S.   Determine Goal of Therapy;  Initiate/Modify Therapy to Achieve Goal

OBJECTIVE

To select an appropriate therapy based on LDL-C baseline level and other risk factors for ASCVD.

ANNOTATION

Treatment should be based on LDL-C and CHD risk. CHD risk factors are age, family history, current smoker, hypertension, diabetes, and HDL-C < 40 mg/dL. Patients with CHD or multiple risk factors require more aggressive treatment. The goals for therapy and treatment are summarized inTable 3b.

Table 3a.  LDL-C Thresholds for Initial Dyslipidemia Treatment

	Baseline LDL-C     [mg/dL]
Risk for ASCVD	>100	>130	>160	>190
Known CHD	Diet/exercise Consider drug	Diet/exercise + drug	Diet/exercise + drug	Diet/exercise + drug
Diabetes (without known CHD)	Diet/exercise Consider drug	Diet/exercise+ drug	Diet/exercise + drug	Diet/exercise + drug
No known CHD but > 2 risk factors	—	Diet/exercise	Diet/exercise + drug	Diet/exercise + drug
No known CHD but < 2 risk factors	—	—	Diet/exercise	Diet/exercise + drug

Adapted from NCEP III, 2001
Note: If one risk factor is diabetes, the diabetes category is used to determine threshold and goal.

Table 3b.  LDL-C Goals in the Treatment of Dyslipidemia.

Risk for ASCVD	LDL-Cholesterol Goal
Known CHD	<120 mg/dl*
Diabetes (without known CHD)	<120 mg/dl*
No known CHD, but > 2 risk factors	<130 mg/dl
No known known, CHD, but 2 risk factors	<160 mg/dl

*NCEP III recommends an LDL-C goal of < 100 mg/dL in patients with known CHD and CHD equivalents (i.e., type 2 diabetes mellitus).

Non-Pharmacologic Therapy

Lifestyle change is indicated in all patients with 2 risk factors and LDL > 130mg/dL (> 100 mg/dL for known CHD or diabetes). Strategies include diet, exercise, smoking cessation, cessation of excessive alcohol, and weight control.
For primary prevention of ASCVD, patients whose initial treatment is diet/exercise should be given three to six months on dietary therapy prior to beginning medication, and longer if lipids are improving and nearing LDL thresholds. Patients failing clinician-initiated efforts may benefit from a MNT consult prior to initiating medications (See Appendix 1 for Medical Nutrition Therapy). The expected response to diet therapy is summarized in the following Table 4. For secondary prevention of recurrent ASCVD events, non-pharmacologic therapy is always indicated, but should not delay appropriate pharmacotherapy.

Table 4.  Expected Percent Change in Serum Lipids in Response to Diet Therapy

	Expected Response to Therapy
	Step I Diet	Step II Diet	Very Low Fat	High Monounsaturated Fatty Acids
LDL	-5 to -20 %	-10 to -25 %	-0 to -20 %	-5 to -20 %
TG	+5 to -10 %	+10 to -10 %	Decrease with weight loss Increase without weight loss	No change or slight decrease

Cardiovascular Nutrition, ADA, 1998

Pharmacologic Therapy

Drug therapy is indicated in CHD/ASCVD patients and moderate-high risk primary prevention patients who remain above LDL thresholds with non-pharmacologic measures. HMG-CoA reductase inhibitors (statins) are first line agents in most situations. They are cost-effective in secondary prevention and high-risk primary prevention risk groups. The dose should be adjusted at 4 to 6 week intervals until the individually-determined LDL-C goals are met. Other agents have been shown to reduce CHD events and angiographic progression, but have had minimal impact on total mortality. The first line drugs and alternatives for lipid disorders are summarized in Table 5.

Table 5.  Dyslipidemia Drug Therapy Recommendations

LIPID DISORDER	MONO THERAPY	EFFICACY		CONSIDERATIONS
LDL-C               Initial	Statins	LDL       -22 to -60%		Caution using statins in hepatic disease Niacin is contraindicated in hepatic disease and relatively contraindicated in DM, gout, and history of complicated/active PUD. Resins may increase TG
Alternate	Niacin	-13 to -21%
	Bile acid resin (resin)	-10 to -20%
LDL-C and TG Initial	Niacin	LDL       -13 to -21%	TG     -10 to -24%	For high TG, use fibrates or niacin For high LDL, use statins
	or statin	-22 to -60%	-06 to -37%
Alternate	Fibrates	+10 to -35%	-32 to -53%
LDL and HDL	Niacin	LDL       -13 to -21%	HDL     +10 to +24%	No preferences in terms of efficacy
	or statin	-22 to -60%	+2 to +12%
	or fibrates	+10 to -35%	+2 to +34%
TG 400-1000 mg/dL	Consider gemfibrozil if HDL-C < 40 mg/dL			For high TG, use direct LDL-C measurement or non-HDL-C as lipid disorder to guide therapy

Adapted from PBM-MAP, 1997.

For CHD/ASCVD Patients

For patients with known CHD/ASCVD who have HDL < 40 mg/dL pharmacotherapy with gemfibrozil is recommended (VA-HIT, 1999)

LDL-C 130 mg/dL And HDL-C < 40 mg/dL

Gemfibrozil

LDL +10 to -35%

HDL +2 to 34%

Outcome data for secondary prevention only

Adapted from PBM-MAP, 1997.

