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Effects of ezetimibe, a new cholesterol absorption inhibitor, on plasma lipids in patients with primary hypercholesterolemia
Prevention of Coronary and Stroke Events With Atorvastatin in Hypertensive Patients Who Have Average or Lower-Than-Average Cholesterol Concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm (ASCOT-LLA): A Multicentre Randomised Controlled Trial
Conclusions: In hypertensives at high risk for cardiovascular events, statin therapy is associated with a large reduction in CV events. Perspective: Despite the entry criteria and high population risk, the coronary event rate was less than 1% in the placebo group. It is important to realize that the event rate would have been considerably higher if the BP was not treated as effectively and the benefit attributable to the statins may have been greater. In a similar study, ALLHAT, pravastatin did not lower CHD or stroke rates, possibly because the usual care group had a substantial use of statins. The British Heart Protection Study showed a benefit of statin therapy in high-risk patients regardless of LDL-C levels. The cost/ benefit of treating middle-aged and elderly men and women with well-treated hypertension, no other risk factors and relatively normal lipids remains unclear. MR
Sever PS, Dahlof B, Poulter NR, et al. Lancet 2003;361:1149 – 58. Study Question: Is there a benefit to cholesterol lowering in patients with hypertension and high risk for coronary events regardless of lipid parameters? Methods: Patients were randomized to one of two antihypertensive regimens with target BP ⬍140/90 mm Hg for non diabetics and ⬍130/80 mm Hg in diabetics, and then randomized to atorvastatin 10 mg vs. placebo. The investigator-initiated multicenter study enrolled 19,342 hypertensive men and women aged 40 –79 years with total cholesterol ⬍250 mg/dL and at least three other coronary risk factors but no known CHD. Coronary risk factors (CRF) included LVH or other ECG abnormalities, type 2 diabetes, PVD, previous TIA or stroke, male gender, age ⬎55 years, smoking, total chol/HDL-C at least 6, microalbuminuria or proteinuria or a family history of premature CAD. Patients had untreated hypertension with sBP ⱖ160 mm Hg, dBP ⱖ100 mm Hg, or both, or treated hypertension with sBP ⱖ140 mm Hg, dBP ⱖ90 mm Hg, or both. The primary end point was the combination of non-fatal MI, silent MI and fatal CHD. Secondary end points were the primary end point without silent events, all-cause mortality, total CVD mortality, fatal and non-fatal stroke, fatal and non-fatal CHF, total coronary end points and total CV events. Results: 10,305 patients were randomized to the lipidlowering arm and median follow-up was 3.3 years. At entry, average age was 63 years, 81% were male, 24% diabetics, 14% had LVH, regular ASA use in 17%, 33% were smokers, average BP was 164/95 mm Hg, mean cholesterol 212 mg/dL, HDL-C 50 mg/dL, triglycerides 146 mg/dL, LDL-C 131 mg/dL and mean number of CRFs 3.7 per patient. Compared to placebo, at 1 year, atorvastatin was associated with about a 45 mg/dL decrease in total (20%) and LDL-C (35%). BP on treatment was similar in both groups at 138/80 mm Hg. At the time of 100 primary events in the atorvastatin group, there were 154 events with placebo, RR 0.64, 95% CI 0.50 – 0.83, p⫽0.0005. The benefit emerged during year 1. There was no significant heterogeneity among pre-specified groups. There was a highly significant reduction in fatal and non-fatal stroke (RR⫽0.73), total CV events (RR⫽0.79) and total coronary events (RR⫽0.71). Surprisingly the primary end point was not significantly lower in diabetics, women, those with LVH, previous vascular disease and those with the metabolic syndrome. There was a non-significant 13% decrease in all-cause deaths and no increase in cancer deaths.
