Mitchel L. Zoler, PhD

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.

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 – 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.

PHILADELPHIA – Family physicians play a major role in delivering emergency-medicine care, especially in rural communities, and family physicians want more people to know that.

Family physicians took a big step toward raising their emergency-care profile 2 years ago, when they started the Special Interest Group in Emergency Medicine (SIG-EM) of the American Academy of Family Physicians (AAFP). When the group held its third annual meeting, during the AAFP’s annual sessions, a top goal was boosting recognition by the health care community that family-practice physicians are the backbone for delivering a large swath of American emergency medicine, especially in places with fewer than 20,000 people.

"I think ACEP sees that a collaborative, cooperative relationship with family medicine needs to happen."

Several SIG-EM members reported numbers documenting this last May at the Association of American Medical Colleges’ Workforce Research Conference in Washington. In U.S. communities with fewer than 20,000 people, emergency department physicians without emergency medicine residency training (primarily family physicians) supplied 40%-50% of the physician workforce, reported Dr. Kim Bullock, Dr. W. Anthony Gerard, and their associates.

During 2008-2010, family physicians specifically provided 42%-51% of emergency care in six states: Arkansas, Montana, Nebraska, North Dakota, South Dakota, and Wyoming. They also provided 32%-41% of emergency medicine care in another seven states: Alabama, Alaska, Idaho, Iowa, Kansas, Louisiana, and Mississippi.

Data presented to the Workforce Research Conference also showed that during 2006-2010, the extent of family physician involvement in delivering emergency care held steady, with 24%-30% of all family physicians providing emergency care as part of their practice. Among family physicians in rural settings, roughly 40% provided emergency care.

"We want to improve recognition of family physicians in emergency medicine among the wider health-care community," Dr. Gerard said in an interview following the SIG-EM meeting.

Family physicians who provide emergency care have shifted from seeking a formal certification process for their subspecialty to just broadened recognition that family-practice physicians play an important role in providing Americans with emergency care, said Dr. Gerard, a family physician and AAFP member who practices as an emergency medicine physician at Good Samaritan Hospital in Lebanon, Pa.

"The reality is that family physicians are the rural emergency-medicine providers," he said. But, "we need to open doors [for emergency medicine] in the city, too."

"The data we compiled showed that all emergency medicine training programs are in urban academic centers," with easy access to technology and specialists, said Dr. Perry A. Pugno, AAFP’s vice president for education at the Academy’s office in Leawood, Kan.

But, "family medicine is the emergency medicine workforce outside urban settings," he added, and emergency medicine organizations have been slow to acknowledge that.

"We can’t produce enough" emergency medicine physicians, but the emergency-medicine organizations and societies "won’t take the step to say that we should work with family medicine because they are the ones who are out there and doing it," Dr. Pugno said.

The American College of Emergency Physicians has noticed the AAFP’s SIG-EM, and that emergency medicine organization has held out the prospect of working with family physicians. ACEP’s senior director for membership and development, Michele Byers, came to last month’s gathering of about 30 AAFP attendees.

During the SIG-EM’s meeting, Ms. Byers acknowledged the role family physicians play in emergency care: "We realize that’s a reality," she said. "We are looking at opportunities to provide CME and information to family physicians working in emergency departments," Ms. Byers said.

"I think ACEP sees that a collaborative, cooperative relationship with family medicine needs to happen," said Dr. Gerard.

"It was no accident that someone from ACEP was here – I think they’re surprised at how quickly this group has grown," said Dr. Pugno. The SIG-EM "is not just an interest group. It is part of the AAFP infrastructure; that’s an important level of endorsement from the AAFP board," he noted.

"This group reports directly to the AAFP education commission," the group responsible for policy on workforce issues and career guidance. Last year, AAFP added to its policies a new section on emergency medicine that in part says family physicians "are qualified to provide emergency care in a variety of settings," particularly rural and remote settings.

"For 20 years, I paid dues to AAFP, but I felt like I didn’t have a home. Now we have a home," the SIG-EM, Dr. Gerard said during the group’s meeting. "We have a name, a place, and support from the [AAFP] Congress of Delegates. The AAFP policy statement is strong; it says that family medicine has a role in the future of emergency medicine."

The SIG-EM decided at its meeting to take its profile a step further by resolving to produce in the next year a policy paper on family physicians who provide emergency care in rural U.S. communities. The AAFP will then use this white paper "when we do advocacy work, when we speak with regulatory agencies" such as the Centers for Medicare and Medicaid Services and the Health Resources and Services Administration, said Dr. Pugno. "We will reference this paper and say we are concerned about continued funding of critical care access hospitals and that family medicine is the primary work force in that venue."

Dr. Gerard, Dr. Pugno, and Ms. Byers had no commercial disclosures. Dr. Pugno is an employee of the American Academy of Family Physicians. Ms. Byers is an employee of the American College of Emergency Physicians.

PHILADELPHIA – Family physicians play a major role in delivering emergency-medicine care, especially in rural communities, and family physicians want more people to know that.

Family physicians took a big step toward raising their emergency-care profile 2 years ago, when they started the Special Interest Group in Emergency Medicine (SIG-EM) of the American Academy of Family Physicians (AAFP). When the group held its third annual meeting, during the AAFP’s annual sessions, a top goal was boosting recognition by the health care community that family-practice physicians are the backbone for delivering a large swath of American emergency medicine, especially in places with fewer than 20,000 people.

"I think ACEP sees that a collaborative, cooperative relationship with family medicine needs to happen."

