Caroline Helwick

A history of foot ulcers is associated with an increased risk of mortality among community-dwelling adults and elderly people with diabetes, according to a 10-year follow-up of the Nord-Trøndelag Health Study (HUNT 2).

The risk persisted after adjustment for comorbidity and depression scores, suggesting the need for close monitoring, said Marjolein M. Iversen of Bergen (Norway) University, and associates.

The study included 155 diabetic persons with a history of foot ulcers, 1,339 diabetic persons without a history of foot ulcers, and 63,632 nondiabetic persons, followed for 10 years with mortality as the end point (Diabetes Care 2009 Sept. 3 [doi: 10.2337/dc09-0651]).

In a Cox regression analysis, having a history of foot ulcers was associated with more than a twofold (2.29 [95% confidence interval 1.82-2.88]) hazard risk for mortality, versus those in the nondiabetic group, and a 47% increase in mortality, versus diabetic persons without a history of foot ulcers.

A history of foot ulcers is associated with an increased risk of mortality among community-dwelling adults and elderly people with diabetes, according to a 10-year follow-up of the Nord-Trøndelag Health Study (HUNT 2).

The risk persisted after adjustment for comorbidity and depression scores, suggesting the need for close monitoring, said Marjolein M. Iversen of Bergen (Norway) University, and associates.

The study included 155 diabetic persons with a history of foot ulcers, 1,339 diabetic persons without a history of foot ulcers, and 63,632 nondiabetic persons, followed for 10 years with mortality as the end point (Diabetes Care 2009 Sept. 3 [doi: 10.2337/dc09-0651]).

In a Cox regression analysis, having a history of foot ulcers was associated with more than a twofold (2.29 [95% confidence interval 1.82-2.88]) hazard risk for mortality, versus those in the nondiabetic group, and a 47% increase in mortality, versus diabetic persons without a history of foot ulcers.

A history of foot ulcers is associated with an increased risk of mortality among community-dwelling adults and elderly people with diabetes, according to a 10-year follow-up of the Nord-Trøndelag Health Study (HUNT 2).

The risk persisted after adjustment for comorbidity and depression scores, suggesting the need for close monitoring, said Marjolein M. Iversen of Bergen (Norway) University, and associates.

The study included 155 diabetic persons with a history of foot ulcers, 1,339 diabetic persons without a history of foot ulcers, and 63,632 nondiabetic persons, followed for 10 years with mortality as the end point (Diabetes Care 2009 Sept. 3 [doi: 10.2337/dc09-0651]).

In a Cox regression analysis, having a history of foot ulcers was associated with more than a twofold (2.29 [95% confidence interval 1.82-2.88]) hazard risk for mortality, versus those in the nondiabetic group, and a 47% increase in mortality, versus diabetic persons without a history of foot ulcers.

NEW ORLEANS — In patients with non-ST-segment elevation acute coronary syndromes, invasive treatment within 24 hours causes no harm, and in high-risk patients it may reduce the risk of adverse cardiovascular events, compared with delaying intervention, according to results of a large international trial.

The Timing of Intervention in Acute Coronary Syndrome (TIMACS) trial, involving 3,031 patients treated at 100 medical centers in 17 countries, “is the largest trial there will ever be on this topic. It is immediately relevant to patients, doctors, and the health care system,” said Dr. Deepak Bhatt, the study's discussant at the annual scientific sessions of the American Heart Association.

TIMACS compared the relative usefulness, safety, and cost-effectiveness of early angiography (within 24 hours), followed by revascularization if necessary, with procedures delayed more than 36 hours after the onset of unstable angina or non-ST-segment elevation myocardial infarction (NSTEMI). Eligible patients were treated with aspirin, clopidogrel, and/or a glycoprotein IIb/IIIa antagonist in accordance with routine practice and were then randomized to receive either early or delayed intervention.

“We have very good data in patients with myocardial infarction that timely thrombolytic therapy is of utmost importance,” the principal author, Shamir R. Mehta, said in describing the rationale for the study. “But we have less information on the importance of timing in patients with unstable angina, threatened MI, or NSTEMI.”

For the primary end point, a composite of death, recurrent MI, or stroke within 6 months, the study found no significant risk reduction in favor of early intervention: 9.7% occurred in the early intervention group, compared with 11.4% in the delayed group, for a 15% relative reduction in risk that did not reach statistical significance, reported Dr. Mehta, director of interventional cardiology at Hamilton (Ont.) Health Sciences.

However, for several secondary outcome measures, differences favored early intervention. These included the composite of death, MI, and refractory ischemia, with rates of 13.1% in the delayed arm and 9.6% with early intervention; the composite of death, MI, stroke, refractory ischemia and repeat intervention, which occurred in 19.7% and 16.7%, respectively; and the outcome of repeat interventions, which occurred in 8.8% and 8.6%, respectively.

But it was the patients considered to be at the highest risk who benefited most from early intervention. Striking differences emerged when patients were stratified by the Global Registry of Acute Coronary Events (GRACE) risk score. Early diagnostic angiography reduced the relative risk of the composite end point of death, repeat MI, or stroke by 35% in a high-risk subset of patients with NSTEMI. For patients with low or intermediate risk for death with acute coronary syndromes (about two-thirds of the cohort), the slower strategy was just as effective, reported Dr. Mehta, also of McMaster University, Hamilton, Ont.

For patients with a high GRACE score (at least 140), the rate of death, MI, or stroke at 6 months was 21.6% with delayed intervention, compared with 14.1% with early treatment, a significant difference. In the low- to intermediate-risk group, the difference between the strategies was not statistically significant, at 6.7% and 7.7%, respectively.

“In the highest risk subset, early intervention appeared superior, and these patients should be taken to the cath lab as soon as possible. With others, the timing depends on additional factors. Since there are no safety concerns with early intervention, and given that it lowers refractory ischemia by about 70%, it is a reasonable routine option for all patients with ACS,” Dr. Mehta concluded.

“There has been a concern that it may be dangerous to take patients with these forms of chest pain to the catheterization lab too quickly, that a period of 'cooling off' with medical therapy may be of benefit. This has been disproved. There is no detriment to going early and there is definitely a shorter hospital stay. In high-risk patients, this trial proves there is clearly a benefit to early intervention, which is consistent with clinical common sense,” said Dr. Bhatt, chief of cardiology at the VA Boston Health Care System and director of the Integrated Interventional Cardiovascular Program at Brigham and Women's Hospital, Boston.

Early intervention 'is a reasonable routine option for all patients with ACS.' DR. MEHTA

NEW ORLEANS — In patients with non-ST-segment elevation acute coronary syndromes, invasive treatment within 24 hours causes no harm, and in high-risk patients it may reduce the risk of adverse cardiovascular events, compared with delaying intervention, according to results of a large international trial.

The Timing of Intervention in Acute Coronary Syndrome (TIMACS) trial, involving 3,031 patients treated at 100 medical centers in 17 countries, “is the largest trial there will ever be on this topic. It is immediately relevant to patients, doctors, and the health care system,” said Dr. Deepak Bhatt, the study's discussant at the annual scientific sessions of the American Heart Association.

TIMACS compared the relative usefulness, safety, and cost-effectiveness of early angiography (within 24 hours), followed by revascularization if necessary, with procedures delayed more than 36 hours after the onset of unstable angina or non-ST-segment elevation myocardial infarction (NSTEMI). Eligible patients were treated with aspirin, clopidogrel, and/or a glycoprotein IIb/IIIa antagonist in accordance with routine practice and were then randomized to receive either early or delayed intervention.

“We have very good data in patients with myocardial infarction that timely thrombolytic therapy is of utmost importance,” the principal author, Shamir R. Mehta, said in describing the rationale for the study. “But we have less information on the importance of timing in patients with unstable angina, threatened MI, or NSTEMI.”

For the primary end point, a composite of death, recurrent MI, or stroke within 6 months, the study found no significant risk reduction in favor of early intervention: 9.7% occurred in the early intervention group, compared with 11.4% in the delayed group, for a 15% relative reduction in risk that did not reach statistical significance, reported Dr. Mehta, director of interventional cardiology at Hamilton (Ont.) Health Sciences.

However, for several secondary outcome measures, differences favored early intervention. These included the composite of death, MI, and refractory ischemia, with rates of 13.1% in the delayed arm and 9.6% with early intervention; the composite of death, MI, stroke, refractory ischemia and repeat intervention, which occurred in 19.7% and 16.7%, respectively; and the outcome of repeat interventions, which occurred in 8.8% and 8.6%, respectively.

But it was the patients considered to be at the highest risk who benefited most from early intervention. Striking differences emerged when patients were stratified by the Global Registry of Acute Coronary Events (GRACE) risk score. Early diagnostic angiography reduced the relative risk of the composite end point of death, repeat MI, or stroke by 35% in a high-risk subset of patients with NSTEMI. For patients with low or intermediate risk for death with acute coronary syndromes (about two-thirds of the cohort), the slower strategy was just as effective, reported Dr. Mehta, also of McMaster University, Hamilton, Ont.

For patients with a high GRACE score (at least 140), the rate of death, MI, or stroke at 6 months was 21.6% with delayed intervention, compared with 14.1% with early treatment, a significant difference. In the low- to intermediate-risk group, the difference between the strategies was not statistically significant, at 6.7% and 7.7%, respectively.

“In the highest risk subset, early intervention appeared superior, and these patients should be taken to the cath lab as soon as possible. With others, the timing depends on additional factors. Since there are no safety concerns with early intervention, and given that it lowers refractory ischemia by about 70%, it is a reasonable routine option for all patients with ACS,” Dr. Mehta concluded.

“There has been a concern that it may be dangerous to take patients with these forms of chest pain to the catheterization lab too quickly, that a period of 'cooling off' with medical therapy may be of benefit. This has been disproved. There is no detriment to going early and there is definitely a shorter hospital stay. In high-risk patients, this trial proves there is clearly a benefit to early intervention, which is consistent with clinical common sense,” said Dr. Bhatt, chief of cardiology at the VA Boston Health Care System and director of the Integrated Interventional Cardiovascular Program at Brigham and Women's Hospital, Boston.

Early intervention 'is a reasonable routine option for all patients with ACS.' DR. MEHTA

NEW ORLEANS — In patients with non-ST-segment elevation acute coronary syndromes, invasive treatment within 24 hours causes no harm, and in high-risk patients it may reduce the risk of adverse cardiovascular events, compared with delaying intervention, according to results of a large international trial.

The Timing of Intervention in Acute Coronary Syndrome (TIMACS) trial, involving 3,031 patients treated at 100 medical centers in 17 countries, “is the largest trial there will ever be on this topic. It is immediately relevant to patients, doctors, and the health care system,” said Dr. Deepak Bhatt, the study's discussant at the annual scientific sessions of the American Heart Association.

TIMACS compared the relative usefulness, safety, and cost-effectiveness of early angiography (within 24 hours), followed by revascularization if necessary, with procedures delayed more than 36 hours after the onset of unstable angina or non-ST-segment elevation myocardial infarction (NSTEMI). Eligible patients were treated with aspirin, clopidogrel, and/or a glycoprotein IIb/IIIa antagonist in accordance with routine practice and were then randomized to receive either early or delayed intervention.

“We have very good data in patients with myocardial infarction that timely thrombolytic therapy is of utmost importance,” the principal author, Shamir R. Mehta, said in describing the rationale for the study. “But we have less information on the importance of timing in patients with unstable angina, threatened MI, or NSTEMI.”

For the primary end point, a composite of death, recurrent MI, or stroke within 6 months, the study found no significant risk reduction in favor of early intervention: 9.7% occurred in the early intervention group, compared with 11.4% in the delayed group, for a 15% relative reduction in risk that did not reach statistical significance, reported Dr. Mehta, director of interventional cardiology at Hamilton (Ont.) Health Sciences.

However, for several secondary outcome measures, differences favored early intervention. These included the composite of death, MI, and refractory ischemia, with rates of 13.1% in the delayed arm and 9.6% with early intervention; the composite of death, MI, stroke, refractory ischemia and repeat intervention, which occurred in 19.7% and 16.7%, respectively; and the outcome of repeat interventions, which occurred in 8.8% and 8.6%, respectively.

But it was the patients considered to be at the highest risk who benefited most from early intervention. Striking differences emerged when patients were stratified by the Global Registry of Acute Coronary Events (GRACE) risk score. Early diagnostic angiography reduced the relative risk of the composite end point of death, repeat MI, or stroke by 35% in a high-risk subset of patients with NSTEMI. For patients with low or intermediate risk for death with acute coronary syndromes (about two-thirds of the cohort), the slower strategy was just as effective, reported Dr. Mehta, also of McMaster University, Hamilton, Ont.

For patients with a high GRACE score (at least 140), the rate of death, MI, or stroke at 6 months was 21.6% with delayed intervention, compared with 14.1% with early treatment, a significant difference. In the low- to intermediate-risk group, the difference between the strategies was not statistically significant, at 6.7% and 7.7%, respectively.

“In the highest risk subset, early intervention appeared superior, and these patients should be taken to the cath lab as soon as possible. With others, the timing depends on additional factors. Since there are no safety concerns with early intervention, and given that it lowers refractory ischemia by about 70%, it is a reasonable routine option for all patients with ACS,” Dr. Mehta concluded.

