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Questions & Answers about CHD Therapy
(by Ernst Schaefer, MD, Tufts University, Boston)
1. How to Make the Diagnosis?
Measure total cholesterol (TC), triglyceride (TG), and high-density lipoprotein (HDL) cholesterol (C) (a lipid profile) after an overnight fast of at least 9-10 hours. Water and black coffee or tea without milk or cream are allowed. (Between fasting and non-fasting TG change significantly, but total cholesterol and HDL cholesterol change very little. Therefore some authorities recommend using the non HDL cholesterol value (total-HDL) or the TC/HDL C ratio. If the patient is fasting and the TG values are < 400 mg/dl, low-density lipoprotein (LDL) C is calculated by subtracting the sum of TG/5 and HDL C from TC. For mmol/L divide TG by 2.2. To convert mg/dl for cholesterol into millimoles/L divide by 38.5, and for TG divide by 88.5. An LDL C > 160 mg/dl or 4.1 mmol/L is high, between 130-160 mg/dl or 3.3-4.1 mmol/L is borderline high. This calculation is accurate up to TG levels of 250 mg/dl or 2.8 mmol/L. At TG values > 400 mg/dl, the calculated value becomes very inaccurate, and a direct LDL C or non HDL C (TC-HDL C) can be calculated and used.
2. What Values are Abnormal?
Increased TC (> 240 mg/dl or 6.2 mmol/L, > 200 mg/dl borderline high), LDL C (>160 mg/dl or 4.1 mmol/L) and non HDL C (> 190 mg/dl or 4.9 mmol/L) are high, and an HDL C < 40 mg/dl in men and < 50 mg/dl in women is considered low, and all these abnormalities have been associated with premature CHD (JAMA 285:2486, 2001). Elevated TC/HDL C ratio > 6.0, Lp(a) >30 mg/dl or 74 nmol/L and CRP > 3.0 mg/L are also significant CHD risk factors. LDL puts cholesterol into the artery wall; therefore, it is an atherogenic lipoprotein particle. HDL removes cholesterol from the artery and other tissues; therefore, it is a protective lipoprotein particle. TG levels >1000 mg/dl or 11.3 mmol/L have been associated with pancreatitis (due to TG or fat deposition in the pancreas, and autodigestion of the gland itself by its own pancreatic lipases). TG >150 mg/dl are considered elevated, and are clearly an independent CHD risk factor in women. The total cholesterol/HDL cholesterol ratio is the most powerful parameter for CHD risk prediction. Lp(a) or lipoprotein (a) is mainly an LDL particle with another protein known as apo(a) attached to the apoB-100 protein of LDL. Apo(a) is similar to plasminogen, a protein that helps break up clot, and high levels of Lp(a) or apo(a) appear to interfere with the action of plasminogen. Morerover Lp(a) like LDL can be deposited in the artery wall. Some experts recommend measuring C reactive protein, a marker of inflammation produced in the liver. Elevated values (> 3 mg/L) have been associated with increased CHD risk. Some authorities recommend measuring apoB or apoA-I, the major proteins of LDL and HDL, respectively, but the data supporting this position are not that strong.
3. What are Secondary Causes?
Order a fasting glucose, creatinine, alkaline phosphatase, SGPT, SGOT, TSH, and urinalysis, and obtain a medication and diet history. Diabetes (fasting glucose > 125 mg/dl) leads to elevated TG and decreased HDL C. Elevated alkaline phosphatase may be a sign of obstructive jaundice, and can cause marked hypercholesterolemia. An elevated TSH (> 6) due to hypothyroidism is avery common cause of secondary hypercholesterolemia. Hypercholesterolemia can also be caused by nephrotic syndrome (high levels of urinary protein), while renal insufficiency (creatinine > 2.5 mg/dl) is often associated with elevated TG and low HDL. Elevated liver enzymes (SGPT and SGOT) more than three times the upper limits of normal can be a sign of liver damage or hepatitis. However in patients with elevated lipids, this finding is often a sign of a fat infiltration in the liver due to high TG levels. Oral estrogens, oral contraceptives, steroids and alcohol (> 2 drinks/day) can all increase TG levels, while anabolic steroids decrease HDL C significantly. Diets high in animal fat and cholesterol increase TC and LDL C, while diets high in sugar increase TG and lower HDL C.
