Patrice Wendling

Major Finding: Cases and controls had nearly identical birth weights (3,208 g vs. 3,219 g) and gestational ages at delivery (38.5 weeks vs. 38.7 weeks).

Data Source: Retrospective cohort analysis of 147 pregnant patients with 2009 H1N1 influenza and 740 pregnant controls.

Disclosures: Dr. Naresh and her coauthors reported no relevant financial disclosures.

CHICAGO – H1N1 influenza infection during the 2009 pandemic did not impact pregnancy outcomes in a retrospective cohort study of 887 women.

Subtle differences were observed, however, among women with severe infection or delayed treatment, Dr. Amber Naresh reported at the meeting.

She presented a retrospective cohort study performed at three tertiary care medical centers of all inpatient and outpatient cases of pregnant women with laboratory-confirmed 2009 H1N1 influenza. For each case, five pregnant women who tested negative for H1N1 influenza or were untested were randomly chosen from each site's database and matched by estimated date of confinement and site.

Based on a preliminary analysis, the 147 H1N1 cases and 740 controls had nearly identical birth weights (average 3,208 g vs. 3,219 g) and gestational ages at delivery (average 38.5 vs. 38.7 weeks).

After the investigators controlled for study site, age, race, multiples, primiparity, medical conditions, and smoking, the cases and controls also had similar rates of the following:

▸ Term low birth weight (5.6% vs. 3.6%; odds ratio, 1.45).

▸ Preterm delivery less than 37 weeks' gestation (13.3% vs. 11.6%; OR, 1.10).

▸ Premature rupture of membranes (1.7% vs. 2.6%; OR, 0.61).

▸ Abruption (0.9% vs. 1.2%; OR, 0.49).

▸ Cesarean section (27.5% vs. 30%; OR, 0.82).

▸ Induction (36% vs. 39%; OR, 0.83).

▸ Fetal anomalies (4.7% vs. 4.9%; OR, 1.24).

▸ Hypertensive disorders of pregnancy (14.3% vs. 13.2%; OR, 0.98).

▸ Neonatal ICU admission (13% vs. 11%; OR, 1.21).

“There did not appear to be any significant differences in pregnancy outcomes between cases and controls,” said Dr. Naresh of Magee-Women's Hospital of the University of Pittsburgh.

Pregnancy outcomes also did not differ when stratified by trimester, although more infections occurred in the second trimester, followed by the third and first trimesters, she said.

Previous case series have suggested an increased rate of preterm delivery, reaching 30% in an early report of H1N1 influenza in pregnancy and 60% among critically ill women. A recent study also reported lower birth weights among 16 women with proven H1N1 infection, compared with 25 women with influenzalike illness (Am. J. Obstet. Gynecol. 2011;204[suppl. 1]:S58–63), she said.

A subgroup analysis of women in the current study with severe disease, defined as requiring hospitalization, identified a nonsignificant trend for lower birth weight, compared with controls (3,013 g vs. 3,219 g), and lower gestational age (37.9 weeks vs. 38.7 weeks).

The combined outcome of term low birth weight, preterm birth, and abruption was significantly more common among the severe H1N1 cases than controls after study site, age, race, multiples, primiparity, medical conditions, and smoking were controlled for (31.4% vs. 15.7%; OR, 2.45). In addition, more than 30% of women in the severe group had complications, compared with only 15% in the control group.

All cases of H1N1 infection were significantly more likely than controls to be black (27% vs. 19%), and to have prepregnancy diabetes (4% vs. 1%), seizure disorder (3.4% vs. 0.8%), and asthma (17% vs. 9%). The average age of the cohort was 28 years.

Major Finding: Cases and controls had nearly identical birth weights (3,208 g vs. 3,219 g) and gestational ages at delivery (38.5 weeks vs. 38.7 weeks).

Data Source: Retrospective cohort analysis of 147 pregnant patients with 2009 H1N1 influenza and 740 pregnant controls.

Disclosures: Dr. Naresh and her coauthors reported no relevant financial disclosures.

CHICAGO – H1N1 influenza infection during the 2009 pandemic did not impact pregnancy outcomes in a retrospective cohort study of 887 women.

Subtle differences were observed, however, among women with severe infection or delayed treatment, Dr. Amber Naresh reported at the meeting.

She presented a retrospective cohort study performed at three tertiary care medical centers of all inpatient and outpatient cases of pregnant women with laboratory-confirmed 2009 H1N1 influenza. For each case, five pregnant women who tested negative for H1N1 influenza or were untested were randomly chosen from each site's database and matched by estimated date of confinement and site.

Based on a preliminary analysis, the 147 H1N1 cases and 740 controls had nearly identical birth weights (average 3,208 g vs. 3,219 g) and gestational ages at delivery (average 38.5 vs. 38.7 weeks).

After the investigators controlled for study site, age, race, multiples, primiparity, medical conditions, and smoking, the cases and controls also had similar rates of the following:

▸ Term low birth weight (5.6% vs. 3.6%; odds ratio, 1.45).

▸ Preterm delivery less than 37 weeks' gestation (13.3% vs. 11.6%; OR, 1.10).

▸ Premature rupture of membranes (1.7% vs. 2.6%; OR, 0.61).

▸ Abruption (0.9% vs. 1.2%; OR, 0.49).

▸ Cesarean section (27.5% vs. 30%; OR, 0.82).

▸ Induction (36% vs. 39%; OR, 0.83).

▸ Fetal anomalies (4.7% vs. 4.9%; OR, 1.24).

▸ Hypertensive disorders of pregnancy (14.3% vs. 13.2%; OR, 0.98).

▸ Neonatal ICU admission (13% vs. 11%; OR, 1.21).

“There did not appear to be any significant differences in pregnancy outcomes between cases and controls,” said Dr. Naresh of Magee-Women's Hospital of the University of Pittsburgh.

Pregnancy outcomes also did not differ when stratified by trimester, although more infections occurred in the second trimester, followed by the third and first trimesters, she said.

Previous case series have suggested an increased rate of preterm delivery, reaching 30% in an early report of H1N1 influenza in pregnancy and 60% among critically ill women. A recent study also reported lower birth weights among 16 women with proven H1N1 infection, compared with 25 women with influenzalike illness (Am. J. Obstet. Gynecol. 2011;204[suppl. 1]:S58–63), she said.

A subgroup analysis of women in the current study with severe disease, defined as requiring hospitalization, identified a nonsignificant trend for lower birth weight, compared with controls (3,013 g vs. 3,219 g), and lower gestational age (37.9 weeks vs. 38.7 weeks).

The combined outcome of term low birth weight, preterm birth, and abruption was significantly more common among the severe H1N1 cases than controls after study site, age, race, multiples, primiparity, medical conditions, and smoking were controlled for (31.4% vs. 15.7%; OR, 2.45). In addition, more than 30% of women in the severe group had complications, compared with only 15% in the control group.

All cases of H1N1 infection were significantly more likely than controls to be black (27% vs. 19%), and to have prepregnancy diabetes (4% vs. 1%), seizure disorder (3.4% vs. 0.8%), and asthma (17% vs. 9%). The average age of the cohort was 28 years.

Major Finding: Cases and controls had nearly identical birth weights (3,208 g vs. 3,219 g) and gestational ages at delivery (38.5 weeks vs. 38.7 weeks).

Data Source: Retrospective cohort analysis of 147 pregnant patients with 2009 H1N1 influenza and 740 pregnant controls.

Disclosures: Dr. Naresh and her coauthors reported no relevant financial disclosures.

CHICAGO – H1N1 influenza infection during the 2009 pandemic did not impact pregnancy outcomes in a retrospective cohort study of 887 women.

Subtle differences were observed, however, among women with severe infection or delayed treatment, Dr. Amber Naresh reported at the meeting.

She presented a retrospective cohort study performed at three tertiary care medical centers of all inpatient and outpatient cases of pregnant women with laboratory-confirmed 2009 H1N1 influenza. For each case, five pregnant women who tested negative for H1N1 influenza or were untested were randomly chosen from each site's database and matched by estimated date of confinement and site.

Based on a preliminary analysis, the 147 H1N1 cases and 740 controls had nearly identical birth weights (average 3,208 g vs. 3,219 g) and gestational ages at delivery (average 38.5 vs. 38.7 weeks).

After the investigators controlled for study site, age, race, multiples, primiparity, medical conditions, and smoking, the cases and controls also had similar rates of the following:

▸ Term low birth weight (5.6% vs. 3.6%; odds ratio, 1.45).

▸ Preterm delivery less than 37 weeks' gestation (13.3% vs. 11.6%; OR, 1.10).

▸ Premature rupture of membranes (1.7% vs. 2.6%; OR, 0.61).

▸ Abruption (0.9% vs. 1.2%; OR, 0.49).

▸ Cesarean section (27.5% vs. 30%; OR, 0.82).

▸ Induction (36% vs. 39%; OR, 0.83).

▸ Fetal anomalies (4.7% vs. 4.9%; OR, 1.24).

▸ Hypertensive disorders of pregnancy (14.3% vs. 13.2%; OR, 0.98).

▸ Neonatal ICU admission (13% vs. 11%; OR, 1.21).

“There did not appear to be any significant differences in pregnancy outcomes between cases and controls,” said Dr. Naresh of Magee-Women's Hospital of the University of Pittsburgh.

Pregnancy outcomes also did not differ when stratified by trimester, although more infections occurred in the second trimester, followed by the third and first trimesters, she said.

Previous case series have suggested an increased rate of preterm delivery, reaching 30% in an early report of H1N1 influenza in pregnancy and 60% among critically ill women. A recent study also reported lower birth weights among 16 women with proven H1N1 infection, compared with 25 women with influenzalike illness (Am. J. Obstet. Gynecol. 2011;204[suppl. 1]:S58–63), she said.

A subgroup analysis of women in the current study with severe disease, defined as requiring hospitalization, identified a nonsignificant trend for lower birth weight, compared with controls (3,013 g vs. 3,219 g), and lower gestational age (37.9 weeks vs. 38.7 weeks).

The combined outcome of term low birth weight, preterm birth, and abruption was significantly more common among the severe H1N1 cases than controls after study site, age, race, multiples, primiparity, medical conditions, and smoking were controlled for (31.4% vs. 15.7%; OR, 2.45). In addition, more than 30% of women in the severe group had complications, compared with only 15% in the control group.

All cases of H1N1 infection were significantly more likely than controls to be black (27% vs. 19%), and to have prepregnancy diabetes (4% vs. 1%), seizure disorder (3.4% vs. 0.8%), and asthma (17% vs. 9%). The average age of the cohort was 28 years.

Major Finding: Among patients with diabetes who took eplerenone, there was a 46% reduction in the primary end point of death from cardiovascular causes or heart failure hospitalization, compared with those who took placebo.

Data Source: Subanalysis of high-risk groups and follow-up analyses of the phase III EMPHASIS-HF trial.

Disclosures: Pfizer sponsored the trial. Dr. Pitt reports financial relationships with several firms excluding Pfizer. His coauthors report similar relationships including employment with Pfizer.

PARIS – The aldosterone antagonist eplerenone cut cardiovascular events and the need for hospitalization significantly across all risk levels in patients with mild heart failure, according to a subanalysis of the EMPHASIS-HF trial.

Eplerenone (Inspra) was also shown to trim troublesome and costly repeat heart failure hospitalizations in a subset of patients followed for up to 10 additional months after the pivotal, phase III trial closed, Dr. Bertram Pitt reported at the congress.

“Overall efficacy, no matter where we looked, was about the same, and we had the same safety,” he told reporters.

EMPHASIS-HF (Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure) was stopped prematurely last spring after eplerenone in addition to standard therapy demonstrated a 37% (hazard ratio, 0.63) improvement over placebo in the primary end point of death from cardiovascular causes or heart failure hospitalization in 2,637 patients with mild New York Heart Association class II systolic heart failure (N. Engl. J. Med. 2011;364:11-21).

Among 1,597 patients who remained on double-blind therapy after study, the primary end point occurred in 21% on eplerenone and 29% on placebo (HR, 0.66), a significant difference, said Dr. Pitt of the University of Michigan, Ann Arbor.

Repeat hospitalization for heart failure was significantly reduced with eplerenone (rate ratio, 0.62).

“This suggests, to us at least, that this is going to have important cost implications and quality of life implications, as well as important implications on survival, since we know that heart failure hospitalization relates to target-organ damage and survival,” he said.

The benefits of eplerenone were particularly compelling in elderly patients and those with diabetes and renal dysfunction, three high-risk populations in whom clinicians are hesitant to use adjuvant aldosterone blockade because of fears of inducing hyperkalemia, Dr. Pitt said. He pointed out that recent head-to-head data show that the aldosterone antagonist spironolactone (Aldactone) raises hemoglobin A1_c and cortisol levels and reduces adiponectin in patients with diabetes, whereas eplerenone does not.

When Dr. Pitt and colleagues looked at patients with diabetes in the subanalysis, the benefit was stronger than that observed in the overall EMPHASIS-HF cohort, with a 46% reduction in the primary end point (HR, 0.54).

Dr. Pitt noted that the current American Heart Association, American College of Cardiology and European Society of Cardiology guidelines for aldosterone blockade do not specify a particular agent, but look at the agents as a class.

“We believe with [these] data, that in the next guidelines there should at least be some consideration for the specific use of eplerenone, at least in the subset of patients with diabetes,” he said.

Among patients with an estimated glomerular filtration rate less than 60 mL per minute per 1.73 m

The study excluded patients with a baseline serum potassium level above 5.0 mmol/L and estimated GFR below 30 mL per minute per 1.73 m

Among elderly patients at least 75 years old, the benefit on the primary end point with eplerenone reached 34%.

Significant benefits were also observed in patients with a left ventricular ejection fraction less than 30% and with a median systolic blood pressure of less than 123 mm Hg.

As seen in the overall EMPHASIS-HF cohort, the benefits of eplerenone were accompanied by a significant increase in the incidence of serum potassium greater than 5.5 mmol/L in each of the high-risk subgroups.

However, there were no significant increases in the incidence of serum potassium above 6 mmol/L, hospitalization leading to treatment discontinuation, hospitalization for/or deaths due to hyperkalemia, or hospitalizations for worsening renal function, Dr. Pitt said.

Invited discussant Dr. Piotr Ponikowski, with the 4th Military Hospital in Wroclaw, Poland, highlighted as important the benefits of eplerenone in people with diabetes and the reduction in repeat hospitalizations. He noted that up to 50% of heart failure patients are rehospitalized and these visits are associated with significant costs and reduced quality of life and mortality. Still, aldosterone antagonists remain underutilized in heart failure patients in Europe as well as the United States.

Physicians frequently question whether clinical trial data are real, consistent, and clinically meaningful, he said. “With the presented data, we can now say that the answer to all these questions is 'yes.'”

View a video interview with Dr. Pitt with the QR code, or by visiting ecardiologynews.com

This is going to have important implications in terms of cost, quality of life, and survival.

Source DR. PITT

Major Finding: Among patients with diabetes who took eplerenone, there was a 46% reduction in the primary end point of death from cardiovascular causes or heart failure hospitalization, compared with those who took placebo.

Data Source: Subanalysis of high-risk groups and follow-up analyses of the phase III EMPHASIS-HF trial.