Effects of Ezetimibe, A New Cholesterol Absorption Inhibitor, on Plasma Lipids in Patients With Primary Hypercholesterolemia Knopp RH, Gitter H, Truit T, et al., for the Ezetimibe Study Group. Eur Heart J 2003;24:729 – 41. Study Question: What is the efficacy and safety of the cholesterol absorption blocker agent ezetimibe in men and women with primary hypercholesterolemia? Methods: A multicenter randomized, double-blind controlled trial comparing ezetimibe 10 mg/d with placebo in mean and women ⬎18 years with and LDL-C of at least 130 mg/dL and triglycerides ⬍350 mg/dL. Adequate wash out of lipid altering agents and an NCEP step I or stricter diet was provided and maintained during the 4-week singleblind placebo run-in and 12-week double-blind treatment phase with a 3:1 ratio of active drug to placebo. The primary end point was percentage reduction in direct LDL-C. Results: 827 patients were randomized (622 active drug) with an average age of 57 years, 32% ⬎64 years, 54% female, average BMI 29 kg/m2, and prior lipid lowering drug use in 25%. Mean baseline LDL-C was 163 mg/dL, apo B 161 mg/dL, apo A-1 151 mg/dL, HDL-C 50 mg/dL, and triglycerides 160 mg/dL. Ezetimibe reduced LDL-C by 18% compared with an 0.8% increase with placebo, reduced apo B by 15%, LDL-C:HDL-C by 18%, and Lp (a) by 7.5%, and increased HDL2-C by 5% (all p⬍0.01 vs. baseline with no effect by placebo). The effect on LDL-C was not influenced by gender, age, menopause, BMI, diabetes, baseline lipids or the number of risk factors. Treatment adverse events were reported in 61% on ezetimibe and 65% on placebo. Ezetimibe had no effect on plasma cortisol before and after corticotropin stimulation and no effect on the levels on lipid soluble vitamins. Conclusions: Ezetimibe significantly reduces LDL-C and favorably affects other lipids, is well tolerated and an effective new option for lipid management.
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Perspective: Ezetimibe can be used alone in statin intolerant patients and is particularly useful in combination with the statins. The combination of ezetimibe 10 mg with the starting dose of a statin provides about the same LDL-C lowering as a quadrupling of the statin dose, the advantage being possibly less hepatotoxicity and possibly cost saving. The cost of ezetimibe is about $35/month. Of course it has none of the non-lipid benefits of the statins, but the increase in HDL2-C is an unexpected gain. MR
in those with hypertension. After subtracting the change in Advice Only, there was a significant mean net reduction in SBP of 3.7 mm Hg in the LSM group and 4.3 mm Hg in the LSM⫹DASH group, a difference of 0.6 mm Hg between groups (p⫽0.43). The prevalence of hypertension reduced from 38% to 26% with Advice Only, to 17% in LSM (p⬍0.01 compared to Advice Only), and 12% in the LSM⫹DASH (p⬍0.001 vs. Advice Only and p⫽0.12 compared to LSM). There was a 53% decrease in risk of developing hypertension in those with LSM⫹DASH counseling than Advice Only. The prevalence of optimal BP control (⬍120/80 mm Hg) was 19% in Advice Only, 30% LSM (p⫽0.005 vs. Advice Only), and 35% in LSM⫹DASH (p⬍0.001 vs. Advice Only and p⫽0.24 vs. LSM). The BP reductions were similar when analyzed by intention to treat and “on treatment” defined as attending ⬎80% of sessions. Conclusions: Persons with above optimal BP, including stage I hypertension, can make multiple lifestyle changes that lower BP and reduce there cardiovascular risk. Perspective: The results appear modest, but it is important to realize that most patients with hypertension do not have the benefit of a 30-minute consultation with a dietitian as was provided to the Advice Only group, that resulted in a highly significant 7 mm Hg reduction in SBP and 4 mm Hg reduction in DBP. Whether the results could be replicated in clinical practice is highly suspect. The participants were highly motivated, well educated, willing and able to attend the majority of 18 visits over 6 months. Additionally, they were a fat group with a high prevalence of the metabolic syndrome for whom the dietary interventions would be of particular value. Nevertheless, the study supports the need for several individual and or group nutrition counseling sessions for patients with hypertension, diabetes, lipid disorders, obesity and atherosclerotic vascular disease. MR
Effect of Comprehensive Lifestyle Modification on Blood Pressure Control Premier Collaborative Research Group. JAMA 2003;289:2083–93. Study Question: Does combining the DASH diet (emphasis on fruits, vegetables, grains, nuts, low saturated fat, red meats and simple carbohydrates) to standard behavioral recommendations of weight loss, sodium restriction, exercise and limited alcohol intake improve blood pressure control? Methods: A randomized trial of 810 hypertensive men and women (age ⬎25 years and BMI between 18.5 and 45 kg/m2) with BP above optimal control or stage 1 hypertension (120 –159 mm Hg systolic and 80 –95 mm Hg diastolic) not taking antihypertensive drugs. Subjects were randomized to one of three groups with about 270 in each: standard lifestyle modification (LSM), LSM plus the DASH diet (LSM⫹DASH) and Advice only and followed for 6 months. Patients were recruited by community advertising and accepted after three screening visits. The following were obtained at baseline and 6 months: weight, fitness, dietary recall, physical activity, 24-hr urine and fasting blood. BP was obtained at entry, upon assignment and at 3 months and 6 months. Advice Only consisted of a 30minute visit with a dietitian who discussed factors that could