AHA Scientific Sessions 2012

LOS ANGELES – The largest-ever U.S. study of the long-term risk of cardiovascular events in survivors of childhood acute Kawasaki disease paints a highly reassuring picture overall.

Indeed, the cardiovascular event rate in 546 patients during an average 15-year follow-up since their acute illness was extremely low – no different, in fact, than in 2,218 matched controls, Dr. Taylor J. Holve reported at the annual scientific sessions of the American Heart Association.

The composite endpoint of acute coronary syndrome, coronary revascularization heart failure, ventricular arrhythmia, valvular heart disease, aortic aneurysm, or all-cause mortality occurred in two patients with a history of Kawasaki disease and in seven controls. That translated to an adjusted incidence rate of 0.246 events per 1,000 person-years in the Kawasaki disease group and a similar figure of 0.217 per 1,000 person-years in controls, according to Dr. Holve of Kaiser San Francisco Medical Center.

Twenty-five patients in the Kawasaki disease group had a persistent coronary artery aneurysm. Both of the cardiovascular events that occurred during long-term follow-up – one case of acute coronary syndrome (ACS), and another of ACS followed by coronary artery bypass surgery – were in the small subgroup with persistent coronary aneurysm.

Other investigators have previously described the increased long-term risk posed by formation of a persistent aneurysm in survivors of acute Kawasaki disease. It’s clear from this large study that survivors with persistent coronary aneurysm are a higher-risk subgroup meriting long-term cardiovascular surveillance. In contrast, Kawasaki disease survivors without persistent aneurysm had a cardiovascular event rate of zero. A caveat: The average age of these patients at 15 years of follow-up was slightly over 21 years; continued follow-up will be required to exclude the possibility of an elevated risk of cardiovascular events once patients without a persistent coronary aneurysm hit their mid-20s and beyond, Dr. Holve noted.

The various treatment strategies employed in treating acute Kawasaki disease showed no association with short- or long-term complication rates.

Dr. Holve reported having no financial conflicts.

b.jancin@elsevier.com

LOS ANGELES – The largest-ever U.S. study of the long-term risk of cardiovascular events in survivors of childhood acute Kawasaki disease paints a highly reassuring picture overall.

Indeed, the cardiovascular event rate in 546 patients during an average 15-year follow-up since their acute illness was extremely low – no different, in fact, than in 2,218 matched controls, Dr. Taylor J. Holve reported at the annual scientific sessions of the American Heart Association.

The composite endpoint of acute coronary syndrome, coronary revascularization heart failure, ventricular arrhythmia, valvular heart disease, aortic aneurysm, or all-cause mortality occurred in two patients with a history of Kawasaki disease and in seven controls. That translated to an adjusted incidence rate of 0.246 events per 1,000 person-years in the Kawasaki disease group and a similar figure of 0.217 per 1,000 person-years in controls, according to Dr. Holve of Kaiser San Francisco Medical Center.

Twenty-five patients in the Kawasaki disease group had a persistent coronary artery aneurysm. Both of the cardiovascular events that occurred during long-term follow-up – one case of acute coronary syndrome (ACS), and another of ACS followed by coronary artery bypass surgery – were in the small subgroup with persistent coronary aneurysm.

Other investigators have previously described the increased long-term risk posed by formation of a persistent aneurysm in survivors of acute Kawasaki disease. It’s clear from this large study that survivors with persistent coronary aneurysm are a higher-risk subgroup meriting long-term cardiovascular surveillance. In contrast, Kawasaki disease survivors without persistent aneurysm had a cardiovascular event rate of zero. A caveat: The average age of these patients at 15 years of follow-up was slightly over 21 years; continued follow-up will be required to exclude the possibility of an elevated risk of cardiovascular events once patients without a persistent coronary aneurysm hit their mid-20s and beyond, Dr. Holve noted.

The various treatment strategies employed in treating acute Kawasaki disease showed no association with short- or long-term complication rates.

Dr. Holve reported having no financial conflicts.

b.jancin@elsevier.com

LOS ANGELES – The largest-ever U.S. study of the long-term risk of cardiovascular events in survivors of childhood acute Kawasaki disease paints a highly reassuring picture overall.

Indeed, the cardiovascular event rate in 546 patients during an average 15-year follow-up since their acute illness was extremely low – no different, in fact, than in 2,218 matched controls, Dr. Taylor J. Holve reported at the annual scientific sessions of the American Heart Association.

The composite endpoint of acute coronary syndrome, coronary revascularization heart failure, ventricular arrhythmia, valvular heart disease, aortic aneurysm, or all-cause mortality occurred in two patients with a history of Kawasaki disease and in seven controls. That translated to an adjusted incidence rate of 0.246 events per 1,000 person-years in the Kawasaki disease group and a similar figure of 0.217 per 1,000 person-years in controls, according to Dr. Holve of Kaiser San Francisco Medical Center.

Twenty-five patients in the Kawasaki disease group had a persistent coronary artery aneurysm. Both of the cardiovascular events that occurred during long-term follow-up – one case of acute coronary syndrome (ACS), and another of ACS followed by coronary artery bypass surgery – were in the small subgroup with persistent coronary aneurysm.

Other investigators have previously described the increased long-term risk posed by formation of a persistent aneurysm in survivors of acute Kawasaki disease. It’s clear from this large study that survivors with persistent coronary aneurysm are a higher-risk subgroup meriting long-term cardiovascular surveillance. In contrast, Kawasaki disease survivors without persistent aneurysm had a cardiovascular event rate of zero. A caveat: The average age of these patients at 15 years of follow-up was slightly over 21 years; continued follow-up will be required to exclude the possibility of an elevated risk of cardiovascular events once patients without a persistent coronary aneurysm hit their mid-20s and beyond, Dr. Holve noted.

The various treatment strategies employed in treating acute Kawasaki disease showed no association with short- or long-term complication rates.

Dr. Holve reported having no financial conflicts.

b.jancin@elsevier.com

LOS ANGELES – Patients with a patent foramen ovale and an implanted defibrillator or pacemaker may be perfect candidates for targeted closure of their heart defect, based on a review of more than 6,000 patients who received a device at one U.S. center.

During an average follow-up of nearly 5 years, patients with a patent foramen ovale (PFO) who received an implantable cardioverter defibrillator (ICD) or a permanent pacemaker were more than fourfold more likely to develop a stroke or transient ischemic attack (TIA) compared with implanted device recipients who did not have a PFO, Dr. Christopher V. DeSimone said at the annual scientific sessions of the American Heart Association.

"We think that this is a high-risk population that might benefit from PFO closure," said Dr. DeSimone, an internal medicine physician at the Mayo Clinic in Rochester, Minn. He acknowledged the poor efficacy of PFO closure for stroke prevention in several recent randomized trials, but noted that patients with a PFO who receive an ICD or permanent pacemaker may constitute a special subgroup that stands to benefit from PFO closure.

"If a patient has a right atrial or ventricular lead and a clot forms and sits there next to the PFO they would be at high risk" for a stroke or TIA, he said in an interview. In fact, trials that have assessed the efficacy of PFO closure explicitly excluded patients with permanent pacemakers as well as many ICD recipients because of their substantially impaired left ventricular function, such as in the CLOSURE I trial (N. Engl. J. Med. 2012;366:991-99). "This needs to be studied prospectively," he added, noting that his study was limited by being retrospective and potentially subject to unadjusted confounding.

Dr. DeSimone and his associates reviewed 6,086 patients who received an ICD or permanent pacemaker at the Mayo Clinic during January 2000 to October 2010. The group included 375 patients with PFOs. Average age of the patients was 67 years; nearly two-thirds were men. About 15% had a history of stroke or TIA, about 44% had atrial fibrillation, and their average CHA2D2-VASc score was 3.1.

During an average follow-up of 4.7 years, the incidence of stroke or TIA was 11% in the PFO patients and 2% in the patients without a PFO. In a multivariate analysis that controlled for baseline demographic and clinical differences, including atrial fibrillation and aspirin and warfarin use, patients with a PFO were 4.6-fold more likely to have a stroke or TIA than were patients without a PFO, a statistically significant difference.

Additional analyses showed that the stroke and TIA rate remained significantly elevated in the PFO patients regardless of whether patients were on treatment with aspirin or on warfarin, and also regardless of whether or not they were older than age 65 or had a history of stroke or TIA, and regardless of whether they had a low or high CHA₂D₂-VASc score, Dr. DeSimone said.

In contrast to the strong, consistent link between PFOs and stroke or TIA, the researchers saw no significant link between the presence of a PFO and all-cause mortality.

The PFO-related difference in the incidence of stroke and TIA first became apparent about 1 year after device placement. The event curves then continued to diverge more and more over time. He hypothesized that micro-emboli that originate on the device leads pass through the PFO and into the pulmonary circulation, causing increased pulmonary-artery pressures during the year after device placement. The increased right-sided pressure then favors a right-to-left shunt and increased embolization.

Also, the stroke risk in this analysis may have underestimated the true risk posed by the combination of a PFO and a heart device because the methods used to detect PFOs and stroke may not have been optimal in many cases.

Dr. Desimone said that he had no disclosures.

m.zoler@elsevier.com

On Twitter @mitchelzoler

LOS ANGELES – Patients with a patent foramen ovale and an implanted defibrillator or pacemaker may be perfect candidates for targeted closure of their heart defect, based on a review of more than 6,000 patients who received a device at one U.S. center.

During an average follow-up of nearly 5 years, patients with a patent foramen ovale (PFO) who received an implantable cardioverter defibrillator (ICD) or a permanent pacemaker were more than fourfold more likely to develop a stroke or transient ischemic attack (TIA) compared with implanted device recipients who did not have a PFO, Dr. Christopher V. DeSimone said at the annual scientific sessions of the American Heart Association.

"We think that this is a high-risk population that might benefit from PFO closure," said Dr. DeSimone, an internal medicine physician at the Mayo Clinic in Rochester, Minn. He acknowledged the poor efficacy of PFO closure for stroke prevention in several recent randomized trials, but noted that patients with a PFO who receive an ICD or permanent pacemaker may constitute a special subgroup that stands to benefit from PFO closure.

"If a patient has a right atrial or ventricular lead and a clot forms and sits there next to the PFO they would be at high risk" for a stroke or TIA, he said in an interview. In fact, trials that have assessed the efficacy of PFO closure explicitly excluded patients with permanent pacemakers as well as many ICD recipients because of their substantially impaired left ventricular function, such as in the CLOSURE I trial (N. Engl. J. Med. 2012;366:991-99). "This needs to be studied prospectively," he added, noting that his study was limited by being retrospective and potentially subject to unadjusted confounding.

Dr. DeSimone and his associates reviewed 6,086 patients who received an ICD or permanent pacemaker at the Mayo Clinic during January 2000 to October 2010. The group included 375 patients with PFOs. Average age of the patients was 67 years; nearly two-thirds were men. About 15% had a history of stroke or TIA, about 44% had atrial fibrillation, and their average CHA2D2-VASc score was 3.1.

During an average follow-up of 4.7 years, the incidence of stroke or TIA was 11% in the PFO patients and 2% in the patients without a PFO. In a multivariate analysis that controlled for baseline demographic and clinical differences, including atrial fibrillation and aspirin and warfarin use, patients with a PFO were 4.6-fold more likely to have a stroke or TIA than were patients without a PFO, a statistically significant difference.

Additional analyses showed that the stroke and TIA rate remained significantly elevated in the PFO patients regardless of whether patients were on treatment with aspirin or on warfarin, and also regardless of whether or not they were older than age 65 or had a history of stroke or TIA, and regardless of whether they had a low or high CHA₂D₂-VASc score, Dr. DeSimone said.

In contrast to the strong, consistent link between PFOs and stroke or TIA, the researchers saw no significant link between the presence of a PFO and all-cause mortality.

The PFO-related difference in the incidence of stroke and TIA first became apparent about 1 year after device placement. The event curves then continued to diverge more and more over time. He hypothesized that micro-emboli that originate on the device leads pass through the PFO and into the pulmonary circulation, causing increased pulmonary-artery pressures during the year after device placement. The increased right-sided pressure then favors a right-to-left shunt and increased embolization.

Also, the stroke risk in this analysis may have underestimated the true risk posed by the combination of a PFO and a heart device because the methods used to detect PFOs and stroke may not have been optimal in many cases.

Dr. Desimone said that he had no disclosures.

m.zoler@elsevier.com

On Twitter @mitchelzoler

LOS ANGELES – Patients with a patent foramen ovale and an implanted defibrillator or pacemaker may be perfect candidates for targeted closure of their heart defect, based on a review of more than 6,000 patients who received a device at one U.S. center.

During an average follow-up of nearly 5 years, patients with a patent foramen ovale (PFO) who received an implantable cardioverter defibrillator (ICD) or a permanent pacemaker were more than fourfold more likely to develop a stroke or transient ischemic attack (TIA) compared with implanted device recipients who did not have a PFO, Dr. Christopher V. DeSimone said at the annual scientific sessions of the American Heart Association.

"We think that this is a high-risk population that might benefit from PFO closure," said Dr. DeSimone, an internal medicine physician at the Mayo Clinic in Rochester, Minn. He acknowledged the poor efficacy of PFO closure for stroke prevention in several recent randomized trials, but noted that patients with a PFO who receive an ICD or permanent pacemaker may constitute a special subgroup that stands to benefit from PFO closure.