Several SIG-EM members reported numbers documenting this last May at the Association of American Medical Colleges’ Workforce Research Conference in Washington. In U.S. communities with fewer than 20,000 people, emergency department physicians without emergency medicine residency training (primarily family physicians) supplied 40%-50% of the physician workforce, reported Dr. Kim Bullock, Dr. W. Anthony Gerard, and their associates.

During 2008-2010, family physicians specifically provided 42%-51% of emergency care in six states: Arkansas, Montana, Nebraska, North Dakota, South Dakota, and Wyoming. They also provided 32%-41% of emergency medicine care in another seven states: Alabama, Alaska, Idaho, Iowa, Kansas, Louisiana, and Mississippi.

Data presented to the Workforce Research Conference also showed that during 2006-2010, the extent of family physician involvement in delivering emergency care held steady, with 24%-30% of all family physicians providing emergency care as part of their practice. Among family physicians in rural settings, roughly 40% provided emergency care.

"We want to improve recognition of family physicians in emergency medicine among the wider health-care community," Dr. Gerard said in an interview following the SIG-EM meeting.

Family physicians who provide emergency care have shifted from seeking a formal certification process for their subspecialty to just broadened recognition that family-practice physicians play an important role in providing Americans with emergency care, said Dr. Gerard, a family physician and AAFP member who practices as an emergency medicine physician at Good Samaritan Hospital in Lebanon, Pa.

"The reality is that family physicians are the rural emergency-medicine providers," he said. But, "we need to open doors [for emergency medicine] in the city, too."

"The data we compiled showed that all emergency medicine training programs are in urban academic centers," with easy access to technology and specialists, said Dr. Perry A. Pugno, AAFP’s vice president for education at the Academy’s office in Leawood, Kan.

But, "family medicine is the emergency medicine workforce outside urban settings," he added, and emergency medicine organizations have been slow to acknowledge that.

"We can’t produce enough" emergency medicine physicians, but the emergency-medicine organizations and societies "won’t take the step to say that we should work with family medicine because they are the ones who are out there and doing it," Dr. Pugno said.

The American College of Emergency Physicians has noticed the AAFP’s SIG-EM, and that emergency medicine organization has held out the prospect of working with family physicians. ACEP’s senior director for membership and development, Michele Byers, came to last month’s gathering of about 30 AAFP attendees.

During the SIG-EM’s meeting, Ms. Byers acknowledged the role family physicians play in emergency care: "We realize that’s a reality," she said. "We are looking at opportunities to provide CME and information to family physicians working in emergency departments," Ms. Byers said.

"I think ACEP sees that a collaborative, cooperative relationship with family medicine needs to happen," said Dr. Gerard.

"It was no accident that someone from ACEP was here – I think they’re surprised at how quickly this group has grown," said Dr. Pugno. The SIG-EM "is not just an interest group. It is part of the AAFP infrastructure; that’s an important level of endorsement from the AAFP board," he noted.

"This group reports directly to the AAFP education commission," the group responsible for policy on workforce issues and career guidance. Last year, AAFP added to its policies a new section on emergency medicine that in part says family physicians "are qualified to provide emergency care in a variety of settings," particularly rural and remote settings.

"For 20 years, I paid dues to AAFP, but I felt like I didn’t have a home. Now we have a home," the SIG-EM, Dr. Gerard said during the group’s meeting. "We have a name, a place, and support from the [AAFP] Congress of Delegates. The AAFP policy statement is strong; it says that family medicine has a role in the future of emergency medicine."

The SIG-EM decided at its meeting to take its profile a step further by resolving to produce in the next year a policy paper on family physicians who provide emergency care in rural U.S. communities. The AAFP will then use this white paper "when we do advocacy work, when we speak with regulatory agencies" such as the Centers for Medicare and Medicaid Services and the Health Resources and Services Administration, said Dr. Pugno. "We will reference this paper and say we are concerned about continued funding of critical care access hospitals and that family medicine is the primary work force in that venue."

Dr. Gerard, Dr. Pugno, and Ms. Byers had no commercial disclosures. Dr. Pugno is an employee of the American Academy of Family Physicians. Ms. Byers is an employee of the American College of Emergency Physicians.

PHILADELPHIA – Family physicians play a major role in delivering emergency-medicine care, especially in rural communities, and family physicians want more people to know that.

Family physicians took a big step toward raising their emergency-care profile 2 years ago, when they started the Special Interest Group in Emergency Medicine (SIG-EM) of the American Academy of Family Physicians (AAFP). When the group held its third annual meeting, during the AAFP’s annual sessions, a top goal was boosting recognition by the health care community that family-practice physicians are the backbone for delivering a large swath of American emergency medicine, especially in places with fewer than 20,000 people.

"I think ACEP sees that a collaborative, cooperative relationship with family medicine needs to happen."

Several SIG-EM members reported numbers documenting this last May at the Association of American Medical Colleges’ Workforce Research Conference in Washington. In U.S. communities with fewer than 20,000 people, emergency department physicians without emergency medicine residency training (primarily family physicians) supplied 40%-50% of the physician workforce, reported Dr. Kim Bullock, Dr. W. Anthony Gerard, and their associates.

During 2008-2010, family physicians specifically provided 42%-51% of emergency care in six states: Arkansas, Montana, Nebraska, North Dakota, South Dakota, and Wyoming. They also provided 32%-41% of emergency medicine care in another seven states: Alabama, Alaska, Idaho, Iowa, Kansas, Louisiana, and Mississippi.

Data presented to the Workforce Research Conference also showed that during 2006-2010, the extent of family physician involvement in delivering emergency care held steady, with 24%-30% of all family physicians providing emergency care as part of their practice. Among family physicians in rural settings, roughly 40% provided emergency care.