4. Are there Familial Lipid Disorders Associated with Heart Disease?
If no secondary causes are present then a familial disorder may be present, and measuring lipids in first degree relatives is warranted especially when elevated lipids or CHD runs in the family: In families with premature CHD 19% have Lp(a) > 30 mg/dl or 74 nmoles/L, 15% have combined hyperlipidemia (elevations of both LDL and TG, with low HDL), 15% have dyslipidemia (high TG and low HDL), 5% have isolated low HDL C, and only 1% have hypercholesterolemia with tendinous xanthomas (Circulation 85:2025; 1992).
5. What About Diet Treatment?
Patients should be placed on a low-saturated fat (<7%), low cholesterol (<200 mg/day), low trans-fat, low sugar diet (ATVB 15:1079, 1995 JAMA 274:1450, 1995). This means restricting foods containing beef, pork, and lamb, as well as eggs, whole milk, butter, and cookies, cakes, and high animal fat, high sugar food items, including avoiding soft drinks except non-calorie drinks. Patients should use chicken, turkey (white meat without skin), and fish, and try to consume at least 5 servings of vegetables and fruits per day, as well as use whole grain products. The vegetable oil of choice is canola oil, and soft canola and or soybean oil margarine is recommended. Dietary intervention in which animal fat has been replaced with vegetable oil has been shown to significantly reduce CHD risk. Calorie restriction in overweight patients and a regular exercise program (60 minutes daily including aerobic exercise and strength training) is important. Neither vitamin E nor combinations of antioxidants (E, C, beta carotene) have been shown to reduce CHD risk (Lancet 354:447, 1999; NEJM 342:154, 2000; Lancet 360:23, 2002). Some subjects (e.g. carrying the ApoE4 allele) are more responsive to diet (JLR 35:1965, 1994). Plant sterol margarines, 1 serving twice daily will lower LDL C 5-15%. Metamucil 1 tablespoon once daily will lower LDL C 5-10%. Fish oil capsules lower TG 25% and can be used in patients who do not get an adequate response to fibrates. Omacor tablets (n3 fatty acid ethyl esters) are now available and the recommended dose for TG lowering is 4/day. Side effects are minimal and include slightly prolonged bleeding time, and a fishy odor with belching. Use of fish or its oil (1-2 g/day) has been shown to decrease CHD death in CHD patients (Lancet 2:757, 1989; Lancet 354:447, 1999).
Diet interventions that have been shown to decrease CHD risk are:
| 1. |
replacing butter with soft margarine and vegetable oils, and trimming off all visible fat from meat |
| 2. |
replacing of red meat with chicken, turkey (white meat) or fish |
| 3. |
replacing whole milk, cream, and 2% milk with 1% low-fat or skim milk |
| 4. |
eliminating high fat/high sugar desserts |
| 5. |
increasing the consumption of fruits, vegetables, and whole grains |
| 6. |
exercising daily for at least 30 minutes. For lifestyle intervention to work it must be intensive and sustained |
6. How Does One Do Global CHD Risk Assessment?
The best predictor of CHD is having a prior CHD event. The second powerful predictor is increased age. In patients without evidence of CHD, stroke, or peripheral vascular disease, use the Framingham point system to calculate the 10 year CHD risk based on Framingham risk assessment (age, systolic blood pressure, smoking status, TC, and HDL C). High risk is >20%, diabetes, or having CHD, moderate risk is 10-20%, and low risk is < 10%.