"If a patient has a right atrial or ventricular lead and a clot forms and sits there next to the PFO they would be at high risk" for a stroke or TIA, he said in an interview. In fact, trials that have assessed the efficacy of PFO closure explicitly excluded patients with permanent pacemakers as well as many ICD recipients because of their substantially impaired left ventricular function, such as in the CLOSURE I trial (N. Engl. J. Med. 2012;366:991-99). "This needs to be studied prospectively," he added, noting that his study was limited by being retrospective and potentially subject to unadjusted confounding.

Dr. DeSimone and his associates reviewed 6,086 patients who received an ICD or permanent pacemaker at the Mayo Clinic during January 2000 to October 2010. The group included 375 patients with PFOs. Average age of the patients was 67 years; nearly two-thirds were men. About 15% had a history of stroke or TIA, about 44% had atrial fibrillation, and their average CHA2D2-VASc score was 3.1.

During an average follow-up of 4.7 years, the incidence of stroke or TIA was 11% in the PFO patients and 2% in the patients without a PFO. In a multivariate analysis that controlled for baseline demographic and clinical differences, including atrial fibrillation and aspirin and warfarin use, patients with a PFO were 4.6-fold more likely to have a stroke or TIA than were patients without a PFO, a statistically significant difference.

Additional analyses showed that the stroke and TIA rate remained significantly elevated in the PFO patients regardless of whether patients were on treatment with aspirin or on warfarin, and also regardless of whether or not they were older than age 65 or had a history of stroke or TIA, and regardless of whether they had a low or high CHA₂D₂-VASc score, Dr. DeSimone said.

In contrast to the strong, consistent link between PFOs and stroke or TIA, the researchers saw no significant link between the presence of a PFO and all-cause mortality.

The PFO-related difference in the incidence of stroke and TIA first became apparent about 1 year after device placement. The event curves then continued to diverge more and more over time. He hypothesized that micro-emboli that originate on the device leads pass through the PFO and into the pulmonary circulation, causing increased pulmonary-artery pressures during the year after device placement. The increased right-sided pressure then favors a right-to-left shunt and increased embolization.

Also, the stroke risk in this analysis may have underestimated the true risk posed by the combination of a PFO and a heart device because the methods used to detect PFOs and stroke may not have been optimal in many cases.

Dr. Desimone said that he had no disclosures.

m.zoler@elsevier.com

On Twitter @mitchelzoler

LOS ANGELES – Oral vitamin D₃ may have a future as adjunctive therapy in patients with heart failure, according to Dr. Rebecca S. Boxer.

Six months of oral vitamin D₃ therapy at 50,000 IU/wk resulted in a 37% decrease in serum aldosterone level in a randomized, double-blind, placebo-controlled trial conducted in vitamin D–deficient patients with heart failure.

Moreover, parathyroid hormone levels, which were elevated at baseline, fell by 41% in the active treatment arm, she reported at the annual scientific sessions of the American Heart Association.

The study involved 64 patients with New York Heart Association class II-IV heart failure, all having a baseline serum vitamin D level below 20 ng/mL. All participants were on maximum tolerated doses of standard heart failure medications. The patients were randomized to oral vitamin D₃ at 50,000 IU/wk plus 400 mg of calcium citrate twice daily for 6 months or to calcium plus placebo.

Mean serum vitamin D levels climbed from 19 ng/mL to 60 ng/mL in treated patients while remaining unchanged over time in controls.

Serum aldosterone levels fell from 10.0 ng/mL to 6.3 ng/dL in the active treatment group and remained static in controls. The mean serum parathyroid hormone level dropped from 62.3 pg/mL to 37.1 pg/mL with vitamin D therapy but stayed steady in controls, said Dr. Boxer of Case Western Reserve University, Cleveland.

The primary endpoint in this randomized trial was change in aerobic capacity; vitamin D supplementation had no effect on this endpoint. Nor did it have any significant impact on heart failure symptoms, echocardiographic findings, body weight, blood pressure, serum renin, or C-reactive protein levels in this relatively small study.

Nonetheless, the finding of a moderate reduction in serum aldosterone level indicates that the effects of vitamin D₃ on the renin-angiotensin-aldosterone system (RAAS) in patients with heart failure warrants further study, including assessment of possible long-term clinical benefit.

Dr. Boxer pointed out that serum aldosterone level in patients with heart failure predicts mortality. And aldosterone blockade with an aldosterone antagonist has been shown to improve clinical outcomes in heart failure patients with a depressed left ventricular ejection fraction in RALES, the Randomized Aldactone Evaluation Study (N. Engl. J. Med. 1999;341:709-17) and EPHESUS, the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (N. Engl. J. Med. 2003;348:1309-21). Aldosterone blockade is also actively under study in heart failure patients with preserved systolic function in the ongoing TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) study, due to report results next year.

"There may be certain patient groups that could greatly benefit from vitamin D₃ therapy, particularly patients who may not be able to tolerate RAAS blockade or those who have aldosterone escape," she said.

The mechanism by which oral vitamin D₃ reduces serum aldosterone is unknown. The mechanism is clearly non–renin-dependent, given that serum renin level remained unchanged. In vitro studies suggest that vitamin D might act through a direct effect on steroidogenesis in adrenal cortical cells, Dr. Boxer said.

The study was funded by the American Heart Association. Dr. Boxer reported having no relevant financial conflicts.

b.jancin@elsevier.com

LOS ANGELES – Oral vitamin D₃ may have a future as adjunctive therapy in patients with heart failure, according to Dr. Rebecca S. Boxer.

Six months of oral vitamin D₃ therapy at 50,000 IU/wk resulted in a 37% decrease in serum aldosterone level in a randomized, double-blind, placebo-controlled trial conducted in vitamin D–deficient patients with heart failure.

Moreover, parathyroid hormone levels, which were elevated at baseline, fell by 41% in the active treatment arm, she reported at the annual scientific sessions of the American Heart Association.

The study involved 64 patients with New York Heart Association class II-IV heart failure, all having a baseline serum vitamin D level below 20 ng/mL. All participants were on maximum tolerated doses of standard heart failure medications. The patients were randomized to oral vitamin D₃ at 50,000 IU/wk plus 400 mg of calcium citrate twice daily for 6 months or to calcium plus placebo.

Mean serum vitamin D levels climbed from 19 ng/mL to 60 ng/mL in treated patients while remaining unchanged over time in controls.

Serum aldosterone levels fell from 10.0 ng/mL to 6.3 ng/dL in the active treatment group and remained static in controls. The mean serum parathyroid hormone level dropped from 62.3 pg/mL to 37.1 pg/mL with vitamin D therapy but stayed steady in controls, said Dr. Boxer of Case Western Reserve University, Cleveland.

The primary endpoint in this randomized trial was change in aerobic capacity; vitamin D supplementation had no effect on this endpoint. Nor did it have any significant impact on heart failure symptoms, echocardiographic findings, body weight, blood pressure, serum renin, or C-reactive protein levels in this relatively small study.

Nonetheless, the finding of a moderate reduction in serum aldosterone level indicates that the effects of vitamin D₃ on the renin-angiotensin-aldosterone system (RAAS) in patients with heart failure warrants further study, including assessment of possible long-term clinical benefit.

Dr. Boxer pointed out that serum aldosterone level in patients with heart failure predicts mortality. And aldosterone blockade with an aldosterone antagonist has been shown to improve clinical outcomes in heart failure patients with a depressed left ventricular ejection fraction in RALES, the Randomized Aldactone Evaluation Study (N. Engl. J. Med. 1999;341:709-17) and EPHESUS, the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (N. Engl. J. Med. 2003;348:1309-21). Aldosterone blockade is also actively under study in heart failure patients with preserved systolic function in the ongoing TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) study, due to report results next year.

"There may be certain patient groups that could greatly benefit from vitamin D₃ therapy, particularly patients who may not be able to tolerate RAAS blockade or those who have aldosterone escape," she said.

The mechanism by which oral vitamin D₃ reduces serum aldosterone is unknown. The mechanism is clearly non–renin-dependent, given that serum renin level remained unchanged. In vitro studies suggest that vitamin D might act through a direct effect on steroidogenesis in adrenal cortical cells, Dr. Boxer said.

The study was funded by the American Heart Association. Dr. Boxer reported having no relevant financial conflicts.

b.jancin@elsevier.com

LOS ANGELES – Oral vitamin D₃ may have a future as adjunctive therapy in patients with heart failure, according to Dr. Rebecca S. Boxer.

Six months of oral vitamin D₃ therapy at 50,000 IU/wk resulted in a 37% decrease in serum aldosterone level in a randomized, double-blind, placebo-controlled trial conducted in vitamin D–deficient patients with heart failure.

Moreover, parathyroid hormone levels, which were elevated at baseline, fell by 41% in the active treatment arm, she reported at the annual scientific sessions of the American Heart Association.

The study involved 64 patients with New York Heart Association class II-IV heart failure, all having a baseline serum vitamin D level below 20 ng/mL. All participants were on maximum tolerated doses of standard heart failure medications. The patients were randomized to oral vitamin D₃ at 50,000 IU/wk plus 400 mg of calcium citrate twice daily for 6 months or to calcium plus placebo.

Mean serum vitamin D levels climbed from 19 ng/mL to 60 ng/mL in treated patients while remaining unchanged over time in controls.

Serum aldosterone levels fell from 10.0 ng/mL to 6.3 ng/dL in the active treatment group and remained static in controls. The mean serum parathyroid hormone level dropped from 62.3 pg/mL to 37.1 pg/mL with vitamin D therapy but stayed steady in controls, said Dr. Boxer of Case Western Reserve University, Cleveland.

The primary endpoint in this randomized trial was change in aerobic capacity; vitamin D supplementation had no effect on this endpoint. Nor did it have any significant impact on heart failure symptoms, echocardiographic findings, body weight, blood pressure, serum renin, or C-reactive protein levels in this relatively small study.

Nonetheless, the finding of a moderate reduction in serum aldosterone level indicates that the effects of vitamin D₃ on the renin-angiotensin-aldosterone system (RAAS) in patients with heart failure warrants further study, including assessment of possible long-term clinical benefit.

Dr. Boxer pointed out that serum aldosterone level in patients with heart failure predicts mortality. And aldosterone blockade with an aldosterone antagonist has been shown to improve clinical outcomes in heart failure patients with a depressed left ventricular ejection fraction in RALES, the Randomized Aldactone Evaluation Study (N. Engl. J. Med. 1999;341:709-17) and EPHESUS, the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (N. Engl. J. Med. 2003;348:1309-21). Aldosterone blockade is also actively under study in heart failure patients with preserved systolic function in the ongoing TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) study, due to report results next year.

"There may be certain patient groups that could greatly benefit from vitamin D₃ therapy, particularly patients who may not be able to tolerate RAAS blockade or those who have aldosterone escape," she said.

The mechanism by which oral vitamin D₃ reduces serum aldosterone is unknown. The mechanism is clearly non–renin-dependent, given that serum renin level remained unchanged. In vitro studies suggest that vitamin D might act through a direct effect on steroidogenesis in adrenal cortical cells, Dr. Boxer said.

The study was funded by the American Heart Association. Dr. Boxer reported having no relevant financial conflicts.

b.jancin@elsevier.com

LOS ANGELES – Use of the antiplatelet drug prasugrel has jumped impressively in the United States since the Food and Drug Administration approved the drug in July 2009 – but not always for the right patients.

From the first quarter of 2010 to the last quarter of 2011, prasugrel prescriptions more than doubled for patients who underwent a percutaneous coronary intervention, from 8% of patients discharged following a PCI during the first 3 months of 2010 to 22% of discharged post-PCI patients during the final 3 months of 2011, according to data collected on 55,821 patients from 44 Michigan hospitals.

But several prasugrel (Effient) prescriptions fell outside of labeled indications in two important ways. First, throughout the 2-year period, 28% of the patients who underwent PCI and received prasugrel did not have an acute coronary syndrome event immediately before their procedure, Dr. Amneet Sandhu and his associates said in a poster at the annual scientific sessions of the American Heart Association. Prasugrel’s U.S. labeling specifies that it should be used following PCI only in patients who have recently had unstable angina or a myocardial infarction.

The second egregious prasugrel use was in patients with labeled contraindications for the drug: a prior history of cerebrovascular disease, weight of 60 kg or less, and age of 75 years or older. According to the reviewed records, 5%-10% of post-PCI patients who were prescribed prasugrel in Michigan had one or more of these contraindications, reported Dr. Sandhu, an internal medicine physician at the University of Michigan, Ann Arbor, and his associates. The most common contraindication in prasugrel recipients was a history of stroke or transient ischemic attack, in just over half of the patients with a contraindication. The next most common was age of 75 or older, which applied to 35% of the prasugrel recipients with a contraindication.

"Prasugrel use in patients with known contraindications is not uncommon, and may be a suitable target for focused quality-improvements efforts," noted the researchers, who used data collected by the Blue Cross Blue Shield of Michigan Cardiovascular Consortium.

Dr. Sandhu said he had no disclosures. Two of his associates received research support from Blue Cross Blue Shield of Michigan, and one associate was an employee of the company.