"We want to improve recognition of family physicians in emergency medicine among the wider health-care community," Dr. Gerard said in an interview following the SIG-EM meeting.

Family physicians who provide emergency care have shifted from seeking a formal certification process for their subspecialty to just broadened recognition that family-practice physicians play an important role in providing Americans with emergency care, said Dr. Gerard, a family physician and AAFP member who practices as an emergency medicine physician at Good Samaritan Hospital in Lebanon, Pa.

"The reality is that family physicians are the rural emergency-medicine providers," he said. But, "we need to open doors [for emergency medicine] in the city, too."

"The data we compiled showed that all emergency medicine training programs are in urban academic centers," with easy access to technology and specialists, said Dr. Perry A. Pugno, AAFP’s vice president for education at the Academy’s office in Leawood, Kan.

But, "family medicine is the emergency medicine workforce outside urban settings," he added, and emergency medicine organizations have been slow to acknowledge that.

"We can’t produce enough" emergency medicine physicians, but the emergency-medicine organizations and societies "won’t take the step to say that we should work with family medicine because they are the ones who are out there and doing it," Dr. Pugno said.

The American College of Emergency Physicians has noticed the AAFP’s SIG-EM, and that emergency medicine organization has held out the prospect of working with family physicians. ACEP’s senior director for membership and development, Michele Byers, came to last month’s gathering of about 30 AAFP attendees.

During the SIG-EM’s meeting, Ms. Byers acknowledged the role family physicians play in emergency care: "We realize that’s a reality," she said. "We are looking at opportunities to provide CME and information to family physicians working in emergency departments," Ms. Byers said.

"I think ACEP sees that a collaborative, cooperative relationship with family medicine needs to happen," said Dr. Gerard.

"It was no accident that someone from ACEP was here – I think they’re surprised at how quickly this group has grown," said Dr. Pugno. The SIG-EM "is not just an interest group. It is part of the AAFP infrastructure; that’s an important level of endorsement from the AAFP board," he noted.

"This group reports directly to the AAFP education commission," the group responsible for policy on workforce issues and career guidance. Last year, AAFP added to its policies a new section on emergency medicine that in part says family physicians "are qualified to provide emergency care in a variety of settings," particularly rural and remote settings.

"For 20 years, I paid dues to AAFP, but I felt like I didn’t have a home. Now we have a home," the SIG-EM, Dr. Gerard said during the group’s meeting. "We have a name, a place, and support from the [AAFP] Congress of Delegates. The AAFP policy statement is strong; it says that family medicine has a role in the future of emergency medicine."

The SIG-EM decided at its meeting to take its profile a step further by resolving to produce in the next year a policy paper on family physicians who provide emergency care in rural U.S. communities. The AAFP will then use this white paper "when we do advocacy work, when we speak with regulatory agencies" such as the Centers for Medicare and Medicaid Services and the Health Resources and Services Administration, said Dr. Pugno. "We will reference this paper and say we are concerned about continued funding of critical care access hospitals and that family medicine is the primary work force in that venue."

Dr. Gerard, Dr. Pugno, and Ms. Byers had no commercial disclosures. Dr. Pugno is an employee of the American Academy of Family Physicians. Ms. Byers is an employee of the American College of Emergency Physicians.

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

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

Mitchel L. Zoler/IMNG Medical Media

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Mitchel L. Zoler/IMNG Medical Media

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Mitchel L. Zoler/IMNG Medical Media

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Mitchel L. Zoler/IMNG Medical Media

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

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

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

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

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

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

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

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

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

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

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

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

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

Mitchel L. Zoler/IMNG Medical Media

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

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

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

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

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

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

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

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

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

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

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

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

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

Mitchel L. Zoler/IMNG Medical Media

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

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

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

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

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

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

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

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

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

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

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

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

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

Mitchel L. Zoler/IMNG Medical Media

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

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

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

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

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

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

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

Mitchel L. Zoler/IMNG Medical Media

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

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

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

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

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

Mitchel L. Zoler/IMNG Medical Media

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

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

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

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

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

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

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

Mitchel L. Zoler/IMNG Medical Media

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

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

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

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

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

Mitchel L. Zoler/IMNG Medical Media

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

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

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

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

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

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

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

Mitchel L. Zoler/IMNG Medical Media

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

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

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

The remarkable reductions of low-density lipoprotein cholesterol levels in several recent phase II trials using antibodies to PCSK9 triggered speculation on how low LDL should go for optimal patient outcomes.

The short answer is that, for secondary prevention of cardiovascular disease, patients may benefit from a goal substantially below the current level of less than 70 mg/dL – perhaps down to below 50 mg/dL and maybe even below 40 mg/dL. The new drug class of antibodies against the PCSK9 human protein that regulates LDL receptors seems capable of safely producing LDL levels that low when used with a potent statin regimen.

Courtesy Wikimedia/Urban/Creative Commons License

The benefit, as well as safety, of serum LDL cholesterol levels so low remains to be proven and won’t be so for a few more years, but those were the some of the LDL levels seen in the phase II anti-PCSK9 data reported earlier this month at the scientific sessions of the American Heart Association in Los Angeles.

The meeting included four reports from phase II studies of the anti-PCSK9 antibody made by Amgen, which involved a total of 981 patients who received some dosage of the drug. When administered on top of maximal dosages of statin or, in a few patients, ezetimibe, the highest antibody dosages – by subcutaneous injection every 2 weeks – produced LDL cuts of as much as 66%. As a result, a large fraction of patients on the antibody reached the sub–70-mg/dL LDL goal.

