Primary Prevention Trials
a)The West of Scotland Coronary Prevention Study (WOSCOPS): The study randomized healthy men between the ages of 45 and 64 years with TC levels higher that 252 mg/dL and LDL cholesterol levels of 174 to 232 mg/dL to pravastatin (40mg/day) or to placebo for an
average of 5 years and demonstrated a 31 per cent relative reduction in the incidence of nonfatal MI or CAD death.
b) The Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS): AFCAPS/TexCAPS capitalized on the increased risk among healthy persons with low HDL levels (mean, 36mg/dL) and high TC levels (mean, 221 mg/dL).Therapy with the cholesterol-lowering drug lovastatin reduced by 36 per cent the risk for first acute major coronary events among healthy adults with average to mildly elevated cholesterol levels and low HDL levels.
c) The Heart Protection Study (HPS) (5) randomized 20,536 subjects to daily simvastatin (40mg) or placebo and to antioxidants or placebo (the antioxidant arm did not show any benefit or harm). The study focused on patients who were deemed high risk but not thought to merit treatment with statins based on the prevalent clinical practice. Increased risk was defined as presence of or history of Coronary Artery Disease, cerebovascular disease,peripheral vascular disease, diabetes mellitus, or treated hypertension in men younger than 65 years. Simvastatin therapy was associated with a 17 per cent relative reduction in the risk of death, driven primarily by a 17 per cent relative risk reduction in nonfatal MI, a 25 per cent relative reduction in the incidence of first stroke, 30 per cent reduction in coronary revascularisation, and 16 per cent reduction in noncoronary revascularization procedures were observed. Event reduction was similar across multiple subgroups and was largely uninfluenced by pretreatment lipoprotein values. Treating LDL levels less than 100mg/dL was also associated with a beneficial reduction in vascular events.
Secondary Prevention Trials
a) The Scandinavian Simvastatin Survival Study (4S) was the first secondary trial to demonstrate a clear reduction in total mortality. Simvastatin reduced total mortality among patients with Coronary Artery Disease by 30 per cent, largely because of a 42 per cent reduction in deaths from Coronary Artery Disease. The 4S treated 4,444 men and women with Coronary Artery Disease and TC levels of 212 to 309 mg/dL. The mean LDL at baseline was 188 mg/dL, with a range of 130 to 266 mg/dL.
b) The randomized, controlled Cholesterol and Recurrent Events Trial (CARE) was designed to evaluate the effects of treatments with pravastatin on 4,000 persons who had experienced acute MI 3 to 20 months before randomization and had moderately elevated TC levels (mean, 209 mg/dL). The benefit of pravastatin therapy in preventing recurrent coronary events were similar in the subset analysis of age, sex, ejection fraction,hypertension, diabetes mellitus, and smoking.
c) The Long-term Intervention with Pravastatin in Ischemic Disease Study (LIPID) was the first to examine the use of a HMG CoA reductase inhibitor for patients with a history of unstable angina. The LIPID study provided new data on noncoronary mortality (i.e., stroke) and on other groups, such as women and patients with diabetes, who previously had been underrepresented in clinical trials. LIPID demonstrated improved Coronary Artery Disease outcomes among all patients, including those with unstable angina.
d) Trials in Patients Undergoing Coronary Revascularization
i)The Post-Coronary Artery Bypass Graft Trial randomized 1,351 patients who had undergone bypass surgery and who had an LDL cholesterol level between 130 and 175mg/dL to aggressive or moderate treatment to lower their LDL cholesterol levels (with lovastatin and, if needed, cholestyramine) and to treatment with warfarin or placebo.Angiography was repeated an average of 4.3 years after baselines were established and revealed decreased progression of vein graft atherosclerosis in patients randomized to aggressive Lipid lowering. There was a 29 per cent reduction in the rate of coronary revascularization in the aggressive LDL-reduction group.
ii) Management of Lipids: Despite overwhelming evidence supporting the treatment of dyslipidemia, a large number of patients remain untreated. The NCEP Adult Treatment Panel III (ATPIII) has released the updated guidelines for treatment of hyperlipidemia in adults. These guidelines focus on identification of risk of cardiovascular morbidity and appropriate targeting therapy.
Guidelines for Primary Prevention of CAD Events Based on the NCEP ATP III
a) TC, LDL-C and HDL-C Levels
All adults 20 years of age or older and without a history of CAD or other atherosclerotic disease should have a fasting lipid panel (i.e. TC, LDL-C and TG) every 5 years. If a nonfasting lipid panel is obtained and the TC level is 200 mg/dl or the HDL-C is less than 40 mg/dl a follow up fasting lipid panel is recommended.
b) Determination of Risk
The patient’s risk of future events is based on presence of known CAD or clinical atherosclerosis in a noncoronary bed, diabetes mellitus, smoking, hypertension (>140/90 mm Hg or use of antihypertensive medication), family history of premature CAD (defined as CAD in first-degree male relatives before age of 55 years and in a first-degree female relative before the age of 65 years), and low.