“There has been a concern that it may be dangerous to take patients with these forms of chest pain to the catheterization lab too quickly, that a period of 'cooling off' with medical therapy may be of benefit. This has been disproved. There is no detriment to going early and there is definitely a shorter hospital stay. In high-risk patients, this trial proves there is clearly a benefit to early intervention, which is consistent with clinical common sense,” said Dr. Bhatt, chief of cardiology at the VA Boston Health Care System and director of the Integrated Interventional Cardiovascular Program at Brigham and Women's Hospital, Boston.

Early intervention 'is a reasonable routine option for all patients with ACS.' DR. MEHTA

NEW ORLEANS — The arteries of obese and dyslipidemic children resemble those of middle-aged adults, possibly heralding the early onset of cardiovascular disease, according to a study presented at the annual scientific sessions of the American Heart Association.

“This is a wake-up call,” said coauthor Dr. Geetha Raghuveer, a cardiologist at Children's Mercy Hospital, Kansas City, Mo., who presented the findings. She noted that childhood obesity has already been shown to “track” into adulthood and to pose multiple risks to the vasculature.

Dr. Raghuveer and colleagues at the University of Missouri, Kansas City, and Children's Mercy Hospital measured the carotid artery intima-media thickness (CIMT) by ultrasound in 34 boys and 36 girls whose average age was 13 years. Most were obese, with a mean weight of 64 kg and mean body mass index of 26 kg/m

Most of the 70 also had abnormal lipid levels. Total cholesterol was greater than 170 mg/dL in 59 children and LDL cholesterol was above 110 mg/dL in 51; in 43 children, HDL cholesterol was less than 35 mg/dL and triglycerides were above 100 mg/dL.

To characterize the state of the carotid arteries in these children, the investigators plotted the CIMT measurements against previously published normative data for 45-year-olds matched by sex and race. The images revealed “advanced vascular age” in 75% of this young obese cohort. Mean CIMT was 0.45 mm, and maximum was 0.75 mm.

“We found that the state of the arteries in these children is more typical of 45-year-olds than of people their age,” reported Dr. Raghuveer. She noted that there are no normative standards of CIMT in children against which to compare the findings.

For example, a 12-year-old white male was shown to have a CIMT of 0.54 mm. Plotted against that of a 45-year-old male, this CIMT measurement fell between the 25th and 50th percentiles of the adult (0.50 and 0.57 mm, respectively). The researchers labeled the arteries as having “advanced age” if the CIMT exceeded the 25th percentile for their matched adult counterpart.

“We then wondered what might be favoring this early advancement in CIMT, and we found that those with advanced age had higher triglyceride levels,” she reported. More children with advanced vascular age had elevated triglyceride levels than normal triglycerides.

The same was found for the 40 most obese children, or those with BMI above the 95th percentile. Of those, 26 had both a vascular age above the 25th percentile of adults as well as a triglyceride level above 100 mg/dL. Children with lower triglycerides were evenly divided between those who scored below or above the 25th percentile on the charts for 45-year-olds. When a cutoff of 120 mg/dL was used to define high triglyceride, the result was stable. “More kids in the high vascular age group had higher triglycerides,” she added.

“Vascular age was advanced the furthest in the children with obesity and high triglyceride levels, so the combination of obesity and high triglycerides should be a red flag to the physician that a child is at high risk of heart disease,” she commented.

Future research should evaluate whether risk factor modification can change the vasculature over time, she said. “We are hoping that it can,” she added.

NEW ORLEANS — The arteries of obese and dyslipidemic children resemble those of middle-aged adults, possibly heralding the early onset of cardiovascular disease, according to a study presented at the annual scientific sessions of the American Heart Association.

“This is a wake-up call,” said coauthor Dr. Geetha Raghuveer, a cardiologist at Children's Mercy Hospital, Kansas City, Mo., who presented the findings. She noted that childhood obesity has already been shown to “track” into adulthood and to pose multiple risks to the vasculature.

Dr. Raghuveer and colleagues at the University of Missouri, Kansas City, and Children's Mercy Hospital measured the carotid artery intima-media thickness (CIMT) by ultrasound in 34 boys and 36 girls whose average age was 13 years. Most were obese, with a mean weight of 64 kg and mean body mass index of 26 kg/m

Most of the 70 also had abnormal lipid levels. Total cholesterol was greater than 170 mg/dL in 59 children and LDL cholesterol was above 110 mg/dL in 51; in 43 children, HDL cholesterol was less than 35 mg/dL and triglycerides were above 100 mg/dL.

To characterize the state of the carotid arteries in these children, the investigators plotted the CIMT measurements against previously published normative data for 45-year-olds matched by sex and race. The images revealed “advanced vascular age” in 75% of this young obese cohort. Mean CIMT was 0.45 mm, and maximum was 0.75 mm.

“We found that the state of the arteries in these children is more typical of 45-year-olds than of people their age,” reported Dr. Raghuveer. She noted that there are no normative standards of CIMT in children against which to compare the findings.

For example, a 12-year-old white male was shown to have a CIMT of 0.54 mm. Plotted against that of a 45-year-old male, this CIMT measurement fell between the 25th and 50th percentiles of the adult (0.50 and 0.57 mm, respectively). The researchers labeled the arteries as having “advanced age” if the CIMT exceeded the 25th percentile for their matched adult counterpart.

“We then wondered what might be favoring this early advancement in CIMT, and we found that those with advanced age had higher triglyceride levels,” she reported. More children with advanced vascular age had elevated triglyceride levels than normal triglycerides.

The same was found for the 40 most obese children, or those with BMI above the 95th percentile. Of those, 26 had both a vascular age above the 25th percentile of adults as well as a triglyceride level above 100 mg/dL. Children with lower triglycerides were evenly divided between those who scored below or above the 25th percentile on the charts for 45-year-olds. When a cutoff of 120 mg/dL was used to define high triglyceride, the result was stable. “More kids in the high vascular age group had higher triglycerides,” she added.

“Vascular age was advanced the furthest in the children with obesity and high triglyceride levels, so the combination of obesity and high triglycerides should be a red flag to the physician that a child is at high risk of heart disease,” she commented.

Future research should evaluate whether risk factor modification can change the vasculature over time, she said. “We are hoping that it can,” she added.

NEW ORLEANS — The arteries of obese and dyslipidemic children resemble those of middle-aged adults, possibly heralding the early onset of cardiovascular disease, according to a study presented at the annual scientific sessions of the American Heart Association.

“This is a wake-up call,” said coauthor Dr. Geetha Raghuveer, a cardiologist at Children's Mercy Hospital, Kansas City, Mo., who presented the findings. She noted that childhood obesity has already been shown to “track” into adulthood and to pose multiple risks to the vasculature.

Dr. Raghuveer and colleagues at the University of Missouri, Kansas City, and Children's Mercy Hospital measured the carotid artery intima-media thickness (CIMT) by ultrasound in 34 boys and 36 girls whose average age was 13 years. Most were obese, with a mean weight of 64 kg and mean body mass index of 26 kg/m

Most of the 70 also had abnormal lipid levels. Total cholesterol was greater than 170 mg/dL in 59 children and LDL cholesterol was above 110 mg/dL in 51; in 43 children, HDL cholesterol was less than 35 mg/dL and triglycerides were above 100 mg/dL.

To characterize the state of the carotid arteries in these children, the investigators plotted the CIMT measurements against previously published normative data for 45-year-olds matched by sex and race. The images revealed “advanced vascular age” in 75% of this young obese cohort. Mean CIMT was 0.45 mm, and maximum was 0.75 mm.

“We found that the state of the arteries in these children is more typical of 45-year-olds than of people their age,” reported Dr. Raghuveer. She noted that there are no normative standards of CIMT in children against which to compare the findings.

For example, a 12-year-old white male was shown to have a CIMT of 0.54 mm. Plotted against that of a 45-year-old male, this CIMT measurement fell between the 25th and 50th percentiles of the adult (0.50 and 0.57 mm, respectively). The researchers labeled the arteries as having “advanced age” if the CIMT exceeded the 25th percentile for their matched adult counterpart.

“We then wondered what might be favoring this early advancement in CIMT, and we found that those with advanced age had higher triglyceride levels,” she reported. More children with advanced vascular age had elevated triglyceride levels than normal triglycerides.

The same was found for the 40 most obese children, or those with BMI above the 95th percentile. Of those, 26 had both a vascular age above the 25th percentile of adults as well as a triglyceride level above 100 mg/dL. Children with lower triglycerides were evenly divided between those who scored below or above the 25th percentile on the charts for 45-year-olds. When a cutoff of 120 mg/dL was used to define high triglyceride, the result was stable. “More kids in the high vascular age group had higher triglycerides,” she added.

“Vascular age was advanced the furthest in the children with obesity and high triglyceride levels, so the combination of obesity and high triglycerides should be a red flag to the physician that a child is at high risk of heart disease,” she commented.

Future research should evaluate whether risk factor modification can change the vasculature over time, she said. “We are hoping that it can,” she added.

NEW ORLEANS — The arteries of obese and dyslipidemic children resemble those of middle-aged adults, possibly heralding the early onset of cardiovascular disease, according to a study presented at the annual scientific sessions of the American Heart Association.

“This is a wake-up call,” said coauthor Dr. Geetha Raghuveer, a cardiologist at Children's Mercy Hospital, Kansas City, Mo., who presented the findings. She noted that childhood obesity has already been shown to “track” into adulthood and to pose multiple risks to the vasculature.

Dr. Raghuveer and colleagues at the University of Missouri, Kansas City, and Children's Mercy Hospital measured the carotid artery intima-media thickness (CIMT) by ultrasound in 34 boys and 36 girls whose average age was 13 years. Most were obese, with a mean weight of 64 kg and mean body mass index of 26 kg/m

Most of the 70 also had abnormal lipid levels. Total cholesterol was greater than 170 mg/dL in 59 children and LDL cholesterol was above 110 mg/dL in 51; in 43 children, HDL cholesterol was less than 35 mg/dL and triglycerides were above 100 mg/dL.

To characterize the state of the carotid arteries in these children, the investigators plotted the CIMT measurements against previously published normative data for 45-year-olds matched by sex and race. The images revealed “advanced vascular age” in 75% of this young obese cohort. Mean CIMT was 0.45 mm, and maximum was 0.75 mm.

“We found that the state of the arteries in these children is more typical of 45-year-olds than of people their age,” reported Dr. Raghuveer. She noted that there are no normative standards of CIMT in children against which to compare the findings.

For example, a 12-year-old white male was shown to have a CIMT of 0.54 mm. Plotted against that of a 45-year-old male, this CIMT measurement fell between the 25th and 50th percentiles of the adult (0.50 and 0.57 mm, respectively). The researchers labeled the arteries as having “advanced age” if the CIMT exceeded the 25th percentile for their matched adult counterpart.

“We then wondered what might be favoring this early advancement in CIMT, and we found that those with advanced age had higher triglyceride levels,” Dr. Raghuveer reported. More children with advanced vascular age had elevated triglyceride levels than normal triglycerides.

The same was found for the 40 most obese children, or those with BMI above the 95th percentile. Of those, 26 had both a vascular age above the 25th percentile of adults as well as a triglyceride level above 100 mg/dL. Children with lower triglycerides were evenly divided between those who scored below or above the 25th percentile on the charts for 45-year-olds. When a cutoff of 120 mg/dL was used to define high triglyceride, the result was stable. “More kids in the high vascular age group had higher triglycerides,” she added.

“Vascular age was advanced the furthest in the children with obesity and high triglyceride levels, so the combination of obesity and high triglycerides should be a red flag to the physician that a child is at high risk of heart disease,” Dr. Raghuveer commented.

“Our take-home message is that obese children with abnormal lipids have arterial wall changes in association with cardiovascular risk factors quite early in life, and these can progress over time,” she concluded.

Future research should evaluate whether risk factor modification can change the vasculature over time, she said. “We are hoping that it can,” Dr. Raghuveer added. “These children do not have hard, calcified arterial plaque as we see in older people, and hopefully we can document some regression with changes in lifestyle [and] behaviors, and if need be, drug therapy.” Currently, children at her clinic who are identified as having advanced vascular age receive nutrition and exercise counseling.

NEW ORLEANS — The arteries of obese and dyslipidemic children resemble those of middle-aged adults, possibly heralding the early onset of cardiovascular disease, according to a study presented at the annual scientific sessions of the American Heart Association.

“This is a wake-up call,” said coauthor Dr. Geetha Raghuveer, a cardiologist at Children's Mercy Hospital, Kansas City, Mo., who presented the findings. She noted that childhood obesity has already been shown to “track” into adulthood and to pose multiple risks to the vasculature.

Dr. Raghuveer and colleagues at the University of Missouri, Kansas City, and Children's Mercy Hospital measured the carotid artery intima-media thickness (CIMT) by ultrasound in 34 boys and 36 girls whose average age was 13 years. Most were obese, with a mean weight of 64 kg and mean body mass index of 26 kg/m

Most of the 70 also had abnormal lipid levels. Total cholesterol was greater than 170 mg/dL in 59 children and LDL cholesterol was above 110 mg/dL in 51; in 43 children, HDL cholesterol was less than 35 mg/dL and triglycerides were above 100 mg/dL.

To characterize the state of the carotid arteries in these children, the investigators plotted the CIMT measurements against previously published normative data for 45-year-olds matched by sex and race. The images revealed “advanced vascular age” in 75% of this young obese cohort. Mean CIMT was 0.45 mm, and maximum was 0.75 mm.