One AHA report analyzed data from a phase II study with 474 antibody-treated patients in terms of how many fell below 70 mg/dL while on the antibody. The highest dosage tested brought 90% of patients to goal, compared with virtually none at the start. Average LDL fell to 47 mg/dL and some patients dropped as low as 16 mg/dL.

What might LDL levels like these mean? In an invited discussion of the PCSK9 antibody results at the meeting, Dutch lipidologist John Kastelein – who called the results a "triumph of LDL goal attainment" and also marveled at the clean safety performance of the Amgen antibody – presented an analysis of data from more than 38,000 patients who received a statin in eight major statin-efficacy trials reported over the past 18 years. The results showed a steady drop in cardiovascular disease events at lower and lower LDL levels.

Patients reaching an LDL of 70-100 mg/dL, for example, had about a 16% rate of CVD events during follow-up. Among those who reached 50-70 mg/dL, the event rate dropped to about 12%, for those who hit 30-50 mg/dL the rate fell to about 5%, and those who slipped to an LDL level below 30 mg/dL had about a 2.5% event rate during follow-up.

The event rates "go down, down, down," as patients near what has been proposed as the true "physiologic" LDL serum level, about 25 mg/dL, Dr. Kastelein said.

Why was the target LDL goal set at 70 mg/dL? "Guideline writers looked at the evidence available" in 2004, when the Adult Treatment Panel III guideline group set its most aggressive goal of less than 70 mg/dL. "They saw where the intensive statin trials had gotten, mostly with 80-mg/day atorvastatin, to LDLs down to 65, 70, 75 mg/dL , so they picked 70 mg/dL as a reasonable target. But now we can get people into the 40s," Dr. Nihar Desai, a cardiologist at Brigham and Women’s Hospital in Boston, said to me after giving one of the anti-PCSK9 reports at the meeting.

Will driving LDLs levels that low help? Dr. Kastelein’s data from more than 38,000 statin-treated patients show that it could, but now it needs to be proved prospectively. A few days ago, Regeneron, one of the companies developing an anti-PCSK9 antibody, announced that its 18,000-patient, phase III trial had begun enrolling patients. A big trial of the Amgen antibody will probably start early next year. Results from both these studies should answer the question in about 3 years.

The remarkable reductions of low-density lipoprotein cholesterol levels in several recent phase II trials using antibodies to PCSK9 triggered speculation on how low LDL should go for optimal patient outcomes.

The short answer is that, for secondary prevention of cardiovascular disease, patients may benefit from a goal substantially below the current level of less than 70 mg/dL – perhaps down to below 50 mg/dL and maybe even below 40 mg/dL. The new drug class of antibodies against the PCSK9 human protein that regulates LDL receptors seems capable of safely producing LDL levels that low when used with a potent statin regimen.

Courtesy Wikimedia/Urban/Creative Commons License

The benefit, as well as safety, of serum LDL cholesterol levels so low remains to be proven and won’t be so for a few more years, but those were the some of the LDL levels seen in the phase II anti-PCSK9 data reported earlier this month at the scientific sessions of the American Heart Association in Los Angeles.

The meeting included four reports from phase II studies of the anti-PCSK9 antibody made by Amgen, which involved a total of 981 patients who received some dosage of the drug. When administered on top of maximal dosages of statin or, in a few patients, ezetimibe, the highest antibody dosages – by subcutaneous injection every 2 weeks – produced LDL cuts of as much as 66%. As a result, a large fraction of patients on the antibody reached the sub–70-mg/dL LDL goal.

One AHA report analyzed data from a phase II study with 474 antibody-treated patients in terms of how many fell below 70 mg/dL while on the antibody. The highest dosage tested brought 90% of patients to goal, compared with virtually none at the start. Average LDL fell to 47 mg/dL and some patients dropped as low as 16 mg/dL.

What might LDL levels like these mean? In an invited discussion of the PCSK9 antibody results at the meeting, Dutch lipidologist John Kastelein – who called the results a "triumph of LDL goal attainment" and also marveled at the clean safety performance of the Amgen antibody – presented an analysis of data from more than 38,000 patients who received a statin in eight major statin-efficacy trials reported over the past 18 years. The results showed a steady drop in cardiovascular disease events at lower and lower LDL levels.

Patients reaching an LDL of 70-100 mg/dL, for example, had about a 16% rate of CVD events during follow-up. Among those who reached 50-70 mg/dL, the event rate dropped to about 12%, for those who hit 30-50 mg/dL the rate fell to about 5%, and those who slipped to an LDL level below 30 mg/dL had about a 2.5% event rate during follow-up.

The event rates "go down, down, down," as patients near what has been proposed as the true "physiologic" LDL serum level, about 25 mg/dL, Dr. Kastelein said.

Why was the target LDL goal set at 70 mg/dL? "Guideline writers looked at the evidence available" in 2004, when the Adult Treatment Panel III guideline group set its most aggressive goal of less than 70 mg/dL. "They saw where the intensive statin trials had gotten, mostly with 80-mg/day atorvastatin, to LDLs down to 65, 70, 75 mg/dL , so they picked 70 mg/dL as a reasonable target. But now we can get people into the 40s," Dr. Nihar Desai, a cardiologist at Brigham and Women’s Hospital in Boston, said to me after giving one of the anti-PCSK9 reports at the meeting.

