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219: The Combination of Niacin Extended-Release with Simvastatin Improves Lipid Levels in Treatment-Naive Patients
Abstracts
221
ommends treatment to reduce non-HDL-C followed by treatment to raise HDL-C and lower TG, if indicated. Purpose: The lipid effects of a novel combination of a proprietary, niacin extended-release plus simvastatin (NER/S) were compared in patients with, and without, elevated TG at baseline (ⱖ 200 mg/dL) who already had well-controlled LDL-C levels, but elevated non-HDL-C levels. Methods: Following a 20 mg/day simvastatin run-in, patients were randomized to one of 3 treatment groups for 24 weeks: simvastatin monotherapy (20 mg/day), NER/S 1000/20 mg/ day, or NER/S 2000/20 mg/day. In this post-hoc subanalysis from SEACOAST I, median percentage changes from baseline at week 24 in lipid parameters were compared in patients with, and without, elevated TG at baseline (ⱖ 200 mg/dL). Results: For all patients receiving 2000/20 mg/day of NER/S, median reductions in non-HDL-C, LDL-C, TG, and Total C:HDL-C were 22.5%, 14.2%, 38.0%, and 31.3%, respectively; similarly, Apo B levels decreased by 18.1%, supporting a substantial reduction in atherogenic particles. Each of these effects of NER/S was more pronounced in patients with elevated TG at baseline than in patients without elevated TG at baseline (P⬍0.0001). The median increase in HDL-C was similar regardless of the baseline TG level [Table]. Conclusions: Treatment with combination NER/S resulted in reductions in lipids and atherogenic particles (LDL-C, nonHDL-C, TG, and Apo B) that were most prominent in patients with elevated TG at baseline. However, unlike other pharmacotherapies, NER/S-mediated increases in HDL-C were substantial and similar in both TG subgroups. Table 1. Effects of niacin ER/simvastatin (NER/S) versus simvastatin monotherapy on lipid parametersa Subgroup TGⱖ200 mg/dL Therapy, mg/day Patients NonHDL-C LDL-C TG Apo B HDL-C
Tot C: HDL-C
NER/S 1000/20 n ⫽ 57 168.0; ⫺18.8ⴱⴱ [⫺39.4; ⫺7.0] 110.3; ⫺15.2ⴱ [⫺43.0; ⫺3.8] 286.3; ⫺38.5 [⫺52.1; ⫺15.2] 109.0; ⫺17.9ⴱⴱ [⫺34.9; ⫺7.6]
Synopsis: Current guidelines for cardiovascular risk reduction emphasize the importance of aggressive management to achieve target levels of multiple lipid components. Purpose: The effect of a novel, proprietary, niacin extended-release (NER) and simvastatin combination (NER/S) on attainment of individual and multiple lipid targets was evaluated. Methods: The OCEANS study obtained baseline lipids for 463 patients following a 4-week run-in of diet modification and 40 mg/day simvastatin. Patients who received NER/S (titrated to 2000/40 mg/day) for at least 24 weeks were included in a post-hoc analysis of each lipid parameter, or combination of parameters, if their baseline lipid values were not at target. Target levels were defined as: HDL-C ⱖ 40 mg/dL; TG ⬍ 150 mg/dL; or cardiovascular risk-adjusted NCEP goals for non-HDL-C or LDL-C. Results: Following treatment with NER/S, ⱖ 64% of patients attained target levels for each metric (non-HDL-C, LDL-C, HDL-C, TG) at week 24 [Figure]. Target lipid levels for LDL-C, HDL-C, and TG were simultaneously attained by 65% of patients. Unanticipated adverse events were not reported. Conclusions: For patients who failed to attain optimal lipid levels following statin monotherapy, the majority attained target levels for each lipid component evaluated following treatment with NER/S, and 65% of patients simultaneously attained target levels for all 3 lipid components (LDL, HDL, and TG). Thus, the combined NER/S formulation significantly improves attainment of multiple lipid goals in patients who failed to do so with statin monotherapy.