“We found that the state of the arteries in these children is more typical of 45-year-olds than of people their age,” reported Dr. Raghuveer. She noted that there are no normative standards of CIMT in children against which to compare the findings.

For example, a 12-year-old white male was shown to have a CIMT of 0.54 mm. Plotted against that of a 45-year-old male, this CIMT measurement fell between the 25th and 50th percentiles of the adult (0.50 and 0.57 mm, respectively). The researchers labeled the arteries as having “advanced age” if the CIMT exceeded the 25th percentile for their matched adult counterpart.

“We then wondered what might be favoring this early advancement in CIMT, and we found that those with advanced age had higher triglyceride levels,” Dr. Raghuveer reported. More children with advanced vascular age had elevated triglyceride levels than normal triglycerides.

The same was found for the 40 most obese children, or those with BMI above the 95th percentile. Of those, 26 had both a vascular age above the 25th percentile of adults as well as a triglyceride level above 100 mg/dL. Children with lower triglycerides were evenly divided between those who scored below or above the 25th percentile on the charts for 45-year-olds. When a cutoff of 120 mg/dL was used to define high triglyceride, the result was stable. “More kids in the high vascular age group had higher triglycerides,” she added.

“Vascular age was advanced the furthest in the children with obesity and high triglyceride levels, so the combination of obesity and high triglycerides should be a red flag to the physician that a child is at high risk of heart disease,” Dr. Raghuveer commented.

“Our take-home message is that obese children with abnormal lipids have arterial wall changes in association with cardiovascular risk factors quite early in life, and these can progress over time,” she concluded.

Future research should evaluate whether risk factor modification can change the vasculature over time, she said. “We are hoping that it can,” Dr. Raghuveer added. “These children do not have hard, calcified arterial plaque as we see in older people, and hopefully we can document some regression with changes in lifestyle [and] behaviors, and if need be, drug therapy.” Currently, children at her clinic who are identified as having advanced vascular age receive nutrition and exercise counseling.

NEW ORLEANS — The arteries of obese and dyslipidemic children resemble those of middle-aged adults, possibly heralding the early onset of cardiovascular disease, according to a study presented at the annual scientific sessions of the American Heart Association.

“This is a wake-up call,” said coauthor Dr. Geetha Raghuveer, a cardiologist at Children's Mercy Hospital, Kansas City, Mo., who presented the findings. She noted that childhood obesity has already been shown to “track” into adulthood and to pose multiple risks to the vasculature.

Dr. Raghuveer and colleagues at the University of Missouri, Kansas City, and Children's Mercy Hospital measured the carotid artery intima-media thickness (CIMT) by ultrasound in 34 boys and 36 girls whose average age was 13 years. Most were obese, with a mean weight of 64 kg and mean body mass index of 26 kg/m

Most of the 70 also had abnormal lipid levels. Total cholesterol was greater than 170 mg/dL in 59 children and LDL cholesterol was above 110 mg/dL in 51; in 43 children, HDL cholesterol was less than 35 mg/dL and triglycerides were above 100 mg/dL.

To characterize the state of the carotid arteries in these children, the investigators plotted the CIMT measurements against previously published normative data for 45-year-olds matched by sex and race. The images revealed “advanced vascular age” in 75% of this young obese cohort. Mean CIMT was 0.45 mm, and maximum was 0.75 mm.

“We found that the state of the arteries in these children is more typical of 45-year-olds than of people their age,” reported Dr. Raghuveer. She noted that there are no normative standards of CIMT in children against which to compare the findings.

For example, a 12-year-old white male was shown to have a CIMT of 0.54 mm. Plotted against that of a 45-year-old male, this CIMT measurement fell between the 25th and 50th percentiles of the adult (0.50 and 0.57 mm, respectively). The researchers labeled the arteries as having “advanced age” if the CIMT exceeded the 25th percentile for their matched adult counterpart.

“We then wondered what might be favoring this early advancement in CIMT, and we found that those with advanced age had higher triglyceride levels,” Dr. Raghuveer reported. More children with advanced vascular age had elevated triglyceride levels than normal triglycerides.

The same was found for the 40 most obese children, or those with BMI above the 95th percentile. Of those, 26 had both a vascular age above the 25th percentile of adults as well as a triglyceride level above 100 mg/dL. Children with lower triglycerides were evenly divided between those who scored below or above the 25th percentile on the charts for 45-year-olds. When a cutoff of 120 mg/dL was used to define high triglyceride, the result was stable. “More kids in the high vascular age group had higher triglycerides,” she added.

“Vascular age was advanced the furthest in the children with obesity and high triglyceride levels, so the combination of obesity and high triglycerides should be a red flag to the physician that a child is at high risk of heart disease,” Dr. Raghuveer commented.

“Our take-home message is that obese children with abnormal lipids have arterial wall changes in association with cardiovascular risk factors quite early in life, and these can progress over time,” she concluded.

Future research should evaluate whether risk factor modification can change the vasculature over time, she said. “We are hoping that it can,” Dr. Raghuveer added. “These children do not have hard, calcified arterial plaque as we see in older people, and hopefully we can document some regression with changes in lifestyle [and] behaviors, and if need be, drug therapy.” Currently, children at her clinic who are identified as having advanced vascular age receive nutrition and exercise counseling.

Philadelphia bureau chief Mitchel L. Zoler contributed to this report.

NEW ORLEANS — In the largest study of exercise training as part of the management of heart failure to date, a guided exercise program was safe and modestly effective, but researchers acknowledged that patients found it hard to keep up the routine.

The safety of exercise training in heart failure patients, outside of a supervised environment, has been a concern. This study proved benefits could be obtained without excess risk, said Dr. Christopher M. O'Connor, presenting results of the Heart Failure and A Controlled Trial Investigating Outcomes of Exercise Training (HF-ACTION) study at the annual scientific sessions of the American Heart Association.

“Over 30 randomized trials have shown increased exercise capacity and possibly improved survival with exercise training, but these were largely single-center studies that were underpowered or lacked adequate controls and produced limited data on safety,” he noted at a press conference.

HF-ACTION, a randomized, phase III trial sponsored by the National Heart, Lung, and Blood Institute, followed 2,331 heart failure patients at 82 international sites for an average of 2.5 years. The relatively young population, median age 59 years, had an average left ventricular ejection fraction (LVEF) of 25%, indicating moderate HF. History of coronary occlusion and prior myocardial infarction was common.

Patients were randomized to an exercise training program aimed at increasing workout intensity and duration or to usual care, where they were encouraged to exercise, based on the American College of Cardiology/AHA recommendations of 30 minutes of moderate exercise most days of the week. Both groups received optimized medical treatment, patient education, and follow-up telephone calls.

The exercise training followed the cardiac rehabilitation model. Patients were prescribed a multistage, guided workout of 36 supervised training sessions of 30 minutes of exercise three times a week. At the 18th session, patients received a treadmill or exercise bicycle for home use, learned how to monitor their heart rate during exercise, and were encouraged to complete five weekly sessions of similar intensity and 40 minutes' duration.

At 4–6 weeks, patients were exercising a median of 95 minutes per week, short of the goal of 120 minutes. This was consistent for the first year and then diminished further.

After 3 years, people were exercising for about 50 minutes. We had wanted them to exercise for 120 minutes. So adherence is extremely difficult,” reported Dr. O'Connor, professor of medicine and director of the heart center at Duke University Medical Center, Durham, N.C.

Exercise training was not associated with a significant reduction in the primary end point, all-cause mortality and hospitalization, or in secondary composite end points: cardiovascular (CV) mortality plus CV, and CV mortality plus HF, he reported.

But improvements in outcomes emerged in the prespecified adjusted analysis that accounted for additional key prognostic variables related to heart failure outcomes. These included exercise duration, LVEF, Beck Depression Inventory score, and history of atrial fibrillation/flutter.

In the adjusted analysis, the primary end point was significantly reduced by 11%, and CV mortality plus heart failure hospitalization was significantly reduced by 15%. The reduction in CV mortality plus CV hospitalization remained a nonsignificant 8%.

“The prespecified adjusted analysis is a fair analysis of these data and is probably closest to the truth,” Dr. O'Connor maintained. “Prognostic factors are most important.”

The study found no excess risk for CV events or fractures with intensive exercise. “Perhaps the most important finding is that exercise training of this degree was safe,” Dr. O'Connor added.

Health status was assessed by the Kansas City Cardiomyopathy Questionnaire (KCCQ). In the exercise group, the average KCCQ score rose by 5 points after the first 3 months of training, a statistically and clinically significant increase that continued for the remainder of the study. In the usual-care group, the average KCCQ score rose by 3 points, which was also maintained. The 3-point increase was statistically significant but fell short of clinical significance. The increase in the usual-care group was significantly less than in the exercise group, reported Kathryn E. Flynn, Ph.D., of the Center for Clinical and Genetic Economics at Duke University, Durham, N.C.

The improvements in outcomes were obtained in a setting of excellent overall cardiac care, as more than 90% of the patients received evidence-based medical therapy for their disease. “We achieved an 11% to 15% meaningful reduction in clinical end points above that, with a safe intervention,” Dr. O'Connor emphasized.

Philadelphia bureau chief Mitchel L. Zoler contributed to this report.

NEW ORLEANS — In the largest study of exercise training as part of the management of heart failure to date, a guided exercise program was safe and modestly effective, but researchers acknowledged that patients found it hard to keep up the routine.

The safety of exercise training in heart failure patients, outside of a supervised environment, has been a concern. This study proved benefits could be obtained without excess risk, said Dr. Christopher M. O'Connor, presenting results of the Heart Failure and A Controlled Trial Investigating Outcomes of Exercise Training (HF-ACTION) study at the annual scientific sessions of the American Heart Association.

“Over 30 randomized trials have shown increased exercise capacity and possibly improved survival with exercise training, but these were largely single-center studies that were underpowered or lacked adequate controls and produced limited data on safety,” he noted at a press conference.

HF-ACTION, a randomized, phase III trial sponsored by the National Heart, Lung, and Blood Institute, followed 2,331 heart failure patients at 82 international sites for an average of 2.5 years. The relatively young population, median age 59 years, had an average left ventricular ejection fraction (LVEF) of 25%, indicating moderate HF. History of coronary occlusion and prior myocardial infarction was common.

Patients were randomized to an exercise training program aimed at increasing workout intensity and duration or to usual care, where they were encouraged to exercise, based on the American College of Cardiology/AHA recommendations of 30 minutes of moderate exercise most days of the week. Both groups received optimized medical treatment, patient education, and follow-up telephone calls.

The exercise training followed the cardiac rehabilitation model. Patients were prescribed a multistage, guided workout of 36 supervised training sessions of 30 minutes of exercise three times a week. At the 18th session, patients received a treadmill or exercise bicycle for home use, learned how to monitor their heart rate during exercise, and were encouraged to complete five weekly sessions of similar intensity and 40 minutes' duration.

At 4–6 weeks, patients were exercising a median of 95 minutes per week, short of the goal of 120 minutes. This was consistent for the first year and then diminished further.

After 3 years, people were exercising for about 50 minutes. We had wanted them to exercise for 120 minutes. So adherence is extremely difficult,” reported Dr. O'Connor, professor of medicine and director of the heart center at Duke University Medical Center, Durham, N.C.

Exercise training was not associated with a significant reduction in the primary end point, all-cause mortality and hospitalization, or in secondary composite end points: cardiovascular (CV) mortality plus CV, and CV mortality plus HF, he reported.

But improvements in outcomes emerged in the prespecified adjusted analysis that accounted for additional key prognostic variables related to heart failure outcomes. These included exercise duration, LVEF, Beck Depression Inventory score, and history of atrial fibrillation/flutter.

In the adjusted analysis, the primary end point was significantly reduced by 11%, and CV mortality plus heart failure hospitalization was significantly reduced by 15%. The reduction in CV mortality plus CV hospitalization remained a nonsignificant 8%.

“The prespecified adjusted analysis is a fair analysis of these data and is probably closest to the truth,” Dr. O'Connor maintained. “Prognostic factors are most important.”

The study found no excess risk for CV events or fractures with intensive exercise. “Perhaps the most important finding is that exercise training of this degree was safe,” Dr. O'Connor added.

Health status was assessed by the Kansas City Cardiomyopathy Questionnaire (KCCQ). In the exercise group, the average KCCQ score rose by 5 points after the first 3 months of training, a statistically and clinically significant increase that continued for the remainder of the study. In the usual-care group, the average KCCQ score rose by 3 points, which was also maintained. The 3-point increase was statistically significant but fell short of clinical significance. The increase in the usual-care group was significantly less than in the exercise group, reported Kathryn E. Flynn, Ph.D., of the Center for Clinical and Genetic Economics at Duke University, Durham, N.C.

The improvements in outcomes were obtained in a setting of excellent overall cardiac care, as more than 90% of the patients received evidence-based medical therapy for their disease. “We achieved an 11% to 15% meaningful reduction in clinical end points above that, with a safe intervention,” Dr. O'Connor emphasized.

Philadelphia bureau chief Mitchel L. Zoler contributed to this report.

NEW ORLEANS — In the largest study of exercise training as part of the management of heart failure to date, a guided exercise program was safe and modestly effective, but researchers acknowledged that patients found it hard to keep up the routine.

