fraction remains both symptom based and empiric, with no specific treatment approved for this indication," the researchers wrote. "Although ACE inhibitors and ARBs have been associated with symptom improvement, increased functional capacity, and reduction in admission to hospital in these patients, existing guidelines state that no treatment has convincingly been shown to reduce morbidity or mortality.

In a phase II trial known as PARAMOUNT, Dr. Solomon and his associates at 65 centers in 13 countries set out to assess the efficacy and safety of LCZ696 in 301 heart failure patients with preserved ejection fraction. LCZ696 is a first-in-class angiotensin receptor neprilysin inhibitor that includes valsartan. The researchers hypothesized that LCA696 works by augmenting the active natriuretic peptides to improve myocardial relaxation and reduce hypertrophy. They recruited patients from November 2009 through March 2011.

Patients were eligible for PARAMOUNT if they were at least 40 years of age, had New York Heart Association class II-III heart failure, a left ventricular ejection fraction (LVEF) of 45% or higher, and an NT-proBNP greater than 400 pg/mL (Lancet 2012 Aug. 26 [http://dx.doi.org/10.1016/S0140-6736(12)61227-6]).

After randomization, 149 patients were started on 50 mg LCZ696 twice daily and 152 were started on 40 mg valsartan twice daily and titrated to their final doses of 200 mg LCZ696 twice daily or 160 mg valsartan twice daily over a period of 2-4 weeks. All patients were treated for 36 weeks; the primary end point was change in NT-proBNP from baseline to 12 weeks. This end point was selected "because raised natriuretic peptide concentrations are associated with adverse outcomes in patients with heart failure, including those with preserved ejection fraction, and reductions in NT-proBNP have been associated with improved outcomes in heart failure," the researchers explained.

Dr. Solomon and his associates reported complete data from 134 patients in the LCZ696 group and 132 patients in the valsartan group. The mean age of patients in both groups was 71 years and more than half (57%) were women. The change in NT-proBNP from baseline to week 12 was significantly reduced in patients in the LCZ696 group (from 783 to 605 pg/mL), compared with patients in the valsartan group (from 862 to 835 pg/mL). This translated into a significant ratio of change between the two treatment groups of 0.77. By week 36, the differences in NT-proBNP between the two groups were no longer significant.

After 36 weeks of treatment, patients in the LCZ696 group experienced significant reductions in left atrial volume and in left atrial dimension, compared with their counterparts in the valsartan group. "Left atrial size has been one of the most powerful predictors of outcome in heart failure, including heart failure with preserved ejection fraction," the researchers wrote. "The reported reduction in left atrial size offers support to the notion that LCZ696 had a sustained physiological benefit to 36 weeks."

LCZ696 was well tolerated and the proportion of patients who experienced one or more serious adverse events was similar between the two groups (15% among those in the LCZ696 group vs. 20% among those in the valsartan group).

Novartis funded the study. Dr. Solomon and six of his coauthors disclosed having received research support from, and have consulted for, Novartis, which is developing LCZ696. Three other coauthors are employed by the company.

Heart failure patients with preserved ejection who received an investigational agent LCA696 experienced a significant reduction of NT-proBNP at 12 weeks, compared with those who received valsartan, a randomized, multicenter, phase II trial demonstrated.

In addition, a reduction in left atrial size at 36 weeks was observed in patients in the LCA696 group, compared with those who received the angiotensin receptor blocker, researchers led by Dr. Scott Solomon of the cardiovascular division at Brigham and Women’s Hospital, Boston, reported in a study published online Aug. 26, 2012, in the Lancet. The study was simultaneously presented at the annual congress of the European Society of Cardiology.

"Present treatment of heart failure with preserved ejection fraction remains both symptom based and empiric, with no specific treatment approved for this indication," the researchers wrote. "Although ACE inhibitors and ARBs have been associated with symptom improvement, increased functional capacity, and reduction in admission to hospital in these patients, existing guidelines state that no treatment has convincingly been shown to reduce morbidity or mortality.

