AHA Scientific Sessions 2012

LOS ANGELES – Patients with advanced chronic kidney disease who receive an implantable cardioverter defibrillator are not like other patients who receive these devices.

But results from a trio of studies reported at the meeting show how hard it is for researchers to get a clear handle on what makes chronic kidney disease patients different, whether they have different outcomes than defibrillator recipients without CKD, and what is the best approach for judiciously using implantable cardioverter defibrillators (ICDs) in patients with renal dysfunction.

Mitchel L. Zoler/IMNG Medical Media

It’s a particularly relevant question because CKD is linked with a substantially increased risk for sudden cardiac death (patients on dialysis have about a fivefold higher risk for sudden cardiac death, compared with patients with normal or mildly impaired renal function), but patients with CKD were excluded from the major trials that proved the efficacy of ICDs for preventing sudden cardiac death. The lack of data from randomized, prospective trials leaves questions about the efficacy, and perhaps as importantly, the cost efficiency of ICDs in CKD patients.

"Should patients with CKD get ICDs? I don’t know the answer, but I don’t think that, categorically, patients with CKD should be excluded from ICD treatment," commented Dr. Matthew Reynolds, a cardiac electrophysiologist and director of the Economics and Quality of Life Research Center at Harvard Medical School in Boston. But many patients with CKD, especially advanced disease, are not good ICD candidates.

"For a lot of patients with CKD, someone decides not to place an ICD. Those patients are not represented" in studies that focus on ICD recipients, said Dr. Reynolds, who cochaired the session where the three studies were presented.

"For every CKD patients who gets an ICD, an electrophysiologist has made a decision that this was a CKD patient who could benefit. It’s hard to extrapolate from that" to all CKD patients, agreed Dr. Paul Varosy, director of electrophysiology at the Denver Veterans Administration Medical Center. "Patients with CKD who get ICDs are fundamentally different patients."

The aim of one of the studies reported was to assess ICD efficacy in CKD patients by comparing survival between patients with ICDs divided into stage III CKD (an estimated glomerular filtration rate [GFR] of 30-59 mL/min per 1.73 m²), stage IV or V (a GFR of less than mL/min per 1.73 m²), or no CKD. The study examined 3-year follow-up data from 556 patients who received an ICD or similar device during 2006-2010 at the Minneapolis Veterans Administration Medical Center at the University of Minnesota. The series included 301 patients with no CKD, 230 with stage III CKD, and 25 patients with more severe CKD.

The analysis showed a similar incidence of appropriate and inappropriate shocks from the ICDs in all three groups, and roughly similar efficacy of the ICDs for preventing sudden cardiac death, Dr. Selcuk Adabag said at the Annual Scientific Sessions of the American Heart Association. But mortality rates rose substantially higher as renal function worsened, rising from 17% in patients without CKD to 30% in those with stage III disease, and to 56% in those with stage IV or V disease, reported Dr. Adabag, a cardiac electrophysiologist at the University of Minnesota in Minneapolis.

The mortality differences were hardly surprising, and they likely have little direct relationship to the ICDs. "In patients with CKD, the worse the disease, the worse their prognosis. CKD is a complex disease with a whole range of [mortality] risk factors; preventable sudden cardiac death is just one" of the risks these patients face, Dr. Varosy said in an interview.

Selection bias makes the ICD observations questionable, Dr. Reynolds said. "I’m very concerned about concluding that ICDs have similar effectiveness in patients with stage IV or V CKD, compared with no CKD. The study had only 25 patients with stage IV or V disease. I have to think that there was some belief that these were good candidates and that there were a lot of other patients with severe CKD where a physician decided not to implant an ICD. Those patients are not represented in the data," Dr. Reynolds said.

Another study ran a pair of meta-analyses to explore the interactions of ICDs and CKD. In both analyses, CKD was defined as patients on dialysis, those with a creatinine clearance of less than 60 mL/kg per 1.73 m², or patients with a serum creatinine of at least 1.5 mg/dL.

The first analysis looked at the impact of ICDs on all-cause death among CKD patients at high risk for sudden cardiac death. The literature search found five reports that addressed this issue, in a total of 17,460 patients, which showed that ICD placement linked with a statistically significant 35% cut in total mortality, compared with similar, propensity-score matched patients who did not get ICDs, Dr. Nader Makki said at the meeting.

The second analysis involved 15 reports with 5,333 patients, and used multivariate adjustment to find that patients who had received an ICD and also had CKD had a statistically significant, 2.9-fold higher mortality rate than did ICD recipients without CKD, highlighting the high risk for nonarrhythmic death that CKD patients face, said Dr. Makki, a researcher at the University of Iowa in Iowa City. "Despite a paucity of randomized trials in the CKD population, these data support use of ICDs for the prevention of sudden cardiac death in patients at risk," he said. "We believe that ICDs are underused in this population," patients with CKD.

But these analyses are compromised by the data they used, said Dr. Reynolds. The data were "heavily weighted with a couple of large studies that used claims data. My concern is the potential for confounding by indication. Patients who get ICDs are somehow not as sick as those who don’t."

The third study looked at the impact of CKD on the aftermath of ICD replacement among the 1,744 patients enrolled in the REPLACE (Implantable Cardiac Pulse Generator Replacement Registry) trial, which tracked the incidence of complications following replacement of ICD generators and leads. Among the enrolled patients, researchers had renal-function data for 1,662 patients. About 80% had either mild or moderate renal dysfunction, while 6% had an estimated GFR less than 30 mL/min per 1.73 m², and the remained had normal renal function.

The incidence of complications was 15% overall, and the analysis showed roughly this rate across all strata of CKD severity. Even among patients with severe CKD, the complication rate was about 20%, and not significantly different from patients with even normal renal function, Dr. Suneet Mittal reported at the meeting. The split between major and minor complications also varied little by renal function, and the incidence of infections was 1%-2% across all five levels of renal function examined.

But CKD severity played a big role in 6-month mortality. A multivariate analysis showed that CKD stage played a significant role in survival; for each stage of worsened renal function the risk of death rose by 50%. (Other significant predictors were recent heart-failure hospitalization, severe heart failure, treatment with an antiarrhythmic drug, and history of cerebrovascular disease.) In actual numbers, the 6-month mortality rate was 2% among patients with either none or mild renal dysfunction that jumped to a 9% rate in patients with an estimated GFR of 15-29 mL/min per 1.73 m², and to 16% in those on dialysis, said Dr. Mittal, a cardiac electrophysiologist at Columbia University in New York. The analyses also showed that the increased mortality risk linked to severe CKD became apparent by a month after ICD replacement, and it was not driven by procedure-related complications.

"Why do these patients [with severe CKD] do so much worse? We thought that if we looked at all their complications we’d pick up the reason, but clearly there are things that we have not yet recognized," Dr. Mittal said. "There are a lot of things that we didn’t capture in the study."

Although the analysis shed little light on what was behind the high mortality risk in severe CKD patients, it effectively highlighted how risky ICD replacements are in any patient.

"The incidence of complications, 15%-23%, was striking. It’s substantially greater than what’s been seen in any registry-based data or administrative-based data," said Dr. Varosy. He cited the unique ability of this registry to capture all the minor complications following ICD replacement.

"These are frightening numbers [because] we tell patients that there is a very small risk" from ICD replacement procedures, commented Dr. Kalyanam Shivkumar, professor and director of the University of California Los Angeles Cardiac Arrhythmia Center.

Dr. Reynolds said that he has been a consultant to Medtronic and Biosense Webster and has received research grants from Edwards Lifesciences. Dr. Varosy had no disclosures. Dr. Adabag said that he had received research grants from Medtronic and Boston Scientific. Dr. Makki had no disclosures. The REPLACE registry was sponsored by Biotronik and Dr. Mittal said that has been a consultant to Biotronik. Dr. Shivkumar had no disclosures.

LOS ANGELES – Patients with advanced chronic kidney disease who receive an implantable cardioverter defibrillator are not like other patients who receive these devices.

But results from a trio of studies reported at the meeting show how hard it is for researchers to get a clear handle on what makes chronic kidney disease patients different, whether they have different outcomes than defibrillator recipients without CKD, and what is the best approach for judiciously using implantable cardioverter defibrillators (ICDs) in patients with renal dysfunction.

Mitchel L. Zoler/IMNG Medical Media

It’s a particularly relevant question because CKD is linked with a substantially increased risk for sudden cardiac death (patients on dialysis have about a fivefold higher risk for sudden cardiac death, compared with patients with normal or mildly impaired renal function), but patients with CKD were excluded from the major trials that proved the efficacy of ICDs for preventing sudden cardiac death. The lack of data from randomized, prospective trials leaves questions about the efficacy, and perhaps as importantly, the cost efficiency of ICDs in CKD patients.

"Should patients with CKD get ICDs? I don’t know the answer, but I don’t think that, categorically, patients with CKD should be excluded from ICD treatment," commented Dr. Matthew Reynolds, a cardiac electrophysiologist and director of the Economics and Quality of Life Research Center at Harvard Medical School in Boston. But many patients with CKD, especially advanced disease, are not good ICD candidates.

"For a lot of patients with CKD, someone decides not to place an ICD. Those patients are not represented" in studies that focus on ICD recipients, said Dr. Reynolds, who cochaired the session where the three studies were presented.

"For every CKD patients who gets an ICD, an electrophysiologist has made a decision that this was a CKD patient who could benefit. It’s hard to extrapolate from that" to all CKD patients, agreed Dr. Paul Varosy, director of electrophysiology at the Denver Veterans Administration Medical Center. "Patients with CKD who get ICDs are fundamentally different patients."

The aim of one of the studies reported was to assess ICD efficacy in CKD patients by comparing survival between patients with ICDs divided into stage III CKD (an estimated glomerular filtration rate [GFR] of 30-59 mL/min per 1.73 m²), stage IV or V (a GFR of less than mL/min per 1.73 m²), or no CKD. The study examined 3-year follow-up data from 556 patients who received an ICD or similar device during 2006-2010 at the Minneapolis Veterans Administration Medical Center at the University of Minnesota. The series included 301 patients with no CKD, 230 with stage III CKD, and 25 patients with more severe CKD.

The analysis showed a similar incidence of appropriate and inappropriate shocks from the ICDs in all three groups, and roughly similar efficacy of the ICDs for preventing sudden cardiac death, Dr. Selcuk Adabag said at the Annual Scientific Sessions of the American Heart Association. But mortality rates rose substantially higher as renal function worsened, rising from 17% in patients without CKD to 30% in those with stage III disease, and to 56% in those with stage IV or V disease, reported Dr. Adabag, a cardiac electrophysiologist at the University of Minnesota in Minneapolis.

The mortality differences were hardly surprising, and they likely have little direct relationship to the ICDs. "In patients with CKD, the worse the disease, the worse their prognosis. CKD is a complex disease with a whole range of [mortality] risk factors; preventable sudden cardiac death is just one" of the risks these patients face, Dr. Varosy said in an interview.

Selection bias makes the ICD observations questionable, Dr. Reynolds said. "I’m very concerned about concluding that ICDs have similar effectiveness in patients with stage IV or V CKD, compared with no CKD. The study had only 25 patients with stage IV or V disease. I have to think that there was some belief that these were good candidates and that there were a lot of other patients with severe CKD where a physician decided not to implant an ICD. Those patients are not represented in the data," Dr. Reynolds said.

Another study ran a pair of meta-analyses to explore the interactions of ICDs and CKD. In both analyses, CKD was defined as patients on dialysis, those with a creatinine clearance of less than 60 mL/kg per 1.73 m², or patients with a serum creatinine of at least 1.5 mg/dL.

The first analysis looked at the impact of ICDs on all-cause death among CKD patients at high risk for sudden cardiac death. The literature search found five reports that addressed this issue, in a total of 17,460 patients, which showed that ICD placement linked with a statistically significant 35% cut in total mortality, compared with similar, propensity-score matched patients who did not get ICDs, Dr. Nader Makki said at the meeting.

The second analysis involved 15 reports with 5,333 patients, and used multivariate adjustment to find that patients who had received an ICD and also had CKD had a statistically significant, 2.9-fold higher mortality rate than did ICD recipients without CKD, highlighting the high risk for nonarrhythmic death that CKD patients face, said Dr. Makki, a researcher at the University of Iowa in Iowa City. "Despite a paucity of randomized trials in the CKD population, these data support use of ICDs for the prevention of sudden cardiac death in patients at risk," he said. "We believe that ICDs are underused in this population," patients with CKD.

But these analyses are compromised by the data they used, said Dr. Reynolds. The data were "heavily weighted with a couple of large studies that used claims data. My concern is the potential for confounding by indication. Patients who get ICDs are somehow not as sick as those who don’t."

The third study looked at the impact of CKD on the aftermath of ICD replacement among the 1,744 patients enrolled in the REPLACE (Implantable Cardiac Pulse Generator Replacement Registry) trial, which tracked the incidence of complications following replacement of ICD generators and leads. Among the enrolled patients, researchers had renal-function data for 1,662 patients. About 80% had either mild or moderate renal dysfunction, while 6% had an estimated GFR less than 30 mL/min per 1.73 m², and the remained had normal renal function.

The incidence of complications was 15% overall, and the analysis showed roughly this rate across all strata of CKD severity. Even among patients with severe CKD, the complication rate was about 20%, and not significantly different from patients with even normal renal function, Dr. Suneet Mittal reported at the meeting. The split between major and minor complications also varied little by renal function, and the incidence of infections was 1%-2% across all five levels of renal function examined.

But CKD severity played a big role in 6-month mortality. A multivariate analysis showed that CKD stage played a significant role in survival; for each stage of worsened renal function the risk of death rose by 50%. (Other significant predictors were recent heart-failure hospitalization, severe heart failure, treatment with an antiarrhythmic drug, and history of cerebrovascular disease.) In actual numbers, the 6-month mortality rate was 2% among patients with either none or mild renal dysfunction that jumped to a 9% rate in patients with an estimated GFR of 15-29 mL/min per 1.73 m², and to 16% in those on dialysis, said Dr. Mittal, a cardiac electrophysiologist at Columbia University in New York. The analyses also showed that the increased mortality risk linked to severe CKD became apparent by a month after ICD replacement, and it was not driven by procedure-related complications.

"Why do these patients [with severe CKD] do so much worse? We thought that if we looked at all their complications we’d pick up the reason, but clearly there are things that we have not yet recognized," Dr. Mittal said. "There are a lot of things that we didn’t capture in the study."

Although the analysis shed little light on what was behind the high mortality risk in severe CKD patients, it effectively highlighted how risky ICD replacements are in any patient.

"The incidence of complications, 15%-23%, was striking. It’s substantially greater than what’s been seen in any registry-based data or administrative-based data," said Dr. Varosy. He cited the unique ability of this registry to capture all the minor complications following ICD replacement.

"These are frightening numbers [because] we tell patients that there is a very small risk" from ICD replacement procedures, commented Dr. Kalyanam Shivkumar, professor and director of the University of California Los Angeles Cardiac Arrhythmia Center.