Disclosures: Pfizer sponsored the trial. Dr. Pitt reports financial relationships with several firms excluding Pfizer. His coauthors report similar relationships including employment with Pfizer.

PARIS – The aldosterone antagonist eplerenone cut cardiovascular events and the need for hospitalization significantly across all risk levels in patients with mild heart failure, according to a subanalysis of the EMPHASIS-HF trial.

Eplerenone (Inspra) was also shown to trim troublesome and costly repeat heart failure hospitalizations in a subset of patients followed for up to 10 additional months after the pivotal, phase III trial closed, Dr. Bertram Pitt reported at the congress.

“Overall efficacy, no matter where we looked, was about the same, and we had the same safety,” he told reporters.

EMPHASIS-HF (Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure) was stopped prematurely last spring after eplerenone in addition to standard therapy demonstrated a 37% (hazard ratio, 0.63) improvement over placebo in the primary end point of death from cardiovascular causes or heart failure hospitalization in 2,637 patients with mild New York Heart Association class II systolic heart failure (N. Engl. J. Med. 2011;364:11-21).

Among 1,597 patients who remained on double-blind therapy after study, the primary end point occurred in 21% on eplerenone and 29% on placebo (HR, 0.66), a significant difference, said Dr. Pitt of the University of Michigan, Ann Arbor.

Repeat hospitalization for heart failure was significantly reduced with eplerenone (rate ratio, 0.62).

“This suggests, to us at least, that this is going to have important cost implications and quality of life implications, as well as important implications on survival, since we know that heart failure hospitalization relates to target-organ damage and survival,” he said.

The benefits of eplerenone were particularly compelling in elderly patients and those with diabetes and renal dysfunction, three high-risk populations in whom clinicians are hesitant to use adjuvant aldosterone blockade because of fears of inducing hyperkalemia, Dr. Pitt said. He pointed out that recent head-to-head data show that the aldosterone antagonist spironolactone (Aldactone) raises hemoglobin A1_c and cortisol levels and reduces adiponectin in patients with diabetes, whereas eplerenone does not.

When Dr. Pitt and colleagues looked at patients with diabetes in the subanalysis, the benefit was stronger than that observed in the overall EMPHASIS-HF cohort, with a 46% reduction in the primary end point (HR, 0.54).

Dr. Pitt noted that the current American Heart Association, American College of Cardiology and European Society of Cardiology guidelines for aldosterone blockade do not specify a particular agent, but look at the agents as a class.

“We believe with [these] data, that in the next guidelines there should at least be some consideration for the specific use of eplerenone, at least in the subset of patients with diabetes,” he said.

Among patients with an estimated glomerular filtration rate less than 60 mL per minute per 1.73 m

The study excluded patients with a baseline serum potassium level above 5.0 mmol/L and estimated GFR below 30 mL per minute per 1.73 m

Among elderly patients at least 75 years old, the benefit on the primary end point with eplerenone reached 34%.

Significant benefits were also observed in patients with a left ventricular ejection fraction less than 30% and with a median systolic blood pressure of less than 123 mm Hg.

As seen in the overall EMPHASIS-HF cohort, the benefits of eplerenone were accompanied by a significant increase in the incidence of serum potassium greater than 5.5 mmol/L in each of the high-risk subgroups.

However, there were no significant increases in the incidence of serum potassium above 6 mmol/L, hospitalization leading to treatment discontinuation, hospitalization for/or deaths due to hyperkalemia, or hospitalizations for worsening renal function, Dr. Pitt said.

Invited discussant Dr. Piotr Ponikowski, with the 4th Military Hospital in Wroclaw, Poland, highlighted as important the benefits of eplerenone in people with diabetes and the reduction in repeat hospitalizations. He noted that up to 50% of heart failure patients are rehospitalized and these visits are associated with significant costs and reduced quality of life and mortality. Still, aldosterone antagonists remain underutilized in heart failure patients in Europe as well as the United States.

Physicians frequently question whether clinical trial data are real, consistent, and clinically meaningful, he said. “With the presented data, we can now say that the answer to all these questions is 'yes.'”

View a video interview with Dr. Pitt with the QR code, or by visiting ecardiologynews.com

This is going to have important implications in terms of cost, quality of life, and survival.

Source DR. PITT

Major Finding: Among patients with diabetes who took eplerenone, there was a 46% reduction in the primary end point of death from cardiovascular causes or heart failure hospitalization, compared with those who took placebo.

Data Source: Subanalysis of high-risk groups and follow-up analyses of the phase III EMPHASIS-HF trial.

Disclosures: Pfizer sponsored the trial. Dr. Pitt reports financial relationships with several firms excluding Pfizer. His coauthors report similar relationships including employment with Pfizer.

PARIS – The aldosterone antagonist eplerenone cut cardiovascular events and the need for hospitalization significantly across all risk levels in patients with mild heart failure, according to a subanalysis of the EMPHASIS-HF trial.

Eplerenone (Inspra) was also shown to trim troublesome and costly repeat heart failure hospitalizations in a subset of patients followed for up to 10 additional months after the pivotal, phase III trial closed, Dr. Bertram Pitt reported at the congress.

“Overall efficacy, no matter where we looked, was about the same, and we had the same safety,” he told reporters.

EMPHASIS-HF (Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure) was stopped prematurely last spring after eplerenone in addition to standard therapy demonstrated a 37% (hazard ratio, 0.63) improvement over placebo in the primary end point of death from cardiovascular causes or heart failure hospitalization in 2,637 patients with mild New York Heart Association class II systolic heart failure (N. Engl. J. Med. 2011;364:11-21).

Among 1,597 patients who remained on double-blind therapy after study, the primary end point occurred in 21% on eplerenone and 29% on placebo (HR, 0.66), a significant difference, said Dr. Pitt of the University of Michigan, Ann Arbor.

Repeat hospitalization for heart failure was significantly reduced with eplerenone (rate ratio, 0.62).

“This suggests, to us at least, that this is going to have important cost implications and quality of life implications, as well as important implications on survival, since we know that heart failure hospitalization relates to target-organ damage and survival,” he said.

The benefits of eplerenone were particularly compelling in elderly patients and those with diabetes and renal dysfunction, three high-risk populations in whom clinicians are hesitant to use adjuvant aldosterone blockade because of fears of inducing hyperkalemia, Dr. Pitt said. He pointed out that recent head-to-head data show that the aldosterone antagonist spironolactone (Aldactone) raises hemoglobin A1_c and cortisol levels and reduces adiponectin in patients with diabetes, whereas eplerenone does not.

When Dr. Pitt and colleagues looked at patients with diabetes in the subanalysis, the benefit was stronger than that observed in the overall EMPHASIS-HF cohort, with a 46% reduction in the primary end point (HR, 0.54).

Dr. Pitt noted that the current American Heart Association, American College of Cardiology and European Society of Cardiology guidelines for aldosterone blockade do not specify a particular agent, but look at the agents as a class.

“We believe with [these] data, that in the next guidelines there should at least be some consideration for the specific use of eplerenone, at least in the subset of patients with diabetes,” he said.

Among patients with an estimated glomerular filtration rate less than 60 mL per minute per 1.73 m

The study excluded patients with a baseline serum potassium level above 5.0 mmol/L and estimated GFR below 30 mL per minute per 1.73 m

Among elderly patients at least 75 years old, the benefit on the primary end point with eplerenone reached 34%.

Significant benefits were also observed in patients with a left ventricular ejection fraction less than 30% and with a median systolic blood pressure of less than 123 mm Hg.

As seen in the overall EMPHASIS-HF cohort, the benefits of eplerenone were accompanied by a significant increase in the incidence of serum potassium greater than 5.5 mmol/L in each of the high-risk subgroups.

However, there were no significant increases in the incidence of serum potassium above 6 mmol/L, hospitalization leading to treatment discontinuation, hospitalization for/or deaths due to hyperkalemia, or hospitalizations for worsening renal function, Dr. Pitt said.

Invited discussant Dr. Piotr Ponikowski, with the 4th Military Hospital in Wroclaw, Poland, highlighted as important the benefits of eplerenone in people with diabetes and the reduction in repeat hospitalizations. He noted that up to 50% of heart failure patients are rehospitalized and these visits are associated with significant costs and reduced quality of life and mortality. Still, aldosterone antagonists remain underutilized in heart failure patients in Europe as well as the United States.

Physicians frequently question whether clinical trial data are real, consistent, and clinically meaningful, he said. “With the presented data, we can now say that the answer to all these questions is 'yes.'”

View a video interview with Dr. Pitt with the QR code, or by visiting ecardiologynews.com

This is going to have important implications in terms of cost, quality of life, and survival.

Source DR. PITT

PARIS – In inoperable patients with severe aortic stenosis, their EuroSCORE – a predicted operative mortality from cardiac surgery – consistently predicted outcomes from transcatheter aortic valve implantation in a prospective, single-center study.

Among 177 consecutive patients declined for surgery, the procedural success rate was 100% in patients with a EuroSCORE of less than 20% and 95.7% in those with a EuroSCORE of more than 20%.

Moreover, there were no deaths at 30 days in the low-risk group, but mortality was 11.1% in the high-risk group. This result was maintained at 1 year (5% vs. 25%), and both differences were highly significant, Dr. Matthieu Godin reported at the congress.

“This may be the first step towards a broader assessment of percutaneous techniques in populations at lower surgical risk, but without forgetting that surgery is currently the … standard,” he said.

Transcatheter aortic valve implantation (TAVI) is not commercially avaliable in the United States. In Europe, however, TAVI is considered a less invasive therapeutic option for severe aortic stenosis among nonsurgical and high–surgical-risk patients, as defined by a logistic EuroSCORE (European System for Cardiac Operative Risk) of more than 20% or a Society of Thoracic Surgeons risk score of more than 10%.

TAVI is frequently performed, however, in patients with low to intermediate logistic EuroSCOREs and contraindications to conventional valve replacement due to comorbidities not included in the surgical risk models, said Dr. Godin of Rouen (France) University Hospital–Charles Nicolle Hospital, hhere the first TAVI was performed in 2002 by coinvestigator Dr. Alain Cribier (Circulation 2002;106:3006-8).

In an effort to address this evolution and an eager marketplace, the American College of Cardiology and Society of Thoracic Surgeons released an expert consensus document that explores key components that will be necessary for successful integration of transcatheter valve therapy into clinical practice (J. Am. Coll. Cardiol. 2011;58:445-55. Epub 2011 Jun 28). While praising the “transformational technology,” the societies cite limited evidence from only one randomized trial in aortic stenosis (PARTNER) and one in mitral insufficiency (EVEREST II) in stating that “adoption of these techniques to populations beyond those studied in these randomized trials, therefore, is not appropriate at the current time.”

Dr. Godin stressed that his results should not be interpreted to suggest that the indication for TAVI should be expanded to low-risk surgical candidates.

The Placement of Aortic Transcatheter Valves (PARTNER) trial enrolled two distinct cohorts. Cohort A included 699 patients (median age 84 years) who were candidates for conventional surgery but were at high surgical risk based on an STS score of at least 10% or on coexisting conditions that would be associated with at least a 15% predicted risk of death by 30 days after surgery. Cohort B included 358 patients (median age 83 years) who were deemed unsuitable for conventional surgery because of coexisting conditions that would be associated with at least a 50% predicted probability of death by 30 days after surgery or a serious irreversible complication (N. Engl. J. Med. 2010;363:1597-607).

Dr. Godin's analysis included 177 patients who presented during 2006-2011 with degenerative aortic stenosis and were implanted with the Edwards Sapien valve up to October 2009 and the Edwards Sapien-XT prosthesis thereafter. A transfemoral approach was used in 72% and a transapical approach in 28%.

In all, 60 patients had a EuroSCORE of less than 20% (mean 12%) and 117 had a EuroSCORE of at least 20% (mean 32%). Their mean ages were 80 years and 84 years, respectively.

Contraindications to conventional surgery in the low-risk group included porcelain aorta in 15%, chest irradiation in 20%, and chest deformity in 8.3%.

The low- and high-risk groups had similar rates of major stroke (1.7% and 0.9%, respectively), major vascular complications (5% and 6%), and definitive pacemaker implantation (5% and 6%). The low-risk group had significantly less life-threatening bleeding (7% vs. 21%) and significantly shorter mean ICU stays (2 days vs. 3 days) and mean hospital stays (9 days vs. 11 days), Dr. Godin reported.

Dr. Godin reported no conflicts. Dr. Cribier is a consultant for Edwards Lifesciences, and two additional coauthors are proctors for the company.

Scan this QR code with your smartphone to see an interview with Dr. Godin.

PARIS – In inoperable patients with severe aortic stenosis, their EuroSCORE – a predicted operative mortality from cardiac surgery – consistently predicted outcomes from transcatheter aortic valve implantation in a prospective, single-center study.

Among 177 consecutive patients declined for surgery, the procedural success rate was 100% in patients with a EuroSCORE of less than 20% and 95.7% in those with a EuroSCORE of more than 20%.

Moreover, there were no deaths at 30 days in the low-risk group, but mortality was 11.1% in the high-risk group. This result was maintained at 1 year (5% vs. 25%), and both differences were highly significant, Dr. Matthieu Godin reported at the congress.

“This may be the first step towards a broader assessment of percutaneous techniques in populations at lower surgical risk, but without forgetting that surgery is currently the … standard,” he said.

Transcatheter aortic valve implantation (TAVI) is not commercially avaliable in the United States. In Europe, however, TAVI is considered a less invasive therapeutic option for severe aortic stenosis among nonsurgical and high–surgical-risk patients, as defined by a logistic EuroSCORE (European System for Cardiac Operative Risk) of more than 20% or a Society of Thoracic Surgeons risk score of more than 10%.

TAVI is frequently performed, however, in patients with low to intermediate logistic EuroSCOREs and contraindications to conventional valve replacement due to comorbidities not included in the surgical risk models, said Dr. Godin of Rouen (France) University Hospital–Charles Nicolle Hospital, hhere the first TAVI was performed in 2002 by coinvestigator Dr. Alain Cribier (Circulation 2002;106:3006-8).

In an effort to address this evolution and an eager marketplace, the American College of Cardiology and Society of Thoracic Surgeons released an expert consensus document that explores key components that will be necessary for successful integration of transcatheter valve therapy into clinical practice (J. Am. Coll. Cardiol. 2011;58:445-55. Epub 2011 Jun 28). While praising the “transformational technology,” the societies cite limited evidence from only one randomized trial in aortic stenosis (PARTNER) and one in mitral insufficiency (EVEREST II) in stating that “adoption of these techniques to populations beyond those studied in these randomized trials, therefore, is not appropriate at the current time.”

Dr. Godin stressed that his results should not be interpreted to suggest that the indication for TAVI should be expanded to low-risk surgical candidates.

The Placement of Aortic Transcatheter Valves (PARTNER) trial enrolled two distinct cohorts. Cohort A included 699 patients (median age 84 years) who were candidates for conventional surgery but were at high surgical risk based on an STS score of at least 10% or on coexisting conditions that would be associated with at least a 15% predicted risk of death by 30 days after surgery. Cohort B included 358 patients (median age 83 years) who were deemed unsuitable for conventional surgery because of coexisting conditions that would be associated with at least a 50% predicted probability of death by 30 days after surgery or a serious irreversible complication (N. Engl. J. Med. 2010;363:1597-607).