The steps involved are to:
| 1. |
determine risk category |
| 2. |
establish an LDL goal of therapy |
| 3. |
determine the need for therapeutic lifestyle changes (TLC) |
| 4. |
determine the LDL cholesterol target value. Established CHD risk factors are: increased age
(> 45 years if male, > 55 years if female, hypertension, smoking, and low HDL cholesterol
(< 40 mg/dl in men and < 50 mg/dl in women) |
7. What Are the Goals of Therapy?
Goals of therapy are LDL cholesterol < 160 mg/dl in low risk subjects (<10% ten year CHD risk or 1 or less risk factors), LDL cholesterol <130 mg/dl in subjects of moderate risk (2 or more risk factors or 10-20% 10 year CHD risk), and LDL cholesterol <100 mg/dl in CHD risk equivalent patients, i.e. those with CHD, those with other vascular disease, stroke, diabetes, or >20% 10 year CHD risk). An optional goal is to get the LDL cholesterol to <70 mg/dl in CHD patients (see next paragraph). Alternative: Include non HDL cholesterol (total cholesterol-HDL cholesterol) of 30 mg/dl higher than LDL cholesterol targets.
Optimal goals in CHD patients, those with diabetes, or those with >20% 10 year CHD high risk are: LDL C <70 mg/dl (1.8 mmol/L) and non-HDL C < 100 mg/dl (2.6 mmol/L); LDL C <130 mg/dl (3.4 mmol/L) in 10-20% risk, and LDL C <160 mg/dl in <10% risk. (JAMA 285:2486, 2001, Circulation 110:227, 2004, current US guidelines update). Other goals in CHD or CHD risk equivalent patients: a TC/HDL ratio < 4.0 (recommended by the Canadians and the Europeans), HDL C >45 mg/dl or 1.2 mmol/L (recommended by the American Diabetes Association), TG <150 mg/dl or 1.7 mmol/L, Lp(a) <30 mg/dl or 74 nmol/L, and CRP < 2.0 mg/L.
8. How to Lower LDL Cholesterol?
The drug of choice is a statin. If additional LDL C lowering is needed, ezetimibe [Zetia]) can be added. Niacin can also be used alone or in combination with a statin or ezetimibe or a resin (WelChol). Lowering LDL has been associated with CHD and stroke risk reduction.
9. How to Lower High Triglycerides (>150 mg/dl or 1.7 mmol/L)?
Control of glucose, exercise, cessation of alcohol, and oral estrogen, if possible, and weight reduction, if indicated, are important. Drug therapy with fenofibrate, fish oil, niacin, or a statin can all be considered. Therapy is especially important in patients with TG >1000 mg/dl (11 mmol/L) because of their high risk of pancreatitis. In these patients control of glucose is very important, and a fibrate is the drug of choice.
10. How to Raise Low HDL (HDL C <40 mg/dl or 1.0 mmol/L)?
Weight reduction and an exercise program are helpful, as well as cessation of smoking if possible. Use a statin to optimize LDL C levels. Then add Niaspan, especially in patients with CHD, diabeties or high risk to optimize HDL cholesterol. If they cannot tolerate Niaspan, consider fenofibrate, especially if triglycerides are elevated at over 250 mg/dl. A new class of agents which inhibit the transfer of cholesteryl ester from HDL to other lipoproteins was recently tested, and a large trial (ILLUMINATE) was stopped because of excess mortality (torcetrapib, NY Times and Wallstreet Journal, December 4, 2006, 1.1% vs. 0.7% mortality over 18 months in CHD patients on atorvastatin, as well as excess heart failure, angina, and angioplasty procedures). This agent actually bound to CETP on HDL particles.
11. How to Lower Elevated Lp(a) Excess?
Use Niaspan (2-3 g/day) to lower Lp(a) in CHD patients with elevated Lp(a), although no randomized trial data to support this as of yet.