Dr. Reynolds said that he has been a consultant to Medtronic and Biosense Webster and has received research grants from Edwards Lifesciences. Dr. Varosy had no disclosures. Dr. Adabag said that he had received research grants from Medtronic and Boston Scientific. Dr. Makki had no disclosures. The REPLACE registry was sponsored by Biotronik and Dr. Mittal said that has been a consultant to Biotronik. Dr. Shivkumar had no disclosures.

LOS ANGELES – Patients with advanced chronic kidney disease who receive an implantable cardioverter defibrillator are not like other patients who receive these devices.

But results from a trio of studies reported at the meeting show how hard it is for researchers to get a clear handle on what makes chronic kidney disease patients different, whether they have different outcomes than defibrillator recipients without CKD, and what is the best approach for judiciously using implantable cardioverter defibrillators (ICDs) in patients with renal dysfunction.

Mitchel L. Zoler/IMNG Medical Media

It’s a particularly relevant question because CKD is linked with a substantially increased risk for sudden cardiac death (patients on dialysis have about a fivefold higher risk for sudden cardiac death, compared with patients with normal or mildly impaired renal function), but patients with CKD were excluded from the major trials that proved the efficacy of ICDs for preventing sudden cardiac death. The lack of data from randomized, prospective trials leaves questions about the efficacy, and perhaps as importantly, the cost efficiency of ICDs in CKD patients.

"Should patients with CKD get ICDs? I don’t know the answer, but I don’t think that, categorically, patients with CKD should be excluded from ICD treatment," commented Dr. Matthew Reynolds, a cardiac electrophysiologist and director of the Economics and Quality of Life Research Center at Harvard Medical School in Boston. But many patients with CKD, especially advanced disease, are not good ICD candidates.

"For a lot of patients with CKD, someone decides not to place an ICD. Those patients are not represented" in studies that focus on ICD recipients, said Dr. Reynolds, who cochaired the session where the three studies were presented.

"For every CKD patients who gets an ICD, an electrophysiologist has made a decision that this was a CKD patient who could benefit. It’s hard to extrapolate from that" to all CKD patients, agreed Dr. Paul Varosy, director of electrophysiology at the Denver Veterans Administration Medical Center. "Patients with CKD who get ICDs are fundamentally different patients."

The aim of one of the studies reported was to assess ICD efficacy in CKD patients by comparing survival between patients with ICDs divided into stage III CKD (an estimated glomerular filtration rate [GFR] of 30-59 mL/min per 1.73 m²), stage IV or V (a GFR of less than mL/min per 1.73 m²), or no CKD. The study examined 3-year follow-up data from 556 patients who received an ICD or similar device during 2006-2010 at the Minneapolis Veterans Administration Medical Center at the University of Minnesota. The series included 301 patients with no CKD, 230 with stage III CKD, and 25 patients with more severe CKD.

The analysis showed a similar incidence of appropriate and inappropriate shocks from the ICDs in all three groups, and roughly similar efficacy of the ICDs for preventing sudden cardiac death, Dr. Selcuk Adabag said at the Annual Scientific Sessions of the American Heart Association. But mortality rates rose substantially higher as renal function worsened, rising from 17% in patients without CKD to 30% in those with stage III disease, and to 56% in those with stage IV or V disease, reported Dr. Adabag, a cardiac electrophysiologist at the University of Minnesota in Minneapolis.

The mortality differences were hardly surprising, and they likely have little direct relationship to the ICDs. "In patients with CKD, the worse the disease, the worse their prognosis. CKD is a complex disease with a whole range of [mortality] risk factors; preventable sudden cardiac death is just one" of the risks these patients face, Dr. Varosy said in an interview.

Selection bias makes the ICD observations questionable, Dr. Reynolds said. "I’m very concerned about concluding that ICDs have similar effectiveness in patients with stage IV or V CKD, compared with no CKD. The study had only 25 patients with stage IV or V disease. I have to think that there was some belief that these were good candidates and that there were a lot of other patients with severe CKD where a physician decided not to implant an ICD. Those patients are not represented in the data," Dr. Reynolds said.

Another study ran a pair of meta-analyses to explore the interactions of ICDs and CKD. In both analyses, CKD was defined as patients on dialysis, those with a creatinine clearance of less than 60 mL/kg per 1.73 m², or patients with a serum creatinine of at least 1.5 mg/dL.

The first analysis looked at the impact of ICDs on all-cause death among CKD patients at high risk for sudden cardiac death. The literature search found five reports that addressed this issue, in a total of 17,460 patients, which showed that ICD placement linked with a statistically significant 35% cut in total mortality, compared with similar, propensity-score matched patients who did not get ICDs, Dr. Nader Makki said at the meeting.

The second analysis involved 15 reports with 5,333 patients, and used multivariate adjustment to find that patients who had received an ICD and also had CKD had a statistically significant, 2.9-fold higher mortality rate than did ICD recipients without CKD, highlighting the high risk for nonarrhythmic death that CKD patients face, said Dr. Makki, a researcher at the University of Iowa in Iowa City. "Despite a paucity of randomized trials in the CKD population, these data support use of ICDs for the prevention of sudden cardiac death in patients at risk," he said. "We believe that ICDs are underused in this population," patients with CKD.

But these analyses are compromised by the data they used, said Dr. Reynolds. The data were "heavily weighted with a couple of large studies that used claims data. My concern is the potential for confounding by indication. Patients who get ICDs are somehow not as sick as those who don’t."

The third study looked at the impact of CKD on the aftermath of ICD replacement among the 1,744 patients enrolled in the REPLACE (Implantable Cardiac Pulse Generator Replacement Registry) trial, which tracked the incidence of complications following replacement of ICD generators and leads. Among the enrolled patients, researchers had renal-function data for 1,662 patients. About 80% had either mild or moderate renal dysfunction, while 6% had an estimated GFR less than 30 mL/min per 1.73 m², and the remained had normal renal function.

The incidence of complications was 15% overall, and the analysis showed roughly this rate across all strata of CKD severity. Even among patients with severe CKD, the complication rate was about 20%, and not significantly different from patients with even normal renal function, Dr. Suneet Mittal reported at the meeting. The split between major and minor complications also varied little by renal function, and the incidence of infections was 1%-2% across all five levels of renal function examined.

But CKD severity played a big role in 6-month mortality. A multivariate analysis showed that CKD stage played a significant role in survival; for each stage of worsened renal function the risk of death rose by 50%. (Other significant predictors were recent heart-failure hospitalization, severe heart failure, treatment with an antiarrhythmic drug, and history of cerebrovascular disease.) In actual numbers, the 6-month mortality rate was 2% among patients with either none or mild renal dysfunction that jumped to a 9% rate in patients with an estimated GFR of 15-29 mL/min per 1.73 m², and to 16% in those on dialysis, said Dr. Mittal, a cardiac electrophysiologist at Columbia University in New York. The analyses also showed that the increased mortality risk linked to severe CKD became apparent by a month after ICD replacement, and it was not driven by procedure-related complications.

"Why do these patients [with severe CKD] do so much worse? We thought that if we looked at all their complications we’d pick up the reason, but clearly there are things that we have not yet recognized," Dr. Mittal said. "There are a lot of things that we didn’t capture in the study."

Although the analysis shed little light on what was behind the high mortality risk in severe CKD patients, it effectively highlighted how risky ICD replacements are in any patient.

"The incidence of complications, 15%-23%, was striking. It’s substantially greater than what’s been seen in any registry-based data or administrative-based data," said Dr. Varosy. He cited the unique ability of this registry to capture all the minor complications following ICD replacement.

"These are frightening numbers [because] we tell patients that there is a very small risk" from ICD replacement procedures, commented Dr. Kalyanam Shivkumar, professor and director of the University of California Los Angeles Cardiac Arrhythmia Center.

Dr. Reynolds said that he has been a consultant to Medtronic and Biosense Webster and has received research grants from Edwards Lifesciences. Dr. Varosy had no disclosures. Dr. Adabag said that he had received research grants from Medtronic and Boston Scientific. Dr. Makki had no disclosures. The REPLACE registry was sponsored by Biotronik and Dr. Mittal said that has been a consultant to Biotronik. Dr. Shivkumar had no disclosures.

LOS ANGELES – Young adults with high blood pressure who regularly saw a primary care physician were substantially less likely to receive a hypertension diagnosis than were older affected patients – and some of the reasons for the greater delay in initial diagnosis are eye opening, said Dr. Heather M. Johnson.

The 18- to 31-year-olds met standard diagnostic criteria for hypertension. Their regularly elevated blood pressure measurements were dutifully entered into their medical records. Yet in a study conducted in a large multispecialty academic group practice, the majority of hypertensive young adults remained undiagnosed after 4 years of regular utilization of primary care, she reported at the annual scientific sessions of the American Heart Association.

That’s consistent with findings from other studies showing that young adults with hypertension have lower rates of diagnosis and hypertension control than middle-aged and elderly patients with high blood pressure, Dr. Johnson noted. Her study went farther, however, exploring possible explanations for the disparity.

The study involved analysis of the electronic medical records of 13,593 patients aged 18 years or older, all of whom regularly utilized primary care services during 2008-2011 and fulfilled national guideline–based criteria for the diagnosis of hypertension.

After 4 years of regular primary care, 67.4% of 18- to 24-year-olds with clear evidence of hypertension in their charts remained undiagnosed. So did 65% of affected 25- to 31-year-olds. These rates were significantly higher than in the older hypertensive patients seen in primary care.

Indeed, after 4 years, 18- to 24-year-olds with high blood pressure were 28% less likely to have received an initial hypertension diagnosis than were affected adults aged 60 years or older. Affected 25- to 31-year-olds were 26% less likely to have been diagnosed than patients aged 60 and up. These results were adjusted statistically for age, sex, race, body weight, primary spoken language, comorbid conditions, provider specialty, and other variables, explained Dr. Johnson, a cardiologist at the University of Wisconsin, Madison.

Rates of undiagnosed hypertension declined steadily with advancing age. Nonetheless, 54% of hypertensive patients aged 60 or older remained undiagnosed after 4 years, despite the objective evidence in their charts.

Intriguingly, the average time to diagnosis for patients whose hypertension was diagnosed within 4 years didn’t vary significantly by age: It was 5-6 months, regardless, she added.

Dr. Johnson pointed to provider, patient, and health care system factors as all being critical determinants of the poor rates of hypertension diagnosis among young adults.

One key independent predictor of delay to initial hypertension diagnosis in young adults identified in her multivariate analysis was patient race. Black young adults with hypertension were 39% more likely to have received the diagnosis than white patients.

"African Americans are known to have a higher prevalence of hypertension and its comorbidities, especially at younger age groups. Our data suggest providers are aware of this," Dr. Johnson said.

Young adults who were current users of tobacco or were regularly exposed to secondhand smoke were 29% less likely than never users to have their hypertension diagnosed.

Those with baseline blood pressures of 140-159/90-99 mm Hg were 35% less likely to receive a hypertension diagnosis within 4 years than those with baseline readings of 160-179/100-109 mm Hg.

On the provider side, physician gender emerged as a major independent predictor of delayed diagnosis in young adults. Female primary care providers were 23% more likely to promptly diagnose hypertension in affected young adults than were their male colleagues.

Family physicians were 16% less likely than general internists, ob.gyns., or other primary care providers to make the diagnosis in affected young adults. This was a finding of borderline statistical significance (P = 0.047), and Dr. Johnson said she doesn’t draw any strong conclusions from it.

She and her coworkers are conducting interviews with primary care providers in the group practice to learn how to improve hypertension diagnosis rates in young adults within the time constraints of a busy practice. The findings from this study will be used to develop tailored primary care interventions. This will entail provider education programs as well as upgraded electronic medical record notification systems.

Her work is funded by the National Heart, Lung, and Blood Institute. She reported having no relevant financial disclosures.

LOS ANGELES – Young adults with high blood pressure who regularly saw a primary care physician were substantially less likely to receive a hypertension diagnosis than were older affected patients – and some of the reasons for the greater delay in initial diagnosis are eye opening, said Dr. Heather M. Johnson.

The 18- to 31-year-olds met standard diagnostic criteria for hypertension. Their regularly elevated blood pressure measurements were dutifully entered into their medical records. Yet in a study conducted in a large multispecialty academic group practice, the majority of hypertensive young adults remained undiagnosed after 4 years of regular utilization of primary care, she reported at the annual scientific sessions of the American Heart Association.

That’s consistent with findings from other studies showing that young adults with hypertension have lower rates of diagnosis and hypertension control than middle-aged and elderly patients with high blood pressure, Dr. Johnson noted. Her study went farther, however, exploring possible explanations for the disparity.

The study involved analysis of the electronic medical records of 13,593 patients aged 18 years or older, all of whom regularly utilized primary care services during 2008-2011 and fulfilled national guideline–based criteria for the diagnosis of hypertension.

After 4 years of regular primary care, 67.4% of 18- to 24-year-olds with clear evidence of hypertension in their charts remained undiagnosed. So did 65% of affected 25- to 31-year-olds. These rates were significantly higher than in the older hypertensive patients seen in primary care.

Indeed, after 4 years, 18- to 24-year-olds with high blood pressure were 28% less likely to have received an initial hypertension diagnosis than were affected adults aged 60 years or older. Affected 25- to 31-year-olds were 26% less likely to have been diagnosed than patients aged 60 and up. These results were adjusted statistically for age, sex, race, body weight, primary spoken language, comorbid conditions, provider specialty, and other variables, explained Dr. Johnson, a cardiologist at the University of Wisconsin, Madison.

Rates of undiagnosed hypertension declined steadily with advancing age. Nonetheless, 54% of hypertensive patients aged 60 or older remained undiagnosed after 4 years, despite the objective evidence in their charts.

Intriguingly, the average time to diagnosis for patients whose hypertension was diagnosed within 4 years didn’t vary significantly by age: It was 5-6 months, regardless, she added.

Dr. Johnson pointed to provider, patient, and health care system factors as all being critical determinants of the poor rates of hypertension diagnosis among young adults.

One key independent predictor of delay to initial hypertension diagnosis in young adults identified in her multivariate analysis was patient race. Black young adults with hypertension were 39% more likely to have received the diagnosis than white patients.

"African Americans are known to have a higher prevalence of hypertension and its comorbidities, especially at younger age groups. Our data suggest providers are aware of this," Dr. Johnson said.

Young adults who were current users of tobacco or were regularly exposed to secondhand smoke were 29% less likely than never users to have their hypertension diagnosed.

Those with baseline blood pressures of 140-159/90-99 mm Hg were 35% less likely to receive a hypertension diagnosis within 4 years than those with baseline readings of 160-179/100-109 mm Hg.

On the provider side, physician gender emerged as a major independent predictor of delayed diagnosis in young adults. Female primary care providers were 23% more likely to promptly diagnose hypertension in affected young adults than were their male colleagues.

Family physicians were 16% less likely than general internists, ob.gyns., or other primary care providers to make the diagnosis in affected young adults. This was a finding of borderline statistical significance (P = 0.047), and Dr. Johnson said she doesn’t draw any strong conclusions from it.

She and her coworkers are conducting interviews with primary care providers in the group practice to learn how to improve hypertension diagnosis rates in young adults within the time constraints of a busy practice. The findings from this study will be used to develop tailored primary care interventions. This will entail provider education programs as well as upgraded electronic medical record notification systems.