Dr. Godin's analysis included 177 patients who presented during 2006-2011 with degenerative aortic stenosis and were implanted with the Edwards Sapien valve up to October 2009 and the Edwards Sapien-XT prosthesis thereafter. A transfemoral approach was used in 72% and a transapical approach in 28%.

In all, 60 patients had a EuroSCORE of less than 20% (mean 12%) and 117 had a EuroSCORE of at least 20% (mean 32%). Their mean ages were 80 years and 84 years, respectively.

Contraindications to conventional surgery in the low-risk group included porcelain aorta in 15%, chest irradiation in 20%, and chest deformity in 8.3%.

The low- and high-risk groups had similar rates of major stroke (1.7% and 0.9%, respectively), major vascular complications (5% and 6%), and definitive pacemaker implantation (5% and 6%). The low-risk group had significantly less life-threatening bleeding (7% vs. 21%) and significantly shorter mean ICU stays (2 days vs. 3 days) and mean hospital stays (9 days vs. 11 days), Dr. Godin reported.

Dr. Godin reported no conflicts. Dr. Cribier is a consultant for Edwards Lifesciences, and two additional coauthors are proctors for the company.

Scan this QR code with your smartphone to see an interview with Dr. Godin.

PARIS – In inoperable patients with severe aortic stenosis, their EuroSCORE – a predicted operative mortality from cardiac surgery – consistently predicted outcomes from transcatheter aortic valve implantation in a prospective, single-center study.

Among 177 consecutive patients declined for surgery, the procedural success rate was 100% in patients with a EuroSCORE of less than 20% and 95.7% in those with a EuroSCORE of more than 20%.

Moreover, there were no deaths at 30 days in the low-risk group, but mortality was 11.1% in the high-risk group. This result was maintained at 1 year (5% vs. 25%), and both differences were highly significant, Dr. Matthieu Godin reported at the congress.

“This may be the first step towards a broader assessment of percutaneous techniques in populations at lower surgical risk, but without forgetting that surgery is currently the … standard,” he said.

Transcatheter aortic valve implantation (TAVI) is not commercially avaliable in the United States. In Europe, however, TAVI is considered a less invasive therapeutic option for severe aortic stenosis among nonsurgical and high–surgical-risk patients, as defined by a logistic EuroSCORE (European System for Cardiac Operative Risk) of more than 20% or a Society of Thoracic Surgeons risk score of more than 10%.

TAVI is frequently performed, however, in patients with low to intermediate logistic EuroSCOREs and contraindications to conventional valve replacement due to comorbidities not included in the surgical risk models, said Dr. Godin of Rouen (France) University Hospital–Charles Nicolle Hospital, hhere the first TAVI was performed in 2002 by coinvestigator Dr. Alain Cribier (Circulation 2002;106:3006-8).

In an effort to address this evolution and an eager marketplace, the American College of Cardiology and Society of Thoracic Surgeons released an expert consensus document that explores key components that will be necessary for successful integration of transcatheter valve therapy into clinical practice (J. Am. Coll. Cardiol. 2011;58:445-55. Epub 2011 Jun 28). While praising the “transformational technology,” the societies cite limited evidence from only one randomized trial in aortic stenosis (PARTNER) and one in mitral insufficiency (EVEREST II) in stating that “adoption of these techniques to populations beyond those studied in these randomized trials, therefore, is not appropriate at the current time.”

Dr. Godin stressed that his results should not be interpreted to suggest that the indication for TAVI should be expanded to low-risk surgical candidates.

The Placement of Aortic Transcatheter Valves (PARTNER) trial enrolled two distinct cohorts. Cohort A included 699 patients (median age 84 years) who were candidates for conventional surgery but were at high surgical risk based on an STS score of at least 10% or on coexisting conditions that would be associated with at least a 15% predicted risk of death by 30 days after surgery. Cohort B included 358 patients (median age 83 years) who were deemed unsuitable for conventional surgery because of coexisting conditions that would be associated with at least a 50% predicted probability of death by 30 days after surgery or a serious irreversible complication (N. Engl. J. Med. 2010;363:1597-607).

Dr. Godin's analysis included 177 patients who presented during 2006-2011 with degenerative aortic stenosis and were implanted with the Edwards Sapien valve up to October 2009 and the Edwards Sapien-XT prosthesis thereafter. A transfemoral approach was used in 72% and a transapical approach in 28%.

In all, 60 patients had a EuroSCORE of less than 20% (mean 12%) and 117 had a EuroSCORE of at least 20% (mean 32%). Their mean ages were 80 years and 84 years, respectively.

Contraindications to conventional surgery in the low-risk group included porcelain aorta in 15%, chest irradiation in 20%, and chest deformity in 8.3%.

The low- and high-risk groups had similar rates of major stroke (1.7% and 0.9%, respectively), major vascular complications (5% and 6%), and definitive pacemaker implantation (5% and 6%). The low-risk group had significantly less life-threatening bleeding (7% vs. 21%) and significantly shorter mean ICU stays (2 days vs. 3 days) and mean hospital stays (9 days vs. 11 days), Dr. Godin reported.

Dr. Godin reported no conflicts. Dr. Cribier is a consultant for Edwards Lifesciences, and two additional coauthors are proctors for the company.

Scan this QR code with your smartphone to see an interview with Dr. Godin.

STOCKHOLM – Coupling everolimus with exemestane has produced such dramatic disease control in women with advanced hormone resistant, estrogen receptor-positive breast cancer that it is expected to transform the management of these patients.

A preplanned interim analysis of the phase III BOLERO-2 trial found that everolimus (Afinitor) increased the primary end point of progression-free survival, by local assessment, from a median of 2.8 months with exemestane (Aromasin) alone to 6.9 months. This corresponds to a 57% risk reduction (hazard ratio 0.43; P less than .0001).

Based on central assessment, everolimus produced a 64% reduction in the risk of progression or death (10.6 months vs. 4.1 months; HR = 0.36; P less than .0001). The trial was stopped early based on the benefit shown in the interim data.

"Everolimus is the first agent to enhance the clinical benefit of hormonal therapy in refractory estrogen receptor (ER)–positive patients," lead author Dr. José Baselga said at the European Multidisciplinary Cancer Congress.

"Our results could represent a paradigm shift in the management of patients with hormone receptor-positive breast cancer," he added

Invited discussant Dr. Fabrice André, from the Institut Gustave Roussy in Villejuif, France, called everolimus the most important advance in breast cancer since trastuzumab (Herceptin).

"The efficacy of everolimus in the BOLERO-2 trial is in the range of the most important advances in medical oncology," he said.

Novartis plans to submit the data for worldwide regulatory approval of everolimus as a treatment for ER-positive advanced breast cancer by year’s end, although the medical oncology community could embrace off-label use in this indication since both drugs are already available.

Everolimus is approved in the United States for progressive neuroendocrine tumors of pancreatic origin, subependymal giant cell astrocytoma associated with inoperable tuberous sclerosis and advanced renal cell carcinoma after sunitinib (Sutent) or sorafenib (Nexavar) treatment failure. Exemestane, an aromatase inhibitor, is approved as neoadjuvant therapy for hormone receptor–positive disease in postmenopausal women.

Everolimus was evaluated because the mammalian target of rapamycin (mTOR) pathway is activated in hormone therapy–resistant advanced breast cancer. Phase II everolimus trials suggested that the mTORC1 inhibitor could reverse resistance to endocrine therapy, said Dr. Baselga, chief of hematology/oncology and associate director of the Massachusetts General Hospital Cancer Center, Boston.

BOLERO-2 enrolled 724 women postmenopausal women with advanced ER-positive, HER2-negative breast cancer who were refractory to letrozole (Femara) or anastrozole (Arimidex). Prior treatment also included chemotherapy for metastatic disease in roughly 25%, tamoxifen in 48% and fulvestrant (Faslodex) in about 16%. Patients were randomized to everolimus 10 mg daily or placebo, with both arms receiving exemestane 25 mg daily.

The overall response rate was 9.5% for the everolimus arm and 0.4% for the placebo arm (P less than .0001).

The clinical benefit rate was 33.4% and 18%, respectively (P less than .0001), Dr. Baselga said at the joint congress of the European Cancer Organization, the European Society for Medical Oncology, and the European Society of Radiotherapy and Oncology.

A progression-free survival subgroup analysis showed consistent results across all subgroups.

At the time of the interim analysis, 83 deaths had occurred (10.6% in the everolimus arm and 13% in the placebo arm), but the data are immature, he said.

Adverse events were consistent with previous everolimus experience including stomatitis, fatigue, noninfectious pneumonitis, and hyperglycemia, Dr. Baselga said.

Dr. André said BOLERO-2 provides robust and clinically relevant data, but added that "preclinical data suggest we can do even better." He pointed out that inhibiting mTORC1 alone is not optimal because of the activation of alternative compensatory or parallel pathways, and he suggested moving to combination trials to inhibit alternative pathways and reverse resistance.

"BOLERO-2 is just part of the iceberg coming," Dr. Jean-Charles Soria, cochair of the Congress scientific program and a cancer specialist at Institut Gustave Roussy in Villejuif, France, said in an interview. "The whole question now is about building a triplet combination that is not too toxic and that is feasible."

He referenced the ongoing phase III BOLERO-1 and BOLERO-3 trials assessing everolimus in combination with paclitaxel and trastuzumab in HER2-positive metastatic breast cancer and the triple combination of everolimus, vinorelbine, and trastuzumab in HER2-positive, locally advanced, taxane-pretreated disease resistant to trastuzumab (Herceptin).

"I’m pretty convinced from what I’ve seen in phase I and II, that the phase IIIs in combination with Herceptin might also come out as positive," he said. "So, the way we think about breast cancer is probably going to change with mTOR inhibitors."

Dr. Baselga reports consulting for several pharmaceutical companies including the study sponsor, Novartis. Dr. André has previously reported no conflicts. Dr. Soria has previously reported consulting for Boehringer Ingelheim, Roche, AstraZeneca Pharmaceuticals, and Pfizer.

STOCKHOLM – Coupling everolimus with exemestane has produced such dramatic disease control in women with advanced hormone resistant, estrogen receptor-positive breast cancer that it is expected to transform the management of these patients.

A preplanned interim analysis of the phase III BOLERO-2 trial found that everolimus (Afinitor) increased the primary end point of progression-free survival, by local assessment, from a median of 2.8 months with exemestane (Aromasin) alone to 6.9 months. This corresponds to a 57% risk reduction (hazard ratio 0.43; P less than .0001).

Based on central assessment, everolimus produced a 64% reduction in the risk of progression or death (10.6 months vs. 4.1 months; HR = 0.36; P less than .0001). The trial was stopped early based on the benefit shown in the interim data.

"Everolimus is the first agent to enhance the clinical benefit of hormonal therapy in refractory estrogen receptor (ER)–positive patients," lead author Dr. José Baselga said at the European Multidisciplinary Cancer Congress.

"Our results could represent a paradigm shift in the management of patients with hormone receptor-positive breast cancer," he added

Invited discussant Dr. Fabrice André, from the Institut Gustave Roussy in Villejuif, France, called everolimus the most important advance in breast cancer since trastuzumab (Herceptin).

"The efficacy of everolimus in the BOLERO-2 trial is in the range of the most important advances in medical oncology," he said.

Novartis plans to submit the data for worldwide regulatory approval of everolimus as a treatment for ER-positive advanced breast cancer by year’s end, although the medical oncology community could embrace off-label use in this indication since both drugs are already available.

Everolimus is approved in the United States for progressive neuroendocrine tumors of pancreatic origin, subependymal giant cell astrocytoma associated with inoperable tuberous sclerosis and advanced renal cell carcinoma after sunitinib (Sutent) or sorafenib (Nexavar) treatment failure. Exemestane, an aromatase inhibitor, is approved as neoadjuvant therapy for hormone receptor–positive disease in postmenopausal women.

Everolimus was evaluated because the mammalian target of rapamycin (mTOR) pathway is activated in hormone therapy–resistant advanced breast cancer. Phase II everolimus trials suggested that the mTORC1 inhibitor could reverse resistance to endocrine therapy, said Dr. Baselga, chief of hematology/oncology and associate director of the Massachusetts General Hospital Cancer Center, Boston.

BOLERO-2 enrolled 724 women postmenopausal women with advanced ER-positive, HER2-negative breast cancer who were refractory to letrozole (Femara) or anastrozole (Arimidex). Prior treatment also included chemotherapy for metastatic disease in roughly 25%, tamoxifen in 48% and fulvestrant (Faslodex) in about 16%. Patients were randomized to everolimus 10 mg daily or placebo, with both arms receiving exemestane 25 mg daily.

The overall response rate was 9.5% for the everolimus arm and 0.4% for the placebo arm (P less than .0001).

The clinical benefit rate was 33.4% and 18%, respectively (P less than .0001), Dr. Baselga said at the joint congress of the European Cancer Organization, the European Society for Medical Oncology, and the European Society of Radiotherapy and Oncology.

A progression-free survival subgroup analysis showed consistent results across all subgroups.

At the time of the interim analysis, 83 deaths had occurred (10.6% in the everolimus arm and 13% in the placebo arm), but the data are immature, he said.

Adverse events were consistent with previous everolimus experience including stomatitis, fatigue, noninfectious pneumonitis, and hyperglycemia, Dr. Baselga said.

Dr. André said BOLERO-2 provides robust and clinically relevant data, but added that "preclinical data suggest we can do even better." He pointed out that inhibiting mTORC1 alone is not optimal because of the activation of alternative compensatory or parallel pathways, and he suggested moving to combination trials to inhibit alternative pathways and reverse resistance.

"BOLERO-2 is just part of the iceberg coming," Dr. Jean-Charles Soria, cochair of the Congress scientific program and a cancer specialist at Institut Gustave Roussy in Villejuif, France, said in an interview. "The whole question now is about building a triplet combination that is not too toxic and that is feasible."

He referenced the ongoing phase III BOLERO-1 and BOLERO-3 trials assessing everolimus in combination with paclitaxel and trastuzumab in HER2-positive metastatic breast cancer and the triple combination of everolimus, vinorelbine, and trastuzumab in HER2-positive, locally advanced, taxane-pretreated disease resistant to trastuzumab (Herceptin).

"I’m pretty convinced from what I’ve seen in phase I and II, that the phase IIIs in combination with Herceptin might also come out as positive," he said. "So, the way we think about breast cancer is probably going to change with mTOR inhibitors."

Dr. Baselga reports consulting for several pharmaceutical companies including the study sponsor, Novartis. Dr. André has previously reported no conflicts. Dr. Soria has previously reported consulting for Boehringer Ingelheim, Roche, AstraZeneca Pharmaceuticals, and Pfizer.

STOCKHOLM – Coupling everolimus with exemestane has produced such dramatic disease control in women with advanced hormone resistant, estrogen receptor-positive breast cancer that it is expected to transform the management of these patients.

A preplanned interim analysis of the phase III BOLERO-2 trial found that everolimus (Afinitor) increased the primary end point of progression-free survival, by local assessment, from a median of 2.8 months with exemestane (Aromasin) alone to 6.9 months. This corresponds to a 57% risk reduction (hazard ratio 0.43; P less than .0001).