In a phase II trial known as PARAMOUNT, Dr. Solomon and his associates at 65 centers in 13 countries set out to assess the efficacy and safety of LCZ696 in 301 heart failure patients with preserved ejection fraction. LCZ696 is a first-in-class angiotensin receptor neprilysin inhibitor that includes valsartan. The researchers hypothesized that LCA696 works by augmenting the active natriuretic peptides to improve myocardial relaxation and reduce hypertrophy. They recruited patients from November 2009 through March 2011.

Patients were eligible for PARAMOUNT if they were at least 40 years of age, had New York Heart Association class II-III heart failure, a left ventricular ejection fraction (LVEF) of 45% or higher, and an NT-proBNP greater than 400 pg/mL (Lancet 2012 Aug. 26 [http://dx.doi.org/10.1016/S0140-6736(12)61227-6]).

After randomization, 149 patients were started on 50 mg LCZ696 twice daily and 152 were started on 40 mg valsartan twice daily and titrated to their final doses of 200 mg LCZ696 twice daily or 160 mg valsartan twice daily over a period of 2-4 weeks. All patients were treated for 36 weeks; the primary end point was change in NT-proBNP from baseline to 12 weeks. This end point was selected "because raised natriuretic peptide concentrations are associated with adverse outcomes in patients with heart failure, including those with preserved ejection fraction, and reductions in NT-proBNP have been associated with improved outcomes in heart failure," the researchers explained.

Dr. Solomon and his associates reported complete data from 134 patients in the LCZ696 group and 132 patients in the valsartan group. The mean age of patients in both groups was 71 years and more than half (57%) were women. The change in NT-proBNP from baseline to week 12 was significantly reduced in patients in the LCZ696 group (from 783 to 605 pg/mL), compared with patients in the valsartan group (from 862 to 835 pg/mL). This translated into a significant ratio of change between the two treatment groups of 0.77. By week 36, the differences in NT-proBNP between the two groups were no longer significant.

After 36 weeks of treatment, patients in the LCZ696 group experienced significant reductions in left atrial volume and in left atrial dimension, compared with their counterparts in the valsartan group. "Left atrial size has been one of the most powerful predictors of outcome in heart failure, including heart failure with preserved ejection fraction," the researchers wrote. "The reported reduction in left atrial size offers support to the notion that LCZ696 had a sustained physiological benefit to 36 weeks."

LCZ696 was well tolerated and the proportion of patients who experienced one or more serious adverse events was similar between the two groups (15% among those in the LCZ696 group vs. 20% among those in the valsartan group).

Novartis funded the study. Dr. Solomon and six of his coauthors disclosed having received research support from, and have consulted for, Novartis, which is developing LCZ696. Three other coauthors are employed by the company.

Heart failure patients with preserved ejection who received an investigational agent LCA696 experienced a significant reduction of NT-proBNP at 12 weeks, compared with those who received valsartan, a randomized, multicenter, phase II trial demonstrated.

In addition, a reduction in left atrial size at 36 weeks was observed in patients in the LCA696 group, compared with those who received the angiotensin receptor blocker, researchers led by Dr. Scott Solomon of the cardiovascular division at Brigham and Women’s Hospital, Boston, reported in a study published online Aug. 26, 2012, in the Lancet. The study was simultaneously presented at the annual congress of the European Society of Cardiology.

"Present treatment of heart failure with preserved ejection fraction remains both symptom based and empiric, with no specific treatment approved for this indication," the researchers wrote. "Although ACE inhibitors and ARBs have been associated with symptom improvement, increased functional capacity, and reduction in admission to hospital in these patients, existing guidelines state that no treatment has convincingly been shown to reduce morbidity or mortality.