Her work is funded by the National Heart, Lung, and Blood Institute. She reported having no relevant financial disclosures.

LOS ANGELES – Young adults with high blood pressure who regularly saw a primary care physician were substantially less likely to receive a hypertension diagnosis than were older affected patients – and some of the reasons for the greater delay in initial diagnosis are eye opening, said Dr. Heather M. Johnson.

The 18- to 31-year-olds met standard diagnostic criteria for hypertension. Their regularly elevated blood pressure measurements were dutifully entered into their medical records. Yet in a study conducted in a large multispecialty academic group practice, the majority of hypertensive young adults remained undiagnosed after 4 years of regular utilization of primary care, she reported at the annual scientific sessions of the American Heart Association.

That’s consistent with findings from other studies showing that young adults with hypertension have lower rates of diagnosis and hypertension control than middle-aged and elderly patients with high blood pressure, Dr. Johnson noted. Her study went farther, however, exploring possible explanations for the disparity.

The study involved analysis of the electronic medical records of 13,593 patients aged 18 years or older, all of whom regularly utilized primary care services during 2008-2011 and fulfilled national guideline–based criteria for the diagnosis of hypertension.

After 4 years of regular primary care, 67.4% of 18- to 24-year-olds with clear evidence of hypertension in their charts remained undiagnosed. So did 65% of affected 25- to 31-year-olds. These rates were significantly higher than in the older hypertensive patients seen in primary care.

Indeed, after 4 years, 18- to 24-year-olds with high blood pressure were 28% less likely to have received an initial hypertension diagnosis than were affected adults aged 60 years or older. Affected 25- to 31-year-olds were 26% less likely to have been diagnosed than patients aged 60 and up. These results were adjusted statistically for age, sex, race, body weight, primary spoken language, comorbid conditions, provider specialty, and other variables, explained Dr. Johnson, a cardiologist at the University of Wisconsin, Madison.

Rates of undiagnosed hypertension declined steadily with advancing age. Nonetheless, 54% of hypertensive patients aged 60 or older remained undiagnosed after 4 years, despite the objective evidence in their charts.

Intriguingly, the average time to diagnosis for patients whose hypertension was diagnosed within 4 years didn’t vary significantly by age: It was 5-6 months, regardless, she added.

Dr. Johnson pointed to provider, patient, and health care system factors as all being critical determinants of the poor rates of hypertension diagnosis among young adults.

One key independent predictor of delay to initial hypertension diagnosis in young adults identified in her multivariate analysis was patient race. Black young adults with hypertension were 39% more likely to have received the diagnosis than white patients.

"African Americans are known to have a higher prevalence of hypertension and its comorbidities, especially at younger age groups. Our data suggest providers are aware of this," Dr. Johnson said.

Young adults who were current users of tobacco or were regularly exposed to secondhand smoke were 29% less likely than never users to have their hypertension diagnosed.

Those with baseline blood pressures of 140-159/90-99 mm Hg were 35% less likely to receive a hypertension diagnosis within 4 years than those with baseline readings of 160-179/100-109 mm Hg.

On the provider side, physician gender emerged as a major independent predictor of delayed diagnosis in young adults. Female primary care providers were 23% more likely to promptly diagnose hypertension in affected young adults than were their male colleagues.

Family physicians were 16% less likely than general internists, ob.gyns., or other primary care providers to make the diagnosis in affected young adults. This was a finding of borderline statistical significance (P = 0.047), and Dr. Johnson said she doesn’t draw any strong conclusions from it.

She and her coworkers are conducting interviews with primary care providers in the group practice to learn how to improve hypertension diagnosis rates in young adults within the time constraints of a busy practice. The findings from this study will be used to develop tailored primary care interventions. This will entail provider education programs as well as upgraded electronic medical record notification systems.

Her work is funded by the National Heart, Lung, and Blood Institute. She reported having no relevant financial disclosures.

LOS ANGELES – Hospital-acquired bleeding in patients admitted for atrial fibrillation is a very costly event, as demonstrated in the first large national study to put a price tag on this occurrence.

This retrospective observational study was undertaken because even though the clinical and economic toll of stroke in patients with atrial fibrillation (AF) has been well characterized, only scanty information has previously been available on the impact of inpatient bleeding in patients with this most common of arrhythmias, Dr. Alpesh N. Amin explained at the annual scientific sessions of the American Heart Association.

He and his coinvestigators searched the Premier Research Database, which contains patient encounter data from more than 500 U.S. hospitals, in order to identify 143,415 adults hospitalized with a primary diagnosis of nonvalvular AF with no bleeding upon admission during 2008-2011.

A bleeding event requiring administration of blood products occurred in 2.1% of patients. Their unadjusted mean length of stay was 8.8 days, compared with 3.4 days in AF patients without bleeding. After adjustment for comorbid conditions, hospital characteristics, patient demographics, and administration of anticoagulants or antiplatelet agents at any time during the hospitalization, the mean length of stay was 6.7 days in AF patients with bleeding, compared with 3.3 days in those without, according to Dr. Amin, professor and chair of the department of medicine and executive director of the hospitalist program at the University of California, Irvine.

The adjusted mean total cost of the hospital stay in AF patients with hospital-acquired bleeding was $16,621, compared with $6,997 in those without bleeding.

In this study population comprising more than 143,000 patients with AF, bleeding during a hospital stay added roughly $30 million in costs and 10,397 extra days in the hospital, compared with no bleeding.

This study was sponsored by Bristol-Myers Squibb and Pfizer. Dr. Amin reported receiving a research grant from Pfizer.

LOS ANGELES – Hospital-acquired bleeding in patients admitted for atrial fibrillation is a very costly event, as demonstrated in the first large national study to put a price tag on this occurrence.

This retrospective observational study was undertaken because even though the clinical and economic toll of stroke in patients with atrial fibrillation (AF) has been well characterized, only scanty information has previously been available on the impact of inpatient bleeding in patients with this most common of arrhythmias, Dr. Alpesh N. Amin explained at the annual scientific sessions of the American Heart Association.

He and his coinvestigators searched the Premier Research Database, which contains patient encounter data from more than 500 U.S. hospitals, in order to identify 143,415 adults hospitalized with a primary diagnosis of nonvalvular AF with no bleeding upon admission during 2008-2011.

A bleeding event requiring administration of blood products occurred in 2.1% of patients. Their unadjusted mean length of stay was 8.8 days, compared with 3.4 days in AF patients without bleeding. After adjustment for comorbid conditions, hospital characteristics, patient demographics, and administration of anticoagulants or antiplatelet agents at any time during the hospitalization, the mean length of stay was 6.7 days in AF patients with bleeding, compared with 3.3 days in those without, according to Dr. Amin, professor and chair of the department of medicine and executive director of the hospitalist program at the University of California, Irvine.

The adjusted mean total cost of the hospital stay in AF patients with hospital-acquired bleeding was $16,621, compared with $6,997 in those without bleeding.

In this study population comprising more than 143,000 patients with AF, bleeding during a hospital stay added roughly $30 million in costs and 10,397 extra days in the hospital, compared with no bleeding.

This study was sponsored by Bristol-Myers Squibb and Pfizer. Dr. Amin reported receiving a research grant from Pfizer.

LOS ANGELES – Hospital-acquired bleeding in patients admitted for atrial fibrillation is a very costly event, as demonstrated in the first large national study to put a price tag on this occurrence.

This retrospective observational study was undertaken because even though the clinical and economic toll of stroke in patients with atrial fibrillation (AF) has been well characterized, only scanty information has previously been available on the impact of inpatient bleeding in patients with this most common of arrhythmias, Dr. Alpesh N. Amin explained at the annual scientific sessions of the American Heart Association.

He and his coinvestigators searched the Premier Research Database, which contains patient encounter data from more than 500 U.S. hospitals, in order to identify 143,415 adults hospitalized with a primary diagnosis of nonvalvular AF with no bleeding upon admission during 2008-2011.

A bleeding event requiring administration of blood products occurred in 2.1% of patients. Their unadjusted mean length of stay was 8.8 days, compared with 3.4 days in AF patients without bleeding. After adjustment for comorbid conditions, hospital characteristics, patient demographics, and administration of anticoagulants or antiplatelet agents at any time during the hospitalization, the mean length of stay was 6.7 days in AF patients with bleeding, compared with 3.3 days in those without, according to Dr. Amin, professor and chair of the department of medicine and executive director of the hospitalist program at the University of California, Irvine.

The adjusted mean total cost of the hospital stay in AF patients with hospital-acquired bleeding was $16,621, compared with $6,997 in those without bleeding.

In this study population comprising more than 143,000 patients with AF, bleeding during a hospital stay added roughly $30 million in costs and 10,397 extra days in the hospital, compared with no bleeding.

This study was sponsored by Bristol-Myers Squibb and Pfizer. Dr. Amin reported receiving a research grant from Pfizer.

LOS ANGELES – A once-daily, fixed-dose combination of four cardiovascular drugs – a polypill – boosted patient adherence by 33% while meaningfully reducing both systolic blood pressure and LDL cholesterol compared with usual care in the large international UMPIRE trial.

UMPIRE (Use of a Multidrug Pill in Reducing Cardiovascular Events) was designed to test the hypothesis that decreasing the cost and complexity of guideline-indicated medications for secondary cardiovascular prevention would improve treatment adherence and outcomes in patients with established atherosclerotic cardiovascular disease or in those at high risk for it.

And UMPIRE was a resounding success, according to Dr. Simon Thom, professor of cardiovascular medicine and pharmacology at Imperial College, London. He presented the results at the annual scientific sessions of the American Heart Association.

The study comprised 2,004 randomized patients in India, Dublin, London, and Utrecht (the Netherlands): 88% had known atherosclerotic cardiovascular disease at baseline; 29% had diabetes. Participants were randomized to the polypill – composed of 75 mg aspirin, 50 mg simvastatin, 10 mg lisinopril, and either 50 mg atenolol or 12.5 mg hydrochlorothiazide, depending upon physician preference – or to usual care, which included individual prescriptions for the same four medications. The polypill was free, while usual care was paid for in the customary local manner.

After a median 15 months of follow-up, treatment adherence was 86% in the polypill arm, compared with 65% with usual care, a relative 33% difference. Systolic blood pressure averaged 129.2 mm Hg in the polypill group, 2.6 mm Hg lower than with usual care. Mean LDL cholesterol was 84.3 mg/dL in the polypill group and 88.6 mg/dL with usual care. Diastolic blood pressure was 72.8 mm Hg with the polypill, compared with 75.2 mm Hg in the usual care group.

All of these differences were statistically significant and clinically meaningful when extrapolated to the rapidly growing global burden of cardiovascular disease. Moreover, quality of life as self-measured on a visual analog scale was significantly better in patients on the fixed-dose combination, Dr. Thom reported.

There were, however, no significant differences between the two study arms in HDL cholesterol, triglycerides, or cardiovascular event rates.

Of note, 61% of UMPIRE subjects were already on all four individual study medications at baseline. That’s an unusually high proportion in the low- and middle-income countries where the polypill will see greatest future use, and it means the UMPIRE results almost certainly underestimate the true benefits to be expected with use of the polypill in clinical practice, he continued.

Side effects were the same in both treatment arms.

Discussant Dr. Andrew M. Tonkin declared UMPIRE to be "an important trial – and the results should be taken on board not only by clinicians, but should really inform government policies and strategies."

Although there is enthusiasm in some quarters for broad use of the polypill for primary prevention – a sort of let’s-put-it-in-the-drinking-water strategy – UMPIRE was the first polypill randomized trial conducted in patients with established cardiovascular disease, and one of very few to date to run longer than about 3 months.

"I believe that UMPIRE firmly establishes the case for using the polypill in those people with manifest atherosclerotic cardiovascular disease," said Dr. Tonkin.

It’s noteworthy that patients with poor baseline adherence to the study medications were 3.4-fold more likely to benefit from use of the polypill. That’s an important finding because the polypill is expected to see its greatest future use in India, China, the Philippines, and other parts of the world where vast numbers of patients with cardiovascular disease now receive little or nothing in the way of pharmacologic secondary prevention, said Dr. Tonkin, professor of preventive medicine and head of the cardiovascular research unit at Monash Hospital in Melbourne.

Moving forward, he added, the responsibility for developing the polypill cannot rest solely with the pharmaceutical industry.

"This is a very low-margin venture using low-cost generic formulations. Major pharma doesn’t want to get interested in this," said Dr. Tonkin.

Both the World Health Organization and the European Commission are publicly on board for the polypill, he noted.

The WHO and Wellcome Trust stated in a 2002 report that demonstration of bioequivalence and improved adherence as reflected in improvements in LDL and systolic blood pressure, as seen in UMPIRE, should be sufficient for regulatory approval of the polypill.

"That, I think, will not carry water in these days, unfortunately. But a meta-analysis of clinical end point data from the various trials is planned. And there are ongoing and planned future phase III trials," Dr. Tonkin said.

While most of the clinical trials, past and present, have taken place in low-income countries, the polypill is also under study in populations in the United States, Canada, Australia, and other relatively well-off nations, he pointed out.

UMPIRE was funded by the European Commission. Dr. Thom and Dr. Tonkin reported having no financial conflicts.

LOS ANGELES – A once-daily, fixed-dose combination of four cardiovascular drugs – a polypill – boosted patient adherence by 33% while meaningfully reducing both systolic blood pressure and LDL cholesterol compared with usual care in the large international UMPIRE trial.

UMPIRE (Use of a Multidrug Pill in Reducing Cardiovascular Events) was designed to test the hypothesis that decreasing the cost and complexity of guideline-indicated medications for secondary cardiovascular prevention would improve treatment adherence and outcomes in patients with established atherosclerotic cardiovascular disease or in those at high risk for it.

And UMPIRE was a resounding success, according to Dr. Simon Thom, professor of cardiovascular medicine and pharmacology at Imperial College, London. He presented the results at the annual scientific sessions of the American Heart Association.

The study comprised 2,004 randomized patients in India, Dublin, London, and Utrecht (the Netherlands): 88% had known atherosclerotic cardiovascular disease at baseline; 29% had diabetes. Participants were randomized to the polypill – composed of 75 mg aspirin, 50 mg simvastatin, 10 mg lisinopril, and either 50 mg atenolol or 12.5 mg hydrochlorothiazide, depending upon physician preference – or to usual care, which included individual prescriptions for the same four medications. The polypill was free, while usual care was paid for in the customary local manner.

After a median 15 months of follow-up, treatment adherence was 86% in the polypill arm, compared with 65% with usual care, a relative 33% difference. Systolic blood pressure averaged 129.2 mm Hg in the polypill group, 2.6 mm Hg lower than with usual care. Mean LDL cholesterol was 84.3 mg/dL in the polypill group and 88.6 mg/dL with usual care. Diastolic blood pressure was 72.8 mm Hg with the polypill, compared with 75.2 mm Hg in the usual care group.

All of these differences were statistically significant and clinically meaningful when extrapolated to the rapidly growing global burden of cardiovascular disease. Moreover, quality of life as self-measured on a visual analog scale was significantly better in patients on the fixed-dose combination, Dr. Thom reported.