affect the BP including weight, fitness, salt intake and the DASH diet. Subjects in the two intervention groups were offered 14 groups meetings and four individual counselling sessions, and were given recommendations for weight, exercise (180 min/week of moderate intensity), alcohol, and salt (⬍6 grams). Primary outcome was change in SBP from baseline to 6 months. Results: There was no between group difference in the following at baseline: mean age of 50 years, 62% women, 34% African-Americans, BMI average of 33 kg/m2, 64% obese defined by BMI ⱖ 30 kg/m2, mean alcohol drinks 0.25/day, the majority were well educated, ⬎20% had a dyslipidemia or were using lipid lowering medication, and 38% were hypertensive. Greater than 70% in both intervention groups attended at least 15 of the 18 sessions offered, and only 8% attended less than five sessions. Both LSM and LSM⫹DASH had significant weight loss, improved fitness and lower sodium intake. LSM⫹DASH had increased fruits, vegetables and dairy intake. The mean reduction in SBP was 6.6 mm Hg in Advice Only, 10.5 mm Hg in LSM, and 11.1 mm Hg in LSM⫹DASH, with the decrease greater
Impact of Electron Beam Tomography With or Without Case Management, on Motivation, Behavioral Change, and Cardiovascular Risk Profile. A Randomized Controlled Trial O’Malley PG, Feuerstein IM, Taylor AJ. JAMA 2003;289:2215–23. Study Question: What is the effect of intensive nurse case management (NCM) and knowing the coronary calcium score (CCS) derived from electron beam computed tomography (EBT) on coronary risk modification? Methods: A randomized controlled trial with a 2⫻2 factorial design in 450 asymptomatic men and women 39 to 45 years undergoing a periodic Army-mandated health evaluation. Patients were randomized to EBT results provided along with usual care or NCM or EBT results withheld in the setting of usual care or NCM. Patients were followed for 1 year with the primary outcome a change in a composite CV risk as determined by the 10-year Framingham Risk Score (FRS), and secondary outcome change in individual risk factors. All patients were made aware of their risk factors
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Conclusions: In hypertensives at high risk for cardiovascular events, statin therapy is associated with a large reduction in CV events. Perspective: Despite the entry criteria and high population risk, the coronary event rate was less than 1% in the placebo group. It is important to realize that the event rate would have been considerably higher if the BP was not treated as effectively and the benefit attributable to the statins may have been greater. In a similar study, ALLHAT, pravastatin did not lower CHD or stroke rates, possibly because the usual care group had a substantial use of statins. The British Heart Protection Study showed a benefit of statin therapy in high-risk patients regardless of LDL-C levels. The cost/ benefit of treating middle-aged and elderly men and women with well-treated hypertension, no other risk factors and relatively normal lipids remains unclear. MR
Sever PS, Dahlof B, Poulter NR, et al. Lancet 2003;361:1149 – 58. Study Question: Is there a benefit to cholesterol lowering in patients with hypertension and high risk for coronary events regardless of lipid parameters? Methods: Patients were randomized to one of two antihypertensive regimens with target BP ⬍140/90 mm Hg for non diabetics and ⬍130/80 mm Hg in diabetics, and then randomized to atorvastatin 10 mg vs. placebo. The investigator-initiated multicenter study enrolled 19,342 hypertensive men and women aged 40 –79 years with total cholesterol ⬍250 mg/dL and at least three other coronary risk factors but no known CHD. Coronary risk factors (CRF) included LVH or other ECG abnormalities, type 2 diabetes, PVD, previous TIA or stroke, male gender, age ⬎55 years, smoking, total chol/HDL-C at least 6, microalbuminuria or proteinuria or a family history of premature CAD. Patients had untreated hypertension with sBP ⱖ160 mm Hg, dBP ⱖ100 mm Hg, or both, or treated hypertension with sBP ⱖ140 mm Hg, dBP ⱖ90 mm Hg, or both. The primary end point was the combination of non-fatal MI, silent MI and fatal CHD. Secondary end points were the primary end point without silent events, all-cause mortality, total CVD mortality, fatal and non-fatal stroke, fatal and non-fatal CHF, total coronary end points and total CV events. Results: 10,305 patients were randomized to the lipidlowering arm and median follow-up was 3.3 years. At entry, average age was 63 years, 81% were male, 24% diabetics, 14% had LVH, regular ASA use in 17%, 33% were smokers, average BP was 164/95 mm Hg, mean cholesterol 212 mg/dL, HDL-C 50 mg/dL, triglycerides 146 mg/dL, LDL-C 131 mg/dL and mean number of CRFs 3.7 per patient. Compared to placebo, at 1 year, atorvastatin was associated with about a 45 mg/dL decrease in total (20%) and LDL-C (35%). BP on treatment was similar in both groups at 138/80 mm Hg. At the time of 100 primary events in the atorvastatin group, there were 154 events with placebo, RR 0.64, 95% CI 0.50 – 0.83, p⫽0.0005. The benefit emerged during year 1. There was no significant heterogeneity among pre-specified groups. There was a highly significant reduction in fatal and non-fatal stroke (RR⫽0.73), total CV events (RR⫽0.79) and total coronary events (RR⫽0.71). Surprisingly the primary end point was not significantly lower in diabetics, women, those with LVH, previous vascular disease and those with the metabolic syndrome. There was a non-significant 13% decrease in all-cause deaths and no increase in cancer deaths.