In a phase II trial known as PARAMOUNT, Dr. Solomon and his associates at 65 centers in 13 countries set out to assess the efficacy and safety of LCZ696 in 301 heart failure patients with preserved ejection fraction. LCZ696 is a first-in-class angiotensin receptor neprilysin inhibitor that includes valsartan. The researchers hypothesized that LCA696 works by augmenting the active natriuretic peptides to improve myocardial relaxation and reduce hypertrophy. They recruited patients from November 2009 through March 2011.

Patients were eligible for PARAMOUNT if they were at least 40 years of age, had New York Heart Association class II-III heart failure, a left ventricular ejection fraction (LVEF) of 45% or higher, and an NT-proBNP greater than 400 pg/mL (Lancet 2012 Aug. 26 [http://dx.doi.org/10.1016/S0140-6736(12)61227-6]).

After randomization, 149 patients were started on 50 mg LCZ696 twice daily and 152 were started on 40 mg valsartan twice daily and titrated to their final doses of 200 mg LCZ696 twice daily or 160 mg valsartan twice daily over a period of 2-4 weeks. All patients were treated for 36 weeks; the primary end point was change in NT-proBNP from baseline to 12 weeks. This end point was selected "because raised natriuretic peptide concentrations are associated with adverse outcomes in patients with heart failure, including those with preserved ejection fraction, and reductions in NT-proBNP have been associated with improved outcomes in heart failure," the researchers explained.

Dr. Solomon and his associates reported complete data from 134 patients in the LCZ696 group and 132 patients in the valsartan group. The mean age of patients in both groups was 71 years and more than half (57%) were women. The change in NT-proBNP from baseline to week 12 was significantly reduced in patients in the LCZ696 group (from 783 to 605 pg/mL), compared with patients in the valsartan group (from 862 to 835 pg/mL). This translated into a significant ratio of change between the two treatment groups of 0.77. By week 36, the differences in NT-proBNP between the two groups were no longer significant.

After 36 weeks of treatment, patients in the LCZ696 group experienced significant reductions in left atrial volume and in left atrial dimension, compared with their counterparts in the valsartan group. "Left atrial size has been one of the most powerful predictors of outcome in heart failure, including heart failure with preserved ejection fraction," the researchers wrote. "The reported reduction in left atrial size offers support to the notion that LCZ696 had a sustained physiological benefit to 36 weeks."

LCZ696 was well tolerated and the proportion of patients who experienced one or more serious adverse events was similar between the two groups (15% among those in the LCZ696 group vs. 20% among those in the valsartan group).

Novartis funded the study. Dr. Solomon and six of his coauthors disclosed having received research support from, and have consulted for, Novartis, which is developing LCZ696. Three other coauthors are employed by the company.

MIAMI BEACH – When it comes to heart failure, women tend to respond better to cardiac resynchronization therapy than do men, but for a long time no one knew why.

Turns out women have some distinct physiologic advantages, specifically more left bundle branch block and more nonischemic cardiomyopathy. Each drives a better response to cardiac resynchronization therapy (CRT), said Dr. David G. Strauss, a medical officer at the Food and Drug Administration’s Center for Devices and Radiologic Health in Silver Spring, Md.

In addition, timing of a specific electrical component within the heart triggers a third important distinction. Women benefit significantly from CRT even when their QRS duration is shorter than 150 msec. This supports the need for new gender-specific criteria for left bundle branch block and, ultimately, better identification of patients most likely to benefit from CRT device placement, Dr. Strauss said at the annual meeting of the International Society on Hypertension in Blacks.

"This is important because different professional societies recently have recommended that CRT be given to patients with QRS duration of 150 msec or more, and primarily in class II heart failure," he said. However, this cutoff "would exclude women with left bundle branch block and QRS duration 130-149 msec that derived significant benefit in MADIT-CRT" (Circulation 2011;123:1061-72).

In MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial–Cardiac Resynchronization Therapy), 1,820 patients were randomly assigned to receive CRT with an implantable cardioverter-defibrillator (ICD) or an ICD alone. In men with QRS duration of 130-140 msec in the study, there was no benefit from CRT and a trend toward harm associated with the device (hazard ratio, 1.69), Dr. Strauss said.

In contrast, women with QRS durations of 130-140 msec "had very significant benefit from CRT with a hazard ratio of 0.20, indicating 80% decrease in heart failure hospitalization or death," Dr. Strauss said.

More nonischemic cardiomyopathy among women translates to less myocardial scar and, ultimately, to a better CRT response. Scar tissue, no matter how it is electrically activated, does not contract, Dr. Strauss said.

Presence of left bundle branch block conferred a significant benefit in terms of reduced heart failure hospitalizations and deaths with use of CRT in the MADIT-CRT research. Conversely, participants without left bundle branch block realized no clinical advantage with CRT.

Be careful, however, to correctly identify left bundle branch block, Dr. Strauss said. Research suggests that one third of patients diagnosed with left bundle branch block by conventional electrocardiographic criteria are misdiagnosed (Am. J. Cardiol. 2011;107:927-34). Patients with intraventricular conduction delays, such as those caused by left ventricular hypertrophy and left ventricular dilation who do not have a blocked left bundle branch, can still display a prolonged QRS duration. This duration can be in the range generally considered diagnostic of left bundle branch block.

New criteria could parlay into better patient selection in the future, Dr. Strauss said. "CRT has been shown to improve heart failure symptoms, reduce heart failure hospitalization, and reduce mortality. However, not all patients benefit and significant risks exist." For example, addition of a CRT device with a left ventricular lead is associated with more complications, compared with ICD alone. "Thus there is a need for better patient risk stratification and patient identification criteria."

Based on results of electrical activation mapping and simulation studies, "My colleagues and I proposed stricter left bundle branch block criteria," he said. For example, they propose QRS duration of 130 msec or greater in women and 140 msec greater in men to replace the conventional 120 msec definition of left bundle branch block in either gender.

Another proposed new requirement is mid-QRS notching in at least two of the electrocardiographic leads of I, aVL, V1, V2, V5, or V6. This is important for diagnosing left bundle branch block because it reflects two events, Dr. Strauss said. There is an initial notch when electrical activation reaches the endocardium of the left ventricle and a second notch when activation reaches the lateral wall opposite the septum.

Other researchers support changing the current criteria for left bundle branch block. In a study of 111 patients, researchers found meeting what they termed "false" criteria was associated with a fourfold higher rate of heart failure hospitalization or death, compared with those meeting strict criteria (Pacing Clin. Electrophysiol. 2012;35:927-34).

CRT is FDA approved for class 3 or 4 heart failure, both of ischemic and nonischemic etiology, with a left ventricular ejection fraction less than 35% and a QRS duration over 120 msec. The FDA also approved CRT for class I ischemic or class II (ischemic or nonischemic) heart failure with an ejection fraction less than 30%, a QRS duration over 130 msec, and left bundle branch block.

Dr. Strauss reported no relevant financial disclosures.

MIAMI BEACH – When it comes to heart failure, women tend to respond better to cardiac resynchronization therapy than do men, but for a long time no one knew why.

Turns out women have some distinct physiologic advantages, specifically more left bundle branch block and more nonischemic cardiomyopathy. Each drives a better response to cardiac resynchronization therapy (CRT), said Dr. David G. Strauss, a medical officer at the Food and Drug Administration’s Center for Devices and Radiologic Health in Silver Spring, Md.

In addition, timing of a specific electrical component within the heart triggers a third important distinction. Women benefit significantly from CRT even when their QRS duration is shorter than 150 msec. This supports the need for new gender-specific criteria for left bundle branch block and, ultimately, better identification of patients most likely to benefit from CRT device placement, Dr. Strauss said at the annual meeting of the International Society on Hypertension in Blacks.