TG⬎200 mg/dL NER/S 2000/20 n ⫽ 34
162.5; ⫺28.9ⴱⴱ [⫺41.4; ⫺4.5] 112.5; ⫺19.1 [⫺34.2; 5.0] 257.5; ⫺53.4ⴱⴱ [⫺62.5; ⫺18.8] 103.5; ⫺26.7ⴱⴱ [⫺33.7; ⫺2.2] 38.5; 37.8; ⫹18.5ⴱⴱ ⫹25.9ⴱⴱⴱ [8.4; 33.3] [19.1; 42.4] 5.4; ⫺30.4ⴱⴱⴱ 5.2; ⫺33.7ⴱⴱⴱ [⫺40.6; ⫺16.4] [⫺40.2; ⫺20.9]
Simvastatin 20 n ⫽ 54
NER/S 1000/20 n ⫽ 51
NER/S 2000/20 n ⫽ 22
Simvastatin 20 n ⫽ 48
161.0; ⫺10.2 [⫺30.7; 5.6] 103.5; ⫺8.9 [⫺23.0; 8.2] 269.3; ⫺24.7 [⫺44.2; 13.1] 105.0; ⫺6.7 [⫺28.1; 4.7]
162.5; ⫺9.7 [⫺22.7; ⫺1.4] 133.3; ⫺7.4 [⫺22.5; 3.4] 150.3; ⫺19.1ⴱⴱ [⫺37.1; 0.2] 96.0; ⫺4.8 [⫺23.8; 10.7] 45.5; ⫹17.9ⴱⴱⴱ [9.3; 28.7] 4.6; ⫺19.6ⴱ [⫺31.2; ⫺5.8]
143.0; ⫺11.9ⴱ [⫺31.6; ⫺4.7] 110.5; ⫺9.4 [⫺35.2; 2.4] 144.0; ⫺33.5ⴱⴱ [⫺41.2; ⫺22.4] 94.5; ⫺7.4ⴱ [⫺37.2; 1.1] 45.5; ⫹24.4ⴱⴱⴱ [14.3; 29.0] 4.4; ⫺29.9ⴱⴱ [⫺40.2; ⫺13.9]
154.0; ⫺4.7 [⫺16.8; 6.3] 127.0; ⫺6.2 [⫺18.0; 5.3] 144.3; ⫺10.2 [⫺26.4; 18.2] 96.0; ⫺1.7 [⫺22.9; 6.9]
37.8; ⫹9.1 [⫺1.7; 17.3] 5.4; ⫺14.6 [⫺34.7; 1.0]
47.5; ⫹3.8 [⫺4.3; 16.2] 4.2; ⫺9.1 [⫺20.0; 2.3]
a Baseline (mg/dL); median change from baseline at week 24 (%); [25th; 75th percentile change from baseline at week 24]. ⴱ P⬍0.05, ⴱⴱP⬍0.01, ⴱⴱⴱP⬍0.001, vs. simvastatin monotherapy.
218 Niacin Extended-Release/Simvastatin Results in Attainment of Optimal Lipid Levels in Patients Who Failed to Attain These Levels on Statin Monotherapy Richard H. Karas, MD, Daiva R. Bajorunas, Michael H. Davidson, Moti Kashyap, Laurence H. Keller, Robert H. Knopp, Robert J. Padley, Roopal B. Thakkar, (Boston, MA)
219 The Combination of Niacin Extended-Release with Simvastatin Improves Lipid Levels in Treatment-Naive Patients Richard H. Karas, MD, Daiva R. Bajorunas, Michael H. Davidson, Moti Kashyap, Laurence H. Keller, Robert H. Knopp, Robert J. Padley, Roopal B. Thakkar, (Boston, MA) Synopsis: High-dose statin therapy that targets LDL-C does not prevent approximately two-thirds of cardiovascular events. This has led to increased attention in evidence-based
222
guidelines to treating multiple lipid abnormalities and greater interest in combination therapy. Purpose: The OCEANS study evaluated the effect of novel proprietary niacin extended-release (NER) and simvastatin combination (NER/S) in patients with mixed dyslipidemia. Methods: Following a 4-week run-in of diet modification and 40 mg/day simvastatin, patients were randomized to an 8- or 12-week NER/S titration scheme to a maximum NER/S dose of 2000 mg/day NER and 40 mg/day simvastatin for 24 weeks. Median changes from screening lipid values, prior to the simvastatin run-in phase, to week 24 in multiple lipid parameters were determined in patients who were lipid treatment-naı¨ve at screening. Results: Following treatment with NER/S (2000/40 mg/d) for 24 weeks, median decreases of 53.0%, 55.9%, and 49.5% in non-HDL-C, LDL-C, and TG, respectively, were observed in treatment-naı¨ve patients (n⫽85) [Figure]. The median increase in HDL-C was 25.0% in these patients. Lastly, a median decrease of 51.4% in the ratio of total cholesterol (Total C) to HDL-C was observed in treatment-naı¨ve patients. Conclusions: In patients with primary Type II or mixed hyperlipidemia, treatment with combination NER/S (2000/40 mg/day) provides substantial improvements in all major lipid parameters associated with the residual risk of cardiovascular events.