Effects of Ezetimibe, A New Cholesterol Absorption Inhibitor, on Plasma Lipids in Patients With Primary Hypercholesterolemia Knopp RH, Gitter H, Truit T, et al., for the Ezetimibe Study Group. Eur Heart J 2003;24:729 – 41. Study Question: What is the efficacy and safety of the cholesterol absorption blocker agent ezetimibe in men and women with primary hypercholesterolemia? Methods: A multicenter randomized, double-blind controlled trial comparing ezetimibe 10 mg/d with placebo in mean and women ⬎18 years with and LDL-C of at least 130 mg/dL and triglycerides ⬍350 mg/dL. Adequate wash out of lipid altering agents and an NCEP step I or stricter diet was provided and maintained during the 4-week singleblind placebo run-in and 12-week double-blind treatment phase with a 3:1 ratio of active drug to placebo. The primary end point was percentage reduction in direct LDL-C. Results: 827 patients were randomized (622 active drug) with an average age of 57 years, 32% ⬎64 years, 54% female, average BMI 29 kg/m2, and prior lipid lowering drug use in 25%. Mean baseline LDL-C was 163 mg/dL, apo B 161 mg/dL, apo A-1 151 mg/dL, HDL-C 50 mg/dL, and triglycerides 160 mg/dL. Ezetimibe reduced LDL-C by 18% compared with an 0.8% increase with placebo, reduced apo B by 15%, LDL-C:HDL-C by 18%, and Lp (a) by 7.5%, and increased HDL2-C by 5% (all p⬍0.01 vs. baseline with no effect by placebo). The effect on LDL-C was not influenced by gender, age, menopause, BMI, diabetes, baseline lipids or the number of risk factors. Treatment adverse events were reported in 61% on ezetimibe and 65% on placebo. Ezetimibe had no effect on plasma cortisol before and after corticotropin stimulation and no effect on the levels on lipid soluble vitamins. Conclusions: Ezetimibe significantly reduces LDL-C and favorably affects other lipids, is well tolerated and an effective new option for lipid management.