"This is important because different professional societies recently have recommended that CRT be given to patients with QRS duration of 150 msec or more, and primarily in class II heart failure," he said. However, this cutoff "would exclude women with left bundle branch block and QRS duration 130-149 msec that derived significant benefit in MADIT-CRT" (Circulation 2011;123:1061-72).

In MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial–Cardiac Resynchronization Therapy), 1,820 patients were randomly assigned to receive CRT with an implantable cardioverter-defibrillator (ICD) or an ICD alone. In men with QRS duration of 130-140 msec in the study, there was no benefit from CRT and a trend toward harm associated with the device (hazard ratio, 1.69), Dr. Strauss said.

In contrast, women with QRS durations of 130-140 msec "had very significant benefit from CRT with a hazard ratio of 0.20, indicating 80% decrease in heart failure hospitalization or death," Dr. Strauss said.

More nonischemic cardiomyopathy among women translates to less myocardial scar and, ultimately, to a better CRT response. Scar tissue, no matter how it is electrically activated, does not contract, Dr. Strauss said.

Presence of left bundle branch block conferred a significant benefit in terms of reduced heart failure hospitalizations and deaths with use of CRT in the MADIT-CRT research. Conversely, participants without left bundle branch block realized no clinical advantage with CRT.

Be careful, however, to correctly identify left bundle branch block, Dr. Strauss said. Research suggests that one third of patients diagnosed with left bundle branch block by conventional electrocardiographic criteria are misdiagnosed (Am. J. Cardiol. 2011;107:927-34). Patients with intraventricular conduction delays, such as those caused by left ventricular hypertrophy and left ventricular dilation who do not have a blocked left bundle branch, can still display a prolonged QRS duration. This duration can be in the range generally considered diagnostic of left bundle branch block.

New criteria could parlay into better patient selection in the future, Dr. Strauss said. "CRT has been shown to improve heart failure symptoms, reduce heart failure hospitalization, and reduce mortality. However, not all patients benefit and significant risks exist." For example, addition of a CRT device with a left ventricular lead is associated with more complications, compared with ICD alone. "Thus there is a need for better patient risk stratification and patient identification criteria."

Based on results of electrical activation mapping and simulation studies, "My colleagues and I proposed stricter left bundle branch block criteria," he said. For example, they propose QRS duration of 130 msec or greater in women and 140 msec greater in men to replace the conventional 120 msec definition of left bundle branch block in either gender.

Another proposed new requirement is mid-QRS notching in at least two of the electrocardiographic leads of I, aVL, V1, V2, V5, or V6. This is important for diagnosing left bundle branch block because it reflects two events, Dr. Strauss said. There is an initial notch when electrical activation reaches the endocardium of the left ventricle and a second notch when activation reaches the lateral wall opposite the septum.

Other researchers support changing the current criteria for left bundle branch block. In a study of 111 patients, researchers found meeting what they termed "false" criteria was associated with a fourfold higher rate of heart failure hospitalization or death, compared with those meeting strict criteria (Pacing Clin. Electrophysiol. 2012;35:927-34).

CRT is FDA approved for class 3 or 4 heart failure, both of ischemic and nonischemic etiology, with a left ventricular ejection fraction less than 35% and a QRS duration over 120 msec. The FDA also approved CRT for class I ischemic or class II (ischemic or nonischemic) heart failure with an ejection fraction less than 30%, a QRS duration over 130 msec, and left bundle branch block.

Dr. Strauss reported no relevant financial disclosures.

MIAMI BEACH – When it comes to heart failure, women tend to respond better to cardiac resynchronization therapy than do men, but for a long time no one knew why.

Turns out women have some distinct physiologic advantages, specifically more left bundle branch block and more nonischemic cardiomyopathy. Each drives a better response to cardiac resynchronization therapy (CRT), said Dr. David G. Strauss, a medical officer at the Food and Drug Administration’s Center for Devices and Radiologic Health in Silver Spring, Md.