LOS ANGELES – Use of the antiplatelet drug prasugrel has jumped impressively in the United States since the Food and Drug Administration approved the drug in July 2009 – but not always for the right patients.

From the first quarter of 2010 to the last quarter of 2011, prasugrel prescriptions more than doubled for patients who underwent a percutaneous coronary intervention, from 8% of patients discharged following a PCI during the first 3 months of 2010 to 22% of discharged post-PCI patients during the final 3 months of 2011, according to data collected on 55,821 patients from 44 Michigan hospitals.

But several prasugrel (Effient) prescriptions fell outside of labeled indications in two important ways. First, throughout the 2-year period, 28% of the patients who underwent PCI and received prasugrel did not have an acute coronary syndrome event immediately before their procedure, Dr. Amneet Sandhu and his associates said in a poster at the annual scientific sessions of the American Heart Association. Prasugrel’s U.S. labeling specifies that it should be used following PCI only in patients who have recently had unstable angina or a myocardial infarction.

The second egregious prasugrel use was in patients with labeled contraindications for the drug: a prior history of cerebrovascular disease, weight of 60 kg or less, and age of 75 years or older. According to the reviewed records, 5%-10% of post-PCI patients who were prescribed prasugrel in Michigan had one or more of these contraindications, reported Dr. Sandhu, an internal medicine physician at the University of Michigan, Ann Arbor, and his associates. The most common contraindication in prasugrel recipients was a history of stroke or transient ischemic attack, in just over half of the patients with a contraindication. The next most common was age of 75 or older, which applied to 35% of the prasugrel recipients with a contraindication.

"Prasugrel use in patients with known contraindications is not uncommon, and may be a suitable target for focused quality-improvements efforts," noted the researchers, who used data collected by the Blue Cross Blue Shield of Michigan Cardiovascular Consortium.

Dr. Sandhu said he had no disclosures. Two of his associates received research support from Blue Cross Blue Shield of Michigan, and one associate was an employee of the company.

LOS ANGELES – Use of the antiplatelet drug prasugrel has jumped impressively in the United States since the Food and Drug Administration approved the drug in July 2009 – but not always for the right patients.

From the first quarter of 2010 to the last quarter of 2011, prasugrel prescriptions more than doubled for patients who underwent a percutaneous coronary intervention, from 8% of patients discharged following a PCI during the first 3 months of 2010 to 22% of discharged post-PCI patients during the final 3 months of 2011, according to data collected on 55,821 patients from 44 Michigan hospitals.

But several prasugrel (Effient) prescriptions fell outside of labeled indications in two important ways. First, throughout the 2-year period, 28% of the patients who underwent PCI and received prasugrel did not have an acute coronary syndrome event immediately before their procedure, Dr. Amneet Sandhu and his associates said in a poster at the annual scientific sessions of the American Heart Association. Prasugrel’s U.S. labeling specifies that it should be used following PCI only in patients who have recently had unstable angina or a myocardial infarction.

The second egregious prasugrel use was in patients with labeled contraindications for the drug: a prior history of cerebrovascular disease, weight of 60 kg or less, and age of 75 years or older. According to the reviewed records, 5%-10% of post-PCI patients who were prescribed prasugrel in Michigan had one or more of these contraindications, reported Dr. Sandhu, an internal medicine physician at the University of Michigan, Ann Arbor, and his associates. The most common contraindication in prasugrel recipients was a history of stroke or transient ischemic attack, in just over half of the patients with a contraindication. The next most common was age of 75 or older, which applied to 35% of the prasugrel recipients with a contraindication.

"Prasugrel use in patients with known contraindications is not uncommon, and may be a suitable target for focused quality-improvements efforts," noted the researchers, who used data collected by the Blue Cross Blue Shield of Michigan Cardiovascular Consortium.

Dr. Sandhu said he had no disclosures. Two of his associates received research support from Blue Cross Blue Shield of Michigan, and one associate was an employee of the company.

LOS ANGELES – The most common intraventricular conduction block following a myocardial infarction is a right bundle branch block, but it is also the least deadly and pathogenic. Left bundle branch blocks produced the most morbidity and mortality in a review of more than 25,000 myocardial infarction survivors from throughout New Jersey during 1994-2009.

The findings also showed that left anterior hemiblocks (LAHB) put post-MI patients in nearly as much jeopardy as did left bundle branch blocks (LBBB), Dr. John S. Pantazopoulos and his associates reported in a poster at the annual scientific sessions of the American Heart Association.

The researchers reviewed 16-year follow-up data from 25,026 patients enrolled in the Myocardial Infarction Data Acquisition System (MIDAS) run by the Cardiovascular Institute of New Jersey in New Brunswick. They excluded post-MI patients with congenital heart disease, a history of mitral regurgitation, atrial fibrillation, heart failure, a pacemaker, coronary bypass surgery, or a percutaneous coronary intervention prior to the first appearance of their intraventricular conduction block.

The most common conduction abnormality was a right bundle branch block (RBBB), in 13,454 patients (54%). LBBB occurred in 27%, 15% had LAHB, and 4% had LAHB plus RBBB. Dr. Pantazopoulos and his associates performed multivariate analyses to determine the morbidity and mortality risk faced by LBBB, LAHB, and LAHB plus RBBB patients compared with patients who only had RBBB. Their analysis controlled for several demographic and clinical confounders, including hypertension, diabetes, and renal failure.

The analysis showed that compared with patients with RBBB, those with LBBB had a 2.7-fold increased risk of cardiovascular death and a 48% increased rate of all-cause death, reported Dr. Pantazopoulos, a cardiologist at the Cardiovascular Institute of the University of Medicine and Dentistry of New Jersey in New Brunswick. Patients with LAHB had a 2.6-fold increased risk of cardiovascular death and 59% increased rate of all-cause death compared with RBBB patients, and those with LAHB plus RBBB had a 2.6-fold higher cardiovascular death rate and a 62% increased all-cause death rate. All these increases were statistically significant.

Patients with LBBB also had a 3.8-fold increased rate of developing heart failure during follow-up, a 68% increased rate of incident mitral regurgitation, and a 34% increased rate of atrial fibrillation compared with patients with RBBB. Patients with LAHB had a 2.6-fold increased rate of new-onset heart failure and a 15% higher rate of atrial fibrillation, and patients with both LAHB and RBBB had a 2.4-fold increased rate of heart failure. All of these increased rates were statistically significant.

Dr. Pantazopoulos said that he had no disclosures. The senior researcher on the study, Dr. John B. Kostis, has been a speaker for Merck, has received honoraria from Sanofi, and has received a research grant from Novartis.

LOS ANGELES – The most common intraventricular conduction block following a myocardial infarction is a right bundle branch block, but it is also the least deadly and pathogenic. Left bundle branch blocks produced the most morbidity and mortality in a review of more than 25,000 myocardial infarction survivors from throughout New Jersey during 1994-2009.

The findings also showed that left anterior hemiblocks (LAHB) put post-MI patients in nearly as much jeopardy as did left bundle branch blocks (LBBB), Dr. John S. Pantazopoulos and his associates reported in a poster at the annual scientific sessions of the American Heart Association.

The researchers reviewed 16-year follow-up data from 25,026 patients enrolled in the Myocardial Infarction Data Acquisition System (MIDAS) run by the Cardiovascular Institute of New Jersey in New Brunswick. They excluded post-MI patients with congenital heart disease, a history of mitral regurgitation, atrial fibrillation, heart failure, a pacemaker, coronary bypass surgery, or a percutaneous coronary intervention prior to the first appearance of their intraventricular conduction block.

The most common conduction abnormality was a right bundle branch block (RBBB), in 13,454 patients (54%). LBBB occurred in 27%, 15% had LAHB, and 4% had LAHB plus RBBB. Dr. Pantazopoulos and his associates performed multivariate analyses to determine the morbidity and mortality risk faced by LBBB, LAHB, and LAHB plus RBBB patients compared with patients who only had RBBB. Their analysis controlled for several demographic and clinical confounders, including hypertension, diabetes, and renal failure.

The analysis showed that compared with patients with RBBB, those with LBBB had a 2.7-fold increased risk of cardiovascular death and a 48% increased rate of all-cause death, reported Dr. Pantazopoulos, a cardiologist at the Cardiovascular Institute of the University of Medicine and Dentistry of New Jersey in New Brunswick. Patients with LAHB had a 2.6-fold increased risk of cardiovascular death and 59% increased rate of all-cause death compared with RBBB patients, and those with LAHB plus RBBB had a 2.6-fold higher cardiovascular death rate and a 62% increased all-cause death rate. All these increases were statistically significant.

Patients with LBBB also had a 3.8-fold increased rate of developing heart failure during follow-up, a 68% increased rate of incident mitral regurgitation, and a 34% increased rate of atrial fibrillation compared with patients with RBBB. Patients with LAHB had a 2.6-fold increased rate of new-onset heart failure and a 15% higher rate of atrial fibrillation, and patients with both LAHB and RBBB had a 2.4-fold increased rate of heart failure. All of these increased rates were statistically significant.

Dr. Pantazopoulos said that he had no disclosures. The senior researcher on the study, Dr. John B. Kostis, has been a speaker for Merck, has received honoraria from Sanofi, and has received a research grant from Novartis.

LOS ANGELES – The most common intraventricular conduction block following a myocardial infarction is a right bundle branch block, but it is also the least deadly and pathogenic. Left bundle branch blocks produced the most morbidity and mortality in a review of more than 25,000 myocardial infarction survivors from throughout New Jersey during 1994-2009.

The findings also showed that left anterior hemiblocks (LAHB) put post-MI patients in nearly as much jeopardy as did left bundle branch blocks (LBBB), Dr. John S. Pantazopoulos and his associates reported in a poster at the annual scientific sessions of the American Heart Association.

The researchers reviewed 16-year follow-up data from 25,026 patients enrolled in the Myocardial Infarction Data Acquisition System (MIDAS) run by the Cardiovascular Institute of New Jersey in New Brunswick. They excluded post-MI patients with congenital heart disease, a history of mitral regurgitation, atrial fibrillation, heart failure, a pacemaker, coronary bypass surgery, or a percutaneous coronary intervention prior to the first appearance of their intraventricular conduction block.

The most common conduction abnormality was a right bundle branch block (RBBB), in 13,454 patients (54%). LBBB occurred in 27%, 15% had LAHB, and 4% had LAHB plus RBBB. Dr. Pantazopoulos and his associates performed multivariate analyses to determine the morbidity and mortality risk faced by LBBB, LAHB, and LAHB plus RBBB patients compared with patients who only had RBBB. Their analysis controlled for several demographic and clinical confounders, including hypertension, diabetes, and renal failure.

The analysis showed that compared with patients with RBBB, those with LBBB had a 2.7-fold increased risk of cardiovascular death and a 48% increased rate of all-cause death, reported Dr. Pantazopoulos, a cardiologist at the Cardiovascular Institute of the University of Medicine and Dentistry of New Jersey in New Brunswick. Patients with LAHB had a 2.6-fold increased risk of cardiovascular death and 59% increased rate of all-cause death compared with RBBB patients, and those with LAHB plus RBBB had a 2.6-fold higher cardiovascular death rate and a 62% increased all-cause death rate. All these increases were statistically significant.

Patients with LBBB also had a 3.8-fold increased rate of developing heart failure during follow-up, a 68% increased rate of incident mitral regurgitation, and a 34% increased rate of atrial fibrillation compared with patients with RBBB. Patients with LAHB had a 2.6-fold increased rate of new-onset heart failure and a 15% higher rate of atrial fibrillation, and patients with both LAHB and RBBB had a 2.4-fold increased rate of heart failure. All of these increased rates were statistically significant.

Dr. Pantazopoulos said that he had no disclosures. The senior researcher on the study, Dr. John B. Kostis, has been a speaker for Merck, has received honoraria from Sanofi, and has received a research grant from Novartis.

LOS ANGELES – When patients receive shocks from implantable cardioverter defibrillators their anxiety level rises, and so does their mortality rate.

Measured anxiety levels significantly correlated with the occurrence of shocks from ICDs, the total number of shocks that patients received, and how recently the shocks occurred, in a prospective study of 704 consecutive ICD recipients from one U.S. center, Dr. Jason George and his associates reported in a poster at the annual scientific sessions of the American Heart Association.

In addition, patients who received three or more shocks had a 15% mortality rate during a median of 2.8 years of follow-up, significantly more than the 6% rate among patients who received fewer than three shocks, based on prospective follow-up of 690 consecutive ICD recipients at the same center, said Dr. George, a physician at the Cleveland Clinic.

CarolinaSmith/iStockphoto.com

The substantial 36% prevalence of mild or greater anxiety found in these ICD patients suggested that "attention to anxiety may help patients who experience any type of shock," and may be especially helpful to patients who received several shocks or recent shocks, the researchers said.

The link found between higher shock number and increased mortality confirms observations previously made in other studies, they added, although unlike prior reports, the current study found this link only for appropriate shocks. The finding raises the question of whether measures designed to suppress shocks might boost patient survival, they said.

The anxiety analysis included patients who received an ICD more than 4 weeks prior to enrollment into the study at the Cleveland Clinic between March 2009 and December 2010. Patient assessment with the Beck Anxiety Inventory (BAI) showed that 36% had a score of at least 8, the threshold for mild anxiety. The average BAI score among the 239 patients (34% of the patients assessed) who had ever received at least one shock was 8.3, while the average score among the other 465 patients was 6.7, showing that nonshocked patients had minimal anxiety. The difference in average scores between these two subgroups was statistically significant, the investigators reported.