Will driving LDLs levels that low help? Dr. Kastelein’s data from more than 38,000 statin-treated patients show that it could, but now it needs to be proved prospectively. A few days ago, Regeneron, one of the companies developing an anti-PCSK9 antibody, announced that its 18,000-patient, phase III trial had begun enrolling patients. A big trial of the Amgen antibody will probably start early next year. Results from both these studies should answer the question in about 3 years.

The remarkable reductions of low-density lipoprotein cholesterol levels in several recent phase II trials using antibodies to PCSK9 triggered speculation on how low LDL should go for optimal patient outcomes.

The short answer is that, for secondary prevention of cardiovascular disease, patients may benefit from a goal substantially below the current level of less than 70 mg/dL – perhaps down to below 50 mg/dL and maybe even below 40 mg/dL. The new drug class of antibodies against the PCSK9 human protein that regulates LDL receptors seems capable of safely producing LDL levels that low when used with a potent statin regimen.

Courtesy Wikimedia/Urban/Creative Commons License

The benefit, as well as safety, of serum LDL cholesterol levels so low remains to be proven and won’t be so for a few more years, but those were the some of the LDL levels seen in the phase II anti-PCSK9 data reported earlier this month at the scientific sessions of the American Heart Association in Los Angeles.

The meeting included four reports from phase II studies of the anti-PCSK9 antibody made by Amgen, which involved a total of 981 patients who received some dosage of the drug. When administered on top of maximal dosages of statin or, in a few patients, ezetimibe, the highest antibody dosages – by subcutaneous injection every 2 weeks – produced LDL cuts of as much as 66%. As a result, a large fraction of patients on the antibody reached the sub–70-mg/dL LDL goal.

One AHA report analyzed data from a phase II study with 474 antibody-treated patients in terms of how many fell below 70 mg/dL while on the antibody. The highest dosage tested brought 90% of patients to goal, compared with virtually none at the start. Average LDL fell to 47 mg/dL and some patients dropped as low as 16 mg/dL.

What might LDL levels like these mean? In an invited discussion of the PCSK9 antibody results at the meeting, Dutch lipidologist John Kastelein – who called the results a "triumph of LDL goal attainment" and also marveled at the clean safety performance of the Amgen antibody – presented an analysis of data from more than 38,000 patients who received a statin in eight major statin-efficacy trials reported over the past 18 years. The results showed a steady drop in cardiovascular disease events at lower and lower LDL levels.

Patients reaching an LDL of 70-100 mg/dL, for example, had about a 16% rate of CVD events during follow-up. Among those who reached 50-70 mg/dL, the event rate dropped to about 12%, for those who hit 30-50 mg/dL the rate fell to about 5%, and those who slipped to an LDL level below 30 mg/dL had about a 2.5% event rate during follow-up.

The event rates "go down, down, down," as patients near what has been proposed as the true "physiologic" LDL serum level, about 25 mg/dL, Dr. Kastelein said.

Why was the target LDL goal set at 70 mg/dL? "Guideline writers looked at the evidence available" in 2004, when the Adult Treatment Panel III guideline group set its most aggressive goal of less than 70 mg/dL. "They saw where the intensive statin trials had gotten, mostly with 80-mg/day atorvastatin, to LDLs down to 65, 70, 75 mg/dL , so they picked 70 mg/dL as a reasonable target. But now we can get people into the 40s," Dr. Nihar Desai, a cardiologist at Brigham and Women’s Hospital in Boston, said to me after giving one of the anti-PCSK9 reports at the meeting.

Will driving LDLs levels that low help? Dr. Kastelein’s data from more than 38,000 statin-treated patients show that it could, but now it needs to be proved prospectively. A few days ago, Regeneron, one of the companies developing an anti-PCSK9 antibody, announced that its 18,000-patient, phase III trial had begun enrolling patients. A big trial of the Amgen antibody will probably start early next year. Results from both these studies should answer the question in about 3 years.

Hungry mornings – as patients wait to get their fasting blood lipids drawn – may come to an end, based on more evidence that fasting has little meaningful impact on lipid levels and management decisions for most patients.

A review of lipid test profiles drawn from more than 200,000 Calgary residents during 6 months in mid-2011 showed that fasting time prior to the blood draw had little association with lipid subclass levels.

"The results presented herein, combined with those of other recent studies, suggest that nonfasting determination of lipid subclasses is a reasonable alternative to fasting determinations," said Dr. Davinder Sidhu and Dr. Christopher Naugler of the University of Calgary (Alta.), in a report published on Nov. 12 (Arch. Int. Med. 2012 [doi: 10.1001/archinternmed.2012.3708]).

Fasting lipid measures or direct measurement of low-density lipoprotein (LDL) cholesterol could be considered for patients with an initial triglyceride measurement greater than 400 mg/dL, they added.

"A growing body of evidence from observational studies and statin clinical trials suggests that nonfasting or fasting blood draws may be used for cardiovascular risk assessment and therapeutic decisions," especially when the lipid subfractions of interest are not LDL cholesterol, wrote Dr. Amit V. Khera and Dr. Samia Mora, both from Brigham and Women’s Hospital in Boston, in an invited commentary published online along with the study report (Arch. Int. Med. 2012 Nov. 12 [doi: 10.1001/2013.jamainternmed.263]). Lipid measures that are not very variable by fasting status include total and high-density lipoprotein (HDL) cholesterol, which each varied by less than 2% regardless of fasting duration. LDL cholesterol varied by less than 10%, and triglycerides varied by less than 20%, regardless of fasting duration.

"Given the current lack of evidence for the superiority of fasting lipid testing, it is reasonable to consider nonfasting lipid testing in most individuals who present for a routine clinic visit," said Dr. Khera and Dr. Mora.