There were, however, no significant differences between the two study arms in HDL cholesterol, triglycerides, or cardiovascular event rates.

Of note, 61% of UMPIRE subjects were already on all four individual study medications at baseline. That’s an unusually high proportion in the low- and middle-income countries where the polypill will see greatest future use, and it means the UMPIRE results almost certainly underestimate the true benefits to be expected with use of the polypill in clinical practice, he continued.

Side effects were the same in both treatment arms.

Discussant Dr. Andrew M. Tonkin declared UMPIRE to be "an important trial – and the results should be taken on board not only by clinicians, but should really inform government policies and strategies."

Although there is enthusiasm in some quarters for broad use of the polypill for primary prevention – a sort of let’s-put-it-in-the-drinking-water strategy – UMPIRE was the first polypill randomized trial conducted in patients with established cardiovascular disease, and one of very few to date to run longer than about 3 months.

"I believe that UMPIRE firmly establishes the case for using the polypill in those people with manifest atherosclerotic cardiovascular disease," said Dr. Tonkin.

It’s noteworthy that patients with poor baseline adherence to the study medications were 3.4-fold more likely to benefit from use of the polypill. That’s an important finding because the polypill is expected to see its greatest future use in India, China, the Philippines, and other parts of the world where vast numbers of patients with cardiovascular disease now receive little or nothing in the way of pharmacologic secondary prevention, said Dr. Tonkin, professor of preventive medicine and head of the cardiovascular research unit at Monash Hospital in Melbourne.

Moving forward, he added, the responsibility for developing the polypill cannot rest solely with the pharmaceutical industry.

"This is a very low-margin venture using low-cost generic formulations. Major pharma doesn’t want to get interested in this," said Dr. Tonkin.

Both the World Health Organization and the European Commission are publicly on board for the polypill, he noted.

The WHO and Wellcome Trust stated in a 2002 report that demonstration of bioequivalence and improved adherence as reflected in improvements in LDL and systolic blood pressure, as seen in UMPIRE, should be sufficient for regulatory approval of the polypill.

"That, I think, will not carry water in these days, unfortunately. But a meta-analysis of clinical end point data from the various trials is planned. And there are ongoing and planned future phase III trials," Dr. Tonkin said.

While most of the clinical trials, past and present, have taken place in low-income countries, the polypill is also under study in populations in the United States, Canada, Australia, and other relatively well-off nations, he pointed out.

UMPIRE was funded by the European Commission. Dr. Thom and Dr. Tonkin reported having no financial conflicts.

LOS ANGELES – A once-daily, fixed-dose combination of four cardiovascular drugs – a polypill – boosted patient adherence by 33% while meaningfully reducing both systolic blood pressure and LDL cholesterol compared with usual care in the large international UMPIRE trial.

UMPIRE (Use of a Multidrug Pill in Reducing Cardiovascular Events) was designed to test the hypothesis that decreasing the cost and complexity of guideline-indicated medications for secondary cardiovascular prevention would improve treatment adherence and outcomes in patients with established atherosclerotic cardiovascular disease or in those at high risk for it.

And UMPIRE was a resounding success, according to Dr. Simon Thom, professor of cardiovascular medicine and pharmacology at Imperial College, London. He presented the results at the annual scientific sessions of the American Heart Association.

The study comprised 2,004 randomized patients in India, Dublin, London, and Utrecht (the Netherlands): 88% had known atherosclerotic cardiovascular disease at baseline; 29% had diabetes. Participants were randomized to the polypill – composed of 75 mg aspirin, 50 mg simvastatin, 10 mg lisinopril, and either 50 mg atenolol or 12.5 mg hydrochlorothiazide, depending upon physician preference – or to usual care, which included individual prescriptions for the same four medications. The polypill was free, while usual care was paid for in the customary local manner.

After a median 15 months of follow-up, treatment adherence was 86% in the polypill arm, compared with 65% with usual care, a relative 33% difference. Systolic blood pressure averaged 129.2 mm Hg in the polypill group, 2.6 mm Hg lower than with usual care. Mean LDL cholesterol was 84.3 mg/dL in the polypill group and 88.6 mg/dL with usual care. Diastolic blood pressure was 72.8 mm Hg with the polypill, compared with 75.2 mm Hg in the usual care group.

All of these differences were statistically significant and clinically meaningful when extrapolated to the rapidly growing global burden of cardiovascular disease. Moreover, quality of life as self-measured on a visual analog scale was significantly better in patients on the fixed-dose combination, Dr. Thom reported.

There were, however, no significant differences between the two study arms in HDL cholesterol, triglycerides, or cardiovascular event rates.

Of note, 61% of UMPIRE subjects were already on all four individual study medications at baseline. That’s an unusually high proportion in the low- and middle-income countries where the polypill will see greatest future use, and it means the UMPIRE results almost certainly underestimate the true benefits to be expected with use of the polypill in clinical practice, he continued.

Side effects were the same in both treatment arms.

Discussant Dr. Andrew M. Tonkin declared UMPIRE to be "an important trial – and the results should be taken on board not only by clinicians, but should really inform government policies and strategies."

Although there is enthusiasm in some quarters for broad use of the polypill for primary prevention – a sort of let’s-put-it-in-the-drinking-water strategy – UMPIRE was the first polypill randomized trial conducted in patients with established cardiovascular disease, and one of very few to date to run longer than about 3 months.

"I believe that UMPIRE firmly establishes the case for using the polypill in those people with manifest atherosclerotic cardiovascular disease," said Dr. Tonkin.

It’s noteworthy that patients with poor baseline adherence to the study medications were 3.4-fold more likely to benefit from use of the polypill. That’s an important finding because the polypill is expected to see its greatest future use in India, China, the Philippines, and other parts of the world where vast numbers of patients with cardiovascular disease now receive little or nothing in the way of pharmacologic secondary prevention, said Dr. Tonkin, professor of preventive medicine and head of the cardiovascular research unit at Monash Hospital in Melbourne.

Moving forward, he added, the responsibility for developing the polypill cannot rest solely with the pharmaceutical industry.

"This is a very low-margin venture using low-cost generic formulations. Major pharma doesn’t want to get interested in this," said Dr. Tonkin.

Both the World Health Organization and the European Commission are publicly on board for the polypill, he noted.

The WHO and Wellcome Trust stated in a 2002 report that demonstration of bioequivalence and improved adherence as reflected in improvements in LDL and systolic blood pressure, as seen in UMPIRE, should be sufficient for regulatory approval of the polypill.

"That, I think, will not carry water in these days, unfortunately. But a meta-analysis of clinical end point data from the various trials is planned. And there are ongoing and planned future phase III trials," Dr. Tonkin said.

While most of the clinical trials, past and present, have taken place in low-income countries, the polypill is also under study in populations in the United States, Canada, Australia, and other relatively well-off nations, he pointed out.

UMPIRE was funded by the European Commission. Dr. Thom and Dr. Tonkin reported having no financial conflicts.

LOS ANGELES – Chronic heart failure patients who ate a special superhigh-flavonol dark chocolate bar daily experienced favorable changes consistent with decreased vascular resistance and diminished left ventricular afterload in a randomized, double-blind, crossover pilot study.

"It should be emphasized that these patients were already on maximal tolerated guideline-indicated therapy. In terms of medical interventions, there weren’t many more things we could do. So I think that in addition to looking at new drugs, we need to look at evidence-based new diets to see if they can reduce morbidity and mortality in heart failure," Dr. Roger Corder said in presenting the chocolate study results at the annual scientific sessions of the American Heart Association.

The likely mechanism of benefit in heart failure patients involves a dark chocolate–induced reduction in endothelial dysfunction.

"Prior studies show consumption of cocoa flavonols in daily doses of 750 mg or more improve endothelial function in patients with coronary artery disease, in healthy subjects, and in diabetics," noted Dr. Corder of Queen Mary University of London.

The study involved 32 patients with stable heart failure on maximal medical therapy, all of whom had a history of ischemic heart disease. They were randomized to daily consumption of a 50-g bar of high-flavonol chocolate or a low-flavonol chocolate bar for 4 weeks, then crossed over to daily consumption of the other bar for another 4 weeks.

The test product contained 1,094 mg of flavonols per bar, while the low-flavonol comparator contained 95 mg. The high-flavonol chocolate bar was a custom-made product whose flavonol content far exceeds anything on the market. Dr. Corder and coinvestigators tested 50 brands of commercially available dark chocolate bars averaging 76% cocoa solids and determined their average flavonol content was 312 mg/50 g.

The study end points were change in diastolic blood pressure and N-terminal prohormone of brain natriuretic peptide (NT-proBNP) levels after 4 weeks of eating each type of chocolate bar.

Twenty-four patients completed the study. Mean NT-proBNP dropped by an average of 39% from a baseline of 200 pmol/L after 4 weeks of eating the high-flavonol chocolate.

"Given that other trials of medications, including angiotensin receptor blockers, have shown a 30% reduction in NT-proBNP is associated with improved clinical outcomes, this looks to us like something of interest to pursue further with additional clinical studies. It’s worth noting that 12 of the 24 patients had a drop in NT-proBNP of 30% or more," Dr. Corder said.

From a baseline blood pressure of 126/71 mm Hg, diastolic pressure fell by 5 mm Hg in conjunction with consumption of the high-flavonol bar. Systolic pressure did not change significantly. Maintenance of systolic blood pressure with a reduction in diastolic pressure implies an increase in cardiac output – "and that would really be the optimum thing to have happened," he continued.

The low-flavonol chocolate bar did not produce changes in blood pressure or NT-proBNP.

A couple of down sides with the experimental high-flavonol chocolate bar emerged during the study. One was taste. Three of the eight study dropouts quit because they found the product’s taste unacceptable, while the others left for reasons unrelated to the study.

"We had an issue with taste. Even the patients who finished the study didn’t like the taste. There may be other countries where dark chocolate is popular, but the East of London would rather have their sweet milk chocolate than dark chocolate," according to Dr. Corder.

Weight gain is another concern. Both chocolate bars contained about 19 g of fat, including 12 g of saturated fat, per 50-g serving, with about 260 calories. From a baseline body weight of 85.7 kg, participants gained roughly 0.3 kg over the course of 4 weeks.

"In terms of long-term therapy, it may not be suitable to take dark chocolate on a daily basis at this level," he said.

However, food scientists involved in the study are tweaking the recipe to improve the taste of the superhigh-flavonol bar. There is also the option of extracting the flavonols and placing them in some other nutraceutical food product.

The study was funded by Swiss chocolate giant Barry Callebaut. Dr. Corder reported receiving a significant research grant from the company.

LOS ANGELES – Chronic heart failure patients who ate a special superhigh-flavonol dark chocolate bar daily experienced favorable changes consistent with decreased vascular resistance and diminished left ventricular afterload in a randomized, double-blind, crossover pilot study.

"It should be emphasized that these patients were already on maximal tolerated guideline-indicated therapy. In terms of medical interventions, there weren’t many more things we could do. So I think that in addition to looking at new drugs, we need to look at evidence-based new diets to see if they can reduce morbidity and mortality in heart failure," Dr. Roger Corder said in presenting the chocolate study results at the annual scientific sessions of the American Heart Association.

The likely mechanism of benefit in heart failure patients involves a dark chocolate–induced reduction in endothelial dysfunction.

"Prior studies show consumption of cocoa flavonols in daily doses of 750 mg or more improve endothelial function in patients with coronary artery disease, in healthy subjects, and in diabetics," noted Dr. Corder of Queen Mary University of London.

The study involved 32 patients with stable heart failure on maximal medical therapy, all of whom had a history of ischemic heart disease. They were randomized to daily consumption of a 50-g bar of high-flavonol chocolate or a low-flavonol chocolate bar for 4 weeks, then crossed over to daily consumption of the other bar for another 4 weeks.

The test product contained 1,094 mg of flavonols per bar, while the low-flavonol comparator contained 95 mg. The high-flavonol chocolate bar was a custom-made product whose flavonol content far exceeds anything on the market. Dr. Corder and coinvestigators tested 50 brands of commercially available dark chocolate bars averaging 76% cocoa solids and determined their average flavonol content was 312 mg/50 g.

The study end points were change in diastolic blood pressure and N-terminal prohormone of brain natriuretic peptide (NT-proBNP) levels after 4 weeks of eating each type of chocolate bar.

Twenty-four patients completed the study. Mean NT-proBNP dropped by an average of 39% from a baseline of 200 pmol/L after 4 weeks of eating the high-flavonol chocolate.

"Given that other trials of medications, including angiotensin receptor blockers, have shown a 30% reduction in NT-proBNP is associated with improved clinical outcomes, this looks to us like something of interest to pursue further with additional clinical studies. It’s worth noting that 12 of the 24 patients had a drop in NT-proBNP of 30% or more," Dr. Corder said.

From a baseline blood pressure of 126/71 mm Hg, diastolic pressure fell by 5 mm Hg in conjunction with consumption of the high-flavonol bar. Systolic pressure did not change significantly. Maintenance of systolic blood pressure with a reduction in diastolic pressure implies an increase in cardiac output – "and that would really be the optimum thing to have happened," he continued.

The low-flavonol chocolate bar did not produce changes in blood pressure or NT-proBNP.

A couple of down sides with the experimental high-flavonol chocolate bar emerged during the study. One was taste. Three of the eight study dropouts quit because they found the product’s taste unacceptable, while the others left for reasons unrelated to the study.

"We had an issue with taste. Even the patients who finished the study didn’t like the taste. There may be other countries where dark chocolate is popular, but the East of London would rather have their sweet milk chocolate than dark chocolate," according to Dr. Corder.

Weight gain is another concern. Both chocolate bars contained about 19 g of fat, including 12 g of saturated fat, per 50-g serving, with about 260 calories. From a baseline body weight of 85.7 kg, participants gained roughly 0.3 kg over the course of 4 weeks.

"In terms of long-term therapy, it may not be suitable to take dark chocolate on a daily basis at this level," he said.

However, food scientists involved in the study are tweaking the recipe to improve the taste of the superhigh-flavonol bar. There is also the option of extracting the flavonols and placing them in some other nutraceutical food product.

The study was funded by Swiss chocolate giant Barry Callebaut. Dr. Corder reported receiving a significant research grant from the company.

LOS ANGELES – Chronic heart failure patients who ate a special superhigh-flavonol dark chocolate bar daily experienced favorable changes consistent with decreased vascular resistance and diminished left ventricular afterload in a randomized, double-blind, crossover pilot study.

"It should be emphasized that these patients were already on maximal tolerated guideline-indicated therapy. In terms of medical interventions, there weren’t many more things we could do. So I think that in addition to looking at new drugs, we need to look at evidence-based new diets to see if they can reduce morbidity and mortality in heart failure," Dr. Roger Corder said in presenting the chocolate study results at the annual scientific sessions of the American Heart Association.

The likely mechanism of benefit in heart failure patients involves a dark chocolate–induced reduction in endothelial dysfunction.

"Prior studies show consumption of cocoa flavonols in daily doses of 750 mg or more improve endothelial function in patients with coronary artery disease, in healthy subjects, and in diabetics," noted Dr. Corder of Queen Mary University of London.