Among patients who had received a shock within 4 weeks of BAI scoring, the average score was 11.2, while among patients who had not received a shock within the prior 4 weeks the average BAI score was 7.1, also a significant difference. The analysis also showed that depression was not significantly associated with shocks.

The mortality analysis performed by Dr. George and his associates at the Cleveland Clinic included 690 patients followed prospectively after they received an ICD between March 2009 and December 2010. During follow-up, a total of 8.3% of the patients died. This analysis showed that patients who received only inappropriate shocks, patients who received two or fewer shocks, and those who received no shocks each had about the same mortality rate, about a 6% rate during the median 2.8 years of follow-up. Patients who received only appropriate shocks had about an 11% mortality rate during follow-up, and patients who received both appropriate and inappropriate shocks had the highest mortality rate, about 22%.

Overall, patients who died received an average of 5.4 shocks, while those who did not die received an average of 2.3 shocks. "These findings suggest that shocks may be a secondary marker of mortality rather than a primary cause of mortality," Dr. George and his associates concluded.

Dr. George and his associates said that they had no disclosures.

LOS ANGELES – When patients receive shocks from implantable cardioverter defibrillators their anxiety level rises, and so does their mortality rate.

Measured anxiety levels significantly correlated with the occurrence of shocks from ICDs, the total number of shocks that patients received, and how recently the shocks occurred, in a prospective study of 704 consecutive ICD recipients from one U.S. center, Dr. Jason George and his associates reported in a poster at the annual scientific sessions of the American Heart Association.

In addition, patients who received three or more shocks had a 15% mortality rate during a median of 2.8 years of follow-up, significantly more than the 6% rate among patients who received fewer than three shocks, based on prospective follow-up of 690 consecutive ICD recipients at the same center, said Dr. George, a physician at the Cleveland Clinic.

CarolinaSmith/iStockphoto.com

The substantial 36% prevalence of mild or greater anxiety found in these ICD patients suggested that "attention to anxiety may help patients who experience any type of shock," and may be especially helpful to patients who received several shocks or recent shocks, the researchers said.

The link found between higher shock number and increased mortality confirms observations previously made in other studies, they added, although unlike prior reports, the current study found this link only for appropriate shocks. The finding raises the question of whether measures designed to suppress shocks might boost patient survival, they said.

The anxiety analysis included patients who received an ICD more than 4 weeks prior to enrollment into the study at the Cleveland Clinic between March 2009 and December 2010. Patient assessment with the Beck Anxiety Inventory (BAI) showed that 36% had a score of at least 8, the threshold for mild anxiety. The average BAI score among the 239 patients (34% of the patients assessed) who had ever received at least one shock was 8.3, while the average score among the other 465 patients was 6.7, showing that nonshocked patients had minimal anxiety. The difference in average scores between these two subgroups was statistically significant, the investigators reported.

Among patients who had received a shock within 4 weeks of BAI scoring, the average score was 11.2, while among patients who had not received a shock within the prior 4 weeks the average BAI score was 7.1, also a significant difference. The analysis also showed that depression was not significantly associated with shocks.

The mortality analysis performed by Dr. George and his associates at the Cleveland Clinic included 690 patients followed prospectively after they received an ICD between March 2009 and December 2010. During follow-up, a total of 8.3% of the patients died. This analysis showed that patients who received only inappropriate shocks, patients who received two or fewer shocks, and those who received no shocks each had about the same mortality rate, about a 6% rate during the median 2.8 years of follow-up. Patients who received only appropriate shocks had about an 11% mortality rate during follow-up, and patients who received both appropriate and inappropriate shocks had the highest mortality rate, about 22%.

Overall, patients who died received an average of 5.4 shocks, while those who did not die received an average of 2.3 shocks. "These findings suggest that shocks may be a secondary marker of mortality rather than a primary cause of mortality," Dr. George and his associates concluded.

Dr. George and his associates said that they had no disclosures.

LOS ANGELES – When patients receive shocks from implantable cardioverter defibrillators their anxiety level rises, and so does their mortality rate.

Measured anxiety levels significantly correlated with the occurrence of shocks from ICDs, the total number of shocks that patients received, and how recently the shocks occurred, in a prospective study of 704 consecutive ICD recipients from one U.S. center, Dr. Jason George and his associates reported in a poster at the annual scientific sessions of the American Heart Association.

In addition, patients who received three or more shocks had a 15% mortality rate during a median of 2.8 years of follow-up, significantly more than the 6% rate among patients who received fewer than three shocks, based on prospective follow-up of 690 consecutive ICD recipients at the same center, said Dr. George, a physician at the Cleveland Clinic.

CarolinaSmith/iStockphoto.com

The substantial 36% prevalence of mild or greater anxiety found in these ICD patients suggested that "attention to anxiety may help patients who experience any type of shock," and may be especially helpful to patients who received several shocks or recent shocks, the researchers said.

The link found between higher shock number and increased mortality confirms observations previously made in other studies, they added, although unlike prior reports, the current study found this link only for appropriate shocks. The finding raises the question of whether measures designed to suppress shocks might boost patient survival, they said.

The anxiety analysis included patients who received an ICD more than 4 weeks prior to enrollment into the study at the Cleveland Clinic between March 2009 and December 2010. Patient assessment with the Beck Anxiety Inventory (BAI) showed that 36% had a score of at least 8, the threshold for mild anxiety. The average BAI score among the 239 patients (34% of the patients assessed) who had ever received at least one shock was 8.3, while the average score among the other 465 patients was 6.7, showing that nonshocked patients had minimal anxiety. The difference in average scores between these two subgroups was statistically significant, the investigators reported.

Among patients who had received a shock within 4 weeks of BAI scoring, the average score was 11.2, while among patients who had not received a shock within the prior 4 weeks the average BAI score was 7.1, also a significant difference. The analysis also showed that depression was not significantly associated with shocks.

The mortality analysis performed by Dr. George and his associates at the Cleveland Clinic included 690 patients followed prospectively after they received an ICD between March 2009 and December 2010. During follow-up, a total of 8.3% of the patients died. This analysis showed that patients who received only inappropriate shocks, patients who received two or fewer shocks, and those who received no shocks each had about the same mortality rate, about a 6% rate during the median 2.8 years of follow-up. Patients who received only appropriate shocks had about an 11% mortality rate during follow-up, and patients who received both appropriate and inappropriate shocks had the highest mortality rate, about 22%.

Overall, patients who died received an average of 5.4 shocks, while those who did not die received an average of 2.3 shocks. "These findings suggest that shocks may be a secondary marker of mortality rather than a primary cause of mortality," Dr. George and his associates concluded.

Dr. George and his associates said that they had no disclosures.

One of the best things about generic drugs is also their Achilles heel: They’re relatively cheap. That makes them good for patients, for the health care system, and for society in general. But it also means that anyone trying to develop a new indication for a generic drug faces a big challenge: how to pay for a big study that proves the generic drug works.

Will this barrier come into play for colchicine as a potential treatment for stable coronary artery disease? Colchicine is an old anti-inflammatory drug, mostly used to treat gout, that had usually been very cheap, and it remains so throughout much of the world. But in October 2009, the Food and Drug Administration awarded a patent to URL Pharma (now owned by drug giant Takeda) for a branded formulation of colchicine, Colcrys, to treat gout on the basis of safety studies that URL funded. That caused the price of colchicine to soar to about $5 a dose. The patent on colchicine for gout treatment supposedly only lasted 3 years, but so far no generic versions have come onto the U.S. market.

Courtesy Wikimedia Commons/Giorgiop2/Creative Commons License

It’s unclear how the controversy over colchicine’s patenting and pricing for gout will play into the report last month that the drug showed a promising, substantial benefit in patients with stable CAD. Briefly, a low dosage of 0.5 mg/day added to standard therapy cut the rate of major cardiovascular events by two-thirds when tested in a randomized controlled trial with 532 patients treated for a median of 3 years, Dr. Mark Nidorf reported at the annual Scientific Sessions of the American Heart Association in November.

It was an impressive result for colchicine, but both Dr. Nidorf, a cardiologist at the Heart Research Institute of Western Australia in Perth, and Dr. Shinya Goto, a Japanese cardiologist who served as the designated discussant for the study, agreed on what needs to come next. This promising finding from a single-center, phase II study needs confirmation in larger, multicenter trials, or at least in several similarly sized trials done in different groups of patients. And the question is who will pay for that?

The 532-patient LoDoCo (Low Dose Colchicine) study that ran for several years in Perth was paid for entirely by the Heart Research Institute.

I spoke with Dr. Nidorf after his talk about the prospects for wider testing of colchicine, and he did not sound optimistic. He felt that a bigger trial stood little chance of getting funding from the Australian government, and he wondered whether he and his associates could possibly get funding from a U.S. government agency.

Last April, Takeda announced that it had begun acquisition of URL Pharma for the express purpose of acquiring URL’s patent on colchicine for treating gout. Takeda also has a respectably sized presence in cardiovascular drugs. Will Takeda decide that it’s worth funding a major trial to test colchicine for treating stable CAD? So far, no word has come from the company about that, but it’s an intriguing possibility. The patenting of colchicine caused controversy and problems for gout patients when the drug’s price soared, but it may also give the best opportunity for pursuing a new CAD indication for this old drug.

--Mitchel L. Zoler (on Twitter @mitchelzoler)

One of the best things about generic drugs is also their Achilles heel: They’re relatively cheap. That makes them good for patients, for the health care system, and for society in general. But it also means that anyone trying to develop a new indication for a generic drug faces a big challenge: how to pay for a big study that proves the generic drug works.

Will this barrier come into play for colchicine as a potential treatment for stable coronary artery disease? Colchicine is an old anti-inflammatory drug, mostly used to treat gout, that had usually been very cheap, and it remains so throughout much of the world. But in October 2009, the Food and Drug Administration awarded a patent to URL Pharma (now owned by drug giant Takeda) for a branded formulation of colchicine, Colcrys, to treat gout on the basis of safety studies that URL funded. That caused the price of colchicine to soar to about $5 a dose. The patent on colchicine for gout treatment supposedly only lasted 3 years, but so far no generic versions have come onto the U.S. market.

Courtesy Wikimedia Commons/Giorgiop2/Creative Commons License

It’s unclear how the controversy over colchicine’s patenting and pricing for gout will play into the report last month that the drug showed a promising, substantial benefit in patients with stable CAD. Briefly, a low dosage of 0.5 mg/day added to standard therapy cut the rate of major cardiovascular events by two-thirds when tested in a randomized controlled trial with 532 patients treated for a median of 3 years, Dr. Mark Nidorf reported at the annual Scientific Sessions of the American Heart Association in November.

It was an impressive result for colchicine, but both Dr. Nidorf, a cardiologist at the Heart Research Institute of Western Australia in Perth, and Dr. Shinya Goto, a Japanese cardiologist who served as the designated discussant for the study, agreed on what needs to come next. This promising finding from a single-center, phase II study needs confirmation in larger, multicenter trials, or at least in several similarly sized trials done in different groups of patients. And the question is who will pay for that?

The 532-patient LoDoCo (Low Dose Colchicine) study that ran for several years in Perth was paid for entirely by the Heart Research Institute.

I spoke with Dr. Nidorf after his talk about the prospects for wider testing of colchicine, and he did not sound optimistic. He felt that a bigger trial stood little chance of getting funding from the Australian government, and he wondered whether he and his associates could possibly get funding from a U.S. government agency.

Last April, Takeda announced that it had begun acquisition of URL Pharma for the express purpose of acquiring URL’s patent on colchicine for treating gout. Takeda also has a respectably sized presence in cardiovascular drugs. Will Takeda decide that it’s worth funding a major trial to test colchicine for treating stable CAD? So far, no word has come from the company about that, but it’s an intriguing possibility. The patenting of colchicine caused controversy and problems for gout patients when the drug’s price soared, but it may also give the best opportunity for pursuing a new CAD indication for this old drug.

--Mitchel L. Zoler (on Twitter @mitchelzoler)

One of the best things about generic drugs is also their Achilles heel: They’re relatively cheap. That makes them good for patients, for the health care system, and for society in general. But it also means that anyone trying to develop a new indication for a generic drug faces a big challenge: how to pay for a big study that proves the generic drug works.

Will this barrier come into play for colchicine as a potential treatment for stable coronary artery disease? Colchicine is an old anti-inflammatory drug, mostly used to treat gout, that had usually been very cheap, and it remains so throughout much of the world. But in October 2009, the Food and Drug Administration awarded a patent to URL Pharma (now owned by drug giant Takeda) for a branded formulation of colchicine, Colcrys, to treat gout on the basis of safety studies that URL funded. That caused the price of colchicine to soar to about $5 a dose. The patent on colchicine for gout treatment supposedly only lasted 3 years, but so far no generic versions have come onto the U.S. market.

Courtesy Wikimedia Commons/Giorgiop2/Creative Commons License

It’s unclear how the controversy over colchicine’s patenting and pricing for gout will play into the report last month that the drug showed a promising, substantial benefit in patients with stable CAD. Briefly, a low dosage of 0.5 mg/day added to standard therapy cut the rate of major cardiovascular events by two-thirds when tested in a randomized controlled trial with 532 patients treated for a median of 3 years, Dr. Mark Nidorf reported at the annual Scientific Sessions of the American Heart Association in November.