DISCUSSION

Primary Prevention

Treatment should be based on risk, which varies widely in this group of patients. CHD risk increases with increasing risk factors (annotation B), and can be easily calculated (Wilson et al., 1998). Lowering cholesterol has been shown to reduce the incidence of CHD, with each 10 percent reduction dropping the incidence by 20 to 30 percent. However, in patients with low absolute risk for developing CHD, even this impressive relative risk reduction results in small change in the absolute risk or total event rate. The National Cholesterol Education Program guidelines recommend LDL targets of < 130mg/dL for two or more CHD risk factors, and < 160mg/dL for zero to one CHD risk factors.

Lifestyle changes are the first mode of treatment. This includes dietary changes, exercise, weight reduction, smoking cessation, and reduction of excessive alcohol. Dietary changes are an important first step in CHD risk reduction. However, the response in clinical practice is often substantially less than that seen in trials. Likewise, multiple risk factor reduction strategies have not yielded consistently improved lipids or outcomes (Ebrahim & Davey Smith, 1999). Patients should be given 3 to 6 months on dietary therapy prior to beginning medication, and longer if lipids are improving and nearing LDL thresholds. All patients failing clinician-initiated efforts should have a MNT consult prior to initiating medications.

Drug therapy should be reserved for those at increased CHD risk who fail to reach LDL targets with lifestyle modifications. Primary prevention trials with statins have demonstrated a reduction in CHD events and total mortality (in a high-risk population). Prior to statins, primary prevention trials had been shown to reduce CHD events, but not mortality. The AFCAPS/TexCAPS study examined outcomes in 5608 men and 997 women with average total cholesterol and LDL, and below average HDL (Downs et al., 1998). Patients randomized to lovastatin had 37 percent fewer first CHD events. The number needed to treat (NNT) to prevent one CHD event was 86. This was a relatively low risk population. The West of Scotland Study (WOSCPS) evaluated a higher risk population, and also found dramatic benefits from statin (pravastatin) treatment (Shepherd et al., 1995). Over five years, CHD events were 31 percent lower, with significant reductions in CHD (32 percent) and total (22 percent) mortality. The NNT to prevent one nonfatal MI or CHD death was 42. Drug therapy was cost effective in the WOSCPS trial (about $12,000 per year of life saved), but it is unlikely that statins will be cost effective in lower risk populations at current pricing. This contrasts with the secondary prevention study (4S, 1994), which was cost effective in all age groups. There are no cost effectiveness studies with niacin in primary prevention, and it is unlikely that resins could be cost effective given their high cost per LDL reduction. Niaspan, a new extended release niacin product, offers once-a-day dosing, and fewer side effects, but at a price comparable to statins.

Secondary Prevention

Secondary prevention refers to patients with known CHD or ASCVD. These individuals are at high risk for recurrent events. Lipid-lowering treatment has been shown to reduce CHD events, cardiac mortality, and total mortality in patients with CHD. Studies have shown that statins and niacin reduce stroke through secondary prevention. A systematic review found that peripheral vascular disease events were reduced as well (Leng et al., 1999). These patients have a high absolute risk for developing vascular events, and so derive significant absolute risk reduction in addition to relative risk reduction. Early trial data with non-statin drug therapy in CHD patients was disappointing. Lipid reductions were not dramatic, dropouts were high (due to side effects), and increases in non-CHD mortality and morbidity reduced overall benefit. Angiographic trials have shown that statins and other agents slow the progression of atherosclerosis as measured by serial coronary angiography. In the past five years, large randomized controlled trials with statins have shown that lipid lowering reduces both CHD and total mortality. Furthermore, the reduction in coronary events appears to be out of proportion to the slowing of atherosclerotic progression, suggesting that much of the benefit from statins occurs by another mechanism (e.g., "plaque stabilization").

Dietary counseling by primary care providers or MNT consultation is indicated if LDL >100mg/dL. Exercise must be tailored to the degree of CHD. Aerobic exercises should be titrated to a level that does not precipitate angina. Patients should exercise at least 30 minutes on most days of the week. How long to give lifestyle change before adding pharmacotherapy for dyslipidemia is unclear, but certainly less than in primary prevention.

HDL Cholesterol < 40 mg/dl with LDL < 130 mg/dl

Large epidemiologic trials have shown that a low HDL is associated with an increased risk for cardiovascular events (Gordon, 1989). In the VA-HIT trial (1999), patients with established cardiovascular disease, an HDL < 40 mg/dL and an LDL < 140 mg/dL were randomized to treatment with gemfibrozil vs. placebo. The mean entry HDL of the treatment arm was 32 mg/dL and the mean entry LDL level was 111 mg/dL. Following a mean follow-up of five years, the gemfibrozil treatment arm saw a 22 percent relative risk reduction in the combined end point of nonfatal myocardial infarction or death due to cardiovascular disease, and a 25% reduction in stroke. Subgroup analysis of VA-HIT strongly suggests that CHD patients with low HDL, triglycerides > 200 mg/dl, hypertension, or impaired fasting glucose were particularly likely to benefit from gemfibrozil therapy. The study was not powered to detect an overall mortality benefit.

For additional information see VHA/DoD guideline for IHD - Modules for Secondary Prevention and Cardiac Rehabilitation.

EVIDENCE

Lifestyle education.  (QE=I, SR=A).  Wilson et al., 1998; Ebrahim & Davey Smith, 1999
Primary prevention.  (QE=I, SR=A).  Downs et al., 1998; Shepard et al., 1995
Secondary prevention.  (QE=I, SR=A).  Scandanavian Simvastatin Survival Study Group (4S), 1994; Leng et al., 1999; NCEP III, 2001; Sacks et al., 1996; Frick et al., 1987; Canner et al., 1986; Post CABG Trial, 1997
Treatment of low HDL.  (QE=1, SR=A).  Gordon et al., 1989; Rubins et al., 1999