LIPID MANAGEMENT CLASS

1. Lifestyle modifications, including daily physical activity and weight management, are strongly recommended for all patients with SIHD (18,496).(Level of Evidence: B)

2. Dietary therapy for all patients should include reduced intake of saturated fats (to⬍7% of total calories),transfatty acids (to⬍1% of total calories), and cholesterol (to⬍200 mg/d) (18,497–500). (Level of Evidence: B)

3. In addition to therapeutic lifestyle changes, a moderate or high dose of a statin therapy should be prescribed, in the absence of contra- indications or documented adverse effects. (18,398,400,458,501). (Level of Evidence: A)

CLASS IIa

1. For patients who do not tolerate statins, LDL cholesterol–lowering therapy with bile acid sequestrants,* niacin,† or both is reasonable (502,504,505).(Level of Evidence: B)

*The use of bile acid sequestrant is relatively contraindicated when triglycerides are

ⱖ200 mg/dL and is contraindicated when triglycerides areⱖ500 mg/dL. †Dietary supplement niacin must not be used as a substitute for prescription niacin.

Epidemiological studies have established serum cholesterol as an important coronary heart disease risk factor. The Framingham Heart Study, Multiple Risk Factor Interven- tion trial, and the Lipid Research Clinics trials all found a continuous, graded increase in coronary events with increas- ing LDL cholesterol in men and women who were initially

free of IHD (502,506 –508). A similar relationship has been

observed among patients with SIHD (509 –511). The asso-

ciation between LDL cholesterol and cardiovascular risk is curvilinear, or log-linear, meaning that the decrease in RR for a given 1-mg/dL decrease in LDL cholesterol seems to be the same at any level of baseline LDL cholesterol. The principal lipid modification strategy recommended by the NCEP ATP-III (National Cholesterol Education Program Adult Treatment Panel III) in patients with SIHD is the

reduction of LDL cholesterol (18,24). This should start

with therapeutic lifestyle changes, including dietary therapy, daily physical activity, and weight management. Most pa- tients also will benefit from cholesterol-lowering drug ther- apy, preferably with a statin.

Effective dietary approaches to lowering LDL cholesterol include replacing saturated andtransfatty acids with dietary carbohydrates or unsaturated fatty acids and reducing di- etary cholesterol. Although the response to dietary inter- ventions is variable, a diet low in saturated fat and choles- terol typically lowers LDL cholesterol by 10% to 15% (497–500). Other beneficial dietary interventions can in- clude addition of plant stanols/sterols (2 g/d), which trials suggest lower LDL cholesterol by 5% to 15%, and addition

of viscous fiber (⬎10 g/d), which reduces LDL cholesterol

by 3% to 5% (512–515). A 10-lb weight loss reduces LDL

cholesterol by 5% to 8% (496). Regular physical activity is

also a key component of therapeutic lifestyle modification. Although exercise does not reliably lower LDL cholesterol, it facilitates weight loss and has other beneficial effects on the lipid profile (516 –518).

Controlled clinical trials of lipid-lowering drug therapy have demonstrated that lowering of LDL cholesterol is associated with a reduced risk of adverse cardiovascular events. Earlier trials used bile acid sequestrants (cholesty- ramine), fibric acid derivatives (gemfibrozil and clofibrate), or niacin. More contemporary studies have convincingly established the efficacy of statins in the primary and sec-

ondary prevention of coronary events (394 –396,398,400,

501,519 –522). In a prospective meta-analysis published by the Cholesterol Treatment Trialist Collaborators in 2010 that examined data from 26 randomized trials of statin therapy (comparing higher- to lower-dose statin therapy or statin therapy to a control regimen), the mean difference in LDL cholesterol was 31 mg/dL, ranging from 12 to 68 mg/dL. Each 40-mg/dL reduction in LDL cholesterol was associated with a 10% reduction in all-cause mortality and a 20% reduction in coronary mortality, with corresponding reductions in nonfatal MI, need for coronary revasculariza- tion, and first nonfatal ischemic stroke (458). The absolute benefit of therapy was a function of an individual’s absolute

risk of fatal MI (458). In trials comparing higher- to

lower-dose statin therapy, the average, weighted reduction in LDL cholesterol at 1 year was 20 mg/dL among those receiving higher-dose regimens. Among patients assigned to more intensive regimens, there was a 15% lower inci- dence of major vascular events (95% CI: 11 to 18;

p⬍0.0001), which reflected a 13% lower risk of coronary

death or nonfatal MI (95% CI: 7 to 19; p⬍0.0001), a 19%

lower risk of undergoing coronary revascularization (95%

CI: 15 to 24; p⬍0.0001), and a 16% lower risk of ischemic

stroke (95% CI: 5 to 26; p⫽0.005). The reductions in serum

LDL cholesterol and in cardiovascular risk were similar in magnitude to those observed in trials comparing statin therapy to a control regimen. The absolute benefit of therapy was defined chiefly by an individual’s absolute risk

of death due to coronary occlusion (458). Appropriate

treatment goals for patients with SIHD have been informed by several trials of intensive lipid-lowering therapy. The HPS (Heart Protection Study) compared simvastatin 40 mg daily to placebo in patients with IHD, other occlusive vascular disease, or diabetes mellitus. On-treatment LDL cholesterol levels averaged 88 mg/dL in those allocated to simvastatin and 127 mg/dL in those randomized to placebo. A consistent and early benefit of therapy was demonstrated, with a 13% reduction in mortality rate and an 18% reduction