It was an impressive result for colchicine, but both Dr. Nidorf, a cardiologist at the Heart Research Institute of Western Australia in Perth, and Dr. Shinya Goto, a Japanese cardiologist who served as the designated discussant for the study, agreed on what needs to come next. This promising finding from a single-center, phase II study needs confirmation in larger, multicenter trials, or at least in several similarly sized trials done in different groups of patients. And the question is who will pay for that?

The 532-patient LoDoCo (Low Dose Colchicine) study that ran for several years in Perth was paid for entirely by the Heart Research Institute.

I spoke with Dr. Nidorf after his talk about the prospects for wider testing of colchicine, and he did not sound optimistic. He felt that a bigger trial stood little chance of getting funding from the Australian government, and he wondered whether he and his associates could possibly get funding from a U.S. government agency.

Last April, Takeda announced that it had begun acquisition of URL Pharma for the express purpose of acquiring URL’s patent on colchicine for treating gout. Takeda also has a respectably sized presence in cardiovascular drugs. Will Takeda decide that it’s worth funding a major trial to test colchicine for treating stable CAD? So far, no word has come from the company about that, but it’s an intriguing possibility. The patenting of colchicine caused controversy and problems for gout patients when the drug’s price soared, but it may also give the best opportunity for pursuing a new CAD indication for this old drug.

--Mitchel L. Zoler (on Twitter @mitchelzoler)

LOS ANGELES – A patient's risk for developing diabetes because of statin treatment seems to depend in part on two factors: the patient's underlying risk for diabetes, and the total number of diabetogenic drugs they receive, based on results from two separate studies reported at the meeting.

But the findings did not seem to persuade at least some physicians that the risk of new-onset diabetes posed by higher-dose statin should deter physicians from prescribing the drugs to patients who need them.

"You could say that new-onset diabetes is one strike against a patient, but sudden death from a cardiovascular event is 100 strikes. I think patients would rather risk developing new-onset diabetes than having a myocardial infarction, stroke, cardiac arrest, or cardiovascular death," said Dr. David D. Waters, who presented one of the two reports at the annual scientific sessions of the American Heart Association.

"All the patients we looked at had established cardiovascular disease, so they probably won’t live for another 30 or 40 years, and new-onset diabetes in these people is probably not as bad for at least the first 10 years as a cardiac event. Also, patients can only have new-onset diabetes once, but they can have multiple cardiovascular events. I think one edge of the ‘double-edged sword’ of statins is a lot sharper than the other," said Dr. Waters, a cardiologist and emeritus professor of medicine at the University of California, San Francisco.

His study examined the rate of incident type 2 diabetes in two large trials that both compared treatment with 80 mg atorvastatin daily against treatment with a lower statin dosage in patients with established cardiovascular disease: the TNT (Treating to New Targets) trial (N. Engl. J. Med. 2005;352:1425-35), which used treatment with 10 mg/day atorvastatin as the comparator regimen, and the IDEAL (Incremental Decrease in Endpoints Through Aggressive Lipid Lowering) trial (JAMA 2005;294:2437-45), which used treatment with 20 mg or 40 mg/day of simvastatin as the control group. The analysis excluded patients who entered the studies with preexisting diabetes or a fasting plasma glucose of 126 mg/dL or higher, as well as those with a missing fasting plasma glucose measurement at baseline or fewer than two measures during the study. After Dr. Waters and his associates applied these exclusions they had a total of 15,056 patients from the two studies, which split nearly equally between those who received 80 mg/day atorvastatin and those who received a lower-dose statin regimen.

The researchers used four criteria to define a patient’s risk for developing new-onset diabetes: a fasting plasma glucose of more than 100 mg/dL, fasting triglycerides of more than 150 mg/dL, a history of hypertension, and a body mass index of more than 30 kg/m². They designated patients with no or one risk factor low risk, which included 8,825 (59%). Patients with two or more diabetes risk factors were considered high risk, and 6,231 patients (41%) fell into this subgroup.

In general, the greater the number of risk factors above one, the greater the rate of developing incident diabetes among patients treated with 80 mg atorvastatin, compared with those treated with a lower stating dose. For example, patients with no or one risk factor had no increased rate of incident diabetes in the higher-dose subgroup, but patients with all four risk factors on high-dose atorvastatin had a relative 36% higher rate of new-onset diabetes that just missed reaching statistically significance.

To simplify the analysis and add statistical power, Dr. Waters and his associates divided the database into patients with low or high risk. Patients at high risk on high-dose atorvastatin had a 2.4 percentage point increased rate of incident diabetes during follow-up, compared with those on lower-dose treatment, a 24% relative risk elevation that was statistically significant. In contrast, low-risk patients on high-dose atorvastatin had an incident diabetes rate identical to that of patients on lower-dose regimens.

The analysis also highlighted the increased potency of the 80 mg/day atorvastatin regimen for cutting the rate of cardiovascular events, compared with lower-dosage statin regimens. The higher dosage reduced cardiovascular events by 1.5 percentage points, a relative risk reduction of 15% that was statistically significant. The amount of risk reduction with higher-dose statin was roughly uniform across all strata of diabetes risk, Dr. Waters said.

The second report used data collected from 161,808 postmenopausal women enrolled in the Women’s Health Initiative clinical trials and observational study to examine the impact of treatment with any of four drug classes on incident diabetes. The researchers who ran this analysis excluded women with diabetes and those on a glucose-modifying drug at baseline, which left 139,554 women for the analysis. The drug classes they included as potential diabetes inducers were statins, antidepressants, beta-blockers, and thiazide diuretics. The study group included 108,096 (77%) on none of these drugs, 26,255 (19%) on one drug, 4,768 (3%) on two of these drug classes, and 435 (fewer than 1%) on drugs from three or all four classes.

In a multivariate analysis that adjusted for several baseline demographic and clinical differences, compared with women on none of these drug types, women on one drug class has a 19% relative increased rate of new-onset diabetes during follow-up, those on drugs from two classes had a 44% relative increased rate, and women on drugs from three or four classes had a relative 57% increased rate, reported Rhonda M. Cooper-Dehoff, Pharm. D., a researcher in the College of Pharmacy at the University of Florida in Gainesville. All the elevated relative risks were statistically significant, said Dr. Cooper-Dehoff. A propensity-matched analysis showed a similar pattern of an incrementally increased rate of incident diabetes as the number of these drug classes used by the women increased.

Although the mechanisms for these effects are not clear, physicians should "consider prescribing drug classes without diabetogenic effects, monitor glucose levels in patients, and encourage patients to make lifestyle modifications" that might blunt the diabetogenic effects, she said.

The TNT and IDEAL studies were funded by Pfizer. Dr. Waters said that he had received honoraria from Genentech, Roche, and Pfizer, and has been a consultant or adviser to Aegerion, Cerenis, Genentech, Roche, Servier, Anthera, Pfizer, Sanofi-Aventis, and Shire. Dr. Cooper-Dehoff said that she had no disclosures.

LOS ANGELES – A patient's risk for developing diabetes because of statin treatment seems to depend in part on two factors: the patient's underlying risk for diabetes, and the total number of diabetogenic drugs they receive, based on results from two separate studies reported at the meeting.

But the findings did not seem to persuade at least some physicians that the risk of new-onset diabetes posed by higher-dose statin should deter physicians from prescribing the drugs to patients who need them.

"You could say that new-onset diabetes is one strike against a patient, but sudden death from a cardiovascular event is 100 strikes. I think patients would rather risk developing new-onset diabetes than having a myocardial infarction, stroke, cardiac arrest, or cardiovascular death," said Dr. David D. Waters, who presented one of the two reports at the annual scientific sessions of the American Heart Association.

"All the patients we looked at had established cardiovascular disease, so they probably won’t live for another 30 or 40 years, and new-onset diabetes in these people is probably not as bad for at least the first 10 years as a cardiac event. Also, patients can only have new-onset diabetes once, but they can have multiple cardiovascular events. I think one edge of the ‘double-edged sword’ of statins is a lot sharper than the other," said Dr. Waters, a cardiologist and emeritus professor of medicine at the University of California, San Francisco.

His study examined the rate of incident type 2 diabetes in two large trials that both compared treatment with 80 mg atorvastatin daily against treatment with a lower statin dosage in patients with established cardiovascular disease: the TNT (Treating to New Targets) trial (N. Engl. J. Med. 2005;352:1425-35), which used treatment with 10 mg/day atorvastatin as the comparator regimen, and the IDEAL (Incremental Decrease in Endpoints Through Aggressive Lipid Lowering) trial (JAMA 2005;294:2437-45), which used treatment with 20 mg or 40 mg/day of simvastatin as the control group. The analysis excluded patients who entered the studies with preexisting diabetes or a fasting plasma glucose of 126 mg/dL or higher, as well as those with a missing fasting plasma glucose measurement at baseline or fewer than two measures during the study. After Dr. Waters and his associates applied these exclusions they had a total of 15,056 patients from the two studies, which split nearly equally between those who received 80 mg/day atorvastatin and those who received a lower-dose statin regimen.

The researchers used four criteria to define a patient’s risk for developing new-onset diabetes: a fasting plasma glucose of more than 100 mg/dL, fasting triglycerides of more than 150 mg/dL, a history of hypertension, and a body mass index of more than 30 kg/m². They designated patients with no or one risk factor low risk, which included 8,825 (59%). Patients with two or more diabetes risk factors were considered high risk, and 6,231 patients (41%) fell into this subgroup.

In general, the greater the number of risk factors above one, the greater the rate of developing incident diabetes among patients treated with 80 mg atorvastatin, compared with those treated with a lower stating dose. For example, patients with no or one risk factor had no increased rate of incident diabetes in the higher-dose subgroup, but patients with all four risk factors on high-dose atorvastatin had a relative 36% higher rate of new-onset diabetes that just missed reaching statistically significance.

To simplify the analysis and add statistical power, Dr. Waters and his associates divided the database into patients with low or high risk. Patients at high risk on high-dose atorvastatin had a 2.4 percentage point increased rate of incident diabetes during follow-up, compared with those on lower-dose treatment, a 24% relative risk elevation that was statistically significant. In contrast, low-risk patients on high-dose atorvastatin had an incident diabetes rate identical to that of patients on lower-dose regimens.

The analysis also highlighted the increased potency of the 80 mg/day atorvastatin regimen for cutting the rate of cardiovascular events, compared with lower-dosage statin regimens. The higher dosage reduced cardiovascular events by 1.5 percentage points, a relative risk reduction of 15% that was statistically significant. The amount of risk reduction with higher-dose statin was roughly uniform across all strata of diabetes risk, Dr. Waters said.

The second report used data collected from 161,808 postmenopausal women enrolled in the Women’s Health Initiative clinical trials and observational study to examine the impact of treatment with any of four drug classes on incident diabetes. The researchers who ran this analysis excluded women with diabetes and those on a glucose-modifying drug at baseline, which left 139,554 women for the analysis. The drug classes they included as potential diabetes inducers were statins, antidepressants, beta-blockers, and thiazide diuretics. The study group included 108,096 (77%) on none of these drugs, 26,255 (19%) on one drug, 4,768 (3%) on two of these drug classes, and 435 (fewer than 1%) on drugs from three or all four classes.

In a multivariate analysis that adjusted for several baseline demographic and clinical differences, compared with women on none of these drug types, women on one drug class has a 19% relative increased rate of new-onset diabetes during follow-up, those on drugs from two classes had a 44% relative increased rate, and women on drugs from three or four classes had a relative 57% increased rate, reported Rhonda M. Cooper-Dehoff, Pharm. D., a researcher in the College of Pharmacy at the University of Florida in Gainesville. All the elevated relative risks were statistically significant, said Dr. Cooper-Dehoff. A propensity-matched analysis showed a similar pattern of an incrementally increased rate of incident diabetes as the number of these drug classes used by the women increased.

Although the mechanisms for these effects are not clear, physicians should "consider prescribing drug classes without diabetogenic effects, monitor glucose levels in patients, and encourage patients to make lifestyle modifications" that might blunt the diabetogenic effects, she said.

The TNT and IDEAL studies were funded by Pfizer. Dr. Waters said that he had received honoraria from Genentech, Roche, and Pfizer, and has been a consultant or adviser to Aegerion, Cerenis, Genentech, Roche, Servier, Anthera, Pfizer, Sanofi-Aventis, and Shire. Dr. Cooper-Dehoff said that she had no disclosures.

LOS ANGELES – A patient's risk for developing diabetes because of statin treatment seems to depend in part on two factors: the patient's underlying risk for diabetes, and the total number of diabetogenic drugs they receive, based on results from two separate studies reported at the meeting.

But the findings did not seem to persuade at least some physicians that the risk of new-onset diabetes posed by higher-dose statin should deter physicians from prescribing the drugs to patients who need them.

"You could say that new-onset diabetes is one strike against a patient, but sudden death from a cardiovascular event is 100 strikes. I think patients would rather risk developing new-onset diabetes than having a myocardial infarction, stroke, cardiac arrest, or cardiovascular death," said Dr. David D. Waters, who presented one of the two reports at the annual scientific sessions of the American Heart Association.