12. How Should One Treat the Diabetic Patient?
Lifestyle modification and glucose control are essential. In the Diabetes Prevention Program with 22 minutes of exercise per day, less fat (25% of calories) and calories (500), and a goal of 7% weight loss, lifestyle (16 classes) reduced diabetes 58% (NEJM 346:393,2002). To optimize LDL C use a statin, for low HDL Niaspan, and for hypertriglyceridemia fenofibrate.
Specific Classes of Medications:
13. Statins or HMG CoA Reductase Inhibitors
These drugs inhibit HMG CoA reductase, the rate limiting enzyme in cholesterol biosynthesis, decrease intracellular cholesterol concentration, resulting in upregulation of LDL receptors, which restores the cellular levels of cholesterol, and lowers LDL C and non HDL C by as much as 60%, TG by as much as 40% and increases HDL C 5-15%. The drugs enhance the clearance of VLDL and LDL clearance. All the statins have a 1-2% incidence of reversible liver enzyme elevation and can cause muscle aches in about 5% with or without CK rise, GI upset, skin rash, and headache. Rarely they cause rhabdomyolysis or muscle breakdown (CK >10 ULN, severe muscle aches, pain, and tenderness, and dark urine) and occasionally renal failure and even death from this cause. Predisposing factors include advanced age, hypothyroidism, and concomitant use of other medications like fibrates, which may interfere with drug metabolism. Liver enzymes should be monitored and the drug discontinued or decreased if values are >3 X upper limits of normal, because statins may occasionally cause liver inflammation and hepatitis. One should obtain a baseline CPK, and monitor liver enzymes every 6 months. Also question the patient about muscle tenderness, aches and pains. There is variability in response based on genotype differences (Atherosclerosis 113:157,1995). The order of efficacy of statins in terms of lowering LDL, non-HDL C, TG and CRP lowering for statins are: rosuvastatin, atorvastatin, simvastatin, lovastatin, pravastatin, and fluvastatin. Statins with the lowest rates of muscle problems are low dose rosuvastatin, pravastatin and fluvastatin.
A. Lovastatin:
In AFCAPS/TEXCAPS lovastatin 20-40 mg/day reduced LDL C 25% and CHD risk 37% in 6605 men >45 years and women >55 with LDL C 130-190 mg/dl (3.38-4.94 mmol/L) and HDL C <50 mg/dl (1.3 mmol/L) (JAMA 279:1615;1998). Available together with Niaspan as Advicor see below.
B. Pravastatin:
In the West of Scotland Study pravastatin at 40 mg/day reduced LDL C 26%, total mortality 22%, fatal and non-fatal MI 31%, and PTCA or CABG 37% in 6595 healthy middle-aged men with hypercholesterolemia over 5 years (NEJM 333:1301;1995). In CARE pravastatin at 40 mg/day lowered LDL C 26%, fatal and non-fatal MI 24%, bypass 26%, PTCA 23%, fatal MI 37%, and stroke 31% in 4159 post-MI patients with normal LDL C 115-174 mg/dl mean 137 (NEJM 335:1001;1996). In LIPID pravastatin 40 mg/day reduced total CHD, and stroke mortality 22%, 24%, and 19%, respectively, in 9013 CHD patients with TC values of 155-271 mg/dl (NEJM 339;1349, 1998). In PROSPER pravastatin 40 mg/day over 3.2 years reduced fatal and non-fatal MI 19% in 5804 elderly men and women. The benefit was seen especially in men with HDL C <43 mg/dl. (Lancet 360:1623-1630, 2002).
C. Simvastatin:
In the Scandinanvian Simvastatin Survival Study (4S) simvastatin 20-40 mg/day decreased LDL C 35%, total mortality 30%, CHD mortality 42%, non-fatal and fatal CHD 34%, stroke 37%, and PTCA or CABG 37% in 4444 CHD patients with moderate hypercholesterolemia 200 mg/dl or 5.2 mmol/L) (Lancet 344:1383;1994) and at 40 mg/day reduced ??(TC CHD by 25% in 20,536 CHD or high-risk patients over 5 years (Lancet 360:75,2002).