The safety of exercise training in heart failure patients, outside of a supervised environment, has been a concern. This study proved benefits could be obtained without excess risk, said Dr. Christopher M. O'Connor, presenting results of the Heart Failure and A Controlled Trial Investigating Outcomes of Exercise Training (HF-ACTION) study at the annual scientific sessions of the American Heart Association.

“Over 30 randomized trials have shown increased exercise capacity and possibly improved survival with exercise training, but these were largely single-center studies that were underpowered or lacked adequate controls and produced limited data on safety,” he noted at a press conference.

HF-ACTION, a randomized, phase III trial sponsored by the National Heart, Lung, and Blood Institute, followed 2,331 heart failure patients at 82 international sites for an average of 2.5 years. The relatively young population, median age 59 years, had an average left ventricular ejection fraction (LVEF) of 25%, indicating moderate HF. History of coronary occlusion and prior myocardial infarction was common.

Patients were randomized to an exercise training program aimed at increasing workout intensity and duration or to usual care, where they were encouraged to exercise, based on the American College of Cardiology/AHA recommendations of 30 minutes of moderate exercise most days of the week. Both groups received optimized medical treatment, patient education, and follow-up telephone calls.

The exercise training followed the cardiac rehabilitation model. Patients were prescribed a multistage, guided workout of 36 supervised training sessions of 30 minutes of exercise three times a week. At the 18th session, patients received a treadmill or exercise bicycle for home use, learned how to monitor their heart rate during exercise, and were encouraged to complete five weekly sessions of similar intensity and 40 minutes' duration.

At 4–6 weeks, patients were exercising a median of 95 minutes per week, short of the goal of 120 minutes. This was consistent for the first year and then diminished further.

After 3 years, people were exercising for about 50 minutes. We had wanted them to exercise for 120 minutes. So adherence is extremely difficult,” reported Dr. O'Connor, professor of medicine and director of the heart center at Duke University Medical Center, Durham, N.C.

Exercise training was not associated with a significant reduction in the primary end point, all-cause mortality and hospitalization, or in secondary composite end points: cardiovascular (CV) mortality plus CV, and CV mortality plus HF, he reported.

But improvements in outcomes emerged in the prespecified adjusted analysis that accounted for additional key prognostic variables related to heart failure outcomes. These included exercise duration, LVEF, Beck Depression Inventory score, and history of atrial fibrillation/flutter.

In the adjusted analysis, the primary end point was significantly reduced by 11%, and CV mortality plus heart failure hospitalization was significantly reduced by 15%. The reduction in CV mortality plus CV hospitalization remained a nonsignificant 8%.

“The prespecified adjusted analysis is a fair analysis of these data and is probably closest to the truth,” Dr. O'Connor maintained. “Prognostic factors are most important.”

The study found no excess risk for CV events or fractures with intensive exercise. “Perhaps the most important finding is that exercise training of this degree was safe,” Dr. O'Connor added.

Health status was assessed by the Kansas City Cardiomyopathy Questionnaire (KCCQ). In the exercise group, the average KCCQ score rose by 5 points after the first 3 months of training, a statistically and clinically significant increase that continued for the remainder of the study. In the usual-care group, the average KCCQ score rose by 3 points, which was also maintained. The 3-point increase was statistically significant but fell short of clinical significance. The increase in the usual-care group was significantly less than in the exercise group, reported Kathryn E. Flynn, Ph.D., of the Center for Clinical and Genetic Economics at Duke University, Durham, N.C.

The improvements in outcomes were obtained in a setting of excellent overall cardiac care, as more than 90% of the patients received evidence-based medical therapy for their disease. “We achieved an 11% to 15% meaningful reduction in clinical end points above that, with a safe intervention,” Dr. O'Connor emphasized.

NEW ORLEANS — Aspirin therapy is commonly used for primary prevention of cardiovascular events in persons with type 2 diabetes, but a Japanese study of 2,539 subjects found no statistically significant reduction in the primary end point of total atherosclerotic events, except in patients aged at least 65 years.

The study, which is the largest primary prevention trial of aspirin in type 2 diabetes, was reported at the annual scientific sessions of the American Heart Association.

In the Japanese Primary Prevention of Atherosclerosis with Aspirin for Diabetes (JPAD) trial, the use of daily low-dose aspirin was associated with a 20% nonsignificant reduction in the risk of the combined end point of coronary, cerebrovascular, and peripheral vascular events in the population as a whole, and a 32% statistically significant reduction in events among those aged 65 and older, reported Dr. Hisao Ogawa of the Kumamoto (Japan) University.

Aspirin use also significantly reduced the composite of fatal coronary and fatal cerebrovascular events.

“Although the effect of low-dose aspirin was not statistically significant for the primary end point, a significant effect was demonstrated on fatal coronary and fatal cerebrovascular events. The trial also suggests that low-dose aspirin might reduce total events in older patients,” he said at a late-breaking trials session.

The results were reported online simultaneously with Dr. Ogawa's presentation (JAMA 2008;300:2134-41).

Japanese investigators from 163 institutions examined the benefit of low-dose aspirin for preventing cardiovascular events in 2,539 patients with type 2 diabetes who had no history of atherosclerotic disease. Average age of the patients was 65 years and 55% were men. Patients were randomly assigned to receive 81-100 mg aspirin per day (n = 1,262) or no aspirin (n = 1,277). The primary end point was the composite of all coronary, cerebrovascular, and peripheral vascular events.

After a median follow-up of 4.4 years, a total of 154 fatal and nonfatal atherosclerotic events had occurred: 68 in the aspirin group and 86 in the nonaspirin group. This represented a rate of 13.6 vs. 17.0 events per 1,000 person-years, for a 20% reduction in risk that was not statistically significant, Dr. Ogawa reported.

Benefit was, however, demonstrated in older patients taking aspirin. Among the 719 patients aged at least 65 in the aspirin arm, 45 events (6.3%) atherosclerotic events occurred, compared with 59 events (9.2%) in the 644 older patients in the nonaspirin group, representing a statistically significant 32% reduction in risk with aspirin use.

The combined secondary end point of fatal coronary events and fatal cerebrovascular events occurred in 1 patient (stroke) in the aspirin group and 10 patients (5 fatal myocardial infarctions and 5 fatal strokes) in the nonaspirin group, for a 90% statistically significant reduction in risk for that outcome.

Adverse effects occurred in 86 persons taking aspirin and 14 not on aspirin. Hemorrhagic events were greater with aspirin (34 vs. 10), including an increase in gastrointestinal bleeding and the need for transfusion for severe GI bleeding in four patients, but there was no increase in hemorrhagic stroke.

“JPAD supports the safety of using low-dose aspirin in diabetics for primary prevention,” he said.

The investigators cautioned that the findings should be interpreted in context of the low incidence of atherosclerotic disease in Japan and the aggressive management of cardiovascular risk factors. “The event rate was lower than anticipated because the patients were so well treated,” Dr. Ogawa said. “They saw their physicians every 2-4 weeks.”

Dr. Marian Limacher, professor of medicine at the University of Florida, Gainesville, said JPAD was “a well-designed and well-conducted study” that aimed to address a question that “some may have thought did not need to be answered,” given the widespread recommendation for the use of aspirin in diabetic patients. “However, the evidence basis for this has been lacking until recently, and JPAD adds to this considerably,” she commented at a press conference.

The findings are congruent with the recently completed Progression of Arterial Disease and Diabetes (POPADAD) study from Great Britain, she noted. POPADAD, involving 1,276 patients with asymptomatic peripheral arterial disease, found no evidence for aspirin's benefit on cardiovascular events and mortality.

As discussant of the paper, Dr. Limacher offered several possible explanations for the lack of effect on the primary end point, including the choice of population, which involved a number of percentage of women who may respond differently to aspirin than do men; the dose, which may have been too low to be protective in some patients; a too-short duration of intervention; the effect of aspirin resistance in some patients; the use of concomitant risk factor-modifying medications; and lack of power to show an effect when event rates were so low.

“We may need to rethink the guidelines,” she suggested, “especially for patients younger than 65.”

NEW ORLEANS — Aspirin therapy is commonly used for primary prevention of cardiovascular events in persons with type 2 diabetes, but a Japanese study of 2,539 subjects found no statistically significant reduction in the primary end point of total atherosclerotic events, except in patients aged at least 65 years.

The study, which is the largest primary prevention trial of aspirin in type 2 diabetes, was reported at the annual scientific sessions of the American Heart Association.

In the Japanese Primary Prevention of Atherosclerosis with Aspirin for Diabetes (JPAD) trial, the use of daily low-dose aspirin was associated with a 20% nonsignificant reduction in the risk of the combined end point of coronary, cerebrovascular, and peripheral vascular events in the population as a whole, and a 32% statistically significant reduction in events among those aged 65 and older, reported Dr. Hisao Ogawa of the Kumamoto (Japan) University.

Aspirin use also significantly reduced the composite of fatal coronary and fatal cerebrovascular events.

“Although the effect of low-dose aspirin was not statistically significant for the primary end point, a significant effect was demonstrated on fatal coronary and fatal cerebrovascular events. The trial also suggests that low-dose aspirin might reduce total events in older patients,” he said at a late-breaking trials session.

The results were reported online simultaneously with Dr. Ogawa's presentation (JAMA 2008;300:2134-41).

Japanese investigators from 163 institutions examined the benefit of low-dose aspirin for preventing cardiovascular events in 2,539 patients with type 2 diabetes who had no history of atherosclerotic disease. Average age of the patients was 65 years and 55% were men. Patients were randomly assigned to receive 81-100 mg aspirin per day (n = 1,262) or no aspirin (n = 1,277). The primary end point was the composite of all coronary, cerebrovascular, and peripheral vascular events.

After a median follow-up of 4.4 years, a total of 154 fatal and nonfatal atherosclerotic events had occurred: 68 in the aspirin group and 86 in the nonaspirin group. This represented a rate of 13.6 vs. 17.0 events per 1,000 person-years, for a 20% reduction in risk that was not statistically significant, Dr. Ogawa reported.

Benefit was, however, demonstrated in older patients taking aspirin. Among the 719 patients aged at least 65 in the aspirin arm, 45 events (6.3%) atherosclerotic events occurred, compared with 59 events (9.2%) in the 644 older patients in the nonaspirin group, representing a statistically significant 32% reduction in risk with aspirin use.

The combined secondary end point of fatal coronary events and fatal cerebrovascular events occurred in 1 patient (stroke) in the aspirin group and 10 patients (5 fatal myocardial infarctions and 5 fatal strokes) in the nonaspirin group, for a 90% statistically significant reduction in risk for that outcome.

Adverse effects occurred in 86 persons taking aspirin and 14 not on aspirin. Hemorrhagic events were greater with aspirin (34 vs. 10), including an increase in gastrointestinal bleeding and the need for transfusion for severe GI bleeding in four patients, but there was no increase in hemorrhagic stroke.

“JPAD supports the safety of using low-dose aspirin in diabetics for primary prevention,” he said.

The investigators cautioned that the findings should be interpreted in context of the low incidence of atherosclerotic disease in Japan and the aggressive management of cardiovascular risk factors. “The event rate was lower than anticipated because the patients were so well treated,” Dr. Ogawa said. “They saw their physicians every 2-4 weeks.”

Dr. Marian Limacher, professor of medicine at the University of Florida, Gainesville, said JPAD was “a well-designed and well-conducted study” that aimed to address a question that “some may have thought did not need to be answered,” given the widespread recommendation for the use of aspirin in diabetic patients. “However, the evidence basis for this has been lacking until recently, and JPAD adds to this considerably,” she commented at a press conference.

The findings are congruent with the recently completed Progression of Arterial Disease and Diabetes (POPADAD) study from Great Britain, she noted. POPADAD, involving 1,276 patients with asymptomatic peripheral arterial disease, found no evidence for aspirin's benefit on cardiovascular events and mortality.

As discussant of the paper, Dr. Limacher offered several possible explanations for the lack of effect on the primary end point, including the choice of population, which involved a number of percentage of women who may respond differently to aspirin than do men; the dose, which may have been too low to be protective in some patients; a too-short duration of intervention; the effect of aspirin resistance in some patients; the use of concomitant risk factor-modifying medications; and lack of power to show an effect when event rates were so low.

“We may need to rethink the guidelines,” she suggested, “especially for patients younger than 65.”

NEW ORLEANS — Aspirin therapy is commonly used for primary prevention of cardiovascular events in persons with type 2 diabetes, but a Japanese study of 2,539 subjects found no statistically significant reduction in the primary end point of total atherosclerotic events, except in patients aged at least 65 years.

The study, which is the largest primary prevention trial of aspirin in type 2 diabetes, was reported at the annual scientific sessions of the American Heart Association.

In the Japanese Primary Prevention of Atherosclerosis with Aspirin for Diabetes (JPAD) trial, the use of daily low-dose aspirin was associated with a 20% nonsignificant reduction in the risk of the combined end point of coronary, cerebrovascular, and peripheral vascular events in the population as a whole, and a 32% statistically significant reduction in events among those aged 65 and older, reported Dr. Hisao Ogawa of the Kumamoto (Japan) University.

Aspirin use also significantly reduced the composite of fatal coronary and fatal cerebrovascular events.

“Although the effect of low-dose aspirin was not statistically significant for the primary end point, a significant effect was demonstrated on fatal coronary and fatal cerebrovascular events. The trial also suggests that low-dose aspirin might reduce total events in older patients,” he said at a late-breaking trials session.