"All the patients we looked at had established cardiovascular disease, so they probably won’t live for another 30 or 40 years, and new-onset diabetes in these people is probably not as bad for at least the first 10 years as a cardiac event. Also, patients can only have new-onset diabetes once, but they can have multiple cardiovascular events. I think one edge of the ‘double-edged sword’ of statins is a lot sharper than the other," said Dr. Waters, a cardiologist and emeritus professor of medicine at the University of California, San Francisco.

His study examined the rate of incident type 2 diabetes in two large trials that both compared treatment with 80 mg atorvastatin daily against treatment with a lower statin dosage in patients with established cardiovascular disease: the TNT (Treating to New Targets) trial (N. Engl. J. Med. 2005;352:1425-35), which used treatment with 10 mg/day atorvastatin as the comparator regimen, and the IDEAL (Incremental Decrease in Endpoints Through Aggressive Lipid Lowering) trial (JAMA 2005;294:2437-45), which used treatment with 20 mg or 40 mg/day of simvastatin as the control group. The analysis excluded patients who entered the studies with preexisting diabetes or a fasting plasma glucose of 126 mg/dL or higher, as well as those with a missing fasting plasma glucose measurement at baseline or fewer than two measures during the study. After Dr. Waters and his associates applied these exclusions they had a total of 15,056 patients from the two studies, which split nearly equally between those who received 80 mg/day atorvastatin and those who received a lower-dose statin regimen.

The researchers used four criteria to define a patient’s risk for developing new-onset diabetes: a fasting plasma glucose of more than 100 mg/dL, fasting triglycerides of more than 150 mg/dL, a history of hypertension, and a body mass index of more than 30 kg/m². They designated patients with no or one risk factor low risk, which included 8,825 (59%). Patients with two or more diabetes risk factors were considered high risk, and 6,231 patients (41%) fell into this subgroup.

In general, the greater the number of risk factors above one, the greater the rate of developing incident diabetes among patients treated with 80 mg atorvastatin, compared with those treated with a lower stating dose. For example, patients with no or one risk factor had no increased rate of incident diabetes in the higher-dose subgroup, but patients with all four risk factors on high-dose atorvastatin had a relative 36% higher rate of new-onset diabetes that just missed reaching statistically significance.

To simplify the analysis and add statistical power, Dr. Waters and his associates divided the database into patients with low or high risk. Patients at high risk on high-dose atorvastatin had a 2.4 percentage point increased rate of incident diabetes during follow-up, compared with those on lower-dose treatment, a 24% relative risk elevation that was statistically significant. In contrast, low-risk patients on high-dose atorvastatin had an incident diabetes rate identical to that of patients on lower-dose regimens.

The analysis also highlighted the increased potency of the 80 mg/day atorvastatin regimen for cutting the rate of cardiovascular events, compared with lower-dosage statin regimens. The higher dosage reduced cardiovascular events by 1.5 percentage points, a relative risk reduction of 15% that was statistically significant. The amount of risk reduction with higher-dose statin was roughly uniform across all strata of diabetes risk, Dr. Waters said.

The second report used data collected from 161,808 postmenopausal women enrolled in the Women’s Health Initiative clinical trials and observational study to examine the impact of treatment with any of four drug classes on incident diabetes. The researchers who ran this analysis excluded women with diabetes and those on a glucose-modifying drug at baseline, which left 139,554 women for the analysis. The drug classes they included as potential diabetes inducers were statins, antidepressants, beta-blockers, and thiazide diuretics. The study group included 108,096 (77%) on none of these drugs, 26,255 (19%) on one drug, 4,768 (3%) on two of these drug classes, and 435 (fewer than 1%) on drugs from three or all four classes.

In a multivariate analysis that adjusted for several baseline demographic and clinical differences, compared with women on none of these drug types, women on one drug class has a 19% relative increased rate of new-onset diabetes during follow-up, those on drugs from two classes had a 44% relative increased rate, and women on drugs from three or four classes had a relative 57% increased rate, reported Rhonda M. Cooper-Dehoff, Pharm. D., a researcher in the College of Pharmacy at the University of Florida in Gainesville. All the elevated relative risks were statistically significant, said Dr. Cooper-Dehoff. A propensity-matched analysis showed a similar pattern of an incrementally increased rate of incident diabetes as the number of these drug classes used by the women increased.

Although the mechanisms for these effects are not clear, physicians should "consider prescribing drug classes without diabetogenic effects, monitor glucose levels in patients, and encourage patients to make lifestyle modifications" that might blunt the diabetogenic effects, she said.

The TNT and IDEAL studies were funded by Pfizer. Dr. Waters said that he had received honoraria from Genentech, Roche, and Pfizer, and has been a consultant or adviser to Aegerion, Cerenis, Genentech, Roche, Servier, Anthera, Pfizer, Sanofi-Aventis, and Shire. Dr. Cooper-Dehoff said that she had no disclosures.

LOS ANGELES – Mechanical venovenous ultrafiltration proved inferior to drug therapy in diuretic-responsive patients hospitalized with acute decompensated heart failure and cardiorenal syndrome in a major multicenter randomized trial.

In the Cardiorenal Rescue Study in Acute Decompensated Heart Failure (CARRESS-HF), weight loss due to elimination of excess fluid was similar at 96 hours in the two treatment arms. However, renal function was significantly worse in the ultrafiltration group at that time point, and it remained so even 60 days from baseline, Dr. Bradley A. Bart reported at the annual scientific sessions of the American Heart Association.

Moreover, the combined rate of the secondary end point comprising death or serious adverse events at 6 months was 72% in the ultrafiltration group, compared with 57% in patients treated with a standardized pharmacologic regimen, for an adjusted 50% increased risk in the ultrafiltration group. Serious adverse events included kidney failure, bleeding complications, and problems due to intravenous catheters.

"Neither group was adequately decongested at the time of hospital discharge. This is a challenging group of patients to treat. The 60-day event rates are very high, and better therapies are needed in the future," said Dr. Bart of the Hennepin County Medical Center, Minneapolis.

Acute cardiorenal syndrome occurs in up to one-third of patients with acute decompensated heart failure. The CARRESS-HF trial randomized 188 affected patients who were diuretic responsive to a stepped pharmacologic care algorithm or to ultrafiltration at a rate of 200 mL/hr using the commercially available Aquadex System 100 device manufactured by CHF Solutions.

Both treatment groups lost about 12 pounds through 96 hours. However, while mean serum creatinine was unchanged from baseline in the drug therapy group, it climbed by 0.25 mg/dL in the ultrafiltration group.

Discussant Dr. Milton Packer agreed with the investigators’ conclusion that the study data offer no support for the use of mechanical ultrafiltration in patients who are responsive to diuretics.

"I still think there’s a role for ultrafiltration in patients who are diuretic unresponsive," added Dr. Packer, professor and chairman of the department of clinical sciences at the University of Texas Southwestern Medical Center, Dallas.

He called CARRESS-HF "a really terrific study and an important one." Ultrafiltration can be programmed to pull fluid off of patients more rapidly than is possible with drug therapy. Had mechanical ultrafiltration performed better than well-managed drug therapy in CARRESS-HF, the message to physicians would have been that they shouldn’t spend much time fiddling with diuretic therapy in such patients, but should instead turn to ultrafiltration much earlier during the hospitalization, even in diuretic-responsive patients.

"What is striking about this study is that the difference in renal function was present not only during the ultrafiltration but afterward. That’s something that, frankly speaking, gives us pause. It may be worthwhile in someone who’s diuretic unresponsive; it’s not worthwhile in someone who is diuretic responsive," according to Dr. Packer.

Simultaneous with Dr. Bart’s presentation of the CARRESS-HF results at the AHA conference, the study findings were published online (N. Engl. J. Med. 2012 [doi:10.1056/NEJMoa1210357]).

In an accompanying editorial, Dr. W.H. Wilson Tang of the Cleveland Clinic called the outcomes in CARRESS-HF "overall dismal," with more than one-third of patients dying or being readmitted for acute decompensated heart failure within 60 days, regardless of their treatment arm. But that’s representative of what happens in everyday clinical practice when acute cardiorenal syndrome occurs (N. Engl. J. Med. 2012 [doi:10.1056/NEJMe1212881]).

It’s unclear why serum creatinine rose further and stayed high in the ultrafiltration-treated patients. Dr. Tang speculated that it might be because the mechanical device drew off fluid so rapidly that kidney perfusion was decreased.

"We may even have to confront the possibility that the pressure to reduce hospital length of stay with a strategy of initial aggressive diuresis in patients with acute decompensated heart failure may actually result in an increased incidence of the acute cardiorenal syndrome and cause unwanted consequences. Perhaps slow and steady may ultimately win the race after all," according to Dr. Tang.

CARRESS-HF was sponsored by the National Heart, Lung, and Blood Institute and carried out by the Heart Failure Clinical Research Network. Dr. Bart, Dr. Packer, and Dr. Tang reported having no relevant financial disclosures.

LOS ANGELES – Mechanical venovenous ultrafiltration proved inferior to drug therapy in diuretic-responsive patients hospitalized with acute decompensated heart failure and cardiorenal syndrome in a major multicenter randomized trial.

In the Cardiorenal Rescue Study in Acute Decompensated Heart Failure (CARRESS-HF), weight loss due to elimination of excess fluid was similar at 96 hours in the two treatment arms. However, renal function was significantly worse in the ultrafiltration group at that time point, and it remained so even 60 days from baseline, Dr. Bradley A. Bart reported at the annual scientific sessions of the American Heart Association.

Moreover, the combined rate of the secondary end point comprising death or serious adverse events at 6 months was 72% in the ultrafiltration group, compared with 57% in patients treated with a standardized pharmacologic regimen, for an adjusted 50% increased risk in the ultrafiltration group. Serious adverse events included kidney failure, bleeding complications, and problems due to intravenous catheters.

"Neither group was adequately decongested at the time of hospital discharge. This is a challenging group of patients to treat. The 60-day event rates are very high, and better therapies are needed in the future," said Dr. Bart of the Hennepin County Medical Center, Minneapolis.

Acute cardiorenal syndrome occurs in up to one-third of patients with acute decompensated heart failure. The CARRESS-HF trial randomized 188 affected patients who were diuretic responsive to a stepped pharmacologic care algorithm or to ultrafiltration at a rate of 200 mL/hr using the commercially available Aquadex System 100 device manufactured by CHF Solutions.

Both treatment groups lost about 12 pounds through 96 hours. However, while mean serum creatinine was unchanged from baseline in the drug therapy group, it climbed by 0.25 mg/dL in the ultrafiltration group.

Discussant Dr. Milton Packer agreed with the investigators’ conclusion that the study data offer no support for the use of mechanical ultrafiltration in patients who are responsive to diuretics.

"I still think there’s a role for ultrafiltration in patients who are diuretic unresponsive," added Dr. Packer, professor and chairman of the department of clinical sciences at the University of Texas Southwestern Medical Center, Dallas.

He called CARRESS-HF "a really terrific study and an important one." Ultrafiltration can be programmed to pull fluid off of patients more rapidly than is possible with drug therapy. Had mechanical ultrafiltration performed better than well-managed drug therapy in CARRESS-HF, the message to physicians would have been that they shouldn’t spend much time fiddling with diuretic therapy in such patients, but should instead turn to ultrafiltration much earlier during the hospitalization, even in diuretic-responsive patients.

"What is striking about this study is that the difference in renal function was present not only during the ultrafiltration but afterward. That’s something that, frankly speaking, gives us pause. It may be worthwhile in someone who’s diuretic unresponsive; it’s not worthwhile in someone who is diuretic responsive," according to Dr. Packer.

Simultaneous with Dr. Bart’s presentation of the CARRESS-HF results at the AHA conference, the study findings were published online (N. Engl. J. Med. 2012 [doi:10.1056/NEJMoa1210357]).

In an accompanying editorial, Dr. W.H. Wilson Tang of the Cleveland Clinic called the outcomes in CARRESS-HF "overall dismal," with more than one-third of patients dying or being readmitted for acute decompensated heart failure within 60 days, regardless of their treatment arm. But that’s representative of what happens in everyday clinical practice when acute cardiorenal syndrome occurs (N. Engl. J. Med. 2012 [doi:10.1056/NEJMe1212881]).

It’s unclear why serum creatinine rose further and stayed high in the ultrafiltration-treated patients. Dr. Tang speculated that it might be because the mechanical device drew off fluid so rapidly that kidney perfusion was decreased.

"We may even have to confront the possibility that the pressure to reduce hospital length of stay with a strategy of initial aggressive diuresis in patients with acute decompensated heart failure may actually result in an increased incidence of the acute cardiorenal syndrome and cause unwanted consequences. Perhaps slow and steady may ultimately win the race after all," according to Dr. Tang.

CARRESS-HF was sponsored by the National Heart, Lung, and Blood Institute and carried out by the Heart Failure Clinical Research Network. Dr. Bart, Dr. Packer, and Dr. Tang reported having no relevant financial disclosures.

LOS ANGELES – Mechanical venovenous ultrafiltration proved inferior to drug therapy in diuretic-responsive patients hospitalized with acute decompensated heart failure and cardiorenal syndrome in a major multicenter randomized trial.