Based on central assessment, everolimus produced a 64% reduction in the risk of progression or death (10.6 months vs. 4.1 months; HR = 0.36; P less than .0001). The trial was stopped early based on the benefit shown in the interim data.

"Everolimus is the first agent to enhance the clinical benefit of hormonal therapy in refractory estrogen receptor (ER)–positive patients," lead author Dr. José Baselga said at the European Multidisciplinary Cancer Congress.

"Our results could represent a paradigm shift in the management of patients with hormone receptor-positive breast cancer," he added

Invited discussant Dr. Fabrice André, from the Institut Gustave Roussy in Villejuif, France, called everolimus the most important advance in breast cancer since trastuzumab (Herceptin).

"The efficacy of everolimus in the BOLERO-2 trial is in the range of the most important advances in medical oncology," he said.

Novartis plans to submit the data for worldwide regulatory approval of everolimus as a treatment for ER-positive advanced breast cancer by year’s end, although the medical oncology community could embrace off-label use in this indication since both drugs are already available.

Everolimus is approved in the United States for progressive neuroendocrine tumors of pancreatic origin, subependymal giant cell astrocytoma associated with inoperable tuberous sclerosis and advanced renal cell carcinoma after sunitinib (Sutent) or sorafenib (Nexavar) treatment failure. Exemestane, an aromatase inhibitor, is approved as neoadjuvant therapy for hormone receptor–positive disease in postmenopausal women.

Everolimus was evaluated because the mammalian target of rapamycin (mTOR) pathway is activated in hormone therapy–resistant advanced breast cancer. Phase II everolimus trials suggested that the mTORC1 inhibitor could reverse resistance to endocrine therapy, said Dr. Baselga, chief of hematology/oncology and associate director of the Massachusetts General Hospital Cancer Center, Boston.

BOLERO-2 enrolled 724 women postmenopausal women with advanced ER-positive, HER2-negative breast cancer who were refractory to letrozole (Femara) or anastrozole (Arimidex). Prior treatment also included chemotherapy for metastatic disease in roughly 25%, tamoxifen in 48% and fulvestrant (Faslodex) in about 16%. Patients were randomized to everolimus 10 mg daily or placebo, with both arms receiving exemestane 25 mg daily.

The overall response rate was 9.5% for the everolimus arm and 0.4% for the placebo arm (P less than .0001).

The clinical benefit rate was 33.4% and 18%, respectively (P less than .0001), Dr. Baselga said at the joint congress of the European Cancer Organization, the European Society for Medical Oncology, and the European Society of Radiotherapy and Oncology.

A progression-free survival subgroup analysis showed consistent results across all subgroups.

At the time of the interim analysis, 83 deaths had occurred (10.6% in the everolimus arm and 13% in the placebo arm), but the data are immature, he said.

Adverse events were consistent with previous everolimus experience including stomatitis, fatigue, noninfectious pneumonitis, and hyperglycemia, Dr. Baselga said.

Dr. André said BOLERO-2 provides robust and clinically relevant data, but added that "preclinical data suggest we can do even better." He pointed out that inhibiting mTORC1 alone is not optimal because of the activation of alternative compensatory or parallel pathways, and he suggested moving to combination trials to inhibit alternative pathways and reverse resistance.

"BOLERO-2 is just part of the iceberg coming," Dr. Jean-Charles Soria, cochair of the Congress scientific program and a cancer specialist at Institut Gustave Roussy in Villejuif, France, said in an interview. "The whole question now is about building a triplet combination that is not too toxic and that is feasible."

He referenced the ongoing phase III BOLERO-1 and BOLERO-3 trials assessing everolimus in combination with paclitaxel and trastuzumab in HER2-positive metastatic breast cancer and the triple combination of everolimus, vinorelbine, and trastuzumab in HER2-positive, locally advanced, taxane-pretreated disease resistant to trastuzumab (Herceptin).

"I’m pretty convinced from what I’ve seen in phase I and II, that the phase IIIs in combination with Herceptin might also come out as positive," he said. "So, the way we think about breast cancer is probably going to change with mTOR inhibitors."

Dr. Baselga reports consulting for several pharmaceutical companies including the study sponsor, Novartis. Dr. André has previously reported no conflicts. Dr. Soria has previously reported consulting for Boehringer Ingelheim, Roche, AstraZeneca Pharmaceuticals, and Pfizer.

STOCKHOLM – Prostate cancer patients with bone metastases may find relief from bone pain in a single infusion of ibandronate instead of standard single-dose palliative radiotherapy.

"Overall, there is no difference in the probability of pain relief after single-dose radiotherapy or single-infusion ibandronate [Boniva], with overall response rates of around 52%," Dr. Peter Hoskin said at the European Multidisciplinary Cancer Congress.

He reported on the RIB (Single-Dose Local Radiation Therapy Compared With Ibandronate in Treating Patients With Localized Metastatic Bone Pain) trial involving 470 patients with prostate cancer or a raised prostate-specific antigen level of more than 100 ng/mL. Participants were evenly randomized to a single dose of 8 Gy local radiotherapy or a single 6-mg IV infusion of ibandronate. All patients were bisphosphonate free for at least 6 months, and roughly 90% were on androgen-deprivation therapy.

Patients provided details on analgesic use and rated their pain over the preceding 3 days using the Brief Pain Inventory (a categorical scale for worst pain, average pain, and least pain).

Pain response was measured using a combination of two different methods of analgesic score: a simple 3-point scale for analgesic strength based on the World Health Organization analgesic ladder, and an opioid equivalence calculated to give a single continuous variable based on the method described by Dr. Sebastiano Mercadante and colleagues.

The overall pain response rate was 51.3% at 4 weeks and 52.7% at 12 weeks, said Dr. Hoskin, a professor of clinical oncology at University College London and a radiation oncologist at Mount Vernon Cancer Centre in Northwood, England. There was no evidence of a treatment effect for change in pain relief from baseline at either 4 or 12 weeks when either pain criterion was used.

The mean change in the WHO response rate at 4 weeks was –3.7% and 6.7% at 12 weeks. The mean change in the Mercadante score was 4.4 units at 4 weeks and –1.5 units at 12 weeks. None of these differences was statistically significant.

At 4 weeks, more patients in the ibandronate group had worse Mercadante scores. This is consistent with more patients’ needing retreatment at 4 weeks after ibandronate; however, by 8 weeks, there was no overall advantage, Dr. Hoskin said. In all, 31% of patients receiving ibandronate and 24% of those receiving radiotherapy crossed over to the opposite treatment (P = .097).

Overall toxicity was the same in both treatment groups, with any toxicity reported in 38% of the ibandronate group and 40% of the radiotherapy group. As expected, the radiotherapy group experienced more diarrhea and nausea, whereas the ibandronate group experienced infusion-related events.

At a median follow-up of 11.6 months, overall median survival was identical at 12.2 months with radiotherapy and 12.8 months with ibandronate, Dr. Hoskin said at the joint congress of the European Cancer Organization (ECCO), the European Society for Medical Oncology (ESMO), and the European Society of Radiotherapy and Oncology (ESTRO).

An analysis of crossover patients revealed a significant improvement in survival in the group receiving ibandronate who crossed over to radiotherapy at 4 weeks. Median survival in this group was 16.8 months, compared with 12.7 months in the group crossing over from radiotherapy to ibandronate.

"Perhaps ultimately, as these studies progress and new studies are undertaken, combined treatment with radiotherapy and bisphosphonate may be optimal and show synergistic action," he said.

Invited discussant Dr. Daniel Zips of the National Center for Radiation Research in Oncology in Dresden, Germany, said that radiotherapy will remain the standard of care for most patients with localized bone pain resulting from metastases, but that ibandronate represents an effective treatment option for special clinical situations such as patients with contraindications to radiotherapy.

"The results of the crossover – and this might even be more important – suggest that radiotherapy or ibandronate represents a treatment option for patients who fail the first treatment," he added.

Given that only 50% overall responded to ibandronate or radiotherapy, Dr. Zips said that better, more effective therapies are clearly needed to improve the treatment of bone metastases.

RIB was sponsored by the Cancer Research UK and UCL Cancer Trials Centre. Dr. Hoskin disclosed no relevant conflicts of interest.

STOCKHOLM – Prostate cancer patients with bone metastases may find relief from bone pain in a single infusion of ibandronate instead of standard single-dose palliative radiotherapy.

"Overall, there is no difference in the probability of pain relief after single-dose radiotherapy or single-infusion ibandronate [Boniva], with overall response rates of around 52%," Dr. Peter Hoskin said at the European Multidisciplinary Cancer Congress.

He reported on the RIB (Single-Dose Local Radiation Therapy Compared With Ibandronate in Treating Patients With Localized Metastatic Bone Pain) trial involving 470 patients with prostate cancer or a raised prostate-specific antigen level of more than 100 ng/mL. Participants were evenly randomized to a single dose of 8 Gy local radiotherapy or a single 6-mg IV infusion of ibandronate. All patients were bisphosphonate free for at least 6 months, and roughly 90% were on androgen-deprivation therapy.

Patients provided details on analgesic use and rated their pain over the preceding 3 days using the Brief Pain Inventory (a categorical scale for worst pain, average pain, and least pain).

Pain response was measured using a combination of two different methods of analgesic score: a simple 3-point scale for analgesic strength based on the World Health Organization analgesic ladder, and an opioid equivalence calculated to give a single continuous variable based on the method described by Dr. Sebastiano Mercadante and colleagues.

The overall pain response rate was 51.3% at 4 weeks and 52.7% at 12 weeks, said Dr. Hoskin, a professor of clinical oncology at University College London and a radiation oncologist at Mount Vernon Cancer Centre in Northwood, England. There was no evidence of a treatment effect for change in pain relief from baseline at either 4 or 12 weeks when either pain criterion was used.

The mean change in the WHO response rate at 4 weeks was –3.7% and 6.7% at 12 weeks. The mean change in the Mercadante score was 4.4 units at 4 weeks and –1.5 units at 12 weeks. None of these differences was statistically significant.

At 4 weeks, more patients in the ibandronate group had worse Mercadante scores. This is consistent with more patients’ needing retreatment at 4 weeks after ibandronate; however, by 8 weeks, there was no overall advantage, Dr. Hoskin said. In all, 31% of patients receiving ibandronate and 24% of those receiving radiotherapy crossed over to the opposite treatment (P = .097).

Overall toxicity was the same in both treatment groups, with any toxicity reported in 38% of the ibandronate group and 40% of the radiotherapy group. As expected, the radiotherapy group experienced more diarrhea and nausea, whereas the ibandronate group experienced infusion-related events.

At a median follow-up of 11.6 months, overall median survival was identical at 12.2 months with radiotherapy and 12.8 months with ibandronate, Dr. Hoskin said at the joint congress of the European Cancer Organization (ECCO), the European Society for Medical Oncology (ESMO), and the European Society of Radiotherapy and Oncology (ESTRO).

An analysis of crossover patients revealed a significant improvement in survival in the group receiving ibandronate who crossed over to radiotherapy at 4 weeks. Median survival in this group was 16.8 months, compared with 12.7 months in the group crossing over from radiotherapy to ibandronate.

"Perhaps ultimately, as these studies progress and new studies are undertaken, combined treatment with radiotherapy and bisphosphonate may be optimal and show synergistic action," he said.

Invited discussant Dr. Daniel Zips of the National Center for Radiation Research in Oncology in Dresden, Germany, said that radiotherapy will remain the standard of care for most patients with localized bone pain resulting from metastases, but that ibandronate represents an effective treatment option for special clinical situations such as patients with contraindications to radiotherapy.

"The results of the crossover – and this might even be more important – suggest that radiotherapy or ibandronate represents a treatment option for patients who fail the first treatment," he added.

Given that only 50% overall responded to ibandronate or radiotherapy, Dr. Zips said that better, more effective therapies are clearly needed to improve the treatment of bone metastases.

RIB was sponsored by the Cancer Research UK and UCL Cancer Trials Centre. Dr. Hoskin disclosed no relevant conflicts of interest.

STOCKHOLM – Prostate cancer patients with bone metastases may find relief from bone pain in a single infusion of ibandronate instead of standard single-dose palliative radiotherapy.

"Overall, there is no difference in the probability of pain relief after single-dose radiotherapy or single-infusion ibandronate [Boniva], with overall response rates of around 52%," Dr. Peter Hoskin said at the European Multidisciplinary Cancer Congress.

He reported on the RIB (Single-Dose Local Radiation Therapy Compared With Ibandronate in Treating Patients With Localized Metastatic Bone Pain) trial involving 470 patients with prostate cancer or a raised prostate-specific antigen level of more than 100 ng/mL. Participants were evenly randomized to a single dose of 8 Gy local radiotherapy or a single 6-mg IV infusion of ibandronate. All patients were bisphosphonate free for at least 6 months, and roughly 90% were on androgen-deprivation therapy.

Patients provided details on analgesic use and rated their pain over the preceding 3 days using the Brief Pain Inventory (a categorical scale for worst pain, average pain, and least pain).

Pain response was measured using a combination of two different methods of analgesic score: a simple 3-point scale for analgesic strength based on the World Health Organization analgesic ladder, and an opioid equivalence calculated to give a single continuous variable based on the method described by Dr. Sebastiano Mercadante and colleagues.

The overall pain response rate was 51.3% at 4 weeks and 52.7% at 12 weeks, said Dr. Hoskin, a professor of clinical oncology at University College London and a radiation oncologist at Mount Vernon Cancer Centre in Northwood, England. There was no evidence of a treatment effect for change in pain relief from baseline at either 4 or 12 weeks when either pain criterion was used.

The mean change in the WHO response rate at 4 weeks was –3.7% and 6.7% at 12 weeks. The mean change in the Mercadante score was 4.4 units at 4 weeks and –1.5 units at 12 weeks. None of these differences was statistically significant.

At 4 weeks, more patients in the ibandronate group had worse Mercadante scores. This is consistent with more patients’ needing retreatment at 4 weeks after ibandronate; however, by 8 weeks, there was no overall advantage, Dr. Hoskin said. In all, 31% of patients receiving ibandronate and 24% of those receiving radiotherapy crossed over to the opposite treatment (P = .097).

Overall toxicity was the same in both treatment groups, with any toxicity reported in 38% of the ibandronate group and 40% of the radiotherapy group. As expected, the radiotherapy group experienced more diarrhea and nausea, whereas the ibandronate group experienced infusion-related events.

At a median follow-up of 11.6 months, overall median survival was identical at 12.2 months with radiotherapy and 12.8 months with ibandronate, Dr. Hoskin said at the joint congress of the European Cancer Organization (ECCO), the European Society for Medical Oncology (ESMO), and the European Society of Radiotherapy and Oncology (ESTRO).

An analysis of crossover patients revealed a significant improvement in survival in the group receiving ibandronate who crossed over to radiotherapy at 4 weeks. Median survival in this group was 16.8 months, compared with 12.7 months in the group crossing over from radiotherapy to ibandronate.

"Perhaps ultimately, as these studies progress and new studies are undertaken, combined treatment with radiotherapy and bisphosphonate may be optimal and show synergistic action," he said.

Invited discussant Dr. Daniel Zips of the National Center for Radiation Research in Oncology in Dresden, Germany, said that radiotherapy will remain the standard of care for most patients with localized bone pain resulting from metastases, but that ibandronate represents an effective treatment option for special clinical situations such as patients with contraindications to radiotherapy.