The results were reported online simultaneously with Dr. Ogawa's presentation (JAMA 2008;300:2134-41).

Japanese investigators from 163 institutions examined the benefit of low-dose aspirin for preventing cardiovascular events in 2,539 patients with type 2 diabetes who had no history of atherosclerotic disease. Average age of the patients was 65 years and 55% were men. Patients were randomly assigned to receive 81-100 mg aspirin per day (n = 1,262) or no aspirin (n = 1,277). The primary end point was the composite of all coronary, cerebrovascular, and peripheral vascular events.

After a median follow-up of 4.4 years, a total of 154 fatal and nonfatal atherosclerotic events had occurred: 68 in the aspirin group and 86 in the nonaspirin group. This represented a rate of 13.6 vs. 17.0 events per 1,000 person-years, for a 20% reduction in risk that was not statistically significant, Dr. Ogawa reported.

Benefit was, however, demonstrated in older patients taking aspirin. Among the 719 patients aged at least 65 in the aspirin arm, 45 events (6.3%) atherosclerotic events occurred, compared with 59 events (9.2%) in the 644 older patients in the nonaspirin group, representing a statistically significant 32% reduction in risk with aspirin use.

The combined secondary end point of fatal coronary events and fatal cerebrovascular events occurred in 1 patient (stroke) in the aspirin group and 10 patients (5 fatal myocardial infarctions and 5 fatal strokes) in the nonaspirin group, for a 90% statistically significant reduction in risk for that outcome.

Adverse effects occurred in 86 persons taking aspirin and 14 not on aspirin. Hemorrhagic events were greater with aspirin (34 vs. 10), including an increase in gastrointestinal bleeding and the need for transfusion for severe GI bleeding in four patients, but there was no increase in hemorrhagic stroke.

“JPAD supports the safety of using low-dose aspirin in diabetics for primary prevention,” he said.

The investigators cautioned that the findings should be interpreted in context of the low incidence of atherosclerotic disease in Japan and the aggressive management of cardiovascular risk factors. “The event rate was lower than anticipated because the patients were so well treated,” Dr. Ogawa said. “They saw their physicians every 2-4 weeks.”

Dr. Marian Limacher, professor of medicine at the University of Florida, Gainesville, said JPAD was “a well-designed and well-conducted study” that aimed to address a question that “some may have thought did not need to be answered,” given the widespread recommendation for the use of aspirin in diabetic patients. “However, the evidence basis for this has been lacking until recently, and JPAD adds to this considerably,” she commented at a press conference.

The findings are congruent with the recently completed Progression of Arterial Disease and Diabetes (POPADAD) study from Great Britain, she noted. POPADAD, involving 1,276 patients with asymptomatic peripheral arterial disease, found no evidence for aspirin's benefit on cardiovascular events and mortality.

As discussant of the paper, Dr. Limacher offered several possible explanations for the lack of effect on the primary end point, including the choice of population, which involved a number of percentage of women who may respond differently to aspirin than do men; the dose, which may have been too low to be protective in some patients; a too-short duration of intervention; the effect of aspirin resistance in some patients; the use of concomitant risk factor-modifying medications; and lack of power to show an effect when event rates were so low.

“We may need to rethink the guidelines,” she suggested, “especially for patients younger than 65.”

NEW ORLEANS — In the largest study of exercise training as part of the management of heart failure to date, a guided exercise program was safe and modestly effective, although investigators acknowledged that patients found it hard to keep up the routine.

The safety of exercise training in heart failure patients, outside of a supervised environment, has been a concern, but this study proved benefits could be obtained without excess risk, said Dr. Christopher M. O'Connor, presenting results of the Heart Failure and A Controlled Trial Investigating Outcomes of Exercise Training (HF-ACTION) trial at the annual scientific sessions of the American Heart Association.

“Over 30 randomized trials have shown increased exercise capacity and possibly improved survival with exercise training, but these were largely single-center studies that were underpowered or lacked adequate controls and produced limited data on safety,” he noted at a press conference.

HF-ACTION, a randomized, phase III trial sponsored by the National Heart, Lung, and Blood Institute, followed 2,331 heart failure patients at 82 international sites for an average of 2.5 years. The relatively young population, median age 59 years, had an average left ventricular ejection fraction (LVEF) of 25%, indicating moderate HF. History of coronary occlusion and prior myocardial infarction was common.

Patients were randomized to an exercise training program aimed at increasing workout intensity and duration or to usual care, where they were encouraged to exercise, based on the American College of Cardiology/AHA recommendations of 30 minutes of moderate exercise most days of the week. Both groups received optimized medical treatment, patient education, and follow-up phone calls.

The exercise training followed the cardiac rehabilitation model. Patients were prescribed a multistage, guided workout of 36 supervised training sessions of 30 minutes of exercise three times a week. At the 18th session, patients received a treadmill or exercise bicycle for home use, learned how to monitor their heart rate during exercise, and were encouraged to complete five weekly sessions of similar intensity and 40 minutes' duration.

At 4–6 weeks, patients were exercising a median of 95 minutes per week, a little short of the goal of 120 minutes. This was consistent for the first year and then diminished further, reported Dr. O'Connor, professor of medicine and director of the heart center at Duke University Medical Center, Durham, N.C.

The diminished adherence is not surprising, he said, because “lifestyle intervention trials are very difficult. At the completion of a drug trial, for example, 85% of patients would still be on the drug. Here, after 3 years people were exercising for about 50 minutes. We had wanted them to exercise for 120 minutes. So adherence is extremely difficult.”

Exercise training was not associated with a significant reduction in the primary end point, all-cause mortality and hospitalization. Adjusted for heart failure etiology, this group experienced a 7% relative risk reduction that was not statistically significant. Secondary composite end points also failed to reach significance: cardiovascular (CV) mortality plus CV hospitalization was reduced by 8%, and CV mortality plus HF hospitalization was reduced by 13%, Dr. O'Connor reported.

However, improvements in outcomes emerged in the prespecified adjusted analysis that accounted for additional key prognostic variables related to heart failure outcomes. These included exercise duration, LVEF, Beck Depression Inventory score, and history of atrial fibrillation flutter.

In the adjusted analysis, the primary end point was significantly reduced by 11%, and CV mortality plus heart failure hospitalization was significantly reduced by 15%. The reduction in CV mortality plus CV hospitalization remained a nonsignificant 8%.

“The prespecified adjusted analysis is a fair analysis of these data and is probably closest to the truth,” Dr. O'Connor maintained. “Prognostic factors are most important. The reductions in risk were in the range of 11%–15%.”

The study found no excess risk for CV events or fractures with intensive exercise. “Perhaps the most important finding is that exercise training of this degree was safe,” Dr. O'Connor added. There was no increase in CV events or fractures with intensive exercise.

The improvements in outcomes were obtained in a setting of excellent overall cardiac care, he added, as more than 90% of patients received evidence-based medical therapy for their disease. “We achieved an 11%–15% meaningful reduction in clinical end points above that, with a safe intervention,” he emphasized.

Discussant Dr. Philip Poole-Wilson said, “This study stresses that the advice to exercise is correct and important. Now, how to persuade the patient is harder.”

“The study missed the primary end point, and some would say that's the end of it. But that would be wrong,” said Dr. Poole-Wilson, professor of medicine at the Imperial College London. “After adjustments, it met many end points, and this means it was a positive trial. The study supports the use of exercise and will strengthen guidelines for the treatment of heart failure, which has wide implications.”

Dr. Clyde Yancy spoke to the financial implications of the study in an interview. He pointed out that the paradigm for exercise has long been established in the form of the cardiac rehabilitation model in which patients enroll in a program over 9–12 weeks to define a new lifestyle,” he said. “When exercise emanates from a structured rehab program, it quadruples adherence rates.

“The important question is whether the study data are sufficient to say that enrollment in a rehab program should become an evidence-based treatment strategy in heart failure. Because if it is guideline-generated then the expectation is that CMS and payers would cover the cost,” said Dr. Yancy, medical director of Baylor University, Dallas.

NEW ORLEANS — In the largest study of exercise training as part of the management of heart failure to date, a guided exercise program was safe and modestly effective, although investigators acknowledged that patients found it hard to keep up the routine.

The safety of exercise training in heart failure patients, outside of a supervised environment, has been a concern, but this study proved benefits could be obtained without excess risk, said Dr. Christopher M. O'Connor, presenting results of the Heart Failure and A Controlled Trial Investigating Outcomes of Exercise Training (HF-ACTION) trial at the annual scientific sessions of the American Heart Association.

“Over 30 randomized trials have shown increased exercise capacity and possibly improved survival with exercise training, but these were largely single-center studies that were underpowered or lacked adequate controls and produced limited data on safety,” he noted at a press conference.

HF-ACTION, a randomized, phase III trial sponsored by the National Heart, Lung, and Blood Institute, followed 2,331 heart failure patients at 82 international sites for an average of 2.5 years. The relatively young population, median age 59 years, had an average left ventricular ejection fraction (LVEF) of 25%, indicating moderate HF. History of coronary occlusion and prior myocardial infarction was common.

Patients were randomized to an exercise training program aimed at increasing workout intensity and duration or to usual care, where they were encouraged to exercise, based on the American College of Cardiology/AHA recommendations of 30 minutes of moderate exercise most days of the week. Both groups received optimized medical treatment, patient education, and follow-up phone calls.

The exercise training followed the cardiac rehabilitation model. Patients were prescribed a multistage, guided workout of 36 supervised training sessions of 30 minutes of exercise three times a week. At the 18th session, patients received a treadmill or exercise bicycle for home use, learned how to monitor their heart rate during exercise, and were encouraged to complete five weekly sessions of similar intensity and 40 minutes' duration.

At 4–6 weeks, patients were exercising a median of 95 minutes per week, a little short of the goal of 120 minutes. This was consistent for the first year and then diminished further, reported Dr. O'Connor, professor of medicine and director of the heart center at Duke University Medical Center, Durham, N.C.

The diminished adherence is not surprising, he said, because “lifestyle intervention trials are very difficult. At the completion of a drug trial, for example, 85% of patients would still be on the drug. Here, after 3 years people were exercising for about 50 minutes. We had wanted them to exercise for 120 minutes. So adherence is extremely difficult.”

Exercise training was not associated with a significant reduction in the primary end point, all-cause mortality and hospitalization. Adjusted for heart failure etiology, this group experienced a 7% relative risk reduction that was not statistically significant. Secondary composite end points also failed to reach significance: cardiovascular (CV) mortality plus CV hospitalization was reduced by 8%, and CV mortality plus HF hospitalization was reduced by 13%, Dr. O'Connor reported.

However, improvements in outcomes emerged in the prespecified adjusted analysis that accounted for additional key prognostic variables related to heart failure outcomes. These included exercise duration, LVEF, Beck Depression Inventory score, and history of atrial fibrillation flutter.

In the adjusted analysis, the primary end point was significantly reduced by 11%, and CV mortality plus heart failure hospitalization was significantly reduced by 15%. The reduction in CV mortality plus CV hospitalization remained a nonsignificant 8%.

“The prespecified adjusted analysis is a fair analysis of these data and is probably closest to the truth,” Dr. O'Connor maintained. “Prognostic factors are most important. The reductions in risk were in the range of 11%–15%.”

The study found no excess risk for CV events or fractures with intensive exercise. “Perhaps the most important finding is that exercise training of this degree was safe,” Dr. O'Connor added. There was no increase in CV events or fractures with intensive exercise.

The improvements in outcomes were obtained in a setting of excellent overall cardiac care, he added, as more than 90% of patients received evidence-based medical therapy for their disease. “We achieved an 11%–15% meaningful reduction in clinical end points above that, with a safe intervention,” he emphasized.

Discussant Dr. Philip Poole-Wilson said, “This study stresses that the advice to exercise is correct and important. Now, how to persuade the patient is harder.”

“The study missed the primary end point, and some would say that's the end of it. But that would be wrong,” said Dr. Poole-Wilson, professor of medicine at the Imperial College London. “After adjustments, it met many end points, and this means it was a positive trial. The study supports the use of exercise and will strengthen guidelines for the treatment of heart failure, which has wide implications.”

Dr. Clyde Yancy spoke to the financial implications of the study in an interview. He pointed out that the paradigm for exercise has long been established in the form of the cardiac rehabilitation model in which patients enroll in a program over 9–12 weeks to define a new lifestyle,” he said. “When exercise emanates from a structured rehab program, it quadruples adherence rates.

“The important question is whether the study data are sufficient to say that enrollment in a rehab program should become an evidence-based treatment strategy in heart failure. Because if it is guideline-generated then the expectation is that CMS and payers would cover the cost,” said Dr. Yancy, medical director of Baylor University, Dallas.

NEW ORLEANS — In the largest study of exercise training as part of the management of heart failure to date, a guided exercise program was safe and modestly effective, although investigators acknowledged that patients found it hard to keep up the routine.

The safety of exercise training in heart failure patients, outside of a supervised environment, has been a concern, but this study proved benefits could be obtained without excess risk, said Dr. Christopher M. O'Connor, presenting results of the Heart Failure and A Controlled Trial Investigating Outcomes of Exercise Training (HF-ACTION) trial at the annual scientific sessions of the American Heart Association.

“Over 30 randomized trials have shown increased exercise capacity and possibly improved survival with exercise training, but these were largely single-center studies that were underpowered or lacked adequate controls and produced limited data on safety,” he noted at a press conference.