Risk Factor Goal
LDL Cholesterol
a)The West of Scotland Coronary Prevention Study (WOSCOPS): The study randomized healthy men between the ages of 45 and 64 years with TC levels higher that 252 mg/dL and LDL cholesterol levels of 174 to 232 mg/dL to pravastatin (40mg/day) or to placebo for an
average of 5 years and demonstrated a 31 per cent relative reduction in the incidence of nonfatal MI or CAD death.
b) The Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS): AFCAPS/TexCAPS capitalized on the increased risk among healthy persons with low HDL levels (mean, 36mg/dL) and high TC levels (mean, 221 mg/dL).Therapy with the cholesterol-lowering drug lovastatin reduced by 36 per cent the risk for first acute major coronary events among healthy adults with average to mildly elevated cholesterol levels and low HDL levels.
c) The Heart Protection Study (HPS) (5) randomized 20,536 subjects to daily simvastatin (40mg) or placebo and to antioxidants or placebo (the antioxidant arm did not show any benefit or harm). The study focused on patients who were deemed high risk but not thought to merit treatment with statins based on the prevalent clinical practice. Increased risk was defined as presence of or history of Coronary Artery Disease, cerebovascular disease,peripheral vascular disease, diabetes mellitus, or treated hypertension in men younger than 65 years. Simvastatin therapy was associated with a 17 per cent relative reduction in the risk of death, driven primarily by a 17 per cent relative risk reduction in nonfatal MI, a 25 per cent relative reduction in the incidence of first stroke, 30 per cent reduction in coronary revascularisation, and 16 per cent reduction in noncoronary revascularization procedures were observed. Event reduction was similar across multiple subgroups and was largely uninfluenced by pretreatment lipoprotein values. Treating LDL levels less than 100mg/dL was also associated with a beneficial reduction in vascular events.
Secondary Prevention Trials
a) The Scandinavian Simvastatin Survival Study (4S) was the first secondary trial to demonstrate a clear reduction in total mortality. Simvastatin reduced total mortality among patients with Coronary Artery Disease by 30 per cent, largely because of a 42 per cent reduction in deaths from Coronary Artery Disease. The 4S treated 4,444 men and women with Coronary Artery Disease and TC levels of 212 to 309 mg/dL. The mean LDL at baseline was 188 mg/dL, with a range of 130 to 266 mg/dL.
b) The randomized, controlled Cholesterol and Recurrent Events Trial (CARE) was designed to evaluate the effects of treatments with pravastatin on 4,000 persons who had experienced acute MI 3 to 20 months before randomization and had moderately elevated TC levels (mean, 209 mg/dL). The benefit of pravastatin therapy in preventing recurrent coronary events were similar in the subset analysis of age, sex, ejection fraction,hypertension, diabetes mellitus, and smoking.
c) The Long-term Intervention with Pravastatin in Ischemic Disease Study (LIPID) was the first to examine the use of a HMG CoA reductase inhibitor for patients with a history of unstable angina. The LIPID study provided new data on noncoronary mortality (i.e., stroke) and on other groups, such as women and patients with diabetes, who previously had been underrepresented in clinical trials. LIPID demonstrated improved Coronary Artery Disease outcomes among all patients, including those with unstable angina.
d) Trials in Patients Undergoing Coronary Revascularization
i)The Post-Coronary Artery Bypass Graft Trial randomized 1,351 patients who had undergone bypass surgery and who had an LDL cholesterol level between 130 and 175mg/dL to aggressive or moderate treatment to lower their LDL cholesterol levels (with lovastatin and, if needed, cholestyramine) and to treatment with warfarin or placebo.Angiography was repeated an average of 4.3 years after baselines were established and revealed decreased progression of vein graft atherosclerosis in patients randomized to aggressive Lipid lowering. There was a 29 per cent reduction in the rate of coronary revascularization in the aggressive LDL-reduction group.
ii) Management of Lipids: Despite overwhelming evidence supporting the treatment of dyslipidemia, a large number of patients remain untreated. The NCEP Adult Treatment Panel III (ATPIII) has released the updated guidelines for treatment of hyperlipidemia in adults. These guidelines focus on identification of risk of cardiovascular morbidity and appropriate targeting therapy.
Guidelines for Primary Prevention of CAD Events Based on the NCEP ATP III
a) TC, LDL-C and HDL-C Levels
All adults 20 years of age or older and without a history of CAD or other atherosclerotic disease should have a fasting lipid panel (i.e. TC, LDL-C and TG) every 5 years. If a nonfasting lipid panel is obtained and the TC level is 200 mg/dl or the HDL-C is less than 40 mg/dl a follow up fasting lipid panel is recommended.
b) Determination of Risk
The patient’s risk of future events is based on presence of known CAD or clinical atherosclerosis in a noncoronary bed, diabetes mellitus, smoking, hypertension (>140/90 mm Hg or use of antihypertensive medication), family history of premature CAD (defined as CAD in first-degree male relatives before age of 55 years and in a first-degree female relative before the age of 65 years), and low.