"The results of the crossover – and this might even be more important – suggest that radiotherapy or ibandronate represents a treatment option for patients who fail the first treatment," he added.

Given that only 50% overall responded to ibandronate or radiotherapy, Dr. Zips said that better, more effective therapies are clearly needed to improve the treatment of bone metastases.

RIB was sponsored by the Cancer Research UK and UCL Cancer Trials Centre. Dr. Hoskin disclosed no relevant conflicts of interest.

STOCKHOLM – The investigational agent radium-223 chloride cut the risk of dying during follow-up by 30% among men with symptomatic, castration-resistant prostate cancer and bone metastases, and resulted in less toxicity than did placebo in a phase III, randomized trial.

Results of the preplanned interim analysis were strong enough to prematurely stop the ALSYMPCA (Alpharadin in Symptomatic Prostate Cancer) trial, and caused a stir at the European Multidisciplinary Cancer Congress.

After a maximum follow-up of 3 years, median overall survival was significantly increased from 11.1 months with placebo to 14.0 months with radium-223 chloride (Alpharadin) (hazard ratio, 0.695; P = .00185).

The survival benefit was maintained across all subgroups studied, regardless of baseline alkaline phosphatase (ALP) level, current bisphosphonate use, prior docetaxel (Taxotere) use, and Eastern Cooperative Oncology Group performance status, lead author Dr. Chris Parker reported.

"In my opinion, radium-223, which has a completely novel mechanism of action, is likely to become a new standard treatment for this disease," he said.

"This is a very important finding, certainly practice changing, and very likely could become the standard of care ... all over the world," European Cancer Organization (ECCO) president Dr. Michael Baumann of the Technical University of Dresden (Germany) said during a press briefing.

Likewise, Dr. Jean Charles Soria of the Institut de Cancérologie Gustave Roussy in Villejuif, France, and cochair of the congress scientific program said that "this is really practice changing, and pending regulatory approval, I think this is going to be a major player in prostate cancer management."

Current bone-targeting therapies such as denosumab (Xgeva) have been shown to improve symptom control but not survival in patients with castration-resistant prostate cancer (CRPC) and bone metastases. More than 90% of men with metastatic CRPC have evidence of bone metastases, conferring almost a fivefold greater risk of death.

Radium-223 chloride is not approved in the United States or Europe, but was granted fast track designation by the Food and Drug Administration in August 2011. Approval could come by the end of 2012, said Dr. Parker, a consultant clinical oncologist at the Royal Marsden Hospital in Sutton, England.

Radium-223 acts as a calcium mimic, and targets new bone growth in and around bone metastases via heavy alpha particles that have an ultrashort range of less than 100 mcm. It takes only a single alpha particle to kill a cancer cell, and the short penetration results in highly localized tumor-cell killing and minimal collateral damage, Dr. Parker explained.

He suggested that it would be relatively straightforward for hospitals to offer radium-223 because it takes 5 minutes to administer as an injection in the outpatient setting. Storage would be limited because of the drug’s short half-life of 11 days, but the agent would not require special radiation protection because alpha radiation is stopped by a piece of paper.

ALSYMPCA randomized 922 patients to best standard treatment plus six injections every 4 weeks of radium-223 (50 kBq/kg) or to placebo. The patients had symptomatic CRPC, at least two bone metastases, and no known visceral metastases; they had previously received or were unfit for docetaxel. Notably, 40% of patients had more than 20 metastases on bone scintigraphy, and 60% had previously received docetaxel.

Radium-223 significantly prolonged the time to first skeletal-related event from 8.4 months with placebo to 13.6 months (P = .00046; HR, 0.61), Dr. Parker said at the joint congress of the ECCO, the European Society for Medical Oncology (ESMO), and the European Society of Radiotherapy and Oncology (ESTRO).

All other secondary end points were met by radium-223 over placebo, including time to total ALP progression (HR, 0.163; P less than .00001); time to prostate-specific antigen progression (HR, 0.671; P = .00015); total ALP response, defined as a 30% reduction (43% vs. 3%; P less than .001); and total ALP normalization (33% vs. 1%; P less than .001).

Dr. Parker pointed out that "ALSYMPCA is one of a very few phase III trials in which the placebo arm had more toxicity than the active intervention arm."

Hematologic events were slightly increased in patients treated with radium-223, compared with placebo, but were rare, he said. There was also an excess of mild diarrhea and vomiting, but severe GI toxicity was not seen.

The placebo arm had more grade 3 or 4 adverse events than did the radium-223 arm (59% vs. 51%), more serious adverse events (55% and 43%), and more treatment discontinuations (20% vs. 13%). Of note, best standard treatment could include bisphosphonates, palliative radiotherapy, and hormonal therapies.

Pain was not studied as part of this trial, but was shown in a previous phase II study to be improved. Quality of life data will be reported at a later date, he said.

Discussant Dr. Wim J.G. Oyen of the St. Radboud University Medical Center Nijmegen, the Netherlands, said that based on phase I/II data suggesting that combining beta radiation–emitting agents with chemotherapy prolongs overall survival, the next logical step would be to add radium-223 in regimens of combination therapy.

"It’s so extremely well tolerated, I do not think we will experience synergistic toxicity, but we may very well experience synergistic effect," he said.

Dr. Oyen said that clinicians could further improve patient outcome by using radium-223 in the adjuvant setting (for example, in patients at high risk of developing clinically overt bone metastases). He said it is widely known that the smaller the tumor, the more advantage an alpha particle has over a beta particle; thus, microscopic disease would theoretically be the better indication over macroscopic disease.

Dr. Parker said in an interview that his preference would be to combine radium-223 with abiraterone acetate (Zytiga) because both improve survival and are extremely well tolerated, but they work in completely different ways.

Two small phase I/II trials are currently underway. One combines radium-223 with docetaxel in patients with CRPC and bone metastases. The second is studying radium-223 in breast cancer patients who have bone-dominant disease and are no longer eligible for endocrine therapy.

Dr. Parker reported serving as an uncompensated consultant to Algeta ASA and Bayer Healthcare Pharmaceuticals, which sponsored the trial. A coauthor reported an ownership interest in and previous employment with Algeta. A second coauthor is a Bayer employee.

STOCKHOLM – The investigational agent radium-223 chloride cut the risk of dying during follow-up by 30% among men with symptomatic, castration-resistant prostate cancer and bone metastases, and resulted in less toxicity than did placebo in a phase III, randomized trial.

Results of the preplanned interim analysis were strong enough to prematurely stop the ALSYMPCA (Alpharadin in Symptomatic Prostate Cancer) trial, and caused a stir at the European Multidisciplinary Cancer Congress.

After a maximum follow-up of 3 years, median overall survival was significantly increased from 11.1 months with placebo to 14.0 months with radium-223 chloride (Alpharadin) (hazard ratio, 0.695; P = .00185).

The survival benefit was maintained across all subgroups studied, regardless of baseline alkaline phosphatase (ALP) level, current bisphosphonate use, prior docetaxel (Taxotere) use, and Eastern Cooperative Oncology Group performance status, lead author Dr. Chris Parker reported.

"In my opinion, radium-223, which has a completely novel mechanism of action, is likely to become a new standard treatment for this disease," he said.

"This is a very important finding, certainly practice changing, and very likely could become the standard of care ... all over the world," European Cancer Organization (ECCO) president Dr. Michael Baumann of the Technical University of Dresden (Germany) said during a press briefing.

Likewise, Dr. Jean Charles Soria of the Institut de Cancérologie Gustave Roussy in Villejuif, France, and cochair of the congress scientific program said that "this is really practice changing, and pending regulatory approval, I think this is going to be a major player in prostate cancer management."

Current bone-targeting therapies such as denosumab (Xgeva) have been shown to improve symptom control but not survival in patients with castration-resistant prostate cancer (CRPC) and bone metastases. More than 90% of men with metastatic CRPC have evidence of bone metastases, conferring almost a fivefold greater risk of death.

Radium-223 chloride is not approved in the United States or Europe, but was granted fast track designation by the Food and Drug Administration in August 2011. Approval could come by the end of 2012, said Dr. Parker, a consultant clinical oncologist at the Royal Marsden Hospital in Sutton, England.

Radium-223 acts as a calcium mimic, and targets new bone growth in and around bone metastases via heavy alpha particles that have an ultrashort range of less than 100 mcm. It takes only a single alpha particle to kill a cancer cell, and the short penetration results in highly localized tumor-cell killing and minimal collateral damage, Dr. Parker explained.

He suggested that it would be relatively straightforward for hospitals to offer radium-223 because it takes 5 minutes to administer as an injection in the outpatient setting. Storage would be limited because of the drug’s short half-life of 11 days, but the agent would not require special radiation protection because alpha radiation is stopped by a piece of paper.

ALSYMPCA randomized 922 patients to best standard treatment plus six injections every 4 weeks of radium-223 (50 kBq/kg) or to placebo. The patients had symptomatic CRPC, at least two bone metastases, and no known visceral metastases; they had previously received or were unfit for docetaxel. Notably, 40% of patients had more than 20 metastases on bone scintigraphy, and 60% had previously received docetaxel.

Radium-223 significantly prolonged the time to first skeletal-related event from 8.4 months with placebo to 13.6 months (P = .00046; HR, 0.61), Dr. Parker said at the joint congress of the ECCO, the European Society for Medical Oncology (ESMO), and the European Society of Radiotherapy and Oncology (ESTRO).

All other secondary end points were met by radium-223 over placebo, including time to total ALP progression (HR, 0.163; P less than .00001); time to prostate-specific antigen progression (HR, 0.671; P = .00015); total ALP response, defined as a 30% reduction (43% vs. 3%; P less than .001); and total ALP normalization (33% vs. 1%; P less than .001).

Dr. Parker pointed out that "ALSYMPCA is one of a very few phase III trials in which the placebo arm had more toxicity than the active intervention arm."

Hematologic events were slightly increased in patients treated with radium-223, compared with placebo, but were rare, he said. There was also an excess of mild diarrhea and vomiting, but severe GI toxicity was not seen.

The placebo arm had more grade 3 or 4 adverse events than did the radium-223 arm (59% vs. 51%), more serious adverse events (55% and 43%), and more treatment discontinuations (20% vs. 13%). Of note, best standard treatment could include bisphosphonates, palliative radiotherapy, and hormonal therapies.

Pain was not studied as part of this trial, but was shown in a previous phase II study to be improved. Quality of life data will be reported at a later date, he said.

Discussant Dr. Wim J.G. Oyen of the St. Radboud University Medical Center Nijmegen, the Netherlands, said that based on phase I/II data suggesting that combining beta radiation–emitting agents with chemotherapy prolongs overall survival, the next logical step would be to add radium-223 in regimens of combination therapy.

"It’s so extremely well tolerated, I do not think we will experience synergistic toxicity, but we may very well experience synergistic effect," he said.

Dr. Oyen said that clinicians could further improve patient outcome by using radium-223 in the adjuvant setting (for example, in patients at high risk of developing clinically overt bone metastases). He said it is widely known that the smaller the tumor, the more advantage an alpha particle has over a beta particle; thus, microscopic disease would theoretically be the better indication over macroscopic disease.

Dr. Parker said in an interview that his preference would be to combine radium-223 with abiraterone acetate (Zytiga) because both improve survival and are extremely well tolerated, but they work in completely different ways.

Two small phase I/II trials are currently underway. One combines radium-223 with docetaxel in patients with CRPC and bone metastases. The second is studying radium-223 in breast cancer patients who have bone-dominant disease and are no longer eligible for endocrine therapy.

Dr. Parker reported serving as an uncompensated consultant to Algeta ASA and Bayer Healthcare Pharmaceuticals, which sponsored the trial. A coauthor reported an ownership interest in and previous employment with Algeta. A second coauthor is a Bayer employee.

STOCKHOLM – The investigational agent radium-223 chloride cut the risk of dying during follow-up by 30% among men with symptomatic, castration-resistant prostate cancer and bone metastases, and resulted in less toxicity than did placebo in a phase III, randomized trial.

Results of the preplanned interim analysis were strong enough to prematurely stop the ALSYMPCA (Alpharadin in Symptomatic Prostate Cancer) trial, and caused a stir at the European Multidisciplinary Cancer Congress.

After a maximum follow-up of 3 years, median overall survival was significantly increased from 11.1 months with placebo to 14.0 months with radium-223 chloride (Alpharadin) (hazard ratio, 0.695; P = .00185).

The survival benefit was maintained across all subgroups studied, regardless of baseline alkaline phosphatase (ALP) level, current bisphosphonate use, prior docetaxel (Taxotere) use, and Eastern Cooperative Oncology Group performance status, lead author Dr. Chris Parker reported.

"In my opinion, radium-223, which has a completely novel mechanism of action, is likely to become a new standard treatment for this disease," he said.

"This is a very important finding, certainly practice changing, and very likely could become the standard of care ... all over the world," European Cancer Organization (ECCO) president Dr. Michael Baumann of the Technical University of Dresden (Germany) said during a press briefing.

Likewise, Dr. Jean Charles Soria of the Institut de Cancérologie Gustave Roussy in Villejuif, France, and cochair of the congress scientific program said that "this is really practice changing, and pending regulatory approval, I think this is going to be a major player in prostate cancer management."

Current bone-targeting therapies such as denosumab (Xgeva) have been shown to improve symptom control but not survival in patients with castration-resistant prostate cancer (CRPC) and bone metastases. More than 90% of men with metastatic CRPC have evidence of bone metastases, conferring almost a fivefold greater risk of death.

Radium-223 chloride is not approved in the United States or Europe, but was granted fast track designation by the Food and Drug Administration in August 2011. Approval could come by the end of 2012, said Dr. Parker, a consultant clinical oncologist at the Royal Marsden Hospital in Sutton, England.

Radium-223 acts as a calcium mimic, and targets new bone growth in and around bone metastases via heavy alpha particles that have an ultrashort range of less than 100 mcm. It takes only a single alpha particle to kill a cancer cell, and the short penetration results in highly localized tumor-cell killing and minimal collateral damage, Dr. Parker explained.

He suggested that it would be relatively straightforward for hospitals to offer radium-223 because it takes 5 minutes to administer as an injection in the outpatient setting. Storage would be limited because of the drug’s short half-life of 11 days, but the agent would not require special radiation protection because alpha radiation is stopped by a piece of paper.

ALSYMPCA randomized 922 patients to best standard treatment plus six injections every 4 weeks of radium-223 (50 kBq/kg) or to placebo. The patients had symptomatic CRPC, at least two bone metastases, and no known visceral metastases; they had previously received or were unfit for docetaxel. Notably, 40% of patients had more than 20 metastases on bone scintigraphy, and 60% had previously received docetaxel.

Radium-223 significantly prolonged the time to first skeletal-related event from 8.4 months with placebo to 13.6 months (P = .00046; HR, 0.61), Dr. Parker said at the joint congress of the ECCO, the European Society for Medical Oncology (ESMO), and the European Society of Radiotherapy and Oncology (ESTRO).

All other secondary end points were met by radium-223 over placebo, including time to total ALP progression (HR, 0.163; P less than .00001); time to prostate-specific antigen progression (HR, 0.671; P = .00015); total ALP response, defined as a 30% reduction (43% vs. 3%; P less than .001); and total ALP normalization (33% vs. 1%; P less than .001).