HF-ACTION, a randomized, phase III trial sponsored by the National Heart, Lung, and Blood Institute, followed 2,331 heart failure patients at 82 international sites for an average of 2.5 years. The relatively young population, median age 59 years, had an average left ventricular ejection fraction (LVEF) of 25%, indicating moderate HF. History of coronary occlusion and prior myocardial infarction was common.

Patients were randomized to an exercise training program aimed at increasing workout intensity and duration or to usual care, where they were encouraged to exercise, based on the American College of Cardiology/AHA recommendations of 30 minutes of moderate exercise most days of the week. Both groups received optimized medical treatment, patient education, and follow-up phone calls.

The exercise training followed the cardiac rehabilitation model. Patients were prescribed a multistage, guided workout of 36 supervised training sessions of 30 minutes of exercise three times a week. At the 18th session, patients received a treadmill or exercise bicycle for home use, learned how to monitor their heart rate during exercise, and were encouraged to complete five weekly sessions of similar intensity and 40 minutes' duration.

At 4–6 weeks, patients were exercising a median of 95 minutes per week, a little short of the goal of 120 minutes. This was consistent for the first year and then diminished further, reported Dr. O'Connor, professor of medicine and director of the heart center at Duke University Medical Center, Durham, N.C.

The diminished adherence is not surprising, he said, because “lifestyle intervention trials are very difficult. At the completion of a drug trial, for example, 85% of patients would still be on the drug. Here, after 3 years people were exercising for about 50 minutes. We had wanted them to exercise for 120 minutes. So adherence is extremely difficult.”

Exercise training was not associated with a significant reduction in the primary end point, all-cause mortality and hospitalization. Adjusted for heart failure etiology, this group experienced a 7% relative risk reduction that was not statistically significant. Secondary composite end points also failed to reach significance: cardiovascular (CV) mortality plus CV hospitalization was reduced by 8%, and CV mortality plus HF hospitalization was reduced by 13%, Dr. O'Connor reported.

However, improvements in outcomes emerged in the prespecified adjusted analysis that accounted for additional key prognostic variables related to heart failure outcomes. These included exercise duration, LVEF, Beck Depression Inventory score, and history of atrial fibrillation flutter.

In the adjusted analysis, the primary end point was significantly reduced by 11%, and CV mortality plus heart failure hospitalization was significantly reduced by 15%. The reduction in CV mortality plus CV hospitalization remained a nonsignificant 8%.

“The prespecified adjusted analysis is a fair analysis of these data and is probably closest to the truth,” Dr. O'Connor maintained. “Prognostic factors are most important. The reductions in risk were in the range of 11%–15%.”

The study found no excess risk for CV events or fractures with intensive exercise. “Perhaps the most important finding is that exercise training of this degree was safe,” Dr. O'Connor added. There was no increase in CV events or fractures with intensive exercise.

The improvements in outcomes were obtained in a setting of excellent overall cardiac care, he added, as more than 90% of patients received evidence-based medical therapy for their disease. “We achieved an 11%–15% meaningful reduction in clinical end points above that, with a safe intervention,” he emphasized.

Discussant Dr. Philip Poole-Wilson said, “This study stresses that the advice to exercise is correct and important. Now, how to persuade the patient is harder.”

“The study missed the primary end point, and some would say that's the end of it. But that would be wrong,” said Dr. Poole-Wilson, professor of medicine at the Imperial College London. “After adjustments, it met many end points, and this means it was a positive trial. The study supports the use of exercise and will strengthen guidelines for the treatment of heart failure, which has wide implications.”

Dr. Clyde Yancy spoke to the financial implications of the study in an interview. He pointed out that the paradigm for exercise has long been established in the form of the cardiac rehabilitation model in which patients enroll in a program over 9–12 weeks to define a new lifestyle,” he said. “When exercise emanates from a structured rehab program, it quadruples adherence rates.

“The important question is whether the study data are sufficient to say that enrollment in a rehab program should become an evidence-based treatment strategy in heart failure. Because if it is guideline-generated then the expectation is that CMS and payers would cover the cost,” said Dr. Yancy, medical director of Baylor University, Dallas.

NEW ORLEANS — Heart failure patients with preserved systolic function did not benefit from treatment with an angiotensin II receptor blocker, according to results of the I-PRESERVE trial, the world's largest placebo-controlled trial of an ARB.

“Disappointingly, for this large group of patients—almost half the patients with heart failure—there remains no specific evidence-based therapy,” concluded Dr. Barry M. Massie, who presented the results of the Irbesartan in Heart Failure with Preserved Systolic Function (I-PRESERVE) trial at the annual scientific sessions of the American Heart Association.

Although no pharmacologic therapy has been shown to be effective in improving outcomes in this type of heart failure, inhibitors of the renin-angiotensin-aldosterone system have been of interest because that system is involved in many of the processes associated with this syndrome, such as hypertension, left ventricular hypertrophy, myocardial fibrosis, and vascular dysfunction. Previous studies have hinted at benefits from ARBs and from ACE inhibitors, but statistically significant improvements have not been established, said Dr. Massie, professor of medicine at the University of California, San Francisco and chief of cardiology at the San Francisco Veterans Affairs Medical Center.

I-PRESERVE included 4,128 patients with class II-IV heart failure and a left ventricular ejection fraction of at least 45%. The population was similar to that seen in prior epidemiologic studies in several important ways. The patients were mostly women, were elderly (median age 72 years), and about 9 of 10 had a history of hypertension. The average left ventricular ejection fraction was 59%.

Patients were randomized to either irbesartan up to 300 mg daily or usual care (placebo). The primary end point was a composite of all-cause death, hospitalization for heart failure, myocardial infarction, unstable angina, arrhythmia, and stroke.

After a mean follow-up of approximately 4 years, the primary outcome rates were nearly identical, occurring in 36% (742 of 2,067) of the irbesartan patients and 37% (763 of 2,061) of the placebo group. Similarly, there were no significant differences in the major secondary end points of cardiovascular death and death or hospitalization due to heart failure, or in any of the eight prespecified subgroups, Dr. Massie reported.

“Irbesartan was unsuccessful in achieving its primary or secondary outcomes,” Dr. Massie announced. The results are consistent with two previous trials in patients with heart failure and preserved ejection fraction that did not show a positive treatment effect with either candesartan or perindopril, he added.

Dr. Massie acknowledged that this was a “very well treated population,” with most patients receiving diuretics and many receiving other medications. “After randomization, there was an intensification of all these therapies,” he observed, explaining that this can confound outcomes.

“For this field to move forward, we need a better understanding of the mechanisms underlying this syndrome, and we need to find potential targets above and beyond those used for low ejection fraction patients. We need to do something. This affects more than 2 million individuals in the United States alone.”

Dr. Margaret M. Redfield, professor of medicine at the Mayo Clinic, Rochester, Minn., called I-PRESERVE, “a very important trial, if only for the fact that ARBs and ACE inhibitors are already widely used for the treatment of heart failure with preserved ejection fraction, even though no randomized trial has shown a benefit. Two huge registries have shown that 60% are treated with these agents despite the lack of evidence.”

In this form of heart failure, she said there is little evidence that activation of the renin-angiotensin system is associated with disease progression, unlike in patients with reduced ejection fractions. “This may be why the trial was negative,” she speculated.

She also observed that patients in I-PRESERVE were largely similar to those in observational studies, but that they had fairly normal hemoglobin levels and renal function, “which is uncommon in the elderly with heart failure,” she pointed out. “Few had concentric hypertrophy, though some had concentric remodeling, and very few had advanced diastolic dysfunction or high filling pressures. So, this was a relatively healthy cohort and not as reflective of this syndrome as we would have hoped.”

The study was funded by Bristol-Myers Squibb Co. and Sanofi-Aventis. The results were simultaneously published online in the New England Journal of Medicine (doi:10.1056/NEJMoa08005450).

NEW ORLEANS — Heart failure patients with preserved systolic function did not benefit from treatment with an angiotensin II receptor blocker, according to results of the I-PRESERVE trial, the world's largest placebo-controlled trial of an ARB.

“Disappointingly, for this large group of patients—almost half the patients with heart failure—there remains no specific evidence-based therapy,” concluded Dr. Barry M. Massie, who presented the results of the Irbesartan in Heart Failure with Preserved Systolic Function (I-PRESERVE) trial at the annual scientific sessions of the American Heart Association.

Although no pharmacologic therapy has been shown to be effective in improving outcomes in this type of heart failure, inhibitors of the renin-angiotensin-aldosterone system have been of interest because that system is involved in many of the processes associated with this syndrome, such as hypertension, left ventricular hypertrophy, myocardial fibrosis, and vascular dysfunction. Previous studies have hinted at benefits from ARBs and from ACE inhibitors, but statistically significant improvements have not been established, said Dr. Massie, professor of medicine at the University of California, San Francisco and chief of cardiology at the San Francisco Veterans Affairs Medical Center.

I-PRESERVE included 4,128 patients with class II-IV heart failure and a left ventricular ejection fraction of at least 45%. The population was similar to that seen in prior epidemiologic studies in several important ways. The patients were mostly women, were elderly (median age 72 years), and about 9 of 10 had a history of hypertension. The average left ventricular ejection fraction was 59%.

Patients were randomized to either irbesartan up to 300 mg daily or usual care (placebo). The primary end point was a composite of all-cause death, hospitalization for heart failure, myocardial infarction, unstable angina, arrhythmia, and stroke.

After a mean follow-up of approximately 4 years, the primary outcome rates were nearly identical, occurring in 36% (742 of 2,067) of the irbesartan patients and 37% (763 of 2,061) of the placebo group. Similarly, there were no significant differences in the major secondary end points of cardiovascular death and death or hospitalization due to heart failure, or in any of the eight prespecified subgroups, Dr. Massie reported.

“Irbesartan was unsuccessful in achieving its primary or secondary outcomes,” Dr. Massie announced. The results are consistent with two previous trials in patients with heart failure and preserved ejection fraction that did not show a positive treatment effect with either candesartan or perindopril, he added.

Dr. Massie acknowledged that this was a “very well treated population,” with most patients receiving diuretics and many receiving other medications. “After randomization, there was an intensification of all these therapies,” he observed, explaining that this can confound outcomes.

“For this field to move forward, we need a better understanding of the mechanisms underlying this syndrome, and we need to find potential targets above and beyond those used for low ejection fraction patients. We need to do something. This affects more than 2 million individuals in the United States alone.”

Dr. Margaret M. Redfield, professor of medicine at the Mayo Clinic, Rochester, Minn., called I-PRESERVE, “a very important trial, if only for the fact that ARBs and ACE inhibitors are already widely used for the treatment of heart failure with preserved ejection fraction, even though no randomized trial has shown a benefit. Two huge registries have shown that 60% are treated with these agents despite the lack of evidence.”

In this form of heart failure, she said there is little evidence that activation of the renin-angiotensin system is associated with disease progression, unlike in patients with reduced ejection fractions. “This may be why the trial was negative,” she speculated.

She also observed that patients in I-PRESERVE were largely similar to those in observational studies, but that they had fairly normal hemoglobin levels and renal function, “which is uncommon in the elderly with heart failure,” she pointed out. “Few had concentric hypertrophy, though some had concentric remodeling, and very few had advanced diastolic dysfunction or high filling pressures. So, this was a relatively healthy cohort and not as reflective of this syndrome as we would have hoped.”

The study was funded by Bristol-Myers Squibb Co. and Sanofi-Aventis. The results were simultaneously published online in the New England Journal of Medicine (doi:10.1056/NEJMoa08005450).

NEW ORLEANS — Heart failure patients with preserved systolic function did not benefit from treatment with an angiotensin II receptor blocker, according to results of the I-PRESERVE trial, the world's largest placebo-controlled trial of an ARB.

“Disappointingly, for this large group of patients—almost half the patients with heart failure—there remains no specific evidence-based therapy,” concluded Dr. Barry M. Massie, who presented the results of the Irbesartan in Heart Failure with Preserved Systolic Function (I-PRESERVE) trial at the annual scientific sessions of the American Heart Association.

Although no pharmacologic therapy has been shown to be effective in improving outcomes in this type of heart failure, inhibitors of the renin-angiotensin-aldosterone system have been of interest because that system is involved in many of the processes associated with this syndrome, such as hypertension, left ventricular hypertrophy, myocardial fibrosis, and vascular dysfunction. Previous studies have hinted at benefits from ARBs and from ACE inhibitors, but statistically significant improvements have not been established, said Dr. Massie, professor of medicine at the University of California, San Francisco and chief of cardiology at the San Francisco Veterans Affairs Medical Center.

I-PRESERVE included 4,128 patients with class II-IV heart failure and a left ventricular ejection fraction of at least 45%. The population was similar to that seen in prior epidemiologic studies in several important ways. The patients were mostly women, were elderly (median age 72 years), and about 9 of 10 had a history of hypertension. The average left ventricular ejection fraction was 59%.

Patients were randomized to either irbesartan up to 300 mg daily or usual care (placebo). The primary end point was a composite of all-cause death, hospitalization for heart failure, myocardial infarction, unstable angina, arrhythmia, and stroke.

After a mean follow-up of approximately 4 years, the primary outcome rates were nearly identical, occurring in 36% (742 of 2,067) of the irbesartan patients and 37% (763 of 2,061) of the placebo group. Similarly, there were no significant differences in the major secondary end points of cardiovascular death and death or hospitalization due to heart failure, or in any of the eight prespecified subgroups, Dr. Massie reported.