Risk Factor Goal
LDL Cholesterol
<100 Optimal 100-129 Near or above optimal
130-159 Borderline high
160-189 High
>190 Very High
Total Cholesterol
<200 Desirable
200-239 Borderline high
>240 High
HDL Cholesterol
<40 Low
>60 High
HDL-C (<40mg/dl). A HDL-C 60 mg/dl or greater counts as a negative risk factor. Patients are classified into three categories of risk based on these factors.
CHD Risk
1)Patients with highest risk of cardiovascular events are those with established CAD or evidence of atherosclerosis in non-coronary beds, diabetes mellitus or presence of multiple risk factors conferring a calculated 10 years risk of adverse events between 10 per cent to 20 per cent. The target LDL-C for this group is less than 100mg/dl.
2) The second category includes patients with multiple risk factors and an estimated 10 years risk of adverse events between 10 per cent to 20 per cent. The target LDL-C for this group is less than 130mg/dl.
3) The third category includes those with no or one risk factor and an estimated 10 years risk of less than 10 per cent. The target LDL-C in this group is less than 160mg/dl.
4) CHD risk equivalent: These patients are at the highest risk of adverse events and therefore benefit the most from aggressive treatment. NCEP III recommends therapy with a statin and TLCs if LDL-C is 130mg/dl or greater. In patients with LDL-C levels between 100 and 130mg/dl it suggests three options: Use of TLCs with or without statin therapy, TLCs with emphasis on weight reduction and increased physical activity in an attempt to achieve target LDL-C concentrations, or use of other lipid modifying agents imparted a survival advantage in all patients, irrespective of the baseline LDL. It can be argued that all patients with CHD risk equivalents should be treated with a statin and TLCs regardless of the LDL-C level.
5) Ten year risk of 10 per cent-20 per cent: The target LDL-C for this group is less than 130mg/dl and these patients should be initially approached with TLCs if the LDL-C is more than 160mg/dl consideration may be given to starting drug therapy in addition to TLCs.
6) Ten year risk less than 10 per cent and zero or one risk factor: These patients should be treated with TLC to achieve a target LDL-C level of less than 160mg/dl. If the LDL-C concentration remains above 160mg/dl after 3 months of TLC, drug therapy may be considered. Pharmacotherapy is recommended in those with LDL-C levels higher than 190mg/dl. Factors favouring use of drugs include a 10year risk close to 10 per cent or the presence of a severe risk factor such as a strong family history of premature CAD, a very low HDL level poorly controlled hypertension, or heavy smoking.
HDL-C (<40mg/dl). A HDL-C 60 mg/dl or greater counts as a negative risk factor. Patients are classified into three categories of risk based on these factors.
CHD Risk
1)Patients with highest risk of cardiovascular events are those with established CAD or evidence of atherosclerosis in non-coronary beds, diabetes mellitus or presence of multiple risk factors conferring a calculated 10 years risk of adverse events between 10 per cent to 20 per cent. The target LDL-C for this group is less than 100mg/dl.
2) The second category includes patients with multiple risk factors and an estimated 10 years risk of adverse events between 10 per cent to 20 per cent. The target LDL-C for this group is less than 130mg/dl.
3) The third category includes those with no or one risk factor and an estimated 10 years risk of less than 10 per cent. The target LDL-C in this group is less than 160mg/dl.
4) CHD risk equivalent: These patients are at the highest risk of adverse events and therefore benefit the most from aggressive treatment. NCEP III recommends therapy with a statin and TLCs if LDL-C is 130mg/dl or greater. In patients with LDL-C levels between 100 and 130mg/dl it suggests three options: Use of TLCs with or without statin therapy, TLCs with emphasis on weight reduction and increased physical activity in an attempt to achieve target LDL-C concentrations, or use of other lipid modifying agents imparted a survival advantage in all patients, irrespective of the baseline LDL. It can be argued that all patients with CHD risk equivalents should be treated with a statin and TLCs regardless of the LDL-C level.
5) Ten year risk of 10 per cent-20 per cent: The target LDL-C for this group is less than 130mg/dl and these patients should be initially approached with TLCs if the LDL-C is more than 160mg/dl consideration may be given to starting drug therapy in addition to TLCs.
6) Ten year risk less than 10 per cent and zero or one risk factor: These patients should be treated with TLC to achieve a target LDL-C level of less than 160mg/dl. If the LDL-C concentration remains above 160mg/dl after 3 months of TLC, drug therapy may be considered. Pharmacotherapy is recommended in those with LDL-C levels higher than 190mg/dl. Factors favouring use of drugs include a 10year risk close to 10 per cent or the presence of a severe risk factor such as a strong family history of premature CAD, a very low HDL level poorly controlled hypertension, or heavy smoking.
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