Achieving Lipoprotein Goals in Patients at High Risk
Achieving Lipoprotein Goals in Patients at High Risk
Background: Despite the efficacy of statins in lowering low-density lipoprotein cholesterol (LDL-C) levels, many patients who are at high risk for heart disease with hypercholesterolemia require additional LDL-C level reduction. The cholesterol absorption inhibitor, ezetimibe, has been shown to provide significant incremental reductions in LDL-C levels when co-administered with statins. This study was performed to compare the efficacy and safety of ezetimibe (10 mg) plus response-based atorvastatin titration versus response-based atorvastatin titration alone in the attainment of LDL-C goals in subjects who are at high risk for coronary heart disease (CHD) and are not at their LDL-C goal on the starting dose of atorvastatin.
Methods: This was a 14-week, multicenter, randomized, double-blind, active-controlled study conducted in 113 clinical research centers in 21 countries. Participants were adults with heterozygous familial hypercholesterolemia (HeFH), CHD, or multiple (≥2) cardiovascular risk factors, and a LDL-C level ≥130 mg/dL after a 6- to10-week dietary stabilization and atorvastatin (10 mg/day) open-label run-in period. Eligible subjects continued to receive atorvastatin (10 mg) and were randomized to receive blinded treatment with ezetimibe (10 mg/day; n = 305) or an additional 10 mg/day of atorvastatin (n = 316). The atorvastatin dose in both groups was doubled after 4 weeks, 9 weeks, or both when the LDL-C level was not at its goal (≤100 mg/dL), so that patients receiving combined therapy could reach 40 mg/day and patients receiving atorvastatin alone could reach 80 mg/day. The primary end point was the proportion of subjects achieving their LDL-C level goal at week 14. A secondary end point was the change in LDL-C level and other lipid parameters at 4 weeks after ezetimibe co-administration with 10 mg/day of atorvastatin versus 20 mg/day of atorvastatin monotherapy.
Results: The proportion of subjects reaching their target LDL-C level goal of ≤100 mg/dL was significantly higher in the co-administration group than in the atorvastatin monotherapy group (22% vs 7%; P <.01). At 4 weeks, levels of LDL-C, triglycerides, and non-high-density lipoprotein cholesterol were reduced significantly more by combination therapy than by doubling the dose of atorvastatin (LDL-C 22.8% versus 8.6%; P <.01). The combination regimen had a safety and tolerability profile similar to that of atorvastatin alone.
Conclusions: The addition of ezetimibe to the starting dose of 10 mg/day of atorvastatin followed by response-based atorvastatin dose titration to a maximum of 40 mg/day provides a more effective means for reducing LDL-C levels in patients at high risk for CHD than continued doubling of atorvastatin as high as 80 mg/day alone.
The reduction of low-density lipoprotein cholesterol (LDL-C) levels in individuals with and without pre-existing coronary heart disease (CHD) and elevated LDL-C levels has been shown to reduce cardiovascular and total mortality rates. These large placebo controlled outcome trials have resulted in international guidelines for dyslipidemia treatment. However, despite the widespread availability and use during the last decade of statins, recent studies have shown that most patients do not reach established goals. In addition, patients who are at high risk, such as those with CHD, multiple cardiovascular risk factors, or the presence of heterozygous familial hypercholesterolemia (HeFH), who are most in need of and likely to benefit from effective LDL-C reduction, are least likely to reach established goals. Both Eurospire II and the Lipid Treatment Assessment Project (L-TAP) studies demonstrated that the proportion of patients achieving National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) II or Joint European specified total or LDL cholesterol target levels ranged from 41% to 18% among patients with CHD in Europe and the USA, respectively. This failure to achieve goal attainment in the higher-risk population has been related to a number of factors, including insufficient pharmacologic effect at the starting dose of a statin and a subsequent lack of willingness to either perform multiple statin dose escalations or a concern for the safety at the highest doses. The L-TAP study authors also suggested that even titration to the maximal dose of available statins would permit the attainment of lipid goals in only a minority of patients. Thus, there is a clear need for either more effective, but safe, single agents or agents that can tolerably, safely, and effectively be combined with current statins to increase the attainment of lipid goals.
Ezetimibe is a cholesterol absorption inhibitor that potently inhibits biliary and dietary cholesterol absorption at the brush border of the intestine without affecting the absorption of fat-soluble vitamins or triglycerides. Co-administration of ezetimibe with statins, including atorvastatin, produced significant incremental LDL-C level reductions and favorably affected total cholesterol, high-density lipoprotein cholesterol (HDL-C), and triglyceride levels.
This prospective randomized double-blind study was performed to test the hypothesis that adding ezetimibe to the 10 mg/day starting dose of atorvastatin, followed by response-based atorvastatin titration to 40 mg/day, would be more effective in lowering LDL-C levels than an initial doubling of atorvastatin and subsequent titration to 80 mg/day in patients with high cardiovascular disease risk.