“Irbesartan was unsuccessful in achieving its primary or secondary outcomes,” Dr. Massie announced. The results are consistent with two previous trials in patients with heart failure and preserved ejection fraction that did not show a positive treatment effect with either candesartan or perindopril, he added.

Dr. Massie acknowledged that this was a “very well treated population,” with most patients receiving diuretics and many receiving other medications. “After randomization, there was an intensification of all these therapies,” he observed, explaining that this can confound outcomes.

“For this field to move forward, we need a better understanding of the mechanisms underlying this syndrome, and we need to find potential targets above and beyond those used for low ejection fraction patients. We need to do something. This affects more than 2 million individuals in the United States alone.”

Dr. Margaret M. Redfield, professor of medicine at the Mayo Clinic, Rochester, Minn., called I-PRESERVE, “a very important trial, if only for the fact that ARBs and ACE inhibitors are already widely used for the treatment of heart failure with preserved ejection fraction, even though no randomized trial has shown a benefit. Two huge registries have shown that 60% are treated with these agents despite the lack of evidence.”

In this form of heart failure, she said there is little evidence that activation of the renin-angiotensin system is associated with disease progression, unlike in patients with reduced ejection fractions. “This may be why the trial was negative,” she speculated.

She also observed that patients in I-PRESERVE were largely similar to those in observational studies, but that they had fairly normal hemoglobin levels and renal function, “which is uncommon in the elderly with heart failure,” she pointed out. “Few had concentric hypertrophy, though some had concentric remodeling, and very few had advanced diastolic dysfunction or high filling pressures. So, this was a relatively healthy cohort and not as reflective of this syndrome as we would have hoped.”

The study was funded by Bristol-Myers Squibb Co. and Sanofi-Aventis. The results were simultaneously published online in the New England Journal of Medicine (doi:10.1056/NEJMoa08005450).

NEW ORLEANS — A tailored approach to dosing the antiplatelet agent clopidogrel significantly reduced the rate of adverse events after nonemergent percutaneous coronary intervention with stenting, in a study by French investigators presented at the annual scientific sessions of the American Heart Association.

The results of the Tailored Clopidogrel Loading Dose According to Platelet Reactivity Monitoring to Prevent Stent Thrombosis trial were presented by Dr. Franck Paganelli, professor of medicine in the division of cardiology, Hôpital Nord, University of Marseille (France).

“The response to clopidogrel is unpredictable, and there is a link between low response and thrombolytic events,” he noted. Investigators therefore aimed to develop an individualized approach to enhance the benefit of clopidogrel by lowering the patient's score on the vasodilator-stimulated phosphoprotein (VASP) index, a phosphorylation analysis that measures antiplatelet response to the drug. A cut-off value of 50% indicates lack of response and deems patients to be at high risk for major adverse cardiac events (MACE).

“Our aim was to demonstrate that a decrease in the VASP index may also reduce thrombosis,” Dr. Paganelli said.

The multicenter prospective study included 429 patients with low responses to clopidogrel (VASP index of at least 50%) drawn from a cohort of 1,122 patients undergoing nonemergent PCI for ACS or stable angina. Of those, 215 were randomized to the control arm to receive usual care with one 600-mg dose of clopidogrel, and the remaining 214 were assigned to the VASP-guided loading dose arm, to receive up to three additional doses of clopidogrel every 24 hours. The primary end point was the rate of early definite stent thrombosis. Secondary end points were the rates of MACE, defined as MI, cardiovascular death, urgent revascularization, and bleeding events.

Platelet reactivity monitoring showed that after the first clopidogrel bolus, all patients in both arms still had a VASP response of at least 50%. After the second 600-mg bolus, 70% of patients achieved a VASP of less than 50%, and the remaining 30% went on to receive a third and sometimes a fourth 600-mg dose until their VASP index fell below 50%. Despite the use of 2,400 gm of clopidogrel, 17 patients (8%) remained unresponsive, with a VASP index that remained above 50%, Dr. Paganelli reported.

Tailored dosing significantly lowered the primary and secondary end points without significantly increasing bleeding. The primary end point—early definite stent thrombosis during 1 month of follow-up—was observed in only 1 patient (0.5%) in the experimental arm, compared with 10 (4.7%) receiving usual care. Subacute stent thrombosis also was significantly reduced, occurring in one patient (0.5%) vs. eight (3.7%). Major bleeding occurred in fewer than 1% of each arm and minor bleeding in about 2%–3%. There were no cases of intracerebral or fatal hemorrhages.

Importantly, rates of MACE also were significantly lower in the individualized treatment group, at 0.5%, compared with 8.9% in the control group. “When you decrease the VASP index, you decrease thrombosis,” Dr. Paganelli noted.

“We also concluded that there are three kinds of patients,” he added: good responders, who have a VASP below 50%; low responders, who have a VASP above 50% and who can be improved with additional clopidogrel loading; and resistant patients, who have a VASP above 50% despite receiving up to 2.4 g of clopidogrel.

“Our message is 'yes, we can,'” he added. “We can develop a therapeutic window for antiplatelet therapy that will avoid MACE in patients undergoing PCI.”

Dr. Elliott M. Antman, professor of medicine at Harvard Medical School and director of the Samuel A. Levine cardiac unit at Brigham and Women's Hospital, both in Boston, discussed the findings. “This is a very important observation,” he told the media at a press conference. “The investigators have studied, in a creative fashion, the optimum loading dose of clopidogrel in patients undergoing PCI.”

“There is considerable variation in response to clopidogrel, one reason being the patient's inability to convert the prodrug clopidogrel into the active form that inhibits platelets,” he explained. “This involves a two-step reaction in the liver, which depends on the integrity of enzymes to convert clopidogrel to the active metabolite. There is marked genetic variation in this … and patients [unable to do this] have a marked increase in thrombotic events with stenting.”

Regarding the tailored dosing approach described in the study, Dr. Antman commented that “giving iterative loading doses of clopidogrel takes some time. It could take 1–3 days to go through the iterative loading process, especially in patients who need to go to three or four doses.”

One means is to empirically give a higher dose, which is being evaluated in ongoing clinical trials. Another is to use a laboratory test, as was done in this study, he said. “We need much more information about the integrity of these tests and how to use them,” he added. “In the future, we may have alternatives to clopidogrel, and this may make it simpler than the iterative dosing technique.”

The investigators creatively studied 'the optimum loading dose of clopidogrel in patients undergoing PCI.' DR. ANTMAN

NEW ORLEANS — A tailored approach to dosing the antiplatelet agent clopidogrel significantly reduced the rate of adverse events after nonemergent percutaneous coronary intervention with stenting, in a study by French investigators presented at the annual scientific sessions of the American Heart Association.

The results of the Tailored Clopidogrel Loading Dose According to Platelet Reactivity Monitoring to Prevent Stent Thrombosis trial were presented by Dr. Franck Paganelli, professor of medicine in the division of cardiology, Hôpital Nord, University of Marseille (France).

“The response to clopidogrel is unpredictable, and there is a link between low response and thrombolytic events,” he noted. Investigators therefore aimed to develop an individualized approach to enhance the benefit of clopidogrel by lowering the patient's score on the vasodilator-stimulated phosphoprotein (VASP) index, a phosphorylation analysis that measures antiplatelet response to the drug. A cut-off value of 50% indicates lack of response and deems patients to be at high risk for major adverse cardiac events (MACE).

“Our aim was to demonstrate that a decrease in the VASP index may also reduce thrombosis,” Dr. Paganelli said.

The multicenter prospective study included 429 patients with low responses to clopidogrel (VASP index of at least 50%) drawn from a cohort of 1,122 patients undergoing nonemergent PCI for ACS or stable angina. Of those, 215 were randomized to the control arm to receive usual care with one 600-mg dose of clopidogrel, and the remaining 214 were assigned to the VASP-guided loading dose arm, to receive up to three additional doses of clopidogrel every 24 hours. The primary end point was the rate of early definite stent thrombosis. Secondary end points were the rates of MACE, defined as MI, cardiovascular death, urgent revascularization, and bleeding events.

Platelet reactivity monitoring showed that after the first clopidogrel bolus, all patients in both arms still had a VASP response of at least 50%. After the second 600-mg bolus, 70% of patients achieved a VASP of less than 50%, and the remaining 30% went on to receive a third and sometimes a fourth 600-mg dose until their VASP index fell below 50%. Despite the use of 2,400 gm of clopidogrel, 17 patients (8%) remained unresponsive, with a VASP index that remained above 50%, Dr. Paganelli reported.

Tailored dosing significantly lowered the primary and secondary end points without significantly increasing bleeding. The primary end point—early definite stent thrombosis during 1 month of follow-up—was observed in only 1 patient (0.5%) in the experimental arm, compared with 10 (4.7%) receiving usual care. Subacute stent thrombosis also was significantly reduced, occurring in one patient (0.5%) vs. eight (3.7%). Major bleeding occurred in fewer than 1% of each arm and minor bleeding in about 2%–3%. There were no cases of intracerebral or fatal hemorrhages.

Importantly, rates of MACE also were significantly lower in the individualized treatment group, at 0.5%, compared with 8.9% in the control group. “When you decrease the VASP index, you decrease thrombosis,” Dr. Paganelli noted.

“We also concluded that there are three kinds of patients,” he added: good responders, who have a VASP below 50%; low responders, who have a VASP above 50% and who can be improved with additional clopidogrel loading; and resistant patients, who have a VASP above 50% despite receiving up to 2.4 g of clopidogrel.

“Our message is 'yes, we can,'” he added. “We can develop a therapeutic window for antiplatelet therapy that will avoid MACE in patients undergoing PCI.”

Dr. Elliott M. Antman, professor of medicine at Harvard Medical School and director of the Samuel A. Levine cardiac unit at Brigham and Women's Hospital, both in Boston, discussed the findings. “This is a very important observation,” he told the media at a press conference. “The investigators have studied, in a creative fashion, the optimum loading dose of clopidogrel in patients undergoing PCI.”

“There is considerable variation in response to clopidogrel, one reason being the patient's inability to convert the prodrug clopidogrel into the active form that inhibits platelets,” he explained. “This involves a two-step reaction in the liver, which depends on the integrity of enzymes to convert clopidogrel to the active metabolite. There is marked genetic variation in this … and patients [unable to do this] have a marked increase in thrombotic events with stenting.”

Regarding the tailored dosing approach described in the study, Dr. Antman commented that “giving iterative loading doses of clopidogrel takes some time. It could take 1–3 days to go through the iterative loading process, especially in patients who need to go to three or four doses.”

One means is to empirically give a higher dose, which is being evaluated in ongoing clinical trials. Another is to use a laboratory test, as was done in this study, he said. “We need much more information about the integrity of these tests and how to use them,” he added. “In the future, we may have alternatives to clopidogrel, and this may make it simpler than the iterative dosing technique.”

The investigators creatively studied 'the optimum loading dose of clopidogrel in patients undergoing PCI.' DR. ANTMAN

NEW ORLEANS — A tailored approach to dosing the antiplatelet agent clopidogrel significantly reduced the rate of adverse events after nonemergent percutaneous coronary intervention with stenting, in a study by French investigators presented at the annual scientific sessions of the American Heart Association.

The results of the Tailored Clopidogrel Loading Dose According to Platelet Reactivity Monitoring to Prevent Stent Thrombosis trial were presented by Dr. Franck Paganelli, professor of medicine in the division of cardiology, Hôpital Nord, University of Marseille (France).

“The response to clopidogrel is unpredictable, and there is a link between low response and thrombolytic events,” he noted. Investigators therefore aimed to develop an individualized approach to enhance the benefit of clopidogrel by lowering the patient's score on the vasodilator-stimulated phosphoprotein (VASP) index, a phosphorylation analysis that measures antiplatelet response to the drug. A cut-off value of 50% indicates lack of response and deems patients to be at high risk for major adverse cardiac events (MACE).

“Our aim was to demonstrate that a decrease in the VASP index may also reduce thrombosis,” Dr. Paganelli said.

The multicenter prospective study included 429 patients with low responses to clopidogrel (VASP index of at least 50%) drawn from a cohort of 1,122 patients undergoing nonemergent PCI for ACS or stable angina. Of those, 215 were randomized to the control arm to receive usual care with one 600-mg dose of clopidogrel, and the remaining 214 were assigned to the VASP-guided loading dose arm, to receive up to three additional doses of clopidogrel every 24 hours. The primary end point was the rate of early definite stent thrombosis. Secondary end points were the rates of MACE, defined as MI, cardiovascular death, urgent revascularization, and bleeding events.

Platelet reactivity monitoring showed that after the first clopidogrel bolus, all patients in both arms still had a VASP response of at least 50%. After the second 600-mg bolus, 70% of patients achieved a VASP of less than 50%, and the remaining 30% went on to receive a third and sometimes a fourth 600-mg dose until their VASP index fell below 50%. Despite the use of 2,400 gm of clopidogrel, 17 patients (8%) remained unresponsive, with a VASP index that remained above 50%, Dr. Paganelli reported.

Tailored dosing significantly lowered the primary and secondary end points without significantly increasing bleeding. The primary end point—early definite stent thrombosis during 1 month of follow-up—was observed in only 1 patient (0.5%) in the experimental arm, compared with 10 (4.7%) receiving usual care. Subacute stent thrombosis also was significantly reduced, occurring in one patient (0.5%) vs. eight (3.7%). Major bleeding occurred in fewer than 1% of each arm and minor bleeding in about 2%–3%. There were no cases of intracerebral or fatal hemorrhages.