Dr. Parker pointed out that "ALSYMPCA is one of a very few phase III trials in which the placebo arm had more toxicity than the active intervention arm."

Hematologic events were slightly increased in patients treated with radium-223, compared with placebo, but were rare, he said. There was also an excess of mild diarrhea and vomiting, but severe GI toxicity was not seen.

The placebo arm had more grade 3 or 4 adverse events than did the radium-223 arm (59% vs. 51%), more serious adverse events (55% and 43%), and more treatment discontinuations (20% vs. 13%). Of note, best standard treatment could include bisphosphonates, palliative radiotherapy, and hormonal therapies.

Pain was not studied as part of this trial, but was shown in a previous phase II study to be improved. Quality of life data will be reported at a later date, he said.

Discussant Dr. Wim J.G. Oyen of the St. Radboud University Medical Center Nijmegen, the Netherlands, said that based on phase I/II data suggesting that combining beta radiation–emitting agents with chemotherapy prolongs overall survival, the next logical step would be to add radium-223 in regimens of combination therapy.

"It’s so extremely well tolerated, I do not think we will experience synergistic toxicity, but we may very well experience synergistic effect," he said.

Dr. Oyen said that clinicians could further improve patient outcome by using radium-223 in the adjuvant setting (for example, in patients at high risk of developing clinically overt bone metastases). He said it is widely known that the smaller the tumor, the more advantage an alpha particle has over a beta particle; thus, microscopic disease would theoretically be the better indication over macroscopic disease.

Dr. Parker said in an interview that his preference would be to combine radium-223 with abiraterone acetate (Zytiga) because both improve survival and are extremely well tolerated, but they work in completely different ways.

Two small phase I/II trials are currently underway. One combines radium-223 with docetaxel in patients with CRPC and bone metastases. The second is studying radium-223 in breast cancer patients who have bone-dominant disease and are no longer eligible for endocrine therapy.

Dr. Parker reported serving as an uncompensated consultant to Algeta ASA and Bayer Healthcare Pharmaceuticals, which sponsored the trial. A coauthor reported an ownership interest in and previous employment with Algeta. A second coauthor is a Bayer employee.

PARIS – Hemodynamic values were sustained up to 3 years after CoreValve transcatheter aortic valve implantation among 393 patients with severe symptomatic aortic stenosis.

Importantly, there were no signs of unexpected early degeneration of the CoreValve prosthesis, lead author Dr. Anke Opitz reported at the annual congress of the European Society of Cardiology.

One of the fundamental questions facing transcatheter aortic valve implantation (TAVI) is whether the durability of transcatheter aortic valves is comparable to that of conventional biological aortic valves, which typically start degenerating at about 10-15 years.

"We expect that the duration will be as long as the conventional biological aortic valves, but this is a completely new style of valve," Dr. Opitz said in an interview. "It’s very different from the conventional valves because you have to crimp these valves [on to the catheter] and sometimes you do post dilation, so there’s a lot more stress on the valves than on the conventional ones."

The CoreValve (Medtronic) and Edwards Sapien (Edwards Lifesciences) transcatheter valves are limited to investigational use in the United States but have been available in Europe since 2007. U.S. approval of the Edwards Sapien valve is expected, however, following a July 20, 2011 U.S. Food and Drug Administration advisory panel vote in favor of the valve for treatment of certain inoperable patients.

Dr. Opitz reported on 393 consecutive patients implanted from June 2007 to June 2011 at the German Heart Center in Munich with the CoreValve device, which consists of a self-expandable nitinol stent with a porcine pericardium valve. Femoral access was possible in 87% of patients; 63% of patients were implanted with a 29-mm prosthesis and 37% with a 26-mm prosthesis.

The patients’ mean age was 80 years, mean EuroSCORE was 19.1%, and mean Society of Thoracic Surgeons risk score was 5.8%.

Transthoracic echocardiography revealed that the effective orifice area increased significantly, from 0.7 cm² at baseline to 1.55 cm² after TAVI, and remained unchanged through 36 months at 1.57 cm² in 20 evaluable patients, Dr. Opitz reported.

The peak aortic valve gradient decreased significantly after TAVI (78 mm Hg vs. 21 mm Hg), as did the mean aortic valve gradient. Both gradients remained low through the 36 months. Severity of stenosis rises with the gradients.

Septal wall thickness also significantly decreased from 14.9 mm preoperatively to 13.1 mm at 36 months.

Left ventricular end diastolic diameter remained unchanged from baseline at 12-, 24-, and 36-month follow-ups. The percentage of patients with a left ventricular ejection fraction less than 35% decreased significantly, from 19% at baseline to 4% at 12 months, 6% at 24 months, and 7% at 36 months, Dr. Opitz said.

Paravalvular aortic valve regurgitation occurred in 64% of patients after TAVI but was trivial or mild in 65%, mild to moderate in 20%, and moderate in 15%, she noted.

Dr. Opitz reported no conflicts of interest.

PARIS – Hemodynamic values were sustained up to 3 years after CoreValve transcatheter aortic valve implantation among 393 patients with severe symptomatic aortic stenosis.

Importantly, there were no signs of unexpected early degeneration of the CoreValve prosthesis, lead author Dr. Anke Opitz reported at the annual congress of the European Society of Cardiology.

One of the fundamental questions facing transcatheter aortic valve implantation (TAVI) is whether the durability of transcatheter aortic valves is comparable to that of conventional biological aortic valves, which typically start degenerating at about 10-15 years.

"We expect that the duration will be as long as the conventional biological aortic valves, but this is a completely new style of valve," Dr. Opitz said in an interview. "It’s very different from the conventional valves because you have to crimp these valves [on to the catheter] and sometimes you do post dilation, so there’s a lot more stress on the valves than on the conventional ones."

The CoreValve (Medtronic) and Edwards Sapien (Edwards Lifesciences) transcatheter valves are limited to investigational use in the United States but have been available in Europe since 2007. U.S. approval of the Edwards Sapien valve is expected, however, following a July 20, 2011 U.S. Food and Drug Administration advisory panel vote in favor of the valve for treatment of certain inoperable patients.

Dr. Opitz reported on 393 consecutive patients implanted from June 2007 to June 2011 at the German Heart Center in Munich with the CoreValve device, which consists of a self-expandable nitinol stent with a porcine pericardium valve. Femoral access was possible in 87% of patients; 63% of patients were implanted with a 29-mm prosthesis and 37% with a 26-mm prosthesis.

The patients’ mean age was 80 years, mean EuroSCORE was 19.1%, and mean Society of Thoracic Surgeons risk score was 5.8%.

Transthoracic echocardiography revealed that the effective orifice area increased significantly, from 0.7 cm² at baseline to 1.55 cm² after TAVI, and remained unchanged through 36 months at 1.57 cm² in 20 evaluable patients, Dr. Opitz reported.

The peak aortic valve gradient decreased significantly after TAVI (78 mm Hg vs. 21 mm Hg), as did the mean aortic valve gradient. Both gradients remained low through the 36 months. Severity of stenosis rises with the gradients.

Septal wall thickness also significantly decreased from 14.9 mm preoperatively to 13.1 mm at 36 months.

Left ventricular end diastolic diameter remained unchanged from baseline at 12-, 24-, and 36-month follow-ups. The percentage of patients with a left ventricular ejection fraction less than 35% decreased significantly, from 19% at baseline to 4% at 12 months, 6% at 24 months, and 7% at 36 months, Dr. Opitz said.

Paravalvular aortic valve regurgitation occurred in 64% of patients after TAVI but was trivial or mild in 65%, mild to moderate in 20%, and moderate in 15%, she noted.

Dr. Opitz reported no conflicts of interest.

PARIS – Hemodynamic values were sustained up to 3 years after CoreValve transcatheter aortic valve implantation among 393 patients with severe symptomatic aortic stenosis.

Importantly, there were no signs of unexpected early degeneration of the CoreValve prosthesis, lead author Dr. Anke Opitz reported at the annual congress of the European Society of Cardiology.

One of the fundamental questions facing transcatheter aortic valve implantation (TAVI) is whether the durability of transcatheter aortic valves is comparable to that of conventional biological aortic valves, which typically start degenerating at about 10-15 years.

"We expect that the duration will be as long as the conventional biological aortic valves, but this is a completely new style of valve," Dr. Opitz said in an interview. "It’s very different from the conventional valves because you have to crimp these valves [on to the catheter] and sometimes you do post dilation, so there’s a lot more stress on the valves than on the conventional ones."

The CoreValve (Medtronic) and Edwards Sapien (Edwards Lifesciences) transcatheter valves are limited to investigational use in the United States but have been available in Europe since 2007. U.S. approval of the Edwards Sapien valve is expected, however, following a July 20, 2011 U.S. Food and Drug Administration advisory panel vote in favor of the valve for treatment of certain inoperable patients.

Dr. Opitz reported on 393 consecutive patients implanted from June 2007 to June 2011 at the German Heart Center in Munich with the CoreValve device, which consists of a self-expandable nitinol stent with a porcine pericardium valve. Femoral access was possible in 87% of patients; 63% of patients were implanted with a 29-mm prosthesis and 37% with a 26-mm prosthesis.

The patients’ mean age was 80 years, mean EuroSCORE was 19.1%, and mean Society of Thoracic Surgeons risk score was 5.8%.

Transthoracic echocardiography revealed that the effective orifice area increased significantly, from 0.7 cm² at baseline to 1.55 cm² after TAVI, and remained unchanged through 36 months at 1.57 cm² in 20 evaluable patients, Dr. Opitz reported.

The peak aortic valve gradient decreased significantly after TAVI (78 mm Hg vs. 21 mm Hg), as did the mean aortic valve gradient. Both gradients remained low through the 36 months. Severity of stenosis rises with the gradients.

Septal wall thickness also significantly decreased from 14.9 mm preoperatively to 13.1 mm at 36 months.

Left ventricular end diastolic diameter remained unchanged from baseline at 12-, 24-, and 36-month follow-ups. The percentage of patients with a left ventricular ejection fraction less than 35% decreased significantly, from 19% at baseline to 4% at 12 months, 6% at 24 months, and 7% at 36 months, Dr. Opitz said.

Paravalvular aortic valve regurgitation occurred in 64% of patients after TAVI but was trivial or mild in 65%, mild to moderate in 20%, and moderate in 15%, she noted.

Dr. Opitz reported no conflicts of interest.

PARIS – In inoperable patients with severe aortic stenosis, their EuroSCORE – a predicted operative mortality from cardiac surgery – consistently predicted outcomes from transcatheter aortic valve implantation in a prospective, single-center study.

Among 177 consecutive patients declined for surgery, the procedural success rate was 100% in patients with a EuroSCORE of less than 20% and 95.7% in those with a EuroSCORE of more than 20%.

Moreover, there were no deaths at 30 days in the low-risk group, but mortality was 11.1% in the high-risk group. This result was maintained at 1 year (5% vs. 25%), and both differences were highly significant, Dr. Matthieu Godin reported at the annual congress of the European Society of Cardiology.

"This may be the first step towards a broader assessment of percutaneous techniques in populations at lower surgical risk, but without forgetting that surgery is currently the ... standard," he said.

Transcatheter aortic valve implantation (TAVI) is not commercially avaliable in the United States. In Europe, however, TAVI is considered a less invasive therapeutic option for severe aortic stenosis among nonsurgical and high–surgical-risk patients, as defined by a logistic EuroSCORE (European System for Cardiac Operative Risk) of more than 20% or a Society of Thoracic Surgeons risk score of more than 10%.

TAVI is frequently performed, however, in patients with low to intermediate logistic EuroSCOREs and contraindications to conventional valve replacement due to comorbidities not included in the surgical risk models, said Dr. Godin of Rouen (France) University Hospital–Charles Nicolle Hospital, where the first TAVI was performed in 2002 by coinvestigator Dr. Alain Cribier (Circulation 2002;106:3006-8).

In an effort to address this evolution and an eager marketplace, the American College of Cardiology and Society of Thoracic Surgeons released an expert consensus document that explores key components that will be necessary for successful integration of transcatheter valve therapy into clinical practice (J. Am. Coll. Cardiol. 2011;58:445-55). While praising the "transformational technology," the societies cite limited evidence from only one randomized trial in aortic stenosis (PARTNER) and one in mitral insufficiency (EVEREST II) in stating that "adoption of these techniques to populations beyond those studied in these randomized trials, therefore, is not appropriate at the current time."

Dr. Godin stressed that his results should not be interpreted to suggest that the indication for TAVI should be expanded to low-risk surgical candidates and said that this would require a large-scale trial like PARTNER and long-term follow-up on the durability of the prostheses.

The Placement of Aortic Transcatheter Valves (PARTNER) trial enrolled two distinct cohorts. Cohort A included 699 patients (median age 84 years) who were candidates for conventional surgery but were at high surgical risk based on an STS score of at least 10% or on coexisting conditions that would be associated with at least a 15% predicted risk of death by 30 days after surgery. Cohort B included 358 patients (median age 83 years) who were deemed unsuitable for conventional surgery because of coexisting conditions that would be associated with at least a 50% predicted probability of death by 30 days after surgery or a serious irreversible complication (N. Engl. J. Med. 2010;363:1597-607).

Dr. Godin’s analysis included 177 patients who presented between 2006 and 2011 with degenerative aortic stenosis and were implanted with the Edwards Sapien valve up to October 2009 and the Edwards Sapien-XT prosthesis thereafter. A transfemoral approach was used in 72% and a transapical approach in 28%.

In all, 60 patients had a EuroSCORE of less than 20% (mean 12%) and 117 had a EuroSCORE of at least 20% (mean 32%). Their mean ages were 80 years and 84 years, respectively.

Contraindications to conventional surgery in the low-risk group included porcelain aorta in 15%, chest irradiation in 20%, and chest deformity in 8.3%.

The low- and high-risk groups had similar rates of major stroke (1.7% and 0.9%, respectively), major vascular complications (5% and 6%), and definitive pacemaker implantation (5% and 6%), Dr. Godin reported.

The low-risk group had significantly less life-threatening bleeding (7% vs. 21%) and significantly shorter mean ICU stays (2 days vs. 3 days) and mean hospital stays (9 days vs. 11 days).

Dr. Godin reported no conflicts. Dr. Cribier is a consultant for Edwards Lifesciences, and two additional coauthors are proctors for the company.

PARIS – In inoperable patients with severe aortic stenosis, their EuroSCORE – a predicted operative mortality from cardiac surgery – consistently predicted outcomes from transcatheter aortic valve implantation in a prospective, single-center study.

Among 177 consecutive patients declined for surgery, the procedural success rate was 100% in patients with a EuroSCORE of less than 20% and 95.7% in those with a EuroSCORE of more than 20%.

Moreover, there were no deaths at 30 days in the low-risk group, but mortality was 11.1% in the high-risk group. This result was maintained at 1 year (5% vs. 25%), and both differences were highly significant, Dr. Matthieu Godin reported at the annual congress of the European Society of Cardiology.

"This may be the first step towards a broader assessment of percutaneous techniques in populations at lower surgical risk, but without forgetting that surgery is currently the ... standard," he said.