They also noted several limitations in the study reported by Dr. Sidhu and Naugler: Most of the blood specimens in the analysis were drawn after at least 9 hours of fasting; because the duration of fasting was not randomized, people who presented to their laboratory nonfasting may differ from those who were fasting in important ways; and the people included in the study were primarily at low risk based on their relatively young age – an average of 53 years – and low total cholesterol level, a mean of 183 mg/dL.

Data for the study came from the records of Calgary Laboratory Services, which is the sole supplier of laboratory services for Calgary, and a population of about 1.4 million people. During the period of April-September 2011, blood samples for lipid measurements were drawn from 209,180 people regardless of fasting duration.

The results of the study suggest that "fasting for routine lipid level determinations is largely unnecessary," concluded Dr. Sidhu and Dr. Naugler.

Dr. Sidhu and Dr. Naugler said they had no disclosures. Dr. Mora disclosed that he has been a consultant to Pfizer and Quest Diagnostics, that he has received speaking honoraria from Abbott, AstraZeneca, and the National Lipid Association, and that he has received research support from AstraZeneca. Dr. Khera had no disclosures.

UPDATED 11/18/12

Hungry mornings – as patients wait to get their fasting blood lipids drawn – may come to an end, based on more evidence that fasting has little meaningful impact on lipid levels and management decisions for most patients.

A review of lipid test profiles drawn from more than 200,000 Calgary residents during 6 months in mid-2011 showed that fasting time prior to the blood draw had little association with lipid subclass levels.

"The results presented herein, combined with those of other recent studies, suggest that nonfasting determination of lipid subclasses is a reasonable alternative to fasting determinations," said Dr. Davinder Sidhu and Dr. Christopher Naugler of the University of Calgary (Alta.), in a report published on Nov. 12 (Arch. Int. Med. 2012 [doi: 10.1001/archinternmed.2012.3708]).

Fasting lipid measures or direct measurement of low-density lipoprotein (LDL) cholesterol could be considered for patients with an initial triglyceride measurement greater than 400 mg/dL, they added.

"A growing body of evidence from observational studies and statin clinical trials suggests that nonfasting or fasting blood draws may be used for cardiovascular risk assessment and therapeutic decisions," especially when the lipid subfractions of interest are not LDL cholesterol, wrote Dr. Amit V. Khera and Dr. Samia Mora, both from Brigham and Women’s Hospital in Boston, in an invited commentary published online along with the study report (Arch. Int. Med. 2012 Nov. 12 [doi: 10.1001/2013.jamainternmed.263]). Lipid measures that are not very variable by fasting status include total and high-density lipoprotein (HDL) cholesterol, which each varied by less than 2% regardless of fasting duration. LDL cholesterol varied by less than 10%, and triglycerides varied by less than 20%, regardless of fasting duration.

"Given the current lack of evidence for the superiority of fasting lipid testing, it is reasonable to consider nonfasting lipid testing in most individuals who present for a routine clinic visit," said Dr. Khera and Dr. Mora.

They also noted several limitations in the study reported by Dr. Sidhu and Naugler: Most of the blood specimens in the analysis were drawn after at least 9 hours of fasting; because the duration of fasting was not randomized, people who presented to their laboratory nonfasting may differ from those who were fasting in important ways; and the people included in the study were primarily at low risk based on their relatively young age – an average of 53 years – and low total cholesterol level, a mean of 183 mg/dL.

Data for the study came from the records of Calgary Laboratory Services, which is the sole supplier of laboratory services for Calgary, and a population of about 1.4 million people. During the period of April-September 2011, blood samples for lipid measurements were drawn from 209,180 people regardless of fasting duration.

The results of the study suggest that "fasting for routine lipid level determinations is largely unnecessary," concluded Dr. Sidhu and Dr. Naugler.

Dr. Sidhu and Dr. Naugler said they had no disclosures. Dr. Mora disclosed that he has been a consultant to Pfizer and Quest Diagnostics, that he has received speaking honoraria from Abbott, AstraZeneca, and the National Lipid Association, and that he has received research support from AstraZeneca. Dr. Khera had no disclosures.

UPDATED 11/18/12

Hungry mornings – as patients wait to get their fasting blood lipids drawn – may come to an end, based on more evidence that fasting has little meaningful impact on lipid levels and management decisions for most patients.

A review of lipid test profiles drawn from more than 200,000 Calgary residents during 6 months in mid-2011 showed that fasting time prior to the blood draw had little association with lipid subclass levels.

"The results presented herein, combined with those of other recent studies, suggest that nonfasting determination of lipid subclasses is a reasonable alternative to fasting determinations," said Dr. Davinder Sidhu and Dr. Christopher Naugler of the University of Calgary (Alta.), in a report published on Nov. 12 (Arch. Int. Med. 2012 [doi: 10.1001/archinternmed.2012.3708]).

Fasting lipid measures or direct measurement of low-density lipoprotein (LDL) cholesterol could be considered for patients with an initial triglyceride measurement greater than 400 mg/dL, they added.

"A growing body of evidence from observational studies and statin clinical trials suggests that nonfasting or fasting blood draws may be used for cardiovascular risk assessment and therapeutic decisions," especially when the lipid subfractions of interest are not LDL cholesterol, wrote Dr. Amit V. Khera and Dr. Samia Mora, both from Brigham and Women’s Hospital in Boston, in an invited commentary published online along with the study report (Arch. Int. Med. 2012 Nov. 12 [doi: 10.1001/2013.jamainternmed.263]). Lipid measures that are not very variable by fasting status include total and high-density lipoprotein (HDL) cholesterol, which each varied by less than 2% regardless of fasting duration. LDL cholesterol varied by less than 10%, and triglycerides varied by less than 20%, regardless of fasting duration.