In the Cardiorenal Rescue Study in Acute Decompensated Heart Failure (CARRESS-HF), weight loss due to elimination of excess fluid was similar at 96 hours in the two treatment arms. However, renal function was significantly worse in the ultrafiltration group at that time point, and it remained so even 60 days from baseline, Dr. Bradley A. Bart reported at the annual scientific sessions of the American Heart Association.

Moreover, the combined rate of the secondary end point comprising death or serious adverse events at 6 months was 72% in the ultrafiltration group, compared with 57% in patients treated with a standardized pharmacologic regimen, for an adjusted 50% increased risk in the ultrafiltration group. Serious adverse events included kidney failure, bleeding complications, and problems due to intravenous catheters.

"Neither group was adequately decongested at the time of hospital discharge. This is a challenging group of patients to treat. The 60-day event rates are very high, and better therapies are needed in the future," said Dr. Bart of the Hennepin County Medical Center, Minneapolis.

Acute cardiorenal syndrome occurs in up to one-third of patients with acute decompensated heart failure. The CARRESS-HF trial randomized 188 affected patients who were diuretic responsive to a stepped pharmacologic care algorithm or to ultrafiltration at a rate of 200 mL/hr using the commercially available Aquadex System 100 device manufactured by CHF Solutions.

Both treatment groups lost about 12 pounds through 96 hours. However, while mean serum creatinine was unchanged from baseline in the drug therapy group, it climbed by 0.25 mg/dL in the ultrafiltration group.

Discussant Dr. Milton Packer agreed with the investigators’ conclusion that the study data offer no support for the use of mechanical ultrafiltration in patients who are responsive to diuretics.

"I still think there’s a role for ultrafiltration in patients who are diuretic unresponsive," added Dr. Packer, professor and chairman of the department of clinical sciences at the University of Texas Southwestern Medical Center, Dallas.

He called CARRESS-HF "a really terrific study and an important one." Ultrafiltration can be programmed to pull fluid off of patients more rapidly than is possible with drug therapy. Had mechanical ultrafiltration performed better than well-managed drug therapy in CARRESS-HF, the message to physicians would have been that they shouldn’t spend much time fiddling with diuretic therapy in such patients, but should instead turn to ultrafiltration much earlier during the hospitalization, even in diuretic-responsive patients.

"What is striking about this study is that the difference in renal function was present not only during the ultrafiltration but afterward. That’s something that, frankly speaking, gives us pause. It may be worthwhile in someone who’s diuretic unresponsive; it’s not worthwhile in someone who is diuretic responsive," according to Dr. Packer.

Simultaneous with Dr. Bart’s presentation of the CARRESS-HF results at the AHA conference, the study findings were published online (N. Engl. J. Med. 2012 [doi:10.1056/NEJMoa1210357]).

In an accompanying editorial, Dr. W.H. Wilson Tang of the Cleveland Clinic called the outcomes in CARRESS-HF "overall dismal," with more than one-third of patients dying or being readmitted for acute decompensated heart failure within 60 days, regardless of their treatment arm. But that’s representative of what happens in everyday clinical practice when acute cardiorenal syndrome occurs (N. Engl. J. Med. 2012 [doi:10.1056/NEJMe1212881]).

It’s unclear why serum creatinine rose further and stayed high in the ultrafiltration-treated patients. Dr. Tang speculated that it might be because the mechanical device drew off fluid so rapidly that kidney perfusion was decreased.

"We may even have to confront the possibility that the pressure to reduce hospital length of stay with a strategy of initial aggressive diuresis in patients with acute decompensated heart failure may actually result in an increased incidence of the acute cardiorenal syndrome and cause unwanted consequences. Perhaps slow and steady may ultimately win the race after all," according to Dr. Tang.

CARRESS-HF was sponsored by the National Heart, Lung, and Blood Institute and carried out by the Heart Failure Clinical Research Network. Dr. Bart, Dr. Packer, and Dr. Tang reported having no relevant financial disclosures.

LOS ANGELES – Two different monoclonal antibodies showed potent activity for safely cutting blood levels of low-density lipoprotein cholesterol in results from five phase II studies reported at the annual scientific sessions of the American Heart Association.

The findings showed that at the highest dosages tested, both antibodies roughly matched the LDL cholesterol lowering achieved by the highest approved dosages of potent statins, and the antibodies’ effects appeared additive to those of statins when physicians prescribed the two classes in tandem. Because they are antibodies, the new agents are administered by subcutaneous injection or intravenous infusion every 2 or 4 weeks.

While phase III trial results and Food and Drug Administration consideration are a few years down the road, many physicians were buoyed by the prospect of soon being able to treat selected patients with a second 50% reduction in LDL on top of the first 50% drop delivered by statins. Treatment with one of the new antibodies, directed against the plasma protein convertase subtilisin/kexin type 9 (PCSK9) that reduces LDL cell-receptor numbers, leads to increased receptor levels that can halve LDL levels.

Mitchel L. Zoler/IMNG Medical Media

Antibodies that inhibit PCSK9 offer a "new paradigm for reducing LDL cholesterol," said Dr. Robert P. Giugliano, who reported data from the largest of the four trials that treated 474 patients with subcutaneous injection of the Amgen 145 antibody either every 2 or 4 weeks.

"We are witnessing the birth of a new treatment. Never have I seen the goal attainments in the lipid area" shown by some of the reports, commented Dr. John J.P. Kastelein, professor and chair of the department of vascular medicine at the Academic Medical Center in Amsterdam. In the results reported by Dr. Giugliano, for example, 90% of patients who received the highest tested antibody dosage every 2 weeks reached their LDL cholesterol goal of less than 70 mg/dL.

Four of the five studies reported at the meeting involved the Amgen 145 antibody:

• The largest of the trials, LAPLACE-TIMI 57 (LDL-C Assessment with PCSK9 Monoclonal Antibody Inhibition Combined with Statin Therapy), treated 631 patients who had LDL cholesterol levels of at least 85 mg/dL despite being on a stable statin regimen that for some patients also included ezetimibe. Patients received one of three subcutaneous dosages of Amgen 145 or placebo either every 2 or 4 weeks for 12 weeks. The study’s primary end point was the percent change in LDL cholesterol during 12 weeks on treatment. Among the 78 patients who received the largest antibody dosage every 2 weeks, average LDL levels fell by 66%, reported Dr. Giugliano, a cardiologist at Brigham and Women’s Hospital in Boston.

None of the 474 total patients who received the Amgen 145 antibody stopped receiving the drug because of a serious adverse event. Four of the 474 patients had a creatine kinase elevation greater than five times the upper limit of normal. None had a liver enzyme elevation greater than three times the upper limit of normal. Results from the study were published online concurrent with Dr. Giugliano’s report at the meeting (Lancer 2012;380 [doi: 10.1016/S0140-6736(12)61770-X]).

Mitchel L. Zoler/IMNG Medical Media

• A second trial with the same antibody, MENDEL (Monoclonal Antibody Against PCSK9 to Reduce Elevated LDL-C in Patients Currently Not Receiving Drug Therapy for Easing Lipid Levels), enrolled 411 people who were not on any other lipid-lowering medication and who did not have clinical conditions that mandated lipid-reduction treatment so that the impact of the antibody could be assessed in isolation. The highest antibody dosage tested, 140 mg administered subcutaneously every 2 weeks (the same as the highest dosage tested in LAPLACE-TIMI 57), produced an average 51% reduction in LDL cholesterol during 12 weeks of treatment, reported Dr. Michael J. Koren, chief executive officer of the Jacksonville (Fla.) Center for Clinical Research. Among all the dosages tested, administered either every 2 or 4 weeks, average LDL cholesterol levels fell by at least 39%.

None of the antibody-treated patients had a treatment-related adverse event that led to drug discontinuation. Four patients among the 271 who received the antibody had a creatine kinase elevation more than five times the upper limit of normal, as did 2 of the 90 patients who received placebo. Results from the study were published online concurrent with Dr. Koren’s report at the meeting (Lancet 2012;380 [doi: 10.1016/S0140-6736(12)61771-1]).

• A third study of the Amgen 145 antibody, RUTHERFORD (Reduction of LDL-C with PCSK9 Inhibition in Heterozygous Familial Hypercholesterolemia Disorder), enrolled 167 patients with heterozygous familial hypercholesterolemia who had LDL cholesterol levels of at least 100 mg/dL despite a stable lipid-lowering regimen. The highest dosage of the antibody tested, 420 mg delivered subcutaneously every 4 weeks, led to an average 55% reduction in LDL cholesterol during 12 weeks of treatment in 56 patients, reported Dr. Frederick Raal, head of the division of endocrinology and metabolism at the University of Witwatersrand in Johannesburg, South Africa. Two-thirds of the patients who received this tested dosage achieved an LDL cholesterol level of less than 70 mg/dL.

Two patients treated with the highest dosage had serious adverse events, compared with none of the 56 placebo-treated patients. Four of the patients on the highest dosage had muscle-related adverse events, compared with two of the placebo patients. In addition, two patients in the highest-dosage group had a creatine kinase elevation greater than five times the upper limit of normal, compared with none of the placebo patients. Results from the study were published online concurrent with Dr. Raal’s report (Circulation 2012;126:2408-17).

• The fourth Amgen 145 study, GAUSS (Goal Achievement after Utilizing an Anti-PCSK9 Antibody in Statin Intolerant Subjects), enrolled 157 patients at cardiovascular risk who were unable to tolerate effective statin doses because of muscle-related adverse effects. The highest dosage of the antibody administered alone tested, 420 mg given subcutaneously every 4 weeks, lowered LDL cholesterol by an average of 51% in 31 patients, reported Dr. Evan A. Stein, director of the Metabolic and Atherosclerosis Research Center in Cincinnati. Among 29 patients who received the same antibody dosage plus 10 mg of ezetimibe daily, average LDL cholesterol fell by 63%.

Three patients who received the antibody stopped treatment because of an adverse effect, compared with two placebo patients. Two of the patients on antibody treatment had creatine kinase elevations greater than 10 times the upper limit of normal. Results from the study were published online concurrent with Dr. Stein’s report (JAMA 2012;308 [doi: 10.1001/jama.2012.25790]).

• The fifth phase II study report at the meeting dealt with an antibody under development by Pfizer, RN316. That study enrolled 135 patients with primary hypercholesterolemia who were not at their goal LDL cholesterol level despite high- or maximal-dosage statin regimens. Patients received one of four dosages of the antibody or placebo as an intravenous infusion every 4 weeks. After 12 weeks of treatment, patients on the highest tested dosage had an average 60% reduction in their LDL cholesterol level, reported Dr. Barry Gumbiner, an endocrinologist and executive director of clinical research for Pfizer in South San Francisco, Calif.

Three patients who received RN316 had a serious adverse event, and one patient stopped the study medication because of an adverse event. Five patients who received the antibody developed myalgia, and one patient had a significant rise in creatinine kinase to greater than 10 times the upper limit of normal. No patients had a clinically significant rise in liver enzymes.

The Amgen 145 studies were sponsored by Amgen. The RN316 study was sponsored by Pfizer. Dr. Giugliano said that he has been a consultant to Amgen. Dr. Koren said that he has received research grants from Amgen. Dr. Raal said that he has received research funding from Amgen and Sanofi. Dr. Stein said that he has been a consultant to Amgen, Adnexus Therapeutics, and Sanofi, and that he has received research support from Amgen, Sanofi, and Regeneron. Dr. Gumbiner said that he is an employee of Pfizer.

LOS ANGELES – Two different monoclonal antibodies showed potent activity for safely cutting blood levels of low-density lipoprotein cholesterol in results from five phase II studies reported at the annual scientific sessions of the American Heart Association.

The findings showed that at the highest dosages tested, both antibodies roughly matched the LDL cholesterol lowering achieved by the highest approved dosages of potent statins, and the antibodies’ effects appeared additive to those of statins when physicians prescribed the two classes in tandem. Because they are antibodies, the new agents are administered by subcutaneous injection or intravenous infusion every 2 or 4 weeks.

While phase III trial results and Food and Drug Administration consideration are a few years down the road, many physicians were buoyed by the prospect of soon being able to treat selected patients with a second 50% reduction in LDL on top of the first 50% drop delivered by statins. Treatment with one of the new antibodies, directed against the plasma protein convertase subtilisin/kexin type 9 (PCSK9) that reduces LDL cell-receptor numbers, leads to increased receptor levels that can halve LDL levels.

Mitchel L. Zoler/IMNG Medical Media

Antibodies that inhibit PCSK9 offer a "new paradigm for reducing LDL cholesterol," said Dr. Robert P. Giugliano, who reported data from the largest of the four trials that treated 474 patients with subcutaneous injection of the Amgen 145 antibody either every 2 or 4 weeks.

"We are witnessing the birth of a new treatment. Never have I seen the goal attainments in the lipid area" shown by some of the reports, commented Dr. John J.P. Kastelein, professor and chair of the department of vascular medicine at the Academic Medical Center in Amsterdam. In the results reported by Dr. Giugliano, for example, 90% of patients who received the highest tested antibody dosage every 2 weeks reached their LDL cholesterol goal of less than 70 mg/dL.