Background: Despite the efficacy of statins in lowering low-density lipoprotein cholesterol (LDL-C) levels, many patients who are at high risk for heart disease with hypercholesterolemia require additional LDL-C level reduction. The cholesterol absorption inhibitor, ezetimibe, has been shown to provide significant incremental reductions in LDL-C levels when co-administered with statins. This study was performed to compare the efficacy and safety of ezetimibe (10 mg) plus response-based atorvastatin titration versus response-based atorvastatin titration alone in the attainment of LDL-C goals in subjects who are at high risk for coronary heart disease (CHD) and are not at their LDL-C goal on the starting dose of atorvastatin.
Methods: This was a 14-week, multicenter, randomized, double-blind, active-controlled study conducted in 113 clinical research centers in 21 countries. Participants were adults with heterozygous familial hypercholesterolemia (HeFH), CHD, or multiple (≥2) cardiovascular risk factors, and a LDL-C level ≥130 mg/dL after a 6- to10-week dietary stabilization and atorvastatin (10 mg/day) open-label run-in period. Eligible subjects continued to receive atorvastatin (10 mg) and were randomized to receive blinded treatment with ezetimibe (10 mg/day; n = 305) or an additional 10 mg/day of atorvastatin (n = 316). The atorvastatin dose in both groups was doubled after 4 weeks, 9 weeks, or both when the LDL-C level was not at its goal (≤100 mg/dL), so that patients receiving combined therapy could reach 40 mg/day and patients receiving atorvastatin alone could reach 80 mg/day. The primary end point was the proportion of subjects achieving their LDL-C level goal at week 14. A secondary end point was the change in LDL-C level and other lipid parameters at 4 weeks after ezetimibe co-administration with 10 mg/day of atorvastatin versus 20 mg/day of atorvastatin monotherapy.
Results: The proportion of subjects reaching their target LDL-C level goal of ≤100 mg/dL was significantly higher in the co-administration group than in the atorvastatin monotherapy group (22% vs 7%; P <.01). At 4 weeks, levels of LDL-C, triglycerides, and non-high-density lipoprotein cholesterol were reduced significantly more by combination therapy than by doubling the dose of atorvastatin (LDL-C 22.8% versus 8.6%; P <.01). The combination regimen had a safety and tolerability profile similar to that of atorvastatin alone.
Conclusions: The addition of ezetimibe to the starting dose of 10 mg/day of atorvastatin followed by response-based atorvastatin dose titration to a maximum of 40 mg/day provides a more effective means for reducing LDL-C levels in patients at high risk for CHD than continued doubling of atorvastatin as high as 80 mg/day alone.
The reduction of low-density lipoprotein cholesterol (LDL-C) levels in individuals with and without pre-existing coronary heart disease (CHD) and elevated LDL-C levels has been shown to reduce cardiovascular and total mortality rates. These large placebo controlled outcome trials have resulted in international guidelines for dyslipidemia treatment. However, despite the widespread availability and use during the last decade of statins, recent studies have shown that most patients do not reach established goals. In addition, patients who are at high risk, such as those with CHD, multiple cardiovascular risk factors, or the presence of heterozygous familial hypercholesterolemia (HeFH), who are most in need of and likely to benefit from effective LDL-C reduction, are least likely to reach established goals. Both Eurospire II and the Lipid Treatment Assessment Project (L-TAP) studies demonstrated that the proportion of patients achieving National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) II or Joint European specified total or LDL cholesterol target levels ranged from 41% to 18% among patients with CHD in Europe and the USA, respectively. This failure to achieve goal attainment in the higher-risk population has been related to a number of factors, including insufficient pharmacologic effect at the starting dose of a statin and a subsequent lack of willingness to either perform multiple statin dose escalations or a concern for the safety at the highest doses. The L-TAP study authors also suggested that even titration to the maximal dose of available statins would permit the attainment of lipid goals in only a minority of patients. Thus, there is a clear need for either more effective, but safe, single agents or agents that can tolerably, safely, and effectively be combined with current statins to increase the attainment of lipid goals.
Ezetimibe is a cholesterol absorption inhibitor that potently inhibits biliary and dietary cholesterol absorption at the brush border of the intestine without affecting the absorption of fat-soluble vitamins or triglycerides. Co-administration of ezetimibe with statins, including atorvastatin, produced significant incremental LDL-C level reductions and favorably affected total cholesterol, high-density lipoprotein cholesterol (HDL-C), and triglyceride levels.
This prospective randomized double-blind study was performed to test the hypothesis that adding ezetimibe to the 10 mg/day starting dose of atorvastatin, followed by response-based atorvastatin titration to 40 mg/day, would be more effective in lowering LDL-C levels than an initial doubling of atorvastatin and subsequent titration to 80 mg/day in patients with high cardiovascular disease risk.