Transcatheter aortic valve implantation (TAVI) is not commercially avaliable in the United States. In Europe, however, TAVI is considered a less invasive therapeutic option for severe aortic stenosis among nonsurgical and high–surgical-risk patients, as defined by a logistic EuroSCORE (European System for Cardiac Operative Risk) of more than 20% or a Society of Thoracic Surgeons risk score of more than 10%.

TAVI is frequently performed, however, in patients with low to intermediate logistic EuroSCOREs and contraindications to conventional valve replacement due to comorbidities not included in the surgical risk models, said Dr. Godin of Rouen (France) University Hospital–Charles Nicolle Hospital, where the first TAVI was performed in 2002 by coinvestigator Dr. Alain Cribier (Circulation 2002;106:3006-8).

In an effort to address this evolution and an eager marketplace, the American College of Cardiology and Society of Thoracic Surgeons released an expert consensus document that explores key components that will be necessary for successful integration of transcatheter valve therapy into clinical practice (J. Am. Coll. Cardiol. 2011;58:445-55). While praising the "transformational technology," the societies cite limited evidence from only one randomized trial in aortic stenosis (PARTNER) and one in mitral insufficiency (EVEREST II) in stating that "adoption of these techniques to populations beyond those studied in these randomized trials, therefore, is not appropriate at the current time."

Dr. Godin stressed that his results should not be interpreted to suggest that the indication for TAVI should be expanded to low-risk surgical candidates and said that this would require a large-scale trial like PARTNER and long-term follow-up on the durability of the prostheses.

The Placement of Aortic Transcatheter Valves (PARTNER) trial enrolled two distinct cohorts. Cohort A included 699 patients (median age 84 years) who were candidates for conventional surgery but were at high surgical risk based on an STS score of at least 10% or on coexisting conditions that would be associated with at least a 15% predicted risk of death by 30 days after surgery. Cohort B included 358 patients (median age 83 years) who were deemed unsuitable for conventional surgery because of coexisting conditions that would be associated with at least a 50% predicted probability of death by 30 days after surgery or a serious irreversible complication (N. Engl. J. Med. 2010;363:1597-607).

Dr. Godin’s analysis included 177 patients who presented between 2006 and 2011 with degenerative aortic stenosis and were implanted with the Edwards Sapien valve up to October 2009 and the Edwards Sapien-XT prosthesis thereafter. A transfemoral approach was used in 72% and a transapical approach in 28%.

In all, 60 patients had a EuroSCORE of less than 20% (mean 12%) and 117 had a EuroSCORE of at least 20% (mean 32%). Their mean ages were 80 years and 84 years, respectively.

Contraindications to conventional surgery in the low-risk group included porcelain aorta in 15%, chest irradiation in 20%, and chest deformity in 8.3%.

The low- and high-risk groups had similar rates of major stroke (1.7% and 0.9%, respectively), major vascular complications (5% and 6%), and definitive pacemaker implantation (5% and 6%), Dr. Godin reported.

The low-risk group had significantly less life-threatening bleeding (7% vs. 21%) and significantly shorter mean ICU stays (2 days vs. 3 days) and mean hospital stays (9 days vs. 11 days).

Dr. Godin reported no conflicts. Dr. Cribier is a consultant for Edwards Lifesciences, and two additional coauthors are proctors for the company.

PARIS – In inoperable patients with severe aortic stenosis, their EuroSCORE – a predicted operative mortality from cardiac surgery – consistently predicted outcomes from transcatheter aortic valve implantation in a prospective, single-center study.

Among 177 consecutive patients declined for surgery, the procedural success rate was 100% in patients with a EuroSCORE of less than 20% and 95.7% in those with a EuroSCORE of more than 20%.

Moreover, there were no deaths at 30 days in the low-risk group, but mortality was 11.1% in the high-risk group. This result was maintained at 1 year (5% vs. 25%), and both differences were highly significant, Dr. Matthieu Godin reported at the annual congress of the European Society of Cardiology.

"This may be the first step towards a broader assessment of percutaneous techniques in populations at lower surgical risk, but without forgetting that surgery is currently the ... standard," he said.

Transcatheter aortic valve implantation (TAVI) is not commercially avaliable in the United States. In Europe, however, TAVI is considered a less invasive therapeutic option for severe aortic stenosis among nonsurgical and high–surgical-risk patients, as defined by a logistic EuroSCORE (European System for Cardiac Operative Risk) of more than 20% or a Society of Thoracic Surgeons risk score of more than 10%.

TAVI is frequently performed, however, in patients with low to intermediate logistic EuroSCOREs and contraindications to conventional valve replacement due to comorbidities not included in the surgical risk models, said Dr. Godin of Rouen (France) University Hospital–Charles Nicolle Hospital, where the first TAVI was performed in 2002 by coinvestigator Dr. Alain Cribier (Circulation 2002;106:3006-8).

In an effort to address this evolution and an eager marketplace, the American College of Cardiology and Society of Thoracic Surgeons released an expert consensus document that explores key components that will be necessary for successful integration of transcatheter valve therapy into clinical practice (J. Am. Coll. Cardiol. 2011;58:445-55). While praising the "transformational technology," the societies cite limited evidence from only one randomized trial in aortic stenosis (PARTNER) and one in mitral insufficiency (EVEREST II) in stating that "adoption of these techniques to populations beyond those studied in these randomized trials, therefore, is not appropriate at the current time."

Dr. Godin stressed that his results should not be interpreted to suggest that the indication for TAVI should be expanded to low-risk surgical candidates and said that this would require a large-scale trial like PARTNER and long-term follow-up on the durability of the prostheses.

The Placement of Aortic Transcatheter Valves (PARTNER) trial enrolled two distinct cohorts. Cohort A included 699 patients (median age 84 years) who were candidates for conventional surgery but were at high surgical risk based on an STS score of at least 10% or on coexisting conditions that would be associated with at least a 15% predicted risk of death by 30 days after surgery. Cohort B included 358 patients (median age 83 years) who were deemed unsuitable for conventional surgery because of coexisting conditions that would be associated with at least a 50% predicted probability of death by 30 days after surgery or a serious irreversible complication (N. Engl. J. Med. 2010;363:1597-607).

Dr. Godin’s analysis included 177 patients who presented between 2006 and 2011 with degenerative aortic stenosis and were implanted with the Edwards Sapien valve up to October 2009 and the Edwards Sapien-XT prosthesis thereafter. A transfemoral approach was used in 72% and a transapical approach in 28%.

In all, 60 patients had a EuroSCORE of less than 20% (mean 12%) and 117 had a EuroSCORE of at least 20% (mean 32%). Their mean ages were 80 years and 84 years, respectively.

Contraindications to conventional surgery in the low-risk group included porcelain aorta in 15%, chest irradiation in 20%, and chest deformity in 8.3%.

The low- and high-risk groups had similar rates of major stroke (1.7% and 0.9%, respectively), major vascular complications (5% and 6%), and definitive pacemaker implantation (5% and 6%), Dr. Godin reported.

The low-risk group had significantly less life-threatening bleeding (7% vs. 21%) and significantly shorter mean ICU stays (2 days vs. 3 days) and mean hospital stays (9 days vs. 11 days).

Dr. Godin reported no conflicts. Dr. Cribier is a consultant for Edwards Lifesciences, and two additional coauthors are proctors for the company.

The investigational CETP inhibitor dalcetrapib does not increase plaque burden, and even appears to prompt positive vascular effects in patients with or at high risk of coronary heart disease, according to data from the dal-PLAQUE trial published online Sept. 12 in the Lancet.

The trial provides reassuring data after the spectacular failure in 2006 of another cholesteryl ester transfer protein (CETP) inhibitor, torcetrapib, raised concerns that HDL cholesterol–raising drugs had proinflammatory or proatherosclerotic effects.

Dalcetrapib was shown to increase HDL cholesterol by 31% without affecting LDL cholesterol or raising blood pressure at 24 months in the recently reported companion dal-VESSEL trial.

The phase IIb exploratory dal-PLAQUE trial used magnetic resonance imaging (MRI) to assess plaque burden and positron emission tomography/computed tomography (PET/CT) measurements of ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) uptake to assess inflammation in an index vessel (right carotid artery, left carotid artery, or ascending thoracic aorta), among 130 patients randomized to dalcetrapib 600 mg per day or placebo in addition to standard medication for 24 months.

"No evidence of pro-atherogenic effect of dalcetrapib therapy was recorded in terms of plaque burden compared with placebo as assessed by MRI after 24 months," lead author Dr. Zahi A. Fayad reported (Lancet 2011 Sept. 12 [doi:10.1016/S0140-6736(11)61383-4]).

Notably, the absolute change from baseline in total carotid vessel area by MRI was significant in patients on dalcetrapib, relative to placebo, at –4.01 mm².

The change in the dalcetrapib group was –2.20 mm² for wall area and 0.60% for normalized wall index, compared with placebo, both nonsignificant differences. All three of these indices were under the predefined limits of no harm.

The change in wall thickness at 24 months was –0.3 mm. The upper confidence interval for this fourth index was beyond the predefined limit of no harm, but there was less increase with dalcetrapib than with placebo (mean 1.19 mm with dalcetrapib vs. 1.27 mm with placebo), observed Dr. Fayad of Mount Sinai School of Medicine, New York.

In an accompanying editorial, Dr. Erik S.G. Stroes and Dr. Diederick F. van Wijk said that first and foremost, it is encouraging that the dalcetrapib group did not show an increase in total vessel area, "which clearly differs from the progression of common carotid artery thickness after torcetrapib administration." Instead, the opposite occurred, with the progression of vessel wall area, indicating outward remodeling in the course of atherogenesis, decreasing in the dalcetrapib group (Lancet 2011 Sept. 12 [doi:10.1016/S0140-6736(11)61421-9]).

The editorialists suggested that the absence of benefit with dalcetrapib on parameters of the aortic vessel wall might be due to the heterogeneity of antiatherosclerotic effects or the small sample size, and said a similar study with the more potent CETP inhibitor anacetrapib could resolve this issue.

"As we await the final verdict on dalcetrapib in 2013, when the dal-OUTCOME study will provide data on cardiovascular end points in 15,600 patients, the findings of Fayad and colleagues bring us one step higher in the ladder of CETP research, after its free fall since 2006," wrote Dr. Stroes and Dr. Wijk, of the Academic Medical Center, Amsterdam, Netherlands.

The dal-PLAQUE investigators reported that the PET/CT measurements of index vessel most-diseased-segment target-to-background ratio (TBR) did not differ significantly between the dalcetrapib and placebo groups at 6 months (2.56 vs. 2.54).

Analysis of the carotid vessel ¹⁸F-FDG-PET/CT data, however, showed a 7.3% reduction in most-diseased-segment TBR in the dalcetrapib group, compared with no change with placebo, Dr. Fayad and his associates reported. Increased HDL cholesterol concentrations appeared to be correlated with decreased TBR. In addition, reductions in TBR at 6 months were noted to be associated with a reduction in the rate of increase in total vessel area by MRI at 24 months.

Notably, systemic inflammation as measured by high-sensitivity C-reactive protein did not decrease in the dalcetrapib group. On the contrary, it rose 33%.

"These findings highlight that the blood and imaging biomarkers of inflammation might provide substantially different information about the vascular inflammatory milieu, the exact nature of which remains incompletely elucidated," wrote the authors of dal-PLAQUE, the first placebo-controlled trial to use noninvasive multimodality imaging as primary end points.

Finally, the editorialists called for additional studies to assess the effect of selective, potent anti-inflammatory drugs on vessel wall inflammation and cardiovascular outcome. As an example, they highlighted the current CANTOS (Canakinumab Anti-Inflammatory Thrombosis Outcome Study) evaluating canakinumab, an antibody that inhibits the endogenous proinflammatory protein interleukin-1 beta in patients with coronary artery disease.

Hoffmann-La Roche funded the study and preparation of the journal article. Dr. Fayad reports research grants from Roche, GlaxoSmithKline, Merck, VBL Therapeutics, Novartis, Bristol-Myers Squibb, and Via Pharmaceuticals, and honoraria from Roche. His coauthors report financial relationships with several firms, including, in some cases, employment with Hoffmann-La Roche. Dr. Stroes and Dr. Wijk report no conflicts.

The investigational CETP inhibitor dalcetrapib does not increase plaque burden, and even appears to prompt positive vascular effects in patients with or at high risk of coronary heart disease, according to data from the dal-PLAQUE trial published online Sept. 12 in the Lancet.

The trial provides reassuring data after the spectacular failure in 2006 of another cholesteryl ester transfer protein (CETP) inhibitor, torcetrapib, raised concerns that HDL cholesterol–raising drugs had proinflammatory or proatherosclerotic effects.

Dalcetrapib was shown to increase HDL cholesterol by 31% without affecting LDL cholesterol or raising blood pressure at 24 months in the recently reported companion dal-VESSEL trial.

The phase IIb exploratory dal-PLAQUE trial used magnetic resonance imaging (MRI) to assess plaque burden and positron emission tomography/computed tomography (PET/CT) measurements of ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) uptake to assess inflammation in an index vessel (right carotid artery, left carotid artery, or ascending thoracic aorta), among 130 patients randomized to dalcetrapib 600 mg per day or placebo in addition to standard medication for 24 months.

"No evidence of pro-atherogenic effect of dalcetrapib therapy was recorded in terms of plaque burden compared with placebo as assessed by MRI after 24 months," lead author Dr. Zahi A. Fayad reported (Lancet 2011 Sept. 12 [doi:10.1016/S0140-6736(11)61383-4]).

Notably, the absolute change from baseline in total carotid vessel area by MRI was significant in patients on dalcetrapib, relative to placebo, at –4.01 mm².

The change in the dalcetrapib group was –2.20 mm² for wall area and 0.60% for normalized wall index, compared with placebo, both nonsignificant differences. All three of these indices were under the predefined limits of no harm.

The change in wall thickness at 24 months was –0.3 mm. The upper confidence interval for this fourth index was beyond the predefined limit of no harm, but there was less increase with dalcetrapib than with placebo (mean 1.19 mm with dalcetrapib vs. 1.27 mm with placebo), observed Dr. Fayad of Mount Sinai School of Medicine, New York.

In an accompanying editorial, Dr. Erik S.G. Stroes and Dr. Diederick F. van Wijk said that first and foremost, it is encouraging that the dalcetrapib group did not show an increase in total vessel area, "which clearly differs from the progression of common carotid artery thickness after torcetrapib administration." Instead, the opposite occurred, with the progression of vessel wall area, indicating outward remodeling in the course of atherogenesis, decreasing in the dalcetrapib group (Lancet 2011 Sept. 12 [doi:10.1016/S0140-6736(11)61421-9]).

The editorialists suggested that the absence of benefit with dalcetrapib on parameters of the aortic vessel wall might be due to the heterogeneity of antiatherosclerotic effects or the small sample size, and said a similar study with the more potent CETP inhibitor anacetrapib could resolve this issue.

"As we await the final verdict on dalcetrapib in 2013, when the dal-OUTCOME study will provide data on cardiovascular end points in 15,600 patients, the findings of Fayad and colleagues bring us one step higher in the ladder of CETP research, after its free fall since 2006," wrote Dr. Stroes and Dr. Wijk, of the Academic Medical Center, Amsterdam, Netherlands.

The dal-PLAQUE investigators reported that the PET/CT measurements of index vessel most-diseased-segment target-to-background ratio (TBR) did not differ significantly between the dalcetrapib and placebo groups at 6 months (2.56 vs. 2.54).