The study involved 32 patients with stable heart failure on maximal medical therapy, all of whom had a history of ischemic heart disease. They were randomized to daily consumption of a 50-g bar of high-flavonol chocolate or a low-flavonol chocolate bar for 4 weeks, then crossed over to daily consumption of the other bar for another 4 weeks.

The test product contained 1,094 mg of flavonols per bar, while the low-flavonol comparator contained 95 mg. The high-flavonol chocolate bar was a custom-made product whose flavonol content far exceeds anything on the market. Dr. Corder and coinvestigators tested 50 brands of commercially available dark chocolate bars averaging 76% cocoa solids and determined their average flavonol content was 312 mg/50 g.

The study end points were change in diastolic blood pressure and N-terminal prohormone of brain natriuretic peptide (NT-proBNP) levels after 4 weeks of eating each type of chocolate bar.

Twenty-four patients completed the study. Mean NT-proBNP dropped by an average of 39% from a baseline of 200 pmol/L after 4 weeks of eating the high-flavonol chocolate.

"Given that other trials of medications, including angiotensin receptor blockers, have shown a 30% reduction in NT-proBNP is associated with improved clinical outcomes, this looks to us like something of interest to pursue further with additional clinical studies. It’s worth noting that 12 of the 24 patients had a drop in NT-proBNP of 30% or more," Dr. Corder said.

From a baseline blood pressure of 126/71 mm Hg, diastolic pressure fell by 5 mm Hg in conjunction with consumption of the high-flavonol bar. Systolic pressure did not change significantly. Maintenance of systolic blood pressure with a reduction in diastolic pressure implies an increase in cardiac output – "and that would really be the optimum thing to have happened," he continued.

The low-flavonol chocolate bar did not produce changes in blood pressure or NT-proBNP.

A couple of down sides with the experimental high-flavonol chocolate bar emerged during the study. One was taste. Three of the eight study dropouts quit because they found the product’s taste unacceptable, while the others left for reasons unrelated to the study.

"We had an issue with taste. Even the patients who finished the study didn’t like the taste. There may be other countries where dark chocolate is popular, but the East of London would rather have their sweet milk chocolate than dark chocolate," according to Dr. Corder.

Weight gain is another concern. Both chocolate bars contained about 19 g of fat, including 12 g of saturated fat, per 50-g serving, with about 260 calories. From a baseline body weight of 85.7 kg, participants gained roughly 0.3 kg over the course of 4 weeks.

"In terms of long-term therapy, it may not be suitable to take dark chocolate on a daily basis at this level," he said.

However, food scientists involved in the study are tweaking the recipe to improve the taste of the superhigh-flavonol bar. There is also the option of extracting the flavonols and placing them in some other nutraceutical food product.

The study was funded by Swiss chocolate giant Barry Callebaut. Dr. Corder reported receiving a significant research grant from the company.

LOS ANGELES – There are perfectly good reasons for hospitals to offer elective percutaneous coronary intervention without on-site cardiac surgery backup, but saving institutional dollars isn't among them.

That's the bottom line from CPORT-E (Cardiovascular Patient Outcomes Research Team/Non-Primary Percutaneous Coronary Intervention Economic Study), the prespecified economic analysis conducted as part of the landmark CPORT trial.

Bruce Jancin/IMNG Medical Media

The estimated medical costs per CPORT participant, including the index revascularization and hospitalization as well as costs incurred during 9 months of follow-up, averaged $29,136 in hospitals without on-site coronary artery bypass surgery backup and $25,412 in centers with backup. This 15% difference did not reach statistical significance, Eric L. Eisenstein, DBA, reported at the annual scientific sessions of the American Heart Association.

Patients assigned to PCI at hospitals without on-site cardiac surgery actually had a shorter average length of stay; however, their total hospitalization costs ran higher because the study protocol dictated that their post-PCI care take place in the intensive care unit. Patients in centers with no on-site CABG backup also had a significantly higher rate of repeat target vessel revascularization during 9 months of follow-up: 6.5% compared with 5.4% when PCI was performed in hospitals with surgical backup, explained Dr. Eisenstein of Duke Clinical Research Institute, Durham, N.C.

CPORT was a randomized, prospective, multicenter trial in which the outcomes of elective PCI performed at hospitals with or without on-site cardiac surgery backup were compared for nearly 19,000 participants. As previously reported (N. Engl. J. Med. 2012; 366:1792-802), there were no significant differences between the two patient populations in terms of the co–primary end points of 6-week mortality (0.9% at hospitals without on-site surgery and 1.0% at those with backup) and 9-month major adverse cardiac events (12.1% without versus 11.2% with on-site surgical backup).

Discussant Dr. Mark A. Hlatky noted that 9-month total costs in CPORT-E were 22% higher at low-PCI-volume sites without surgery but only 7% higher at high-volume sites without surgery than at hospitals having on-site CABG backup.

"That’s a very interesting issue: The crucial factor driving costs may not be whether surgery is present on site or not, but the PCI volume at the site. If we have a low-volume site there may be higher costs and more adverse events. Whenever you do something in higher volumes you’re more efficient economically and you may actually do a little bit better job," said Dr. Hlatky, professor of health research and policy and of cardiovascular medicine at Stanford (Calif.) University.

As a matter of health policy, introducing elective PCI at hospitals without on-site cardiac surgery is attractive because it improves access, particularly for patients in rural areas where the nearest medical center with surgical backup may be a considerable distance away. Another consideration is that these centers without on-site surgery may be available for emergency PCI, thereby avoiding the delays inherent in patient transfer to a distant center, he observed.

Discussant Dr. David O. Williams pronounced CPORT "an extremely well-organized and well-conducted trial. It was a large study and the findings, I believe, are quite valid. To be applicable, however, hospitals will need to replicate all the necessary operational and training activities inherent in the trial, which were really quite extensive."

That means not taking money-saving shortcuts, such as eliminating the post-PCI stay in the ICU.

"I do believe this trial is significant and will likely impact the manner in which PCI is performed in the U.S. The performance of PCI in hospitals without on-site CABG surgery, I believe, will be adopted and become the standard of care," predicted Dr. Williams, an interventional cardiologist at Brigham and Women’s Hospital, Boston.

The CPORT-E study was funded by Johns Hopkins University. Dr. Eisenstein reported receiving research grants from Medtronic and Eli Lilly. Dr. Williams is the recipient of research grants from medical device companies. Dr. Hlatky reported having no relevant financial interests.

LOS ANGELES – There are perfectly good reasons for hospitals to offer elective percutaneous coronary intervention without on-site cardiac surgery backup, but saving institutional dollars isn't among them.

That's the bottom line from CPORT-E (Cardiovascular Patient Outcomes Research Team/Non-Primary Percutaneous Coronary Intervention Economic Study), the prespecified economic analysis conducted as part of the landmark CPORT trial.

Bruce Jancin/IMNG Medical Media

The estimated medical costs per CPORT participant, including the index revascularization and hospitalization as well as costs incurred during 9 months of follow-up, averaged $29,136 in hospitals without on-site coronary artery bypass surgery backup and $25,412 in centers with backup. This 15% difference did not reach statistical significance, Eric L. Eisenstein, DBA, reported at the annual scientific sessions of the American Heart Association.

Patients assigned to PCI at hospitals without on-site cardiac surgery actually had a shorter average length of stay; however, their total hospitalization costs ran higher because the study protocol dictated that their post-PCI care take place in the intensive care unit. Patients in centers with no on-site CABG backup also had a significantly higher rate of repeat target vessel revascularization during 9 months of follow-up: 6.5% compared with 5.4% when PCI was performed in hospitals with surgical backup, explained Dr. Eisenstein of Duke Clinical Research Institute, Durham, N.C.

CPORT was a randomized, prospective, multicenter trial in which the outcomes of elective PCI performed at hospitals with or without on-site cardiac surgery backup were compared for nearly 19,000 participants. As previously reported (N. Engl. J. Med. 2012; 366:1792-802), there were no significant differences between the two patient populations in terms of the co–primary end points of 6-week mortality (0.9% at hospitals without on-site surgery and 1.0% at those with backup) and 9-month major adverse cardiac events (12.1% without versus 11.2% with on-site surgical backup).

Discussant Dr. Mark A. Hlatky noted that 9-month total costs in CPORT-E were 22% higher at low-PCI-volume sites without surgery but only 7% higher at high-volume sites without surgery than at hospitals having on-site CABG backup.

"That’s a very interesting issue: The crucial factor driving costs may not be whether surgery is present on site or not, but the PCI volume at the site. If we have a low-volume site there may be higher costs and more adverse events. Whenever you do something in higher volumes you’re more efficient economically and you may actually do a little bit better job," said Dr. Hlatky, professor of health research and policy and of cardiovascular medicine at Stanford (Calif.) University.

As a matter of health policy, introducing elective PCI at hospitals without on-site cardiac surgery is attractive because it improves access, particularly for patients in rural areas where the nearest medical center with surgical backup may be a considerable distance away. Another consideration is that these centers without on-site surgery may be available for emergency PCI, thereby avoiding the delays inherent in patient transfer to a distant center, he observed.

Discussant Dr. David O. Williams pronounced CPORT "an extremely well-organized and well-conducted trial. It was a large study and the findings, I believe, are quite valid. To be applicable, however, hospitals will need to replicate all the necessary operational and training activities inherent in the trial, which were really quite extensive."

That means not taking money-saving shortcuts, such as eliminating the post-PCI stay in the ICU.

"I do believe this trial is significant and will likely impact the manner in which PCI is performed in the U.S. The performance of PCI in hospitals without on-site CABG surgery, I believe, will be adopted and become the standard of care," predicted Dr. Williams, an interventional cardiologist at Brigham and Women’s Hospital, Boston.

The CPORT-E study was funded by Johns Hopkins University. Dr. Eisenstein reported receiving research grants from Medtronic and Eli Lilly. Dr. Williams is the recipient of research grants from medical device companies. Dr. Hlatky reported having no relevant financial interests.

LOS ANGELES – There are perfectly good reasons for hospitals to offer elective percutaneous coronary intervention without on-site cardiac surgery backup, but saving institutional dollars isn't among them.

That's the bottom line from CPORT-E (Cardiovascular Patient Outcomes Research Team/Non-Primary Percutaneous Coronary Intervention Economic Study), the prespecified economic analysis conducted as part of the landmark CPORT trial.

Bruce Jancin/IMNG Medical Media

The estimated medical costs per CPORT participant, including the index revascularization and hospitalization as well as costs incurred during 9 months of follow-up, averaged $29,136 in hospitals without on-site coronary artery bypass surgery backup and $25,412 in centers with backup. This 15% difference did not reach statistical significance, Eric L. Eisenstein, DBA, reported at the annual scientific sessions of the American Heart Association.

Patients assigned to PCI at hospitals without on-site cardiac surgery actually had a shorter average length of stay; however, their total hospitalization costs ran higher because the study protocol dictated that their post-PCI care take place in the intensive care unit. Patients in centers with no on-site CABG backup also had a significantly higher rate of repeat target vessel revascularization during 9 months of follow-up: 6.5% compared with 5.4% when PCI was performed in hospitals with surgical backup, explained Dr. Eisenstein of Duke Clinical Research Institute, Durham, N.C.

CPORT was a randomized, prospective, multicenter trial in which the outcomes of elective PCI performed at hospitals with or without on-site cardiac surgery backup were compared for nearly 19,000 participants. As previously reported (N. Engl. J. Med. 2012; 366:1792-802), there were no significant differences between the two patient populations in terms of the co–primary end points of 6-week mortality (0.9% at hospitals without on-site surgery and 1.0% at those with backup) and 9-month major adverse cardiac events (12.1% without versus 11.2% with on-site surgical backup).

Discussant Dr. Mark A. Hlatky noted that 9-month total costs in CPORT-E were 22% higher at low-PCI-volume sites without surgery but only 7% higher at high-volume sites without surgery than at hospitals having on-site CABG backup.

"That’s a very interesting issue: The crucial factor driving costs may not be whether surgery is present on site or not, but the PCI volume at the site. If we have a low-volume site there may be higher costs and more adverse events. Whenever you do something in higher volumes you’re more efficient economically and you may actually do a little bit better job," said Dr. Hlatky, professor of health research and policy and of cardiovascular medicine at Stanford (Calif.) University.

As a matter of health policy, introducing elective PCI at hospitals without on-site cardiac surgery is attractive because it improves access, particularly for patients in rural areas where the nearest medical center with surgical backup may be a considerable distance away. Another consideration is that these centers without on-site surgery may be available for emergency PCI, thereby avoiding the delays inherent in patient transfer to a distant center, he observed.

Discussant Dr. David O. Williams pronounced CPORT "an extremely well-organized and well-conducted trial. It was a large study and the findings, I believe, are quite valid. To be applicable, however, hospitals will need to replicate all the necessary operational and training activities inherent in the trial, which were really quite extensive."

That means not taking money-saving shortcuts, such as eliminating the post-PCI stay in the ICU.

"I do believe this trial is significant and will likely impact the manner in which PCI is performed in the U.S. The performance of PCI in hospitals without on-site CABG surgery, I believe, will be adopted and become the standard of care," predicted Dr. Williams, an interventional cardiologist at Brigham and Women’s Hospital, Boston.

The CPORT-E study was funded by Johns Hopkins University. Dr. Eisenstein reported receiving research grants from Medtronic and Eli Lilly. Dr. Williams is the recipient of research grants from medical device companies. Dr. Hlatky reported having no relevant financial interests.

LOS ANGELES – Hodgkin’s lymphoma survivors who underwent mediastinal radiation therapy for their cancer have a high prevalence of occult cardiovascular disease, a systematic examination of 182 patients showed.

Among 182 asymptomatic, radiation-treated Hodgkin’s lymphoma patients with no prior history of cardiovascular disease, 47 (26%) showed signs of "significant" coronary artery disease (CAD), valvular disease, or left ventricular systolic dysfunction with screening echocardiography done at least 5 years and an average of 15 years after finishing radiation therapy, Dr. Ming Hui Chen reported at the annual scientific sessions of the American Heart Association.

Mitchel L. Zoler/IMNG Medical Media

Patients had this high prevalence despite their relatively young age, which ranged from 21 to 65 years and averaged 43 years. Among the subgroup with identified coronary or valvular disease, the average age was 48, ranging from 36 to 65 years, said Dr. Chen, a cardiologist and associate director of the noninvasive cardiac laboratory at Brigham and Women’s Hospital in Boston.

Her analysis also showed that hypertension was the only modifiable risk factor associated with screening-detected CAD and valve disease in these patients. Based on that, "blood pressure modification would likely result in considerable calculated risk reduction for CAD and valve disease in Hodgkin’s lymphoma survivors cured by mediastinal radiation," she concluded.

"The key question is, does radiation directly cause [CAD or valve disease] or does it do so indirectly through hypertension and other cardiac risk factors? Does the hypertension reflect an interaction with arterial stiffness caused by radiation itself?" she asked.

It’s "quite possible" that the hypertension is caused by radiation of "the most distensible part of the arterial system that is mostly responsible for buffering the pulses of the heart," commented Dr. Michael O’Rourke. The problem with this hypothesis is that, if true, "you would expect more systolic than diastolic hypertension," which wasn’t what the data showed, said Dr. O’Rourke, professor of medicine at the University of New South Wales in Sydney.