D. Fluvastatin:
Lescol XL 80 mg/day lowers LDL C by 35%. Benefit in decreasing CAD progression has been shown (Am J Cardiol 80:278, 1997).
E. Atorvastatin:
Lowers LDL C 37-52%, TG up to 30%, and raises HDL C about 5%, also effective in patients with high triglycerides (ATVB 15:678;1995; JAMA 275:128;1996). In ASCOT 10, 305 hypertensive patients with TC <250 mg/dl randomized to 10 mg atorvastatin had a 36% reduction in fatal and nonfatal MI and 27% reduction in stroke over 3 years versus placebo (Lancet 361:1149, 2003). In PROVE IT and REVERSAL atorvastatin 80 mg/day superior to pravastatin 40 mg/day for event rates in acute coronary syndrome (NEJM, 2004) and for preventing plaque progression by IVUS. (JAMA, 2004) In 2805 diabetics 10 mg/day reduced CHD by 37% in the CARDS study (Lancet 2004).
F. Rosuvastatin:
Decreases LDL C by 41%, 47%, 52%, and 55%; HDL C increases of 14%, 8%, 10%, and 10%; and TG decreases of 20%, 20%, 24%, and 26%, will lower CRP by 30% (STELLAR Study, Am J Cardiol 92:152, 2003). It has the longest plasma residence time of any statin at 20 hours. Rosuvastatin is the most effective statin on the market with a safety profile similar to other statins (FDA website, March 2005), and is the only statin reported to promote regression of coronary atherosclerosis (JAMA 2006; 295:1556-1565).
14. Cholesterol Absorption Inhibitors:
A. Ezetimibe:
This agent blocks the intestinal cholesterol transporter NPC1L1 (Niemann Pick C Like Transporter), preventing cholesterol uptake by the enterocyte. Ezetimibe lowers LDL C by about 18%, is generally well tolerated, and is especially helpful in hypo-responders to statins or those unable tolerate statins. Ezetimibe can cause occasional GI upset and as Vytorin (simvastatin 10-80 mg/day plus ezetimibe 10 mg/day) can lower LDL C up to 60%, TG 30%, and raise HDL C 10% at the maximal 80/10 dose.
15. Fibric Acid Derivatives:
These agents are peroxisomal proliferator activating receptor (PPAR) alpha agonists and increase lipoprotein lipase, apoA-I and apoA-II, and decrease apoC-III gene expression, resulting in triglyceride lowering up to 50%, very slight LDL reductions, and modest increases in HDL C. They can cause GI upset and myositis. Greatest benefit from fibrates is in those with insulin levels >25 microunits/per ml (Arch Intern Med 2002;162,2597).
A. Gemfibrozil:
The drug should not be used in patients with renal insufficiency because of myositis, which is especially a problem when gemfibrozil is given with a statin. Gemfibrozill is also known to increase coumadin action. Gemfibrozil reduced CHD risk prospectively by 34% in over 5000 healthy men with non-HDL C >200 mg/dl or 5.2 mmol/L (Helsinki Heart Study), but had no effect on total mortality. The greatest benefit was in those with low HDL (NEJM 317:1237;1987). In the VA HDL Intervention Trial 2561 men 40 mg/dl and LDL Cwith CHD and HDL C <140 mg/dl had significant 22% CHD risk reduction with gemfibrozil vs. placebo over 5 years, related in part to a modest 6% HDL C increase (NEJM 341:410, 1999). The greatest benefit was observed in those with insulin > 25 micromoles/L, who also had weight loss.
B. Fenofibrate:
In the DAIS study in 416 diabetics fenofibrate 160 mg/day reduced TG by 30%, coronary atherosclerosis progression by 22%, and raised HDL C by 6% versus placebo (Lancet 357:905-910, 2001). Fenofibrate, unlike gemfibrozil, is well tolerated together with statins. In the FIELD Trial in 10,000 patients with diabetes, the use of fenofibrate was only associated with an 11% reduction in CVD risk, which increased to 19% after adjusting for greater statin use in the placebo group (Lancet, 2006).