Analysis of the carotid vessel ¹⁸F-FDG-PET/CT data, however, showed a 7.3% reduction in most-diseased-segment TBR in the dalcetrapib group, compared with no change with placebo, Dr. Fayad and his associates reported. Increased HDL cholesterol concentrations appeared to be correlated with decreased TBR. In addition, reductions in TBR at 6 months were noted to be associated with a reduction in the rate of increase in total vessel area by MRI at 24 months.

Notably, systemic inflammation as measured by high-sensitivity C-reactive protein did not decrease in the dalcetrapib group. On the contrary, it rose 33%.

"These findings highlight that the blood and imaging biomarkers of inflammation might provide substantially different information about the vascular inflammatory milieu, the exact nature of which remains incompletely elucidated," wrote the authors of dal-PLAQUE, the first placebo-controlled trial to use noninvasive multimodality imaging as primary end points.

Finally, the editorialists called for additional studies to assess the effect of selective, potent anti-inflammatory drugs on vessel wall inflammation and cardiovascular outcome. As an example, they highlighted the current CANTOS (Canakinumab Anti-Inflammatory Thrombosis Outcome Study) evaluating canakinumab, an antibody that inhibits the endogenous proinflammatory protein interleukin-1 beta in patients with coronary artery disease.

Hoffmann-La Roche funded the study and preparation of the journal article. Dr. Fayad reports research grants from Roche, GlaxoSmithKline, Merck, VBL Therapeutics, Novartis, Bristol-Myers Squibb, and Via Pharmaceuticals, and honoraria from Roche. His coauthors report financial relationships with several firms, including, in some cases, employment with Hoffmann-La Roche. Dr. Stroes and Dr. Wijk report no conflicts.

The investigational CETP inhibitor dalcetrapib does not increase plaque burden, and even appears to prompt positive vascular effects in patients with or at high risk of coronary heart disease, according to data from the dal-PLAQUE trial published online Sept. 12 in the Lancet.

The trial provides reassuring data after the spectacular failure in 2006 of another cholesteryl ester transfer protein (CETP) inhibitor, torcetrapib, raised concerns that HDL cholesterol–raising drugs had proinflammatory or proatherosclerotic effects.

Dalcetrapib was shown to increase HDL cholesterol by 31% without affecting LDL cholesterol or raising blood pressure at 24 months in the recently reported companion dal-VESSEL trial.

The phase IIb exploratory dal-PLAQUE trial used magnetic resonance imaging (MRI) to assess plaque burden and positron emission tomography/computed tomography (PET/CT) measurements of ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) uptake to assess inflammation in an index vessel (right carotid artery, left carotid artery, or ascending thoracic aorta), among 130 patients randomized to dalcetrapib 600 mg per day or placebo in addition to standard medication for 24 months.

"No evidence of pro-atherogenic effect of dalcetrapib therapy was recorded in terms of plaque burden compared with placebo as assessed by MRI after 24 months," lead author Dr. Zahi A. Fayad reported (Lancet 2011 Sept. 12 [doi:10.1016/S0140-6736(11)61383-4]).

Notably, the absolute change from baseline in total carotid vessel area by MRI was significant in patients on dalcetrapib, relative to placebo, at –4.01 mm².

The change in the dalcetrapib group was –2.20 mm² for wall area and 0.60% for normalized wall index, compared with placebo, both nonsignificant differences. All three of these indices were under the predefined limits of no harm.

The change in wall thickness at 24 months was –0.3 mm. The upper confidence interval for this fourth index was beyond the predefined limit of no harm, but there was less increase with dalcetrapib than with placebo (mean 1.19 mm with dalcetrapib vs. 1.27 mm with placebo), observed Dr. Fayad of Mount Sinai School of Medicine, New York.

In an accompanying editorial, Dr. Erik S.G. Stroes and Dr. Diederick F. van Wijk said that first and foremost, it is encouraging that the dalcetrapib group did not show an increase in total vessel area, "which clearly differs from the progression of common carotid artery thickness after torcetrapib administration." Instead, the opposite occurred, with the progression of vessel wall area, indicating outward remodeling in the course of atherogenesis, decreasing in the dalcetrapib group (Lancet 2011 Sept. 12 [doi:10.1016/S0140-6736(11)61421-9]).

The editorialists suggested that the absence of benefit with dalcetrapib on parameters of the aortic vessel wall might be due to the heterogeneity of antiatherosclerotic effects or the small sample size, and said a similar study with the more potent CETP inhibitor anacetrapib could resolve this issue.

"As we await the final verdict on dalcetrapib in 2013, when the dal-OUTCOME study will provide data on cardiovascular end points in 15,600 patients, the findings of Fayad and colleagues bring us one step higher in the ladder of CETP research, after its free fall since 2006," wrote Dr. Stroes and Dr. Wijk, of the Academic Medical Center, Amsterdam, Netherlands.

The dal-PLAQUE investigators reported that the PET/CT measurements of index vessel most-diseased-segment target-to-background ratio (TBR) did not differ significantly between the dalcetrapib and placebo groups at 6 months (2.56 vs. 2.54).

Analysis of the carotid vessel ¹⁸F-FDG-PET/CT data, however, showed a 7.3% reduction in most-diseased-segment TBR in the dalcetrapib group, compared with no change with placebo, Dr. Fayad and his associates reported. Increased HDL cholesterol concentrations appeared to be correlated with decreased TBR. In addition, reductions in TBR at 6 months were noted to be associated with a reduction in the rate of increase in total vessel area by MRI at 24 months.

Notably, systemic inflammation as measured by high-sensitivity C-reactive protein did not decrease in the dalcetrapib group. On the contrary, it rose 33%.

"These findings highlight that the blood and imaging biomarkers of inflammation might provide substantially different information about the vascular inflammatory milieu, the exact nature of which remains incompletely elucidated," wrote the authors of dal-PLAQUE, the first placebo-controlled trial to use noninvasive multimodality imaging as primary end points.

Finally, the editorialists called for additional studies to assess the effect of selective, potent anti-inflammatory drugs on vessel wall inflammation and cardiovascular outcome. As an example, they highlighted the current CANTOS (Canakinumab Anti-Inflammatory Thrombosis Outcome Study) evaluating canakinumab, an antibody that inhibits the endogenous proinflammatory protein interleukin-1 beta in patients with coronary artery disease.

Hoffmann-La Roche funded the study and preparation of the journal article. Dr. Fayad reports research grants from Roche, GlaxoSmithKline, Merck, VBL Therapeutics, Novartis, Bristol-Myers Squibb, and Via Pharmaceuticals, and honoraria from Roche. His coauthors report financial relationships with several firms, including, in some cases, employment with Hoffmann-La Roche. Dr. Stroes and Dr. Wijk report no conflicts.

PARIS – Eliciting truthful dialogue from patients with depression may be as elusive as a simple cure for the condition.

A large Internet-based survey involving 2,020 patients who had received treatment for depression within the past year found that a full 70.2% had lied, at least once, during treatment.

More than two-thirds, or 69%, fibbed about daily activities such as work, while 52.6% failed, on purpose, to accurately report their symptoms, Dr. Norifusa Sawada reported at the annual meeting of the European College of Neuropsychopharmacology.

"The fact that more than 70% of patients with depression do not disclose the truth emphasizes the need for clinical suspicion, as well as more objective assessment of their symptoms and medication adherence," he suggested.

Men were significantly more likely than women to be dishonest about daily activities and intake of alcohol and illicit drugs.

In contrast, women were more likely to be dishonest about adherence to prescribed medication and data such as body temperature and weight.

The most frequent (49%) reason why patients didn’t tell the truth was because they found it difficult to talk to their doctor, reported Dr. Sawada, a psychiatrist at Keio University in Toyko. In all, 30% of Japanese patients said they were embarrassed to tell the truth. A disconcerting 36.5%, however, failed to tell the truth because "I thought my doctor would not take it seriously, even if I told him or her."

Female patients were significantly more likely than males to cite this reason, but also said they were less than frank about the truth because they could not trust their doctor or their doctor looked busy.

In contrast, men were significantly more likely to report they didn’t tell the truth because of concerns that their physician would recommend they take sick leave or quit their job.

Logistic regression analysis found significant associations between not telling the truth and lower satisfaction in communication with their physicians (odds ratio, 1.98 for not satisfied and OR, 2.78 for dissatisfied; P value less than .001 for both).

Other significant predictors were female sex (OR, 1.54, P less than .001) and younger age (20-29 years vs. 50-59 years OR, 0.65, P = .004; 20-29 years vs. 60-69 years, OR, 0.29, P = .027). Physician age and gender, and patient income had no effect.

All patients, aged 20-69 years, had received treatment within the past year for a diagnosis of major depressive disorder by a psychiatrist. None had bipolar, and all were registered with Macromill, one of the largest online research companies in Japan.

In all, 32% of patients reported quitting treatment for depression without consulting their physician, and 45% discontinued antidepressants without consultation, Dr. Sawada noted.

The researchers previously reported that only 44% of 367 outpatients with major depressive disorder continued their antidepressants for 6 months (BMC Psychiatry 2009;9:38).

In the current analysis, the most common reason patients gave for discontinuing treatment was that their symptoms got better, followed by, "I did not get along with my doctor," and that they could not or did not want to go out.

"When communication between patients and their physician is suboptimal, patient status and behavior should be monitored with more objective vigilance in an effort to avoid undesirable premature withdrawal from antidepressants." This also underscores the importance of a good patient-physician alliance to gather relevant information toward a successful treatment, Dr. Sawada said.

Pfizer sponsored the study. The authors report no conflicts.

PARIS – Eliciting truthful dialogue from patients with depression may be as elusive as a simple cure for the condition.

A large Internet-based survey involving 2,020 patients who had received treatment for depression within the past year found that a full 70.2% had lied, at least once, during treatment.

More than two-thirds, or 69%, fibbed about daily activities such as work, while 52.6% failed, on purpose, to accurately report their symptoms, Dr. Norifusa Sawada reported at the annual meeting of the European College of Neuropsychopharmacology.

"The fact that more than 70% of patients with depression do not disclose the truth emphasizes the need for clinical suspicion, as well as more objective assessment of their symptoms and medication adherence," he suggested.

Men were significantly more likely than women to be dishonest about daily activities and intake of alcohol and illicit drugs.

In contrast, women were more likely to be dishonest about adherence to prescribed medication and data such as body temperature and weight.

The most frequent (49%) reason why patients didn’t tell the truth was because they found it difficult to talk to their doctor, reported Dr. Sawada, a psychiatrist at Keio University in Toyko. In all, 30% of Japanese patients said they were embarrassed to tell the truth. A disconcerting 36.5%, however, failed to tell the truth because "I thought my doctor would not take it seriously, even if I told him or her."

Female patients were significantly more likely than males to cite this reason, but also said they were less than frank about the truth because they could not trust their doctor or their doctor looked busy.

In contrast, men were significantly more likely to report they didn’t tell the truth because of concerns that their physician would recommend they take sick leave or quit their job.

Logistic regression analysis found significant associations between not telling the truth and lower satisfaction in communication with their physicians (odds ratio, 1.98 for not satisfied and OR, 2.78 for dissatisfied; P value less than .001 for both).

Other significant predictors were female sex (OR, 1.54, P less than .001) and younger age (20-29 years vs. 50-59 years OR, 0.65, P = .004; 20-29 years vs. 60-69 years, OR, 0.29, P = .027). Physician age and gender, and patient income had no effect.

All patients, aged 20-69 years, had received treatment within the past year for a diagnosis of major depressive disorder by a psychiatrist. None had bipolar, and all were registered with Macromill, one of the largest online research companies in Japan.

In all, 32% of patients reported quitting treatment for depression without consulting their physician, and 45% discontinued antidepressants without consultation, Dr. Sawada noted.

The researchers previously reported that only 44% of 367 outpatients with major depressive disorder continued their antidepressants for 6 months (BMC Psychiatry 2009;9:38).

In the current analysis, the most common reason patients gave for discontinuing treatment was that their symptoms got better, followed by, "I did not get along with my doctor," and that they could not or did not want to go out.

"When communication between patients and their physician is suboptimal, patient status and behavior should be monitored with more objective vigilance in an effort to avoid undesirable premature withdrawal from antidepressants." This also underscores the importance of a good patient-physician alliance to gather relevant information toward a successful treatment, Dr. Sawada said.

Pfizer sponsored the study. The authors report no conflicts.

PARIS – Eliciting truthful dialogue from patients with depression may be as elusive as a simple cure for the condition.

A large Internet-based survey involving 2,020 patients who had received treatment for depression within the past year found that a full 70.2% had lied, at least once, during treatment.

More than two-thirds, or 69%, fibbed about daily activities such as work, while 52.6% failed, on purpose, to accurately report their symptoms, Dr. Norifusa Sawada reported at the annual meeting of the European College of Neuropsychopharmacology.

"The fact that more than 70% of patients with depression do not disclose the truth emphasizes the need for clinical suspicion, as well as more objective assessment of their symptoms and medication adherence," he suggested.

Men were significantly more likely than women to be dishonest about daily activities and intake of alcohol and illicit drugs.

In contrast, women were more likely to be dishonest about adherence to prescribed medication and data such as body temperature and weight.

The most frequent (49%) reason why patients didn’t tell the truth was because they found it difficult to talk to their doctor, reported Dr. Sawada, a psychiatrist at Keio University in Toyko. In all, 30% of Japanese patients said they were embarrassed to tell the truth. A disconcerting 36.5%, however, failed to tell the truth because "I thought my doctor would not take it seriously, even if I told him or her."

Female patients were significantly more likely than males to cite this reason, but also said they were less than frank about the truth because they could not trust their doctor or their doctor looked busy.

In contrast, men were significantly more likely to report they didn’t tell the truth because of concerns that their physician would recommend they take sick leave or quit their job.

Logistic regression analysis found significant associations between not telling the truth and lower satisfaction in communication with their physicians (odds ratio, 1.98 for not satisfied and OR, 2.78 for dissatisfied; P value less than .001 for both).

Other significant predictors were female sex (OR, 1.54, P less than .001) and younger age (20-29 years vs. 50-59 years OR, 0.65, P = .004; 20-29 years vs. 60-69 years, OR, 0.29, P = .027). Physician age and gender, and patient income had no effect.

All patients, aged 20-69 years, had received treatment within the past year for a diagnosis of major depressive disorder by a psychiatrist. None had bipolar, and all were registered with Macromill, one of the largest online research companies in Japan.

In all, 32% of patients reported quitting treatment for depression without consulting their physician, and 45% discontinued antidepressants without consultation, Dr. Sawada noted.

The researchers previously reported that only 44% of 367 outpatients with major depressive disorder continued their antidepressants for 6 months (BMC Psychiatry 2009;9:38).

In the current analysis, the most common reason patients gave for discontinuing treatment was that their symptoms got better, followed by, "I did not get along with my doctor," and that they could not or did not want to go out.

"When communication between patients and their physician is suboptimal, patient status and behavior should be monitored with more objective vigilance in an effort to avoid undesirable premature withdrawal from antidepressants." This also underscores the importance of a good patient-physician alliance to gather relevant information toward a successful treatment, Dr. Sawada said.

Pfizer sponsored the study. The authors report no conflicts.