Dr. Chen and her associates performed screening echocardiography on long-term survivors of Hodgkin’s lymphoma who received mediastinal radiation therapy because results from prior studies had shown that cardiovascular disease is three to five times more prevalent in this population, but despite that, routine screening of these patients for cardiovascular disease is rarely done, she said.

They examined 182 former patients treated for Hodgkin’s lymphoma with mediastinal radiation at any of four Boston-area hospitals during 1967-2006 who were asymptomatic and had no history of cardiovascular disease. All patients underwent transthoracic and stress echocardiographic examinations, and those with findings suggestive of ischemic coronary disease also underwent confirmatory angiography. During cancer treatment the patients had received an average total radiation dose of 3,960 Gy.

Screening identified 24 patients with CAD or valvular disease, and 26 with left ventricular systolic dysfunction (3 of the 47 affected patients had both categories of cardiovascular disease). Some patients had valve disease so advanced that they needed emergency surgery. The most common type of valve disease was aortic stenosis.

Among the people examined, 81% had at least one modifiable cardiac risk factor, including 24 patients with a history of hypertension, and another 24 with a new diagnosis of hypertension. Analysis of all the identified cardiovascular disease risk factors showed that hypertension, an elevated level of high-sensitivity C-reactive protein, and older age were each significantly more prevalent among patients with CAD or valve disease, compared with those without.

But results from a multivariate-adjusted analysis showed that hypertension was the only modifiable risk factor to significantly link with CAD or valve disease. Patients with hypertension were 4.5-fold more likely to have CAD or valve disease, compared with patients without hypertension.

The analysis also showed that for each 5-mm Hg rise in systolic blood pressure, the rate of coronary and valve disease rose by 29%, and for each 5 mm Hg rise in diastolic pressure, the rate of disease rose by 35%, both statistically significant effects, Dr. Chen reported.

Dr. Chen said that she has no disclosures. Dr. O’Rourke is medical director and cofounder of AtCor Medical.

LOS ANGELES – Hodgkin’s lymphoma survivors who underwent mediastinal radiation therapy for their cancer have a high prevalence of occult cardiovascular disease, a systematic examination of 182 patients showed.

Among 182 asymptomatic, radiation-treated Hodgkin’s lymphoma patients with no prior history of cardiovascular disease, 47 (26%) showed signs of "significant" coronary artery disease (CAD), valvular disease, or left ventricular systolic dysfunction with screening echocardiography done at least 5 years and an average of 15 years after finishing radiation therapy, Dr. Ming Hui Chen reported at the annual scientific sessions of the American Heart Association.

Mitchel L. Zoler/IMNG Medical Media

Patients had this high prevalence despite their relatively young age, which ranged from 21 to 65 years and averaged 43 years. Among the subgroup with identified coronary or valvular disease, the average age was 48, ranging from 36 to 65 years, said Dr. Chen, a cardiologist and associate director of the noninvasive cardiac laboratory at Brigham and Women’s Hospital in Boston.

Her analysis also showed that hypertension was the only modifiable risk factor associated with screening-detected CAD and valve disease in these patients. Based on that, "blood pressure modification would likely result in considerable calculated risk reduction for CAD and valve disease in Hodgkin’s lymphoma survivors cured by mediastinal radiation," she concluded.

"The key question is, does radiation directly cause [CAD or valve disease] or does it do so indirectly through hypertension and other cardiac risk factors? Does the hypertension reflect an interaction with arterial stiffness caused by radiation itself?" she asked.

It’s "quite possible" that the hypertension is caused by radiation of "the most distensible part of the arterial system that is mostly responsible for buffering the pulses of the heart," commented Dr. Michael O’Rourke. The problem with this hypothesis is that, if true, "you would expect more systolic than diastolic hypertension," which wasn’t what the data showed, said Dr. O’Rourke, professor of medicine at the University of New South Wales in Sydney.

Dr. Chen and her associates performed screening echocardiography on long-term survivors of Hodgkin’s lymphoma who received mediastinal radiation therapy because results from prior studies had shown that cardiovascular disease is three to five times more prevalent in this population, but despite that, routine screening of these patients for cardiovascular disease is rarely done, she said.

They examined 182 former patients treated for Hodgkin’s lymphoma with mediastinal radiation at any of four Boston-area hospitals during 1967-2006 who were asymptomatic and had no history of cardiovascular disease. All patients underwent transthoracic and stress echocardiographic examinations, and those with findings suggestive of ischemic coronary disease also underwent confirmatory angiography. During cancer treatment the patients had received an average total radiation dose of 3,960 Gy.

Screening identified 24 patients with CAD or valvular disease, and 26 with left ventricular systolic dysfunction (3 of the 47 affected patients had both categories of cardiovascular disease). Some patients had valve disease so advanced that they needed emergency surgery. The most common type of valve disease was aortic stenosis.

Among the people examined, 81% had at least one modifiable cardiac risk factor, including 24 patients with a history of hypertension, and another 24 with a new diagnosis of hypertension. Analysis of all the identified cardiovascular disease risk factors showed that hypertension, an elevated level of high-sensitivity C-reactive protein, and older age were each significantly more prevalent among patients with CAD or valve disease, compared with those without.

But results from a multivariate-adjusted analysis showed that hypertension was the only modifiable risk factor to significantly link with CAD or valve disease. Patients with hypertension were 4.5-fold more likely to have CAD or valve disease, compared with patients without hypertension.

The analysis also showed that for each 5-mm Hg rise in systolic blood pressure, the rate of coronary and valve disease rose by 29%, and for each 5 mm Hg rise in diastolic pressure, the rate of disease rose by 35%, both statistically significant effects, Dr. Chen reported.

Dr. Chen said that she has no disclosures. Dr. O’Rourke is medical director and cofounder of AtCor Medical.

LOS ANGELES – Hodgkin’s lymphoma survivors who underwent mediastinal radiation therapy for their cancer have a high prevalence of occult cardiovascular disease, a systematic examination of 182 patients showed.

Among 182 asymptomatic, radiation-treated Hodgkin’s lymphoma patients with no prior history of cardiovascular disease, 47 (26%) showed signs of "significant" coronary artery disease (CAD), valvular disease, or left ventricular systolic dysfunction with screening echocardiography done at least 5 years and an average of 15 years after finishing radiation therapy, Dr. Ming Hui Chen reported at the annual scientific sessions of the American Heart Association.

Mitchel L. Zoler/IMNG Medical Media

Patients had this high prevalence despite their relatively young age, which ranged from 21 to 65 years and averaged 43 years. Among the subgroup with identified coronary or valvular disease, the average age was 48, ranging from 36 to 65 years, said Dr. Chen, a cardiologist and associate director of the noninvasive cardiac laboratory at Brigham and Women’s Hospital in Boston.

Her analysis also showed that hypertension was the only modifiable risk factor associated with screening-detected CAD and valve disease in these patients. Based on that, "blood pressure modification would likely result in considerable calculated risk reduction for CAD and valve disease in Hodgkin’s lymphoma survivors cured by mediastinal radiation," she concluded.

"The key question is, does radiation directly cause [CAD or valve disease] or does it do so indirectly through hypertension and other cardiac risk factors? Does the hypertension reflect an interaction with arterial stiffness caused by radiation itself?" she asked.

It’s "quite possible" that the hypertension is caused by radiation of "the most distensible part of the arterial system that is mostly responsible for buffering the pulses of the heart," commented Dr. Michael O’Rourke. The problem with this hypothesis is that, if true, "you would expect more systolic than diastolic hypertension," which wasn’t what the data showed, said Dr. O’Rourke, professor of medicine at the University of New South Wales in Sydney.

Dr. Chen and her associates performed screening echocardiography on long-term survivors of Hodgkin’s lymphoma who received mediastinal radiation therapy because results from prior studies had shown that cardiovascular disease is three to five times more prevalent in this population, but despite that, routine screening of these patients for cardiovascular disease is rarely done, she said.

They examined 182 former patients treated for Hodgkin’s lymphoma with mediastinal radiation at any of four Boston-area hospitals during 1967-2006 who were asymptomatic and had no history of cardiovascular disease. All patients underwent transthoracic and stress echocardiographic examinations, and those with findings suggestive of ischemic coronary disease also underwent confirmatory angiography. During cancer treatment the patients had received an average total radiation dose of 3,960 Gy.

Screening identified 24 patients with CAD or valvular disease, and 26 with left ventricular systolic dysfunction (3 of the 47 affected patients had both categories of cardiovascular disease). Some patients had valve disease so advanced that they needed emergency surgery. The most common type of valve disease was aortic stenosis.

Among the people examined, 81% had at least one modifiable cardiac risk factor, including 24 patients with a history of hypertension, and another 24 with a new diagnosis of hypertension. Analysis of all the identified cardiovascular disease risk factors showed that hypertension, an elevated level of high-sensitivity C-reactive protein, and older age were each significantly more prevalent among patients with CAD or valve disease, compared with those without.

But results from a multivariate-adjusted analysis showed that hypertension was the only modifiable risk factor to significantly link with CAD or valve disease. Patients with hypertension were 4.5-fold more likely to have CAD or valve disease, compared with patients without hypertension.

The analysis also showed that for each 5-mm Hg rise in systolic blood pressure, the rate of coronary and valve disease rose by 29%, and for each 5 mm Hg rise in diastolic pressure, the rate of disease rose by 35%, both statistically significant effects, Dr. Chen reported.

Dr. Chen said that she has no disclosures. Dr. O’Rourke is medical director and cofounder of AtCor Medical.

LOS ANGELES – The idea that raising blood levels of high-density lipoprotein cholesterol will cut cardiovascular events in patients with coronary disease took another hit with the flat clinical impact of dalcetrapib in a pivotal phase III trial with more than 15,000 patients.

Dalcetrapib did what it was supposed to do, at least physiologically: It raised patients’ HDL cholesterol levels by an average of about 30% compared with placebo. Despite that, patients who received the drug showed absolutely no drop in cardiovascular event rates during a median 31 months’ follow-up, Dr. Gregory G. Schwartz reported at the annual scientific sessions of the American Heart Association.

Mitchel L. Zoler/IMNG Medical Media

Because of the lack of any suggestion of benefit from treatment, the trial’s Data and Safety Monitoring Board recommended stopping the dal-OUTCOMES trial because of futility at one of the study’s prespecified review points.

The disappointing result made dalcetrapib, a cholesterol ester transfer protein (CETP) inhibitor, the second agent from this class to strike out in phase III testing. Five years ago, torcetrapib, the first CETP inhibitor drug to enter advanced clinical testing, crashed and burned in a phase III trial when it significantly boosted patient morbidity and mortality despite raising HDL cholesterol by 72% and cutting LDL levels by 25%, possibly because torcetrapib also boosted systolic blood pressure by an average of about 5 mm Hg (N. Engl. J. Med. 2007;357:2109-22).

Dalcetrapib was not nearly as dangerous as torcetrapib. In the new study, treatment with dalcetrapib was linked to a modest, average 0.6-mm rise in systolic blood pressure, and an equally slight 0.2-mg average increase in blood levels of C-reactive protein. Whether these effects had an impact on the clinical bottom line remains unknown, but the study results showed that the primary efficacy event curve for patients on dalcetrapib was completely superimposed with the curve for patients on placebo, reported Dr. Schwartz, chief of cardiology at the Denver VA Medical Center.

Both Dr. Schwartz and Dr. Alan Tall, the designated discussant for the study at the meeting, agreed that the disappointing performances of dalcetrapib and torcetrapib in phase III trials did not automatically mean that the CETP drug class has totally washed out. They both cited the importance of waiting for results from two other phase III studies now in progress that are testing two more CETP agents that are molecularly distinct from the two that did not pan out. Those agents are anacetrapib, currently being tested in a 30,000-patient study, the REVEAL (Randomized Evaluation of the Effects of Anacetrapib Through Lipid-Modification) trial, with results expected in 2017; and evacetrapib, now being tested in an 11,000-patient study, the ACCELERATE (Assessment of Clinical Effects of Cholesteryl Ester Transfer Protein Inhibition With Evacetrapib in Patients at a High-Risk for Vascular Outcomes) trial, with results expected in 2015.

"All four drugs have different chemical structures and biological effects," and so the outcomes seen so far with dalcetrapib and torcetrapib "are not necessarily harbingers" of what might lie ahead with the anacetrapib and evacetrapib trials, said Dr. Tall, professor and director of the Center of Research in Molecular Medicine and Atherosclerosis at Columbia University in New York.

"The results from anacetrapib and evacetrapib [in phase II studies] make a blood pressure increase [caused by either drug] unlikely," noted Dr. Schwartz. In addition, "dalcetrapib has no effect on LDL cholesterol, while anacetrapib and evacetrapib both increase LDL considerably."

But another possibility – that any agent that works primarily by raising HDL cholesterol may have little clinical benefit – cannot be dismissed based on current knowledge, Dr. Schwartz warned.

Mitchel L. Zoler/IMNG Medical Media

"The modified risk produced by raising HDL cholesterol may not be significant compared with other treatments that patients get," Dr. Schwartz cautioned. In the dal-OUTCOMES trial, the average LDL cholesterol level was 76 mg/dL. Against this background, "even in the quartile of about 1,600 patients in the dalcetrapib group who achieved the highest level of HDL cholesterol, a level of about 70-75 mg/dL, we saw no apparent reduction in risk."

Concurrent with Dr. Schwartz’s report at the meeting, the results of the dal-OUTCOMES study were published online (N. Engl. J. Med. 2012 Nov. 9 [doi: 10.1056/NEJMoa1206797]).

The dal-OUTCOMES trial was sponsored by Hoffman-La Roche, the company developing dalcetrapib. Dr. Schwartz said that he has received grant support from Anthera, Resverlogix, Roche, and Sanofi. Dr. Tall had no disclosures.

LOS ANGELES – The idea that raising blood levels of high-density lipoprotein cholesterol will cut cardiovascular events in patients with coronary disease took another hit with the flat clinical impact of dalcetrapib in a pivotal phase III trial with more than 15,000 patients.

Dalcetrapib did what it was supposed to do, at least physiologically: It raised patients’ HDL cholesterol levels by an average of about 30% compared with placebo. Despite that, patients who received the drug showed absolutely no drop in cardiovascular event rates during a median 31 months’ follow-up, Dr. Gregory G. Schwartz reported at the annual scientific sessions of the American Heart Association.

Mitchel L. Zoler/IMNG Medical Media

Because of the lack of any suggestion of benefit from treatment, the trial’s Data and Safety Monitoring Board recommended stopping the dal-OUTCOMES trial because of futility at one of the study’s prespecified review points.

The disappointing result made dalcetrapib, a cholesterol ester transfer protein (CETP) inhibitor, the second agent from this class to strike out in phase III testing. Five years ago, torcetrapib, the first CETP inhibitor drug to enter advanced clinical testing, crashed and burned in a phase III trial when it significantly boosted patient morbidity and mortality despite raising HDL cholesterol by 72% and cutting LDL levels by 25%, possibly because torcetrapib also boosted systolic blood pressure by an average of about 5 mm Hg (N. Engl. J. Med. 2007;357:2109-22).