16. Niacin:
Niacin preparations decrease output of TG and VLDL and less LDL being produced, while HDL C is increased due to delayed clearance and less cholesteryl ester transfer from HDL to TG rich particles.
A. Niaspan:
a prescription item, is given at doses of 500-2000 mg/day, available in 500, 750 and 1000 mg po QPM. Start at 500 mg po HS and every two weeks increase by 500 mg po HS up to 2000 mg po HS. At 2000 mg/day. Niaspan decreases LDL C by 20%, TG by 30%,, Lp(a) by 25%, and increases HDL C by 25%. Side effects may include flushing, gastric irritation, and elevations of uric acid, glucose, and liver enzymes in some patients. Niaspan is much better tolerated than immediate release niacin, which is given three times per day with meals and is titrated up from 100 mg po TID to 1000 mg po TID, and has similar lipid effects but more flushing. Do not use in patients with liver disease or history of an ulcer. One aspirin po HS will minimize flushing. Discontinue niacin if liver enzymes increase to over 3 times upper normal limit. Niacin has been found to reduce CHD risk by 27% and cholesterol and total mortality by 11% in the Coronary Drug Project (JACC 8:1245;1986). Niaspan has been found to be effective in lipid modification and safe in diabetics (JAMA 284:1263 ,2000). Niacin plus statin promoted plaque regression and events in the HATS Trial (in CHD patients with low HDL) (n=160) (NEJM, 345:1583,2001). Advicor (lovastatin/Niaspan combination pill) is now available as a 20 mg/500 mg pill and a 20 mg/1000 mg pill and will lower LDL C by about 50%, TG by 35%, Lp(a) by 25%, and raise HDL C by 30%. Trial is now underway to test simvastatin alone or with Niaspan in CHD patients with low HDL (n=4000). This trial should provide definitive data on potential benefits of HDL raising and Lp(a) lowering. Simcor is a combination of Niaspan and simvastatin and was approved in early 2008. It reduces LDL-C 5-15% and increases HDL-C 20-29%. In Europe, Tredaptive, a combination of an extended release form of nicotinic acid and the flushing inhibitor Laropiprant was recently approved. Tredaptive lowers LDL-C 18% and increases HDL-C 20% at max dose. In combination with simwastatin, LDL-C was reduced by 48% and HDL-C increased 28%.
17. Anion Exchange Resins (Third Line Agents for LDL Lowering)
Cholestyramine and colestipol are anion exchange resins which bind bile acids, increase conversion of liver cholesterol to bile acids, and upregulate LDL receptors in liver, decreasing plasma LDL by about 20%. Side effects include bloating and constipation, elevation of triglycerides, and interference with the absorption of digoxin, tetracycline, d-thyroxine, phenylbutazone, and coumadin (give drugs 1 hour earlier or 4 hours after resin). Cholestyramine has been shown to reduce CHD prospectively by 19% and LDL C by 11%, but had no effect on mortality in the large Lipid Research Clinics Trial (JAMA 251:365;1984).
A. Colesevalam:
A new resin, Welchol, is now available and is given at a dose of three 625 mg tabs twice per day, with reductions of 16-18%.
18. Combination Therapy:
For LDL lowering, statins can be used with ezetimibe. For HDL raising or Lp(a) lowering, add niacin to a statin, but monitor liver enzymes, uric acid, glucose, and CPK. For TG lowering, fenofibrate and a statin can be used together, but monitor for muscle problems and CPK. Fenofibrate with fish oil capsules can be used to lower triglycerides in those with severe hypertriglyceridemia. The use of fish oil reduces CHD risk and may prevent dementia.
All brand names referred to above trademarked and copyrighted by respective company.
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