Four of the five studies reported at the meeting involved the Amgen 145 antibody:

• The largest of the trials, LAPLACE-TIMI 57 (LDL-C Assessment with PCSK9 Monoclonal Antibody Inhibition Combined with Statin Therapy), treated 631 patients who had LDL cholesterol levels of at least 85 mg/dL despite being on a stable statin regimen that for some patients also included ezetimibe. Patients received one of three subcutaneous dosages of Amgen 145 or placebo either every 2 or 4 weeks for 12 weeks. The study’s primary end point was the percent change in LDL cholesterol during 12 weeks on treatment. Among the 78 patients who received the largest antibody dosage every 2 weeks, average LDL levels fell by 66%, reported Dr. Giugliano, a cardiologist at Brigham and Women’s Hospital in Boston.

None of the 474 total patients who received the Amgen 145 antibody stopped receiving the drug because of a serious adverse event. Four of the 474 patients had a creatine kinase elevation greater than five times the upper limit of normal. None had a liver enzyme elevation greater than three times the upper limit of normal. Results from the study were published online concurrent with Dr. Giugliano’s report at the meeting (Lancer 2012;380 [doi: 10.1016/S0140-6736(12)61770-X]).

Mitchel L. Zoler/IMNG Medical Media

• A second trial with the same antibody, MENDEL (Monoclonal Antibody Against PCSK9 to Reduce Elevated LDL-C in Patients Currently Not Receiving Drug Therapy for Easing Lipid Levels), enrolled 411 people who were not on any other lipid-lowering medication and who did not have clinical conditions that mandated lipid-reduction treatment so that the impact of the antibody could be assessed in isolation. The highest antibody dosage tested, 140 mg administered subcutaneously every 2 weeks (the same as the highest dosage tested in LAPLACE-TIMI 57), produced an average 51% reduction in LDL cholesterol during 12 weeks of treatment, reported Dr. Michael J. Koren, chief executive officer of the Jacksonville (Fla.) Center for Clinical Research. Among all the dosages tested, administered either every 2 or 4 weeks, average LDL cholesterol levels fell by at least 39%.

None of the antibody-treated patients had a treatment-related adverse event that led to drug discontinuation. Four patients among the 271 who received the antibody had a creatine kinase elevation more than five times the upper limit of normal, as did 2 of the 90 patients who received placebo. Results from the study were published online concurrent with Dr. Koren’s report at the meeting (Lancet 2012;380 [doi: 10.1016/S0140-6736(12)61771-1]).

• A third study of the Amgen 145 antibody, RUTHERFORD (Reduction of LDL-C with PCSK9 Inhibition in Heterozygous Familial Hypercholesterolemia Disorder), enrolled 167 patients with heterozygous familial hypercholesterolemia who had LDL cholesterol levels of at least 100 mg/dL despite a stable lipid-lowering regimen. The highest dosage of the antibody tested, 420 mg delivered subcutaneously every 4 weeks, led to an average 55% reduction in LDL cholesterol during 12 weeks of treatment in 56 patients, reported Dr. Frederick Raal, head of the division of endocrinology and metabolism at the University of Witwatersrand in Johannesburg, South Africa. Two-thirds of the patients who received this tested dosage achieved an LDL cholesterol level of less than 70 mg/dL.

Two patients treated with the highest dosage had serious adverse events, compared with none of the 56 placebo-treated patients. Four of the patients on the highest dosage had muscle-related adverse events, compared with two of the placebo patients. In addition, two patients in the highest-dosage group had a creatine kinase elevation greater than five times the upper limit of normal, compared with none of the placebo patients. Results from the study were published online concurrent with Dr. Raal’s report (Circulation 2012;126:2408-17).

• The fourth Amgen 145 study, GAUSS (Goal Achievement after Utilizing an Anti-PCSK9 Antibody in Statin Intolerant Subjects), enrolled 157 patients at cardiovascular risk who were unable to tolerate effective statin doses because of muscle-related adverse effects. The highest dosage of the antibody administered alone tested, 420 mg given subcutaneously every 4 weeks, lowered LDL cholesterol by an average of 51% in 31 patients, reported Dr. Evan A. Stein, director of the Metabolic and Atherosclerosis Research Center in Cincinnati. Among 29 patients who received the same antibody dosage plus 10 mg of ezetimibe daily, average LDL cholesterol fell by 63%.

Three patients who received the antibody stopped treatment because of an adverse effect, compared with two placebo patients. Two of the patients on antibody treatment had creatine kinase elevations greater than 10 times the upper limit of normal. Results from the study were published online concurrent with Dr. Stein’s report (JAMA 2012;308 [doi: 10.1001/jama.2012.25790]).

• The fifth phase II study report at the meeting dealt with an antibody under development by Pfizer, RN316. That study enrolled 135 patients with primary hypercholesterolemia who were not at their goal LDL cholesterol level despite high- or maximal-dosage statin regimens. Patients received one of four dosages of the antibody or placebo as an intravenous infusion every 4 weeks. After 12 weeks of treatment, patients on the highest tested dosage had an average 60% reduction in their LDL cholesterol level, reported Dr. Barry Gumbiner, an endocrinologist and executive director of clinical research for Pfizer in South San Francisco, Calif.

Three patients who received RN316 had a serious adverse event, and one patient stopped the study medication because of an adverse event. Five patients who received the antibody developed myalgia, and one patient had a significant rise in creatinine kinase to greater than 10 times the upper limit of normal. No patients had a clinically significant rise in liver enzymes.

The Amgen 145 studies were sponsored by Amgen. The RN316 study was sponsored by Pfizer. Dr. Giugliano said that he has been a consultant to Amgen. Dr. Koren said that he has received research grants from Amgen. Dr. Raal said that he has received research funding from Amgen and Sanofi. Dr. Stein said that he has been a consultant to Amgen, Adnexus Therapeutics, and Sanofi, and that he has received research support from Amgen, Sanofi, and Regeneron. Dr. Gumbiner said that he is an employee of Pfizer.

LOS ANGELES – Two different monoclonal antibodies showed potent activity for safely cutting blood levels of low-density lipoprotein cholesterol in results from five phase II studies reported at the annual scientific sessions of the American Heart Association.

The findings showed that at the highest dosages tested, both antibodies roughly matched the LDL cholesterol lowering achieved by the highest approved dosages of potent statins, and the antibodies’ effects appeared additive to those of statins when physicians prescribed the two classes in tandem. Because they are antibodies, the new agents are administered by subcutaneous injection or intravenous infusion every 2 or 4 weeks.

While phase III trial results and Food and Drug Administration consideration are a few years down the road, many physicians were buoyed by the prospect of soon being able to treat selected patients with a second 50% reduction in LDL on top of the first 50% drop delivered by statins. Treatment with one of the new antibodies, directed against the plasma protein convertase subtilisin/kexin type 9 (PCSK9) that reduces LDL cell-receptor numbers, leads to increased receptor levels that can halve LDL levels.

Mitchel L. Zoler/IMNG Medical Media

Antibodies that inhibit PCSK9 offer a "new paradigm for reducing LDL cholesterol," said Dr. Robert P. Giugliano, who reported data from the largest of the four trials that treated 474 patients with subcutaneous injection of the Amgen 145 antibody either every 2 or 4 weeks.

"We are witnessing the birth of a new treatment. Never have I seen the goal attainments in the lipid area" shown by some of the reports, commented Dr. John J.P. Kastelein, professor and chair of the department of vascular medicine at the Academic Medical Center in Amsterdam. In the results reported by Dr. Giugliano, for example, 90% of patients who received the highest tested antibody dosage every 2 weeks reached their LDL cholesterol goal of less than 70 mg/dL.

Four of the five studies reported at the meeting involved the Amgen 145 antibody:

• The largest of the trials, LAPLACE-TIMI 57 (LDL-C Assessment with PCSK9 Monoclonal Antibody Inhibition Combined with Statin Therapy), treated 631 patients who had LDL cholesterol levels of at least 85 mg/dL despite being on a stable statin regimen that for some patients also included ezetimibe. Patients received one of three subcutaneous dosages of Amgen 145 or placebo either every 2 or 4 weeks for 12 weeks. The study’s primary end point was the percent change in LDL cholesterol during 12 weeks on treatment. Among the 78 patients who received the largest antibody dosage every 2 weeks, average LDL levels fell by 66%, reported Dr. Giugliano, a cardiologist at Brigham and Women’s Hospital in Boston.

None of the 474 total patients who received the Amgen 145 antibody stopped receiving the drug because of a serious adverse event. Four of the 474 patients had a creatine kinase elevation greater than five times the upper limit of normal. None had a liver enzyme elevation greater than three times the upper limit of normal. Results from the study were published online concurrent with Dr. Giugliano’s report at the meeting (Lancer 2012;380 [doi: 10.1016/S0140-6736(12)61770-X]).

Mitchel L. Zoler/IMNG Medical Media

• A second trial with the same antibody, MENDEL (Monoclonal Antibody Against PCSK9 to Reduce Elevated LDL-C in Patients Currently Not Receiving Drug Therapy for Easing Lipid Levels), enrolled 411 people who were not on any other lipid-lowering medication and who did not have clinical conditions that mandated lipid-reduction treatment so that the impact of the antibody could be assessed in isolation. The highest antibody dosage tested, 140 mg administered subcutaneously every 2 weeks (the same as the highest dosage tested in LAPLACE-TIMI 57), produced an average 51% reduction in LDL cholesterol during 12 weeks of treatment, reported Dr. Michael J. Koren, chief executive officer of the Jacksonville (Fla.) Center for Clinical Research. Among all the dosages tested, administered either every 2 or 4 weeks, average LDL cholesterol levels fell by at least 39%.

None of the antibody-treated patients had a treatment-related adverse event that led to drug discontinuation. Four patients among the 271 who received the antibody had a creatine kinase elevation more than five times the upper limit of normal, as did 2 of the 90 patients who received placebo. Results from the study were published online concurrent with Dr. Koren’s report at the meeting (Lancet 2012;380 [doi: 10.1016/S0140-6736(12)61771-1]).

• A third study of the Amgen 145 antibody, RUTHERFORD (Reduction of LDL-C with PCSK9 Inhibition in Heterozygous Familial Hypercholesterolemia Disorder), enrolled 167 patients with heterozygous familial hypercholesterolemia who had LDL cholesterol levels of at least 100 mg/dL despite a stable lipid-lowering regimen. The highest dosage of the antibody tested, 420 mg delivered subcutaneously every 4 weeks, led to an average 55% reduction in LDL cholesterol during 12 weeks of treatment in 56 patients, reported Dr. Frederick Raal, head of the division of endocrinology and metabolism at the University of Witwatersrand in Johannesburg, South Africa. Two-thirds of the patients who received this tested dosage achieved an LDL cholesterol level of less than 70 mg/dL.

Two patients treated with the highest dosage had serious adverse events, compared with none of the 56 placebo-treated patients. Four of the patients on the highest dosage had muscle-related adverse events, compared with two of the placebo patients. In addition, two patients in the highest-dosage group had a creatine kinase elevation greater than five times the upper limit of normal, compared with none of the placebo patients. Results from the study were published online concurrent with Dr. Raal’s report (Circulation 2012;126:2408-17).

• The fourth Amgen 145 study, GAUSS (Goal Achievement after Utilizing an Anti-PCSK9 Antibody in Statin Intolerant Subjects), enrolled 157 patients at cardiovascular risk who were unable to tolerate effective statin doses because of muscle-related adverse effects. The highest dosage of the antibody administered alone tested, 420 mg given subcutaneously every 4 weeks, lowered LDL cholesterol by an average of 51% in 31 patients, reported Dr. Evan A. Stein, director of the Metabolic and Atherosclerosis Research Center in Cincinnati. Among 29 patients who received the same antibody dosage plus 10 mg of ezetimibe daily, average LDL cholesterol fell by 63%.

Three patients who received the antibody stopped treatment because of an adverse effect, compared with two placebo patients. Two of the patients on antibody treatment had creatine kinase elevations greater than 10 times the upper limit of normal. Results from the study were published online concurrent with Dr. Stein’s report (JAMA 2012;308 [doi: 10.1001/jama.2012.25790]).

• The fifth phase II study report at the meeting dealt with an antibody under development by Pfizer, RN316. That study enrolled 135 patients with primary hypercholesterolemia who were not at their goal LDL cholesterol level despite high- or maximal-dosage statin regimens. Patients received one of four dosages of the antibody or placebo as an intravenous infusion every 4 weeks. After 12 weeks of treatment, patients on the highest tested dosage had an average 60% reduction in their LDL cholesterol level, reported Dr. Barry Gumbiner, an endocrinologist and executive director of clinical research for Pfizer in South San Francisco, Calif.

Three patients who received RN316 had a serious adverse event, and one patient stopped the study medication because of an adverse event. Five patients who received the antibody developed myalgia, and one patient had a significant rise in creatinine kinase to greater than 10 times the upper limit of normal. No patients had a clinically significant rise in liver enzymes.

The Amgen 145 studies were sponsored by Amgen. The RN316 study was sponsored by Pfizer. Dr. Giugliano said that he has been a consultant to Amgen. Dr. Koren said that he has received research grants from Amgen. Dr. Raal said that he has received research funding from Amgen and Sanofi. Dr. Stein said that he has been a consultant to Amgen, Adnexus Therapeutics, and Sanofi, and that he has received research support from Amgen, Sanofi, and Regeneron. Dr. Gumbiner said that he is an employee of Pfizer.