Journal of Clinical Lipidology, Vol 2, No 3, June 2008 health by providing an anchor for lipid and lipoprotein measurements in epidemiologic studies and clinical trials. Among the studies standardized by LSP are the National Health and Nutrition Evaluation Surveys (NHANES), the Framingham Heart Study, the Lipid Research Clinics Coronary Primary Prevention Trial, the Women’s Health Study, the Multiple Risk Factor Intervention Trial (MRFIT), the Atherosclerosis Risk in Communities (ARIC), and the World Health Organization MONItoring CArdiovascular disease (MONICA) Study. Purpose: The purpose of the LSP is to ensure that the data generated from epidemiologic studies and clinical trials are comparable between studies and over space and time. Methods: LSP uses the reference methods for cholesterol, HDL cholesterol (HDLC), and triglycerides (TG) to assign values to frozen human serum reference materials. The reference materials are prepared using a protocol that results in high-quality, commutable materials that behave like freshly collected samples and are distributed quarterly to enrolled laboratories. The LSP applies the inaccuracy and imprecision performance guidelines for laboratories recommended by the National Cholesterol Education Program (NCEP). The statistical design for the LSP protocol ensures that a laboratory with the NCEP maximum allowable bias and imprecision will have a 95% chance of passing the bias evaluation. LSP initiates interactions with laboratories that fail to meet the criteria, providing expertise and assisting them to improve performance. Results: 93 research and clinical trial laboratories (52 domestic and 41 international) participated in the LSP during 2007. During the first 3 quarters of 2007, the pass rates for total cholesterol (TC), TG and HDLC were 94.9%, 92.5% and 87.2%, respectively. Laboratories failed bias criteria for TC, TG and HDLC 3.7%, 7.1% and 9.9% of the time, respectively. Laboratories failed precision criteria for TC, TG and HDLC 2.6%, 1.9% and 4.6% of the time, respectively. Conclusions: The LSP provides a stable accuracy base for laboratories measuring lipids and lipoproteins in epidemiologic studies and clinical trials. This ensures that the data generated from these studies can be compared. The LSP serves as a model for standardization of other biomarkers of clinical importance.
220
221
CDC’s Lipid Standardization Program: Assuring Quality in Epidemiologic Studies for 50 Years Mary M. Kimberly, PhD, Samuel P. Caudill, Gerald R. Cooper, Mahnaz Dasti, Elizabeth Monsell, Gary L. Myers, William E. Slazyk, Parvin P. Waymack, (Atlanta, GA)
Effects of Prescription Omega-3-Acid Ethyl Esters Plus Simvastatin on Lipids and Lipoprotein Particles in Mixed Dyslipidemia Kevin Carl Maki, PhD, Mary R. Dicklin, Barry C. Lubin, James M. McKenney, Matthew S. Reeves, (Glen Ellyn, IL)
Synopsis: The Centers for Disease Control and PreventionNational Heart, Lung, and Blood Institute Lipid Standardization Program (LSP) has worked to provide an accuracybased standard of performance for laboratory testing of risk factors for assessing cardiovascular disease (CVD) for 50 years. The LSP continues to have a major impact on public
Synopsis: Prescription Omega-3-acid ethyl esters (P-OM3) have been approved in the United States as an adjunct to diet for reducing very high triglyceride (TG) levels (ⱖ 500 mg/dL) and in Europe for secondary prevention of coronary heart disease. POM3 is frequently used in combination with a statin. Purpose: This trial examined the effects on lipids and lipoprotein particles of open-label simvastatin (S) 20 mg/d