In addition, timing of a specific electrical component within the heart triggers a third important distinction. Women benefit significantly from CRT even when their QRS duration is shorter than 150 msec. This supports the need for new gender-specific criteria for left bundle branch block and, ultimately, better identification of patients most likely to benefit from CRT device placement, Dr. Strauss said at the annual meeting of the International Society on Hypertension in Blacks.

"This is important because different professional societies recently have recommended that CRT be given to patients with QRS duration of 150 msec or more, and primarily in class II heart failure," he said. However, this cutoff "would exclude women with left bundle branch block and QRS duration 130-149 msec that derived significant benefit in MADIT-CRT" (Circulation 2011;123:1061-72).

In MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial–Cardiac Resynchronization Therapy), 1,820 patients were randomly assigned to receive CRT with an implantable cardioverter-defibrillator (ICD) or an ICD alone. In men with QRS duration of 130-140 msec in the study, there was no benefit from CRT and a trend toward harm associated with the device (hazard ratio, 1.69), Dr. Strauss said.

In contrast, women with QRS durations of 130-140 msec "had very significant benefit from CRT with a hazard ratio of 0.20, indicating 80% decrease in heart failure hospitalization or death," Dr. Strauss said.

More nonischemic cardiomyopathy among women translates to less myocardial scar and, ultimately, to a better CRT response. Scar tissue, no matter how it is electrically activated, does not contract, Dr. Strauss said.

Presence of left bundle branch block conferred a significant benefit in terms of reduced heart failure hospitalizations and deaths with use of CRT in the MADIT-CRT research. Conversely, participants without left bundle branch block realized no clinical advantage with CRT.

Be careful, however, to correctly identify left bundle branch block, Dr. Strauss said. Research suggests that one third of patients diagnosed with left bundle branch block by conventional electrocardiographic criteria are misdiagnosed (Am. J. Cardiol. 2011;107:927-34). Patients with intraventricular conduction delays, such as those caused by left ventricular hypertrophy and left ventricular dilation who do not have a blocked left bundle branch, can still display a prolonged QRS duration. This duration can be in the range generally considered diagnostic of left bundle branch block.

New criteria could parlay into better patient selection in the future, Dr. Strauss said. "CRT has been shown to improve heart failure symptoms, reduce heart failure hospitalization, and reduce mortality. However, not all patients benefit and significant risks exist." For example, addition of a CRT device with a left ventricular lead is associated with more complications, compared with ICD alone. "Thus there is a need for better patient risk stratification and patient identification criteria."

Based on results of electrical activation mapping and simulation studies, "My colleagues and I proposed stricter left bundle branch block criteria," he said. For example, they propose QRS duration of 130 msec or greater in women and 140 msec greater in men to replace the conventional 120 msec definition of left bundle branch block in either gender.

Another proposed new requirement is mid-QRS notching in at least two of the electrocardiographic leads of I, aVL, V1, V2, V5, or V6. This is important for diagnosing left bundle branch block because it reflects two events, Dr. Strauss said. There is an initial notch when electrical activation reaches the endocardium of the left ventricle and a second notch when activation reaches the lateral wall opposite the septum.

Other researchers support changing the current criteria for left bundle branch block. In a study of 111 patients, researchers found meeting what they termed "false" criteria was associated with a fourfold higher rate of heart failure hospitalization or death, compared with those meeting strict criteria (Pacing Clin. Electrophysiol. 2012;35:927-34).

CRT is FDA approved for class 3 or 4 heart failure, both of ischemic and nonischemic etiology, with a left ventricular ejection fraction less than 35% and a QRS duration over 120 msec. The FDA also approved CRT for class I ischemic or class II (ischemic or nonischemic) heart failure with an ejection fraction less than 30%, a QRS duration over 130 msec, and left bundle branch block.

Dr. Strauss reported no relevant financial disclosures.