Dalcetrapib was not nearly as dangerous as torcetrapib. In the new study, treatment with dalcetrapib was linked to a modest, average 0.6-mm rise in systolic blood pressure, and an equally slight 0.2-mg average increase in blood levels of C-reactive protein. Whether these effects had an impact on the clinical bottom line remains unknown, but the study results showed that the primary efficacy event curve for patients on dalcetrapib was completely superimposed with the curve for patients on placebo, reported Dr. Schwartz, chief of cardiology at the Denver VA Medical Center.

Both Dr. Schwartz and Dr. Alan Tall, the designated discussant for the study at the meeting, agreed that the disappointing performances of dalcetrapib and torcetrapib in phase III trials did not automatically mean that the CETP drug class has totally washed out. They both cited the importance of waiting for results from two other phase III studies now in progress that are testing two more CETP agents that are molecularly distinct from the two that did not pan out. Those agents are anacetrapib, currently being tested in a 30,000-patient study, the REVEAL (Randomized Evaluation of the Effects of Anacetrapib Through Lipid-Modification) trial, with results expected in 2017; and evacetrapib, now being tested in an 11,000-patient study, the ACCELERATE (Assessment of Clinical Effects of Cholesteryl Ester Transfer Protein Inhibition With Evacetrapib in Patients at a High-Risk for Vascular Outcomes) trial, with results expected in 2015.

"All four drugs have different chemical structures and biological effects," and so the outcomes seen so far with dalcetrapib and torcetrapib "are not necessarily harbingers" of what might lie ahead with the anacetrapib and evacetrapib trials, said Dr. Tall, professor and director of the Center of Research in Molecular Medicine and Atherosclerosis at Columbia University in New York.

"The results from anacetrapib and evacetrapib [in phase II studies] make a blood pressure increase [caused by either drug] unlikely," noted Dr. Schwartz. In addition, "dalcetrapib has no effect on LDL cholesterol, while anacetrapib and evacetrapib both increase LDL considerably."

But another possibility – that any agent that works primarily by raising HDL cholesterol may have little clinical benefit – cannot be dismissed based on current knowledge, Dr. Schwartz warned.

Mitchel L. Zoler/IMNG Medical Media

"The modified risk produced by raising HDL cholesterol may not be significant compared with other treatments that patients get," Dr. Schwartz cautioned. In the dal-OUTCOMES trial, the average LDL cholesterol level was 76 mg/dL. Against this background, "even in the quartile of about 1,600 patients in the dalcetrapib group who achieved the highest level of HDL cholesterol, a level of about 70-75 mg/dL, we saw no apparent reduction in risk."

Concurrent with Dr. Schwartz’s report at the meeting, the results of the dal-OUTCOMES study were published online (N. Engl. J. Med. 2012 Nov. 9 [doi: 10.1056/NEJMoa1206797]).

The dal-OUTCOMES trial was sponsored by Hoffman-La Roche, the company developing dalcetrapib. Dr. Schwartz said that he has received grant support from Anthera, Resverlogix, Roche, and Sanofi. Dr. Tall had no disclosures.

LOS ANGELES – The idea that raising blood levels of high-density lipoprotein cholesterol will cut cardiovascular events in patients with coronary disease took another hit with the flat clinical impact of dalcetrapib in a pivotal phase III trial with more than 15,000 patients.

Dalcetrapib did what it was supposed to do, at least physiologically: It raised patients’ HDL cholesterol levels by an average of about 30% compared with placebo. Despite that, patients who received the drug showed absolutely no drop in cardiovascular event rates during a median 31 months’ follow-up, Dr. Gregory G. Schwartz reported at the annual scientific sessions of the American Heart Association.

Mitchel L. Zoler/IMNG Medical Media

Because of the lack of any suggestion of benefit from treatment, the trial’s Data and Safety Monitoring Board recommended stopping the dal-OUTCOMES trial because of futility at one of the study’s prespecified review points.

The disappointing result made dalcetrapib, a cholesterol ester transfer protein (CETP) inhibitor, the second agent from this class to strike out in phase III testing. Five years ago, torcetrapib, the first CETP inhibitor drug to enter advanced clinical testing, crashed and burned in a phase III trial when it significantly boosted patient morbidity and mortality despite raising HDL cholesterol by 72% and cutting LDL levels by 25%, possibly because torcetrapib also boosted systolic blood pressure by an average of about 5 mm Hg (N. Engl. J. Med. 2007;357:2109-22).

Dalcetrapib was not nearly as dangerous as torcetrapib. In the new study, treatment with dalcetrapib was linked to a modest, average 0.6-mm rise in systolic blood pressure, and an equally slight 0.2-mg average increase in blood levels of C-reactive protein. Whether these effects had an impact on the clinical bottom line remains unknown, but the study results showed that the primary efficacy event curve for patients on dalcetrapib was completely superimposed with the curve for patients on placebo, reported Dr. Schwartz, chief of cardiology at the Denver VA Medical Center.

Both Dr. Schwartz and Dr. Alan Tall, the designated discussant for the study at the meeting, agreed that the disappointing performances of dalcetrapib and torcetrapib in phase III trials did not automatically mean that the CETP drug class has totally washed out. They both cited the importance of waiting for results from two other phase III studies now in progress that are testing two more CETP agents that are molecularly distinct from the two that did not pan out. Those agents are anacetrapib, currently being tested in a 30,000-patient study, the REVEAL (Randomized Evaluation of the Effects of Anacetrapib Through Lipid-Modification) trial, with results expected in 2017; and evacetrapib, now being tested in an 11,000-patient study, the ACCELERATE (Assessment of Clinical Effects of Cholesteryl Ester Transfer Protein Inhibition With Evacetrapib in Patients at a High-Risk for Vascular Outcomes) trial, with results expected in 2015.

"All four drugs have different chemical structures and biological effects," and so the outcomes seen so far with dalcetrapib and torcetrapib "are not necessarily harbingers" of what might lie ahead with the anacetrapib and evacetrapib trials, said Dr. Tall, professor and director of the Center of Research in Molecular Medicine and Atherosclerosis at Columbia University in New York.

"The results from anacetrapib and evacetrapib [in phase II studies] make a blood pressure increase [caused by either drug] unlikely," noted Dr. Schwartz. In addition, "dalcetrapib has no effect on LDL cholesterol, while anacetrapib and evacetrapib both increase LDL considerably."

But another possibility – that any agent that works primarily by raising HDL cholesterol may have little clinical benefit – cannot be dismissed based on current knowledge, Dr. Schwartz warned.

Mitchel L. Zoler/IMNG Medical Media

"The modified risk produced by raising HDL cholesterol may not be significant compared with other treatments that patients get," Dr. Schwartz cautioned. In the dal-OUTCOMES trial, the average LDL cholesterol level was 76 mg/dL. Against this background, "even in the quartile of about 1,600 patients in the dalcetrapib group who achieved the highest level of HDL cholesterol, a level of about 70-75 mg/dL, we saw no apparent reduction in risk."

Concurrent with Dr. Schwartz’s report at the meeting, the results of the dal-OUTCOMES study were published online (N. Engl. J. Med. 2012 Nov. 9 [doi: 10.1056/NEJMoa1206797]).

The dal-OUTCOMES trial was sponsored by Hoffman-La Roche, the company developing dalcetrapib. Dr. Schwartz said that he has received grant support from Anthera, Resverlogix, Roche, and Sanofi. Dr. Tall had no disclosures.

LOS ANGELES – The distinct possibility that using dipeptidyl peptidase-4 inhibitors to treat hyperglycemia in type 2 diabetic patients may substantially reduce the risk of major cardiovascular events has been raised in a comprehensive new meta-analysis of randomized controlled trials.

This finding must be viewed as hypothesis generating and nondefinitive in light of the well-known limitations of meta-analysis as applied to numerous small randomized trials, Dr. Kari A.O. Tikkinen cautioned at the annual scientific sessions of the American Heart Association.

"These results are encouraging, but large-scale confirmatory studies are needed before these drugs can be prescribed to lower the risk of cardiovascular events," said Dr. Tikkinen of McMaster University, Hamilton, Ontario.

Definitive answers as to whether the dipeptidyl peptidase-4 (DPP-4) inhibitors protect patients with type 2 diabetes against MI and other major adverse cardiovascular events must await the outcome of four ongoing large prospective randomized trials due to report results in 2-4 years.

Nevertheless, in the interim, the new meta-analysis provides a high degree of reassurance on one score: "We think it’s extremely unlikely that these drugs increase cardiovascular events," he declared.

Several prior meta-analyses by other investigators have been published. All had significant methodologic shortcomings, including inappropriate inclusion of "soft" cardiovascular end points and lack of grading of the quality of the evidence. This was the impetus for the new meta-analysis, which was restricted to randomized trials of at least 12 weeks’ duration in which a DPP-4 inhibitor was compared to placebo, usual care, or other active agents, most often metformin.

All trials included in the new meta-analysis showed evidence of a concerted effort by investigators to systematically capture cardiovascular events. That’s important because scrupulous attention to cardiovascular events did not always occur in studies completed prior to 2008, when the FDA issued an edict emphasizing the necessity of doing so in reaction to the unexpected finding that rosiglitazone increased cardiovascular risk, Dr. Tikkinen explained.

In the new meta-analysis, methodologically trained reviewers searched Medline, the Cochrane Library, EMBASE, and the Food and Drug Administration and European regulatory databases. They identified 42 randomized trials of DDP-4 inhibitors and 13 trials of glucagon-like peptide-1 (GLP-1) agonists that qualified. Dr. Tikkinen restricted his comments to the meta-analysis of the DPP-4 inhibitor trials; the GLP-1 agonist meta-analysis will be presented at a later date.

Nineteen DPP-4 inhibitor trials involved sitagliptin, 10 involved saxagliptin, 7 vildagliptin, and 6 alogliptin. Follow-up was 12-104 weeks, with 10 of the 42 trials featuring follow-up times in excess of 26 weeks. Nineteen trials focused on DPP-4 inhibitor monotherapy; the other 23 addressed the drugs as add-on therapy.

The primary composite end point chosen for the meta-analysis was comprised of cardiovascular death, MI, and stroke. One hundred ten of these events occurred in 24,215 randomized patients. The bottom line: The relative risk was reduced by 49% in patients on a DPP-4 inhibitor. Most of this benefit was the result of a 72% relative risk reduction in MIs in DPP-4 inhibitor-treated patients.

Patients randomized to a DPP-4 inhibitor as monotherapy had only a modest, nonsignificant reduction in the primary end point rate. In contrast, patients on add-on DPP-4 inhibitor therapy had a 54% relative risk reduction (P = .049).

"Our results suggest that add-on therapy would be more effective. However, this is borderline statistically significant and a subgroup analysis, so you should be very cautious in interpreting it," according to Dr. Tikkinen.

No difference in treatment effect was found between study durations of 12-26 weeks and more than 26 weeks. And there was no significant difference in cardioprotective efficacy between the four DPP-4 inhibitors.

"The confidence intervals overlapped, so we can’t say from our study which of these drugs is the best," he said.

Using statistical analytic methods, the investigators determined that 39 of the 42 clinical trials included in their study had a low risk of bias.

The DPP-4 inhibitors decrease blood glucose levels by enhancing activity of the incretins glucose-dependent insulinotropic peptide and glucagon-like peptide-1.

The meta-analysis was funded by Bristol-Myers Squibb and AstraZeneca. Dr. Tikkinen reported having no financial conflicts.

LOS ANGELES – The distinct possibility that using dipeptidyl peptidase-4 inhibitors to treat hyperglycemia in type 2 diabetic patients may substantially reduce the risk of major cardiovascular events has been raised in a comprehensive new meta-analysis of randomized controlled trials.

This finding must be viewed as hypothesis generating and nondefinitive in light of the well-known limitations of meta-analysis as applied to numerous small randomized trials, Dr. Kari A.O. Tikkinen cautioned at the annual scientific sessions of the American Heart Association.

"These results are encouraging, but large-scale confirmatory studies are needed before these drugs can be prescribed to lower the risk of cardiovascular events," said Dr. Tikkinen of McMaster University, Hamilton, Ontario.

Definitive answers as to whether the dipeptidyl peptidase-4 (DPP-4) inhibitors protect patients with type 2 diabetes against MI and other major adverse cardiovascular events must await the outcome of four ongoing large prospective randomized trials due to report results in 2-4 years.

Nevertheless, in the interim, the new meta-analysis provides a high degree of reassurance on one score: "We think it’s extremely unlikely that these drugs increase cardiovascular events," he declared.

Several prior meta-analyses by other investigators have been published. All had significant methodologic shortcomings, including inappropriate inclusion of "soft" cardiovascular end points and lack of grading of the quality of the evidence. This was the impetus for the new meta-analysis, which was restricted to randomized trials of at least 12 weeks’ duration in which a DPP-4 inhibitor was compared to placebo, usual care, or other active agents, most often metformin.

All trials included in the new meta-analysis showed evidence of a concerted effort by investigators to systematically capture cardiovascular events. That’s important because scrupulous attention to cardiovascular events did not always occur in studies completed prior to 2008, when the FDA issued an edict emphasizing the necessity of doing so in reaction to the unexpected finding that rosiglitazone increased cardiovascular risk, Dr. Tikkinen explained.

In the new meta-analysis, methodologically trained reviewers searched Medline, the Cochrane Library, EMBASE, and the Food and Drug Administration and European regulatory databases. They identified 42 randomized trials of DDP-4 inhibitors and 13 trials of glucagon-like peptide-1 (GLP-1) agonists that qualified. Dr. Tikkinen restricted his comments to the meta-analysis of the DPP-4 inhibitor trials; the GLP-1 agonist meta-analysis will be presented at a later date.

Nineteen DPP-4 inhibitor trials involved sitagliptin, 10 involved saxagliptin, 7 vildagliptin, and 6 alogliptin. Follow-up was 12-104 weeks, with 10 of the 42 trials featuring follow-up times in excess of 26 weeks. Nineteen trials focused on DPP-4 inhibitor monotherapy; the other 23 addressed the drugs as add-on therapy.

The primary composite end point chosen for the meta-analysis was comprised of cardiovascular death, MI, and stroke. One hundred ten of these events occurred in 24,215 randomized patients. The bottom line: The relative risk was reduced by 49% in patients on a DPP-4 inhibitor. Most of this benefit was the result of a 72% relative risk reduction in MIs in DPP-4 inhibitor-treated patients.

Patients randomized to a DPP-4 inhibitor as monotherapy had only a modest, nonsignificant reduction in the primary end point rate. In contrast, patients on add-on DPP-4 inhibitor therapy had a 54% relative risk reduction (P = .049).

"Our results suggest that add-on therapy would be more effective. However, this is borderline statistically significant and a subgroup analysis, so you should be very cautious in interpreting it," according to Dr. Tikkinen.

No difference in treatment effect was found between study durations of 12-26 weeks and more than 26 weeks. And there was no significant difference in cardioprotective efficacy between the four DPP-4 inhibitors.

"The confidence intervals overlapped, so we can’t say from our study which of these drugs is the best," he said.