221
ommends treatment to reduce non-HDL-C followed by treatment to raise HDL-C and lower TG, if indicated. Purpose: The lipid effects of a novel combination of a proprietary, niacin extended-release plus simvastatin (NER/S) were compared in patients with, and without, elevated TG at baseline (ⱖ 200 mg/dL) who already had well-controlled LDL-C levels, but elevated non-HDL-C levels. Methods: Following a 20 mg/day simvastatin run-in, patients were randomized to one of 3 treatment groups for 24 weeks: simvastatin monotherapy (20 mg/day), NER/S 1000/20 mg/ day, or NER/S 2000/20 mg/day. In this post-hoc subanalysis from SEACOAST I, median percentage changes from baseline at week 24 in lipid parameters were compared in patients with, and without, elevated TG at baseline (ⱖ 200 mg/dL). Results: For all patients receiving 2000/20 mg/day of NER/S, median reductions in non-HDL-C, LDL-C, TG, and Total C:HDL-C were 22.5%, 14.2%, 38.0%, and 31.3%, respectively; similarly, Apo B levels decreased by 18.1%, supporting a substantial reduction in atherogenic particles. Each of these effects of NER/S was more pronounced in patients with elevated TG at baseline than in patients without elevated TG at baseline (P⬍0.0001). The median increase in HDL-C was similar regardless of the baseline TG level [Table]. Conclusions: Treatment with combination NER/S resulted in reductions in lipids and atherogenic particles (LDL-C, nonHDL-C, TG, and Apo B) that were most prominent in patients with elevated TG at baseline. However, unlike other pharmacotherapies, NER/S-mediated increases in HDL-C were substantial and similar in both TG subgroups. Table 1. Effects of niacin ER/simvastatin (NER/S) versus simvastatin monotherapy on lipid parametersa Subgroup TGⱖ200 mg/dL Therapy, mg/day Patients NonHDL-C LDL-C TG Apo B HDL-C
Tot C: HDL-C
NER/S 1000/20 n ⫽ 57 168.0; ⫺18.8ⴱⴱ [⫺39.4; ⫺7.0] 110.3; ⫺15.2ⴱ [⫺43.0; ⫺3.8] 286.3; ⫺38.5 [⫺52.1; ⫺15.2] 109.0; ⫺17.9ⴱⴱ [⫺34.9; ⫺7.6]
Synopsis: Current guidelines for cardiovascular risk reduction emphasize the importance of aggressive management to achieve target levels of multiple lipid components. Purpose: The effect of a novel, proprietary, niacin extended-release (NER) and simvastatin combination (NER/S) on attainment of individual and multiple lipid targets was evaluated. Methods: The OCEANS study obtained baseline lipids for 463 patients following a 4-week run-in of diet modification and 40 mg/day simvastatin. Patients who received NER/S (titrated to 2000/40 mg/day) for at least 24 weeks were included in a post-hoc analysis of each lipid parameter, or combination of parameters, if their baseline lipid values were not at target. Target levels were defined as: HDL-C ⱖ 40 mg/dL; TG ⬍ 150 mg/dL; or cardiovascular risk-adjusted NCEP goals for non-HDL-C or LDL-C. Results: Following treatment with NER/S, ⱖ 64% of patients attained target levels for each metric (non-HDL-C, LDL-C, HDL-C, TG) at week 24 [Figure]. Target lipid levels for LDL-C, HDL-C, and TG were simultaneously attained by 65% of patients. Unanticipated adverse events were not reported. Conclusions: For patients who failed to attain optimal lipid levels following statin monotherapy, the majority attained target levels for each lipid component evaluated following treatment with NER/S, and 65% of patients simultaneously attained target levels for all 3 lipid components (LDL, HDL, and TG). Thus, the combined NER/S formulation significantly improves attainment of multiple lipid goals in patients who failed to do so with statin monotherapy.