"Given the current lack of evidence for the superiority of fasting lipid testing, it is reasonable to consider nonfasting lipid testing in most individuals who present for a routine clinic visit," said Dr. Khera and Dr. Mora.

They also noted several limitations in the study reported by Dr. Sidhu and Naugler: Most of the blood specimens in the analysis were drawn after at least 9 hours of fasting; because the duration of fasting was not randomized, people who presented to their laboratory nonfasting may differ from those who were fasting in important ways; and the people included in the study were primarily at low risk based on their relatively young age – an average of 53 years – and low total cholesterol level, a mean of 183 mg/dL.

Data for the study came from the records of Calgary Laboratory Services, which is the sole supplier of laboratory services for Calgary, and a population of about 1.4 million people. During the period of April-September 2011, blood samples for lipid measurements were drawn from 209,180 people regardless of fasting duration.

The results of the study suggest that "fasting for routine lipid level determinations is largely unnecessary," concluded Dr. Sidhu and Dr. Naugler.

Dr. Sidhu and Dr. Naugler said they had no disclosures. Dr. Mora disclosed that he has been a consultant to Pfizer and Quest Diagnostics, that he has received speaking honoraria from Abbott, AstraZeneca, and the National Lipid Association, and that he has received research support from AstraZeneca. Dr. Khera had no disclosures.

UPDATED 11/18/12

LOS ANGELES – Full left-atrial ablation by the modified Cox MAZE procedure to treat atrial fibrillation led to significant reductions in left atrial function, based on a detailed assessment of 31 patients who underwent this treatment using bilateral bipolar radiofrequency.

The damaging effect of complete left-atrial ablation contrasted with the impact of a less extensive procedure, pulmonary vein isolation, which kept left-atrial function intact and even improved it by some parameters. Opinions split on the implications of these findings.

"Our advice is that left-atrial ablation should be restricted to those cases where pulmonary vein isolation will likely be insufficient" to restore and maintain sinus rhythm, Dr. Marieke G. Compier said as she presented the findings at the annual scientific sessions of the American Heart Association on Nov. 6.

But a cardiac surgeon who heard the results disagreed, contending that the top priority is performing the procedure that will result in durable prevention of atrial fibrillation (AF) recurrence.

"Recurrence of atrial fibrillation is a more important determinant of [successful] clinical outcomes than preserved atrial function," said Dr. Pierre Page, chief of cardiac surgery at the University of Montreal. "The data we have today show that left-atrial ablation is very beneficial," Dr. Page said in an interview.

Dr. Compier and her associates used echocardiography to assess left-atrial function in 31 patients who underwent a modified Cox-MAZE procedure for complete left-atrial ablation using bilateral bipolar radiofrequency, and 31 patients who underwent pulmonary-vein isolation (PVI) only. In the full ablation group, 25 patients had persistent AF and 6 had paroxysmal AF; in the PVI group, 25 patients had paroxysmal disease and 6 had persistent AF. All patients also underwent concurrent coronary artery bypass, valve surgery, or both.

The researchers assessed the efficacy of AF treatment using 24-hour ECG monitoring at 3, 6, and 12 months following surgery. They also used two-dimensional echocardiography to assess left atrial size and function at 3 months and 1 year after surgery.

After 1 year, 68% of the patients who had full ablation and 81% of those who underwent PVI were free of AF and completely off anti-arrhythmic drug treatment; the other patients in each group had AF recurrences. The different long-term success in maintaining sinus rhythm in the two groups probably stemmed from the unbalanced distribution of patients with paroxysmal and persistent AF, said Dr. Compier, a cardiologist in the Heart Center at Leiden (the Netherlands) University Medical Center. "I think this is why full ablation seemed less successful," she said.

After 1 year, echocardiographic examinations showed that patients treated with full ablation had statistically significant reductions in left atrial volume and strain, and 42% of patients had A-wave restoration. Compared with measurements made prior to surgery, strain rate fell by an average of about 50%, peak A-wave dropped by an average of about a third, and average left-atrial ejection fraction and filling fraction each dropped by about 20%. All of these changes were statistically significant, compared with baseline.

In contrast, patients who underwent PVI had no significant change in their strain rate or peak A wave, and their average left-atrial ejection fraction and filling fraction each rose by about 10% compared with baseline, statistically significant differences. A-wave restoration occurred in 87% of the PVI patients.

Stepwise regression analysis of baseline differences between the two study groups showed that the follow-up differences seen in left-atrial size and function were best explained by the different ablation treatments the two groups received, Dr. Compier said.

Dr. Compier said that she had no disclosures.

LOS ANGELES – Full left-atrial ablation by the modified Cox MAZE procedure to treat atrial fibrillation led to significant reductions in left atrial function, based on a detailed assessment of 31 patients who underwent this treatment using bilateral bipolar radiofrequency.

The damaging effect of complete left-atrial ablation contrasted with the impact of a less extensive procedure, pulmonary vein isolation, which kept left-atrial function intact and even improved it by some parameters. Opinions split on the implications of these findings.

"Our advice is that left-atrial ablation should be restricted to those cases where pulmonary vein isolation will likely be insufficient" to restore and maintain sinus rhythm, Dr. Marieke G. Compier said as she presented the findings at the annual scientific sessions of the American Heart Association on Nov. 6.

But a cardiac surgeon who heard the results disagreed, contending that the top priority is performing the procedure that will result in durable prevention of atrial fibrillation (AF) recurrence.