in coronary death rate (398). Similar reductions in RR were

observed regardless of baseline levels of LDL cholesterol,

including in those with initial levels⬍116 mg/dL or⬍97

mg/dL. (Of note, LDL cholesterol levels in the HPS were not drawn with patients in the fasting state and were measured values rather than the calculated values used in clinical practice and in most trials; measured LDL choles- terol is generally about 15% higher than calculated LDL

cholesterol) (398). In the TNT (Treating to New Targets)

trial, patients with clinically apparent IHD and LDL

cholesterol⬎130 mg/dL were randomly assigned to either

10 mg or 80 mg of atorvastatin per day. The mean LDL cholesterols were 77 mg/dL during treatment with 80 mg of atorvastatin and 101 mg/dL during treatment with 10 mg of atorvastatin. There was a 22% reduction in a composite cardiovascular endpoint and a 20% reduction in cardiac deaths with more intensive therapy but no reduction in

all-cause mortality (400). In the IDEAL (Incremental

Decrease in End Points Through Aggressive Lipid Lower- ing) study patients with a past history of MI were randomly assigned to intensive lipid-lowering therapy with atorvasta- tin 80 mg daily or simvastatin 20 mg daily. During treat- ment, mean LDL cholesterol levels were 104 mg/dL in the simvastatin group and 80 mg/dL in the atorvastatin group. The results showed a nonsignificant trend toward reduction of the primary composite endpoint of coronary death, nonfatal MI, or cardiac arrest (hazard ratio: 0.89; 95% CI: 0.78 to 1.01); significant reductions in some secondary endpoints such as nonfatal MI and coronary revascular-

ization; and no effect on all-cause mortality (501). It

regimens and did not directly test the benefit of achieving a given level of LDL cholesterol and that, to date, there is no clear evidence that treating to a specific target, as opposed to treating with a higher dose of a higher- potency statin, is beneficial. The mean achieved LDL cholesterol levels among patients treated in the high-dose atorvastatin arms of the TNT and IDEAL studies were 77 and 81 mg/dL, respectively.

These data support intensive LDL cholesterol lowering with statins in patients with SIHD. An update of the

ATP-III report (18,24) recommends treatment to an LDL

cholesterol level⬍100 mg/dL in patients with established

CAD or other high-risk features, with an LDL cholesterol

goal of⬍70 mg/dL as a therapeutic option in patients at

very high risk. However, as discussed above, although the presence of data confirming the use of a specific, numeric target LDL cholesterol level for all patients with SIHD has been challenged, the benefit of therapy with moderate- to high-dose statin therapy is well established (458). For this reason, the recommendations in this guideline stress the importance of prescribing a statin in at least a moderate dose. The ATP-IV report is anticipated later in 2012 and is expected to provide guidance for the treatment of LDL cholesterol levels on the basis of the results of an extensive systematic review. Factors that identify patients at very high risk in the ATP-III update include the presence of estab- lished coronary vascular disease, plus 1) multiple major risk factors, especially diabetes mellitus; 2) severe and poorly controlled risk factors, especially continued tobacco use; and 3) multiple risk factors for the metabolic syndrome. Again, it should be acknowledged that no studies have assessed the benefits of titrating lipid-lowering drugs to achieve a specific LDL cholesterol target. In addition, trials of intensive lipid lowering for secondary prevention have used statins alone. Although the addition of other agents could lower LDL cholesterol in patients in whom a target level cannot be achieved with a statin, the utility of this approach in reducing risk of cardiovascular morbidity and mortality has not been firmly established.

A secondary target of therapy introduced by ATP-III is non–HDL cholesterol in patients with elevated triglycerides (18,24). Non–HDL cholesterol is defined as the difference between total cholesterol and HDL cholesterol. It includes all cholesterol and lipoprotein particles that are considered atherogenic, including LDL cholesterol, lipoprotein, intermediate-density lipoprotein, and very-low-density li- poprotein, and is a predictor of cardiovascular death (523). Because statins lower LDL cholesterol and non–HDL cholesterol to a similar extent, the relative benefits of lowering these 2 lipid measures cannot be distinguished from recent clinical trials. Fibrates could reduce the risk of coronary events in patients with high triglycerides and low HDL cholesterol levels and could have an adjunctive role in

these patients in combination with statins (503,524). Nic-

otinic acid raises HDL cholesterol, and several trials support

the efficacy of niacin when used alone or in combination with statins (504,505,525).

Observational studies and treatment trials suggest that consumption of omega-3 fatty acids reduces cardiovascular risk. Cohort and case– control studies have found an RR reduction of about 15% for fish consumption versus little or

no fish consumption (526). In the GISSI (Gruppo Italiano

per lo Studio della Sopravvivenza nell’Infarto Miocardico) Prevention study in patients with prior MI, 1 g daily of fish oil supplement resulted in a 20% reduction in mortality at

42 months (527). Pharmacological treatment with fish oil at

higher doses (2 to 4 g daily) is effective in reducing triglyceride levels (528).

4.4.1.2. BLOOD PRESSURE MANAGEMENT