TG⬎200 mg/dL NER/S 2000/20 n ⫽ 34
162.5; ⫺28.9ⴱⴱ [⫺41.4; ⫺4.5] 112.5; ⫺19.1 [⫺34.2; 5.0] 257.5; ⫺53.4ⴱⴱ [⫺62.5; ⫺18.8] 103.5; ⫺26.7ⴱⴱ [⫺33.7; ⫺2.2] 38.5; 37.8; ⫹18.5ⴱⴱ ⫹25.9ⴱⴱⴱ [8.4; 33.3] [19.1; 42.4] 5.4; ⫺30.4ⴱⴱⴱ 5.2; ⫺33.7ⴱⴱⴱ [⫺40.6; ⫺16.4] [⫺40.2; ⫺20.9]
Simvastatin 20 n ⫽ 54
NER/S 1000/20 n ⫽ 51
NER/S 2000/20 n ⫽ 22
Simvastatin 20 n ⫽ 48
161.0; ⫺10.2 [⫺30.7; 5.6] 103.5; ⫺8.9 [⫺23.0; 8.2] 269.3; ⫺24.7 [⫺44.2; 13.1] 105.0; ⫺6.7 [⫺28.1; 4.7]
162.5; ⫺9.7 [⫺22.7; ⫺1.4] 133.3; ⫺7.4 [⫺22.5; 3.4] 150.3; ⫺19.1ⴱⴱ [⫺37.1; 0.2] 96.0; ⫺4.8 [⫺23.8; 10.7] 45.5; ⫹17.9ⴱⴱⴱ [9.3; 28.7] 4.6; ⫺19.6ⴱ [⫺31.2; ⫺5.8]
143.0; ⫺11.9ⴱ [⫺31.6; ⫺4.7] 110.5; ⫺9.4 [⫺35.2; 2.4] 144.0; ⫺33.5ⴱⴱ [⫺41.2; ⫺22.4] 94.5; ⫺7.4ⴱ [⫺37.2; 1.1] 45.5; ⫹24.4ⴱⴱⴱ [14.3; 29.0] 4.4; ⫺29.9ⴱⴱ [⫺40.2; ⫺13.9]
154.0; ⫺4.7 [⫺16.8; 6.3] 127.0; ⫺6.2 [⫺18.0; 5.3] 144.3; ⫺10.2 [⫺26.4; 18.2] 96.0; ⫺1.7 [⫺22.9; 6.9]
37.8; ⫹9.1 [⫺1.7; 17.3] 5.4; ⫺14.6 [⫺34.7; 1.0]
47.5; ⫹3.8 [⫺4.3; 16.2] 4.2; ⫺9.1 [⫺20.0; 2.3]
a Baseline (mg/dL); median change from baseline at week 24 (%); [25th; 75th percentile change from baseline at week 24]. ⴱ P⬍0.05, ⴱⴱP⬍0.01, ⴱⴱⴱP⬍0.001, vs. simvastatin monotherapy.
218 Niacin Extended-Release/Simvastatin Results in Attainment of Optimal Lipid Levels in Patients Who Failed to Attain These Levels on Statin Monotherapy Richard H. Karas, MD, Daiva R. Bajorunas, Michael H. Davidson, Moti Kashyap, Laurence H. Keller, Robert H. Knopp, Robert J. Padley, Roopal B. Thakkar, (Boston, MA)
219 The Combination of Niacin Extended-Release with Simvastatin Improves Lipid Levels in Treatment-Naive Patients Richard H. Karas, MD, Daiva R. Bajorunas, Michael H. Davidson, Moti Kashyap, Laurence H. Keller, Robert H. Knopp, Robert J. Padley, Roopal B. Thakkar, (Boston, MA) Synopsis: High-dose statin therapy that targets LDL-C does not prevent approximately two-thirds of cardiovascular events. This has led to increased attention in evidence-based
222
guidelines to treating multiple lipid abnormalities and greater interest in combination therapy. Purpose: The OCEANS study evaluated the effect of novel proprietary niacin extended-release (NER) and simvastatin combination (NER/S) in patients with mixed dyslipidemia. Methods: Following a 4-week run-in of diet modification and 40 mg/day simvastatin, patients were randomized to an 8- or 12-week NER/S titration scheme to a maximum NER/S dose of 2000 mg/day NER and 40 mg/day simvastatin for 24 weeks. Median changes from screening lipid values, prior to the simvastatin run-in phase, to week 24 in multiple lipid parameters were determined in patients who were lipid treatment-naı¨ve at screening. Results: Following treatment with NER/S (2000/40 mg/d) for 24 weeks, median decreases of 53.0%, 55.9%, and 49.5% in non-HDL-C, LDL-C, and TG, respectively, were observed in treatment-naı¨ve patients (n⫽85) [Figure]. The median increase in HDL-C was 25.0% in these patients. Lastly, a median decrease of 51.4% in the ratio of total cholesterol (Total C) to HDL-C was observed in treatment-naı¨ve patients. Conclusions: In patients with primary Type II or mixed hyperlipidemia, treatment with combination NER/S (2000/40 mg/day) provides substantial improvements in all major lipid parameters associated with the residual risk of cardiovascular events.