"Recurrence of atrial fibrillation is a more important determinant of [successful] clinical outcomes than preserved atrial function," said Dr. Pierre Page, chief of cardiac surgery at the University of Montreal. "The data we have today show that left-atrial ablation is very beneficial," Dr. Page said in an interview.

Dr. Compier and her associates used echocardiography to assess left-atrial function in 31 patients who underwent a modified Cox-MAZE procedure for complete left-atrial ablation using bilateral bipolar radiofrequency, and 31 patients who underwent pulmonary-vein isolation (PVI) only. In the full ablation group, 25 patients had persistent AF and 6 had paroxysmal AF; in the PVI group, 25 patients had paroxysmal disease and 6 had persistent AF. All patients also underwent concurrent coronary artery bypass, valve surgery, or both.

The researchers assessed the efficacy of AF treatment using 24-hour ECG monitoring at 3, 6, and 12 months following surgery. They also used two-dimensional echocardiography to assess left atrial size and function at 3 months and 1 year after surgery.

After 1 year, 68% of the patients who had full ablation and 81% of those who underwent PVI were free of AF and completely off anti-arrhythmic drug treatment; the other patients in each group had AF recurrences. The different long-term success in maintaining sinus rhythm in the two groups probably stemmed from the unbalanced distribution of patients with paroxysmal and persistent AF, said Dr. Compier, a cardiologist in the Heart Center at Leiden (the Netherlands) University Medical Center. "I think this is why full ablation seemed less successful," she said.

After 1 year, echocardiographic examinations showed that patients treated with full ablation had statistically significant reductions in left atrial volume and strain, and 42% of patients had A-wave restoration. Compared with measurements made prior to surgery, strain rate fell by an average of about 50%, peak A-wave dropped by an average of about a third, and average left-atrial ejection fraction and filling fraction each dropped by about 20%. All of these changes were statistically significant, compared with baseline.

In contrast, patients who underwent PVI had no significant change in their strain rate or peak A wave, and their average left-atrial ejection fraction and filling fraction each rose by about 10% compared with baseline, statistically significant differences. A-wave restoration occurred in 87% of the PVI patients.

Stepwise regression analysis of baseline differences between the two study groups showed that the follow-up differences seen in left-atrial size and function were best explained by the different ablation treatments the two groups received, Dr. Compier said.

Dr. Compier said that she had no disclosures.

LOS ANGELES – Full left-atrial ablation by the modified Cox MAZE procedure to treat atrial fibrillation led to significant reductions in left atrial function, based on a detailed assessment of 31 patients who underwent this treatment using bilateral bipolar radiofrequency.

The damaging effect of complete left-atrial ablation contrasted with the impact of a less extensive procedure, pulmonary vein isolation, which kept left-atrial function intact and even improved it by some parameters. Opinions split on the implications of these findings.

"Our advice is that left-atrial ablation should be restricted to those cases where pulmonary vein isolation will likely be insufficient" to restore and maintain sinus rhythm, Dr. Marieke G. Compier said as she presented the findings at the annual scientific sessions of the American Heart Association on Nov. 6.

But a cardiac surgeon who heard the results disagreed, contending that the top priority is performing the procedure that will result in durable prevention of atrial fibrillation (AF) recurrence.

"Recurrence of atrial fibrillation is a more important determinant of [successful] clinical outcomes than preserved atrial function," said Dr. Pierre Page, chief of cardiac surgery at the University of Montreal. "The data we have today show that left-atrial ablation is very beneficial," Dr. Page said in an interview.

Dr. Compier and her associates used echocardiography to assess left-atrial function in 31 patients who underwent a modified Cox-MAZE procedure for complete left-atrial ablation using bilateral bipolar radiofrequency, and 31 patients who underwent pulmonary-vein isolation (PVI) only. In the full ablation group, 25 patients had persistent AF and 6 had paroxysmal AF; in the PVI group, 25 patients had paroxysmal disease and 6 had persistent AF. All patients also underwent concurrent coronary artery bypass, valve surgery, or both.

The researchers assessed the efficacy of AF treatment using 24-hour ECG monitoring at 3, 6, and 12 months following surgery. They also used two-dimensional echocardiography to assess left atrial size and function at 3 months and 1 year after surgery.

After 1 year, 68% of the patients who had full ablation and 81% of those who underwent PVI were free of AF and completely off anti-arrhythmic drug treatment; the other patients in each group had AF recurrences. The different long-term success in maintaining sinus rhythm in the two groups probably stemmed from the unbalanced distribution of patients with paroxysmal and persistent AF, said Dr. Compier, a cardiologist in the Heart Center at Leiden (the Netherlands) University Medical Center. "I think this is why full ablation seemed less successful," she said.

After 1 year, echocardiographic examinations showed that patients treated with full ablation had statistically significant reductions in left atrial volume and strain, and 42% of patients had A-wave restoration. Compared with measurements made prior to surgery, strain rate fell by an average of about 50%, peak A-wave dropped by an average of about a third, and average left-atrial ejection fraction and filling fraction each dropped by about 20%. All of these changes were statistically significant, compared with baseline.

In contrast, patients who underwent PVI had no significant change in their strain rate or peak A wave, and their average left-atrial ejection fraction and filling fraction each rose by about 10% compared with baseline, statistically significant differences. A-wave restoration occurred in 87% of the PVI patients.

Stepwise regression analysis of baseline differences between the two study groups showed that the follow-up differences seen in left-atrial size and function were best explained by the different ablation treatments the two groups received, Dr. Compier said.

Dr. Compier said that she had no disclosures.