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Perspective: Ezetimibe can be used alone in statin intolerant patients and is particularly useful in combination with the statins. The combination of ezetimibe 10 mg with the starting dose of a statin provides about the same LDL-C lowering as a quadrupling of the statin dose, the advantage being possibly less hepatotoxicity and possibly cost saving. The cost of ezetimibe is about $35/month. Of course it has none of the non-lipid benefits of the statins, but the increase in HDL2-C is an unexpected gain. MR
in those with hypertension. After subtracting the change in Advice Only, there was a significant mean net reduction in SBP of 3.7 mm Hg in the LSM group and 4.3 mm Hg in the LSM⫹DASH group, a difference of 0.6 mm Hg between groups (p⫽0.43). The prevalence of hypertension reduced from 38% to 26% with Advice Only, to 17% in LSM (p⬍0.01 compared to Advice Only), and 12% in the LSM⫹DASH (p⬍0.001 vs. Advice Only and p⫽0.12 compared to LSM). There was a 53% decrease in risk of developing hypertension in those with LSM⫹DASH counseling than Advice Only. The prevalence of optimal BP control (⬍120/80 mm Hg) was 19% in Advice Only, 30% LSM (p⫽0.005 vs. Advice Only), and 35% in LSM⫹DASH (p⬍0.001 vs. Advice Only and p⫽0.24 vs. LSM). The BP reductions were similar when analyzed by intention to treat and “on treatment” defined as attending ⬎80% of sessions. Conclusions: Persons with above optimal BP, including stage I hypertension, can make multiple lifestyle changes that lower BP and reduce there cardiovascular risk. Perspective: The results appear modest, but it is important to realize that most patients with hypertension do not have the benefit of a 30-minute consultation with a dietitian as was provided to the Advice Only group, that resulted in a highly significant 7 mm Hg reduction in SBP and 4 mm Hg reduction in DBP. Whether the results could be replicated in clinical practice is highly suspect. The participants were highly motivated, well educated, willing and able to attend the majority of 18 visits over 6 months. Additionally, they were a fat group with a high prevalence of the metabolic syndrome for whom the dietary interventions would be of particular value. Nevertheless, the study supports the need for several individual and or group nutrition counseling sessions for patients with hypertension, diabetes, lipid disorders, obesity and atherosclerotic vascular disease. MR
Effect of Comprehensive Lifestyle Modification on Blood Pressure Control Premier Collaborative Research Group. JAMA 2003;289:2083–93. Study Question: Does combining the DASH diet (emphasis on fruits, vegetables, grains, nuts, low saturated fat, red meats and simple carbohydrates) to standard behavioral recommendations of weight loss, sodium restriction, exercise and limited alcohol intake improve blood pressure control? Methods: A randomized trial of 810 hypertensive men and women (age ⬎25 years and BMI between 18.5 and 45 kg/m2) with BP above optimal control or stage 1 hypertension (120 –159 mm Hg systolic and 80 –95 mm Hg diastolic) not taking antihypertensive drugs. Subjects were randomized to one of three groups with about 270 in each: standard lifestyle modification (LSM), LSM plus the DASH diet (LSM⫹DASH) and Advice only and followed for 6 months. Patients were recruited by community advertising and accepted after three screening visits. The following were obtained at baseline and 6 months: weight, fitness, dietary recall, physical activity, 24-hr urine and fasting blood. BP was obtained at entry, upon assignment and at 3 months and 6 months. Advice Only consisted of a 30minute visit with a dietitian who discussed factors that could affect the BP including weight, fitness, salt intake and the DASH diet. Subjects in the two intervention groups were offered 14 groups meetings and four individual counselling sessions, and were given recommendations for weight, exercise (180 min/week of moderate intensity), alcohol, and salt (⬍6 grams). Primary outcome was change in SBP from baseline to 6 months. Results: There was no between group difference in the following at baseline: mean age of 50 years, 62% women, 34% African-Americans, BMI average of 33 kg/m2, 64% obese defined by BMI ⱖ 30 kg/m2, mean alcohol drinks 0.25/day, the majority were well educated, ⬎20% had a dyslipidemia or were using lipid lowering medication, and 38% were hypertensive. Greater than 70% in both intervention groups attended at least 15 of the 18 sessions offered, and only 8% attended less than five sessions. Both LSM and LSM⫹DASH had significant weight loss, improved fitness and lower sodium intake. LSM⫹DASH had increased fruits, vegetables and dairy intake. The mean reduction in SBP was 6.6 mm Hg in Advice Only, 10.5 mm Hg in LSM, and 11.1 mm Hg in LSM⫹DASH, with the decrease greater
Impact of Electron Beam Tomography With or Without Case Management, on Motivation, Behavioral Change, and Cardiovascular Risk Profile. A Randomized Controlled Trial O’Malley PG, Feuerstein IM, Taylor AJ. JAMA 2003;289:2215–23. Study Question: What is the effect of intensive nurse case management (NCM) and knowing the coronary calcium score (CCS) derived from electron beam computed tomography (EBT) on coronary risk modification? Methods: A randomized controlled trial with a 2⫻2 factorial design in 450 asymptomatic men and women 39 to 45 years undergoing a periodic Army-mandated health evaluation. Patients were randomized to EBT results provided along with usual care or NCM or EBT results withheld in the setting of usual care or NCM. Patients were followed for 1 year with the primary outcome a change in a composite CV risk as determined by the 10-year Framingham Risk Score (FRS), and secondary outcome change in individual risk factors. All patients were made aware of their risk factors
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