Journal of Clinical Lipidology, Vol 2, No 3, June 2008 health by providing an anchor for lipid and lipoprotein measurements in epidemiologic studies and clinical trials. Among the studies standardized by LSP are the National Health and Nutrition Evaluation Surveys (NHANES), the Framingham Heart Study, the Lipid Research Clinics Coronary Primary Prevention Trial, the Women’s Health Study, the Multiple Risk Factor Intervention Trial (MRFIT), the Atherosclerosis Risk in Communities (ARIC), and the World Health Organization MONItoring CArdiovascular disease (MONICA) Study. Purpose: The purpose of the LSP is to ensure that the data generated from epidemiologic studies and clinical trials are comparable between studies and over space and time. Methods: LSP uses the reference methods for cholesterol, HDL cholesterol (HDLC), and triglycerides (TG) to assign values to frozen human serum reference materials. The reference materials are prepared using a protocol that results in high-quality, commutable materials that behave like freshly collected samples and are distributed quarterly to enrolled laboratories. The LSP applies the inaccuracy and imprecision performance guidelines for laboratories recommended by the National Cholesterol Education Program (NCEP). The statistical design for the LSP protocol ensures that a laboratory with the NCEP maximum allowable bias and imprecision will have a 95% chance of passing the bias evaluation. LSP initiates interactions with laboratories that fail to meet the criteria, providing expertise and assisting them to improve performance. Results: 93 research and clinical trial laboratories (52 domestic and 41 international) participated in the LSP during 2007. During the first 3 quarters of 2007, the pass rates for total cholesterol (TC), TG and HDLC were 94.9%, 92.5% and 87.2%, respectively. Laboratories failed bias criteria for TC, TG and HDLC 3.7%, 7.1% and 9.9% of the time, respectively. Laboratories failed precision criteria for TC, TG and HDLC 2.6%, 1.9% and 4.6% of the time, respectively. Conclusions: The LSP provides a stable accuracy base for laboratories measuring lipids and lipoproteins in epidemiologic studies and clinical trials. This ensures that the data generated from these studies can be compared. The LSP serves as a model for standardization of other biomarkers of clinical importance.
220
221
CDC’s Lipid Standardization Program: Assuring Quality in Epidemiologic Studies for 50 Years Mary M. Kimberly, PhD, Samuel P. Caudill, Gerald R. Cooper, Mahnaz Dasti, Elizabeth Monsell, Gary L. Myers, William E. Slazyk, Parvin P. Waymack, (Atlanta, GA)
Effects of Prescription Omega-3-Acid Ethyl Esters Plus Simvastatin on Lipids and Lipoprotein Particles in Mixed Dyslipidemia Kevin Carl Maki, PhD, Mary R. Dicklin, Barry C. Lubin, James M. McKenney, Matthew S. Reeves, (Glen Ellyn, IL)
Synopsis: The Centers for Disease Control and PreventionNational Heart, Lung, and Blood Institute Lipid Standardization Program (LSP) has worked to provide an accuracybased standard of performance for laboratory testing of risk factors for assessing cardiovascular disease (CVD) for 50 years. The LSP continues to have a major impact on public
Synopsis: Prescription Omega-3-acid ethyl esters (P-OM3) have been approved in the United States as an adjunct to diet for reducing very high triglyceride (TG) levels (ⱖ 500 mg/dL) and in Europe for secondary prevention of coronary heart disease. POM3 is frequently used in combination with a statin. Purpose: This trial examined the effects on lipids and lipoprotein particles of open-label simvastatin (S) 20 mg/d