Using statistical analytic methods, the investigators determined that 39 of the 42 clinical trials included in their study had a low risk of bias.

The DPP-4 inhibitors decrease blood glucose levels by enhancing activity of the incretins glucose-dependent insulinotropic peptide and glucagon-like peptide-1.

The meta-analysis was funded by Bristol-Myers Squibb and AstraZeneca. Dr. Tikkinen reported having no financial conflicts.

LOS ANGELES – The distinct possibility that using dipeptidyl peptidase-4 inhibitors to treat hyperglycemia in type 2 diabetic patients may substantially reduce the risk of major cardiovascular events has been raised in a comprehensive new meta-analysis of randomized controlled trials.

This finding must be viewed as hypothesis generating and nondefinitive in light of the well-known limitations of meta-analysis as applied to numerous small randomized trials, Dr. Kari A.O. Tikkinen cautioned at the annual scientific sessions of the American Heart Association.

"These results are encouraging, but large-scale confirmatory studies are needed before these drugs can be prescribed to lower the risk of cardiovascular events," said Dr. Tikkinen of McMaster University, Hamilton, Ontario.

Definitive answers as to whether the dipeptidyl peptidase-4 (DPP-4) inhibitors protect patients with type 2 diabetes against MI and other major adverse cardiovascular events must await the outcome of four ongoing large prospective randomized trials due to report results in 2-4 years.

Nevertheless, in the interim, the new meta-analysis provides a high degree of reassurance on one score: "We think it’s extremely unlikely that these drugs increase cardiovascular events," he declared.

Several prior meta-analyses by other investigators have been published. All had significant methodologic shortcomings, including inappropriate inclusion of "soft" cardiovascular end points and lack of grading of the quality of the evidence. This was the impetus for the new meta-analysis, which was restricted to randomized trials of at least 12 weeks’ duration in which a DPP-4 inhibitor was compared to placebo, usual care, or other active agents, most often metformin.

All trials included in the new meta-analysis showed evidence of a concerted effort by investigators to systematically capture cardiovascular events. That’s important because scrupulous attention to cardiovascular events did not always occur in studies completed prior to 2008, when the FDA issued an edict emphasizing the necessity of doing so in reaction to the unexpected finding that rosiglitazone increased cardiovascular risk, Dr. Tikkinen explained.

In the new meta-analysis, methodologically trained reviewers searched Medline, the Cochrane Library, EMBASE, and the Food and Drug Administration and European regulatory databases. They identified 42 randomized trials of DDP-4 inhibitors and 13 trials of glucagon-like peptide-1 (GLP-1) agonists that qualified. Dr. Tikkinen restricted his comments to the meta-analysis of the DPP-4 inhibitor trials; the GLP-1 agonist meta-analysis will be presented at a later date.

Nineteen DPP-4 inhibitor trials involved sitagliptin, 10 involved saxagliptin, 7 vildagliptin, and 6 alogliptin. Follow-up was 12-104 weeks, with 10 of the 42 trials featuring follow-up times in excess of 26 weeks. Nineteen trials focused on DPP-4 inhibitor monotherapy; the other 23 addressed the drugs as add-on therapy.

The primary composite end point chosen for the meta-analysis was comprised of cardiovascular death, MI, and stroke. One hundred ten of these events occurred in 24,215 randomized patients. The bottom line: The relative risk was reduced by 49% in patients on a DPP-4 inhibitor. Most of this benefit was the result of a 72% relative risk reduction in MIs in DPP-4 inhibitor-treated patients.

Patients randomized to a DPP-4 inhibitor as monotherapy had only a modest, nonsignificant reduction in the primary end point rate. In contrast, patients on add-on DPP-4 inhibitor therapy had a 54% relative risk reduction (P = .049).

"Our results suggest that add-on therapy would be more effective. However, this is borderline statistically significant and a subgroup analysis, so you should be very cautious in interpreting it," according to Dr. Tikkinen.

No difference in treatment effect was found between study durations of 12-26 weeks and more than 26 weeks. And there was no significant difference in cardioprotective efficacy between the four DPP-4 inhibitors.

"The confidence intervals overlapped, so we can’t say from our study which of these drugs is the best," he said.

Using statistical analytic methods, the investigators determined that 39 of the 42 clinical trials included in their study had a low risk of bias.

The DPP-4 inhibitors decrease blood glucose levels by enhancing activity of the incretins glucose-dependent insulinotropic peptide and glucagon-like peptide-1.

The meta-analysis was funded by Bristol-Myers Squibb and AstraZeneca. Dr. Tikkinen reported having no financial conflicts.

LOS ANGELES – Cardiac resynchronization therapy may be on the verge of a strong new indication for the prevention of progression of heart failure in patients with atrioventricular block who are not candidates for the device therapy on the basis of current criteria.

Results of the BLOCK-HF trial comparing biventricular pacing using a CRT device to standard right ventricular pacing demonstrated that in patients with AV block and systolic heart failure, biventricular pacing led to a significant 26% reduction in the combined end point of death, heart failure–related urgent care, or deterioration in heart function as defined echocardiographically by more than a 15% increase in the left ventricular end systolic volume index, Dr. Anne B. Curtis reported at the annual scientific sessions of the American Heart Association.

BLOCK-HF (Biventricular Versus Right Ventricular Pacing in Heart Failure Patients With Atrioventricular Block) was a randomized, double-blind, prospective, multicenter study of 691 patients with class I-III heart failure, a left ventricular ejection fraction (LVEF) of 50% or less, and AV block necessitating pacing. None had a class I indication for CRT by current guidelines. All participants received a CRT device programmed for right ventricular pacing only while optimal medical therapy was established, which took 30-60 days. Once that occurred, subjects were randomized double-blind to biventricular or right ventricular pacing. Analysis was by intent-to-treat.

Of those participants, 207 patients received a combined CRT/defibrillator device because they met criteria for a primary prevention implantable cardioverter-defibrillator; the rest got a CRT pacemaker-only device, said Dr. Curtis, BLOCK-HF principal investigator and professor and chair of the department of medicine at the University at Buffalo (N.Y.).

At an average of 36 months’ follow-up, the combined primary end point had occurred in roughly 60% of the biventricular pacing group, representing a 26% relative risk reduction compared with conventional right ventricular pacing. The rate of the two clinical components of the primary end point – mortality and heart failure–related urgent care – was 27% lower in the biventricular pacing group.

Results were the same in patients with a CRT pacing-only device as for those with a CRT/defibrillator, even though those with the CRT/defibrillator had an average LVEF of 33%, compared with an LVEF of 44% in those who got the pacing-only device. Dr. Curtis said that although a formal subgroup analysis based on heart failure functional class is planned, it’s her anecdotal impression that the benefits of biventricular pacing were similar across the board.

A pronounced imbalance in crossovers between the two study arms occurred: 25% of subjects randomized to right ventricular pacing crossed over to biventricular pacing, while 5% assigned to biventricular pacing crossed to right ventricular pacing.

"If anything, this would tend to minimize the differences we found," Dr. Curtis noted.

Roughly 1 million people in the United States have AV block, and there are 6 million individuals with the diagnosis of heart failure.

Discussant Dr. Gerasimos S. Filippatos of the University of Athens declared that the BLOCK-HF results will certainly lead to a reconsideration of current European Society of Cardiology and joint American College of Cardiology/AHA/Heart Rhythm Society guidelines for heart failure patients with heart block.

As a heart failure specialist and nonelectrophysiologist, Dr. Filippatos said he found the procedure-related complication rates notably high: 33% in recipients of CRT pacing-only devices and 17% in those who got a CRT/defibrillator.

Dr. Curtis replied that complication rates are always higher when putting in a left ventricular lead because it’s a more difficult procedure than putting in a right ventricular lead. One of the key points of BLOCK-HF, she added, was to look at whether or not putting patients through the added difficulty of implanting a biventricular pacing device has clear benefits – and the answer is yes.

The BLOCK-HF trial was sponsored by Medtronic. Dr. Curtis reported serving as a consultant to that company and to Biosense Webster, Sanofi-Aventis, and Bristol-Myers Squibb. Dr. Filippatos is a consultant to Novartis.

LOS ANGELES – Cardiac resynchronization therapy may be on the verge of a strong new indication for the prevention of progression of heart failure in patients with atrioventricular block who are not candidates for the device therapy on the basis of current criteria.

Results of the BLOCK-HF trial comparing biventricular pacing using a CRT device to standard right ventricular pacing demonstrated that in patients with AV block and systolic heart failure, biventricular pacing led to a significant 26% reduction in the combined end point of death, heart failure–related urgent care, or deterioration in heart function as defined echocardiographically by more than a 15% increase in the left ventricular end systolic volume index, Dr. Anne B. Curtis reported at the annual scientific sessions of the American Heart Association.

BLOCK-HF (Biventricular Versus Right Ventricular Pacing in Heart Failure Patients With Atrioventricular Block) was a randomized, double-blind, prospective, multicenter study of 691 patients with class I-III heart failure, a left ventricular ejection fraction (LVEF) of 50% or less, and AV block necessitating pacing. None had a class I indication for CRT by current guidelines. All participants received a CRT device programmed for right ventricular pacing only while optimal medical therapy was established, which took 30-60 days. Once that occurred, subjects were randomized double-blind to biventricular or right ventricular pacing. Analysis was by intent-to-treat.

Of those participants, 207 patients received a combined CRT/defibrillator device because they met criteria for a primary prevention implantable cardioverter-defibrillator; the rest got a CRT pacemaker-only device, said Dr. Curtis, BLOCK-HF principal investigator and professor and chair of the department of medicine at the University at Buffalo (N.Y.).

At an average of 36 months’ follow-up, the combined primary end point had occurred in roughly 60% of the biventricular pacing group, representing a 26% relative risk reduction compared with conventional right ventricular pacing. The rate of the two clinical components of the primary end point – mortality and heart failure–related urgent care – was 27% lower in the biventricular pacing group.

Results were the same in patients with a CRT pacing-only device as for those with a CRT/defibrillator, even though those with the CRT/defibrillator had an average LVEF of 33%, compared with an LVEF of 44% in those who got the pacing-only device. Dr. Curtis said that although a formal subgroup analysis based on heart failure functional class is planned, it’s her anecdotal impression that the benefits of biventricular pacing were similar across the board.

A pronounced imbalance in crossovers between the two study arms occurred: 25% of subjects randomized to right ventricular pacing crossed over to biventricular pacing, while 5% assigned to biventricular pacing crossed to right ventricular pacing.

"If anything, this would tend to minimize the differences we found," Dr. Curtis noted.

Roughly 1 million people in the United States have AV block, and there are 6 million individuals with the diagnosis of heart failure.

Discussant Dr. Gerasimos S. Filippatos of the University of Athens declared that the BLOCK-HF results will certainly lead to a reconsideration of current European Society of Cardiology and joint American College of Cardiology/AHA/Heart Rhythm Society guidelines for heart failure patients with heart block.

As a heart failure specialist and nonelectrophysiologist, Dr. Filippatos said he found the procedure-related complication rates notably high: 33% in recipients of CRT pacing-only devices and 17% in those who got a CRT/defibrillator.

Dr. Curtis replied that complication rates are always higher when putting in a left ventricular lead because it’s a more difficult procedure than putting in a right ventricular lead. One of the key points of BLOCK-HF, she added, was to look at whether or not putting patients through the added difficulty of implanting a biventricular pacing device has clear benefits – and the answer is yes.

The BLOCK-HF trial was sponsored by Medtronic. Dr. Curtis reported serving as a consultant to that company and to Biosense Webster, Sanofi-Aventis, and Bristol-Myers Squibb. Dr. Filippatos is a consultant to Novartis.

LOS ANGELES – Cardiac resynchronization therapy may be on the verge of a strong new indication for the prevention of progression of heart failure in patients with atrioventricular block who are not candidates for the device therapy on the basis of current criteria.

Results of the BLOCK-HF trial comparing biventricular pacing using a CRT device to standard right ventricular pacing demonstrated that in patients with AV block and systolic heart failure, biventricular pacing led to a significant 26% reduction in the combined end point of death, heart failure–related urgent care, or deterioration in heart function as defined echocardiographically by more than a 15% increase in the left ventricular end systolic volume index, Dr. Anne B. Curtis reported at the annual scientific sessions of the American Heart Association.

BLOCK-HF (Biventricular Versus Right Ventricular Pacing in Heart Failure Patients With Atrioventricular Block) was a randomized, double-blind, prospective, multicenter study of 691 patients with class I-III heart failure, a left ventricular ejection fraction (LVEF) of 50% or less, and AV block necessitating pacing. None had a class I indication for CRT by current guidelines. All participants received a CRT device programmed for right ventricular pacing only while optimal medical therapy was established, which took 30-60 days. Once that occurred, subjects were randomized double-blind to biventricular or right ventricular pacing. Analysis was by intent-to-treat.

Of those participants, 207 patients received a combined CRT/defibrillator device because they met criteria for a primary prevention implantable cardioverter-defibrillator; the rest got a CRT pacemaker-only device, said Dr. Curtis, BLOCK-HF principal investigator and professor and chair of the department of medicine at the University at Buffalo (N.Y.).

At an average of 36 months’ follow-up, the combined primary end point had occurred in roughly 60% of the biventricular pacing group, representing a 26% relative risk reduction compared with conventional right ventricular pacing. The rate of the two clinical components of the primary end point – mortality and heart failure–related urgent care – was 27% lower in the biventricular pacing group.

Results were the same in patients with a CRT pacing-only device as for those with a CRT/defibrillator, even though those with the CRT/defibrillator had an average LVEF of 33%, compared with an LVEF of 44% in those who got the pacing-only device. Dr. Curtis said that although a formal subgroup analysis based on heart failure functional class is planned, it’s her anecdotal impression that the benefits of biventricular pacing were similar across the board.

A pronounced imbalance in crossovers between the two study arms occurred: 25% of subjects randomized to right ventricular pacing crossed over to biventricular pacing, while 5% assigned to biventricular pacing crossed to right ventricular pacing.

"If anything, this would tend to minimize the differences we found," Dr. Curtis noted.

Roughly 1 million people in the United States have AV block, and there are 6 million individuals with the diagnosis of heart failure.

Discussant Dr. Gerasimos S. Filippatos of the University of Athens declared that the BLOCK-HF results will certainly lead to a reconsideration of current European Society of Cardiology and joint American College of Cardiology/AHA/Heart Rhythm Society guidelines for heart failure patients with heart block.

As a heart failure specialist and nonelectrophysiologist, Dr. Filippatos said he found the procedure-related complication rates notably high: 33% in recipients of CRT pacing-only devices and 17% in those who got a CRT/defibrillator.

Dr. Curtis replied that complication rates are always higher when putting in a left ventricular lead because it’s a more difficult procedure than putting in a right ventricular lead. One of the key points of BLOCK-HF, she added, was to look at whether or not putting patients through the added difficulty of implanting a biventricular pacing device has clear benefits – and the answer is yes.

The BLOCK-HF trial was sponsored by Medtronic. Dr. Curtis reported serving as a consultant to that company and to Biosense Webster, Sanofi-Aventis, and Bristol-Myers Squibb. Dr. Filippatos is a consultant to Novartis.