Importantly, rates of MACE also were significantly lower in the individualized treatment group, at 0.5%, compared with 8.9% in the control group. “When you decrease the VASP index, you decrease thrombosis,” Dr. Paganelli noted.

“We also concluded that there are three kinds of patients,” he added: good responders, who have a VASP below 50%; low responders, who have a VASP above 50% and who can be improved with additional clopidogrel loading; and resistant patients, who have a VASP above 50% despite receiving up to 2.4 g of clopidogrel.

“Our message is 'yes, we can,'” he added. “We can develop a therapeutic window for antiplatelet therapy that will avoid MACE in patients undergoing PCI.”

Dr. Elliott M. Antman, professor of medicine at Harvard Medical School and director of the Samuel A. Levine cardiac unit at Brigham and Women's Hospital, both in Boston, discussed the findings. “This is a very important observation,” he told the media at a press conference. “The investigators have studied, in a creative fashion, the optimum loading dose of clopidogrel in patients undergoing PCI.”

“There is considerable variation in response to clopidogrel, one reason being the patient's inability to convert the prodrug clopidogrel into the active form that inhibits platelets,” he explained. “This involves a two-step reaction in the liver, which depends on the integrity of enzymes to convert clopidogrel to the active metabolite. There is marked genetic variation in this … and patients [unable to do this] have a marked increase in thrombotic events with stenting.”

Regarding the tailored dosing approach described in the study, Dr. Antman commented that “giving iterative loading doses of clopidogrel takes some time. It could take 1–3 days to go through the iterative loading process, especially in patients who need to go to three or four doses.”

One means is to empirically give a higher dose, which is being evaluated in ongoing clinical trials. Another is to use a laboratory test, as was done in this study, he said. “We need much more information about the integrity of these tests and how to use them,” he added. “In the future, we may have alternatives to clopidogrel, and this may make it simpler than the iterative dosing technique.”

The investigators creatively studied 'the optimum loading dose of clopidogrel in patients undergoing PCI.' DR. ANTMAN

NEW ORLEANS—Aspirin therapy is commonly used for primary prevention of cardiovascular events in persons with type 2 diabetes, but a Japanese study of 2,539 subjects found no significant reduction in the primary end point of total atherosclerotic events, except in patients aged at least 65 years.

The study, which is the largest primary prevention trial of aspirin in type 2 diabetes, was reported at the annual scientific sessions of the American Heart Association.

In the Japanese Primary Prevention of Atherosclerosis with Aspirin for Diabetes (JPAD) trial, the use of daily low-dose aspirin was associated with a 20% nonsignificant reduction in the risk of the primary end point (a composite of coronary, cerebrovascular, and peripheral vascular events) in the population as a whole, and a 32% statistically significant reduction in events among those aged 65 and older, reported Dr. Hisao Ogawa of the Kumamoto (Japan) University.

Aspirin use also significantly reduced the composite of fatal coronary and fatal cerebrovascular events.

“Although the effect of low-dose aspirin was not statistically significant for the primary end point, a significant effect was demonstrated on fatal coronary and fatal cerebrovascular events. The trial also suggests that low-dose aspirin might reduce total events in older patients,” he said at a late-breaking trials session.

The results were reported online simultaneously with Dr. Ogawa's presentation (JAMA 2008;300:2134–41).

Japanese investigators from 163 institutions examined the benefit of low-dose aspirin for preventing cardiovascular events in 2,539 patients with type 2 diabetes who had no history of atherosclerotic disease. Average age of the patients was 65 years, and 55% were men. Patients were randomly assigned to receive 81–100 mg aspirin per day (n = 1,262) or no aspirin (n = 1,277).

After a median follow-up of 4.4 years, a total of 154 fatal and nonfatal atherosclerotic events had occurred: 68 in the aspirin group and 86 in the nonaspirin group. This represented a rate of 13.6 vs. 17.0 events per 1,000 person-years, for a 20% reduction in risk that was not statistically significant, Dr. Ogawa reported.

Among the 719 patients aged at least 65 in the aspirin arm, 45 events (6.3%) atherosclerotic events occurred, compared with 59 events (9.2%) in the 644 older patients in the nonaspirin group, representing a statistically significant 32% reduction in risk with aspirin use.

The combined secondary end point of fatal coronary events and fatal cerebrovascular events occurred in 1 patient (stroke) in the aspirin group and 10 patients (five fatal myocardial infarctions and five fatal strokes) in the nonaspirin group, for a 90% statistically significant reduction in risk for that outcome.

Adverse effects occurred in 86 patients taking aspirin and 14 not on aspirin. Hemorrhagic events were greater with aspirin (34 vs. 10), including an increase in gastrointestinal bleeding and the need for transfusion for severe GI bleeding in four patients, but there was no increase in hemorrhagic stroke.

“JPAD supports the safety of using low-dose aspirin in diabetics for primary prevention,” he said.

The investigators cautioned that the findings should be interpreted in context of the low incidence of atherosclerotic disease in Japan and the aggressive management of cardiovascular risk factors. “The event rate was lower than anticipated because the patients were so well treated,” Dr. Ogawa said. “They saw their physicians every 2–4 weeks.”

Dr. Marian Limacher, professor of medicine at the University of Florida, Gainesville, said JPAD was “a well-designed and well-conducted study” that aimed to address a question that “some may have thought did not need to be answered,” given the widespread recommendation for the use of aspirin in diabetic patients. “However, the evidence basis for this has been lacking until recently, and JPAD adds to this considerably,” she commented at a press briefing.

The findings are congruent with the recently completed Progression of Arterial Disease and Diabetes (POPADAD) study from the United Kingdom, she noted. POPADAD, involving 1,276 patients with asymptomatic peripheral artery disease, found no evidence for aspirin's benefit on cardiovascular events and mortality.

NEW ORLEANS—Aspirin therapy is commonly used for primary prevention of cardiovascular events in persons with type 2 diabetes, but a Japanese study of 2,539 subjects found no significant reduction in the primary end point of total atherosclerotic events, except in patients aged at least 65 years.

The study, which is the largest primary prevention trial of aspirin in type 2 diabetes, was reported at the annual scientific sessions of the American Heart Association.

In the Japanese Primary Prevention of Atherosclerosis with Aspirin for Diabetes (JPAD) trial, the use of daily low-dose aspirin was associated with a 20% nonsignificant reduction in the risk of the primary end point (a composite of coronary, cerebrovascular, and peripheral vascular events) in the population as a whole, and a 32% statistically significant reduction in events among those aged 65 and older, reported Dr. Hisao Ogawa of the Kumamoto (Japan) University.

Aspirin use also significantly reduced the composite of fatal coronary and fatal cerebrovascular events.

“Although the effect of low-dose aspirin was not statistically significant for the primary end point, a significant effect was demonstrated on fatal coronary and fatal cerebrovascular events. The trial also suggests that low-dose aspirin might reduce total events in older patients,” he said at a late-breaking trials session.

The results were reported online simultaneously with Dr. Ogawa's presentation (JAMA 2008;300:2134–41).

Japanese investigators from 163 institutions examined the benefit of low-dose aspirin for preventing cardiovascular events in 2,539 patients with type 2 diabetes who had no history of atherosclerotic disease. Average age of the patients was 65 years, and 55% were men. Patients were randomly assigned to receive 81–100 mg aspirin per day (n = 1,262) or no aspirin (n = 1,277).

After a median follow-up of 4.4 years, a total of 154 fatal and nonfatal atherosclerotic events had occurred: 68 in the aspirin group and 86 in the nonaspirin group. This represented a rate of 13.6 vs. 17.0 events per 1,000 person-years, for a 20% reduction in risk that was not statistically significant, Dr. Ogawa reported.

Among the 719 patients aged at least 65 in the aspirin arm, 45 events (6.3%) atherosclerotic events occurred, compared with 59 events (9.2%) in the 644 older patients in the nonaspirin group, representing a statistically significant 32% reduction in risk with aspirin use.

The combined secondary end point of fatal coronary events and fatal cerebrovascular events occurred in 1 patient (stroke) in the aspirin group and 10 patients (five fatal myocardial infarctions and five fatal strokes) in the nonaspirin group, for a 90% statistically significant reduction in risk for that outcome.

Adverse effects occurred in 86 patients taking aspirin and 14 not on aspirin. Hemorrhagic events were greater with aspirin (34 vs. 10), including an increase in gastrointestinal bleeding and the need for transfusion for severe GI bleeding in four patients, but there was no increase in hemorrhagic stroke.

“JPAD supports the safety of using low-dose aspirin in diabetics for primary prevention,” he said.

The investigators cautioned that the findings should be interpreted in context of the low incidence of atherosclerotic disease in Japan and the aggressive management of cardiovascular risk factors. “The event rate was lower than anticipated because the patients were so well treated,” Dr. Ogawa said. “They saw their physicians every 2–4 weeks.”

Dr. Marian Limacher, professor of medicine at the University of Florida, Gainesville, said JPAD was “a well-designed and well-conducted study” that aimed to address a question that “some may have thought did not need to be answered,” given the widespread recommendation for the use of aspirin in diabetic patients. “However, the evidence basis for this has been lacking until recently, and JPAD adds to this considerably,” she commented at a press briefing.

The findings are congruent with the recently completed Progression of Arterial Disease and Diabetes (POPADAD) study from the United Kingdom, she noted. POPADAD, involving 1,276 patients with asymptomatic peripheral artery disease, found no evidence for aspirin's benefit on cardiovascular events and mortality.

NEW ORLEANS—Aspirin therapy is commonly used for primary prevention of cardiovascular events in persons with type 2 diabetes, but a Japanese study of 2,539 subjects found no significant reduction in the primary end point of total atherosclerotic events, except in patients aged at least 65 years.

The study, which is the largest primary prevention trial of aspirin in type 2 diabetes, was reported at the annual scientific sessions of the American Heart Association.

In the Japanese Primary Prevention of Atherosclerosis with Aspirin for Diabetes (JPAD) trial, the use of daily low-dose aspirin was associated with a 20% nonsignificant reduction in the risk of the primary end point (a composite of coronary, cerebrovascular, and peripheral vascular events) in the population as a whole, and a 32% statistically significant reduction in events among those aged 65 and older, reported Dr. Hisao Ogawa of the Kumamoto (Japan) University.

Aspirin use also significantly reduced the composite of fatal coronary and fatal cerebrovascular events.

“Although the effect of low-dose aspirin was not statistically significant for the primary end point, a significant effect was demonstrated on fatal coronary and fatal cerebrovascular events. The trial also suggests that low-dose aspirin might reduce total events in older patients,” he said at a late-breaking trials session.

The results were reported online simultaneously with Dr. Ogawa's presentation (JAMA 2008;300:2134–41).

Japanese investigators from 163 institutions examined the benefit of low-dose aspirin for preventing cardiovascular events in 2,539 patients with type 2 diabetes who had no history of atherosclerotic disease. Average age of the patients was 65 years, and 55% were men. Patients were randomly assigned to receive 81–100 mg aspirin per day (n = 1,262) or no aspirin (n = 1,277).

After a median follow-up of 4.4 years, a total of 154 fatal and nonfatal atherosclerotic events had occurred: 68 in the aspirin group and 86 in the nonaspirin group. This represented a rate of 13.6 vs. 17.0 events per 1,000 person-years, for a 20% reduction in risk that was not statistically significant, Dr. Ogawa reported.

Among the 719 patients aged at least 65 in the aspirin arm, 45 events (6.3%) atherosclerotic events occurred, compared with 59 events (9.2%) in the 644 older patients in the nonaspirin group, representing a statistically significant 32% reduction in risk with aspirin use.

The combined secondary end point of fatal coronary events and fatal cerebrovascular events occurred in 1 patient (stroke) in the aspirin group and 10 patients (five fatal myocardial infarctions and five fatal strokes) in the nonaspirin group, for a 90% statistically significant reduction in risk for that outcome.

Adverse effects occurred in 86 patients taking aspirin and 14 not on aspirin. Hemorrhagic events were greater with aspirin (34 vs. 10), including an increase in gastrointestinal bleeding and the need for transfusion for severe GI bleeding in four patients, but there was no increase in hemorrhagic stroke.

“JPAD supports the safety of using low-dose aspirin in diabetics for primary prevention,” he said.

The investigators cautioned that the findings should be interpreted in context of the low incidence of atherosclerotic disease in Japan and the aggressive management of cardiovascular risk factors. “The event rate was lower than anticipated because the patients were so well treated,” Dr. Ogawa said. “They saw their physicians every 2–4 weeks.”

Dr. Marian Limacher, professor of medicine at the University of Florida, Gainesville, said JPAD was “a well-designed and well-conducted study” that aimed to address a question that “some may have thought did not need to be answered,” given the widespread recommendation for the use of aspirin in diabetic patients. “However, the evidence basis for this has been lacking until recently, and JPAD adds to this considerably,” she commented at a press briefing.

The findings are congruent with the recently completed Progression of Arterial Disease and Diabetes (POPADAD) study from the United Kingdom, she noted. POPADAD, involving 1,276 patients with asymptomatic peripheral artery disease, found no evidence for aspirin's benefit on cardiovascular events and mortality.