A 39-Year-Old Woman With Hypercholesterolemia

DR REYNOLDS: Ms T is a 39-year-old African American woman with elevated lipid levels.

Ms T had her lipids checked during a routine office visit; she was not fasting. Because her levels had been elevated previously, the test was repeated after a 12-hour fast and after several months of following a low-fat diet. Her values were consistent with previous measurements: total cholesterol, 277 mg/dL (7.17 mmol/L); high-density lipoprotein (HDL) cholesterol, 64 mg/dL (1.66 mmol/L); low-density lipoprotein (LDL) cholesterol, 197 mg/dL (5.10 mmol/L); and triglycerides, 80 mg/dL (2.07 mmol/L).

Ms T's medical history is significant for hypertension, initially discovered during a pregnancy but now persistent and treated with hydrochlorothiazide, 25 mg daily. She has had one pregnancy that was complicated by hypertension and preeclampsia; she is otherwise well. Ms T's mother died of breast cancer at the age of 49 years, and her maternal grandmother was diagnosed with breast cancer at age 50 years. Ms T's brother had a stroke in his 30s and is now receiving lipid-lowering therapy for a mild elevation of his LDL cholesterol level; there is no known premature coronary disease or hypercholesterolemia in her family.

Ms T lives with her 3-year-old child; she works in transportation. She is a former smoker; she has smoked 35 pack-years since the age of 14 years but has not smoked in the past several years. She does not drink alcohol to excess or use recreational drugs. She is active but does not exercise regularly; she has been trying to eat low-fat foods.

On physical examination, Ms T is 69 inches tall and weighs 162 pounds; her body mass index is 24. Her blood pressure is 128/78 mm Hg; her heart rate is 72/min and regular. She has no xanthomas. The remainder of her examination results were normal.

Measurement of Ms T's blood glucose, thyroid stimulating hormone, and liver-associated enzyme levels were all normal. A urinalysis did not contain any protein.

There's no one in my family that I can think of that had high cholesterol . . . as far as I know I’m the only one. And I’m thinking maybe it’s because I have just been eating the wrong foods for so long.

Hopefully, I can try to change my eating habits and change my diet and exercise, and hopefully I won't have to take medication. Hopefully, that's not going to be a big concern in my life as far as health reasons go.

My big health concern is breast cancer. It runs in our family. My grandmother had it, and my mother passed away from it. So that is my biggest concern in the next 30 years. Once I found out my cholesterol was high, I immediately joined the gym and I work out 2 to 3 times a week now. I try to eat less red meat. I try to eat less dairy products. I don't drink, I don't smoke. I don't eat pork. I drink skim milk, no whole milk. I try to cut down on my cheese.

It hasn't been easy at all. Especially when you're so used to eating the wrong things and you have a taste for something that tastes really good and now you have to change your diet to something that tastes really bland. So it's been really hard, but I’m doing it.

I don't particularly like taking medications because when you take a medication for one thing, it has side effects that can cause other problems.

I went into a vitamin store and asked the woman if she had anything for high cholesterol. She gave me a supplement to take. She said it was good for high cholesterol, it was good for women, and it is good for your heart. Now I would like to know, can I take these supplements instead of taking medication and would the supplement make my cholesterol go down?

If I do take medication and my cholesterol level goes down, and then I stop taking the medication for it, is the cholesterol going to go right back up again? If my cholesterol goes down through medication, can I start to eat normal again—the junk foods—or do I have to watch my diet for the rest of my life?

What is the epidemiology of elevated lipids and how should screening be performed? What are Ms T's short- and long-term risks of atherosclerotic coronary disease? What is the evidence that lipid-lowering therapies are effective? What evidence supports primary prevention with drugs, especially in African Americans and women? What are the adverse effects of statins? How should we monitor treatment? What should our goal for therapy be? What do you recommend for Ms T?

DR MITTLEMAN: Ms T is a 39-year-old African American woman with recently diagnosed hypercholesterolemia. Her LDL cholesterol level remained quite elevated at 197 mg/dL [5.10 mmol/L] despite appropriate dietary counseling. She reports that she decreased her intake of saturated fat and increased her level of physical activity since she was found to have elevated cholesterol levels. The remainder of her lipid profile was normal with a triglyceride level of 80 mg/dL [2.07 mmol/L] and an HDL cholesterol level of 64 mg/dL [1.66 mmol/L]. Her high HDL cholesterol level and favorable total cholesterol:HDL cholesterol ratio of 4.3 help to lower her risk of developing coronary heart disease (CHD). Her other cardiac risk factors include hypertension, which is well-controlled with hydrochlorothiazide (25 mg daily), and a history of cigarette smoking. Although she does not have a family history of premature coronary artery disease, we are told that her brother had a stroke in his 30s and is now being treated with lipid-lowering therapy for an elevated LDL cholesterol level. Ms T has a family history of breast cancer in her mother and maternal grandmother, and her risk of breast cancer is her most pressing health concern.

Elevated cholesterol is extremely common among adults in the United States. The National Health and Nutrition Examination Survey (NHANES), 1999 to 2000, found that the mean age-adjusted total cholesterol level among adults 20 years of age or older was 203 mg/dL (5.26 mmol/L).¹ Average cholesterol levels increase from the second to the sixth decade and then plateau.^{1 - 4} Overall, high total cholesterol is more common among men than women; however, this pattern is apparent at younger ages and is reversed after 55 years of age. The prevalence of high total cholesterol (defined as total cholesterol ≥200 mg/dL [5.18 mmol/L] or current treatment with a lipid-lowering medication) increased from 29.8% among 20- to 34-year-old women to 84.5% among 65- to 74-year-old women.¹ Approximately 20% of men and 18% of women in the United States have an LDL cholesterol level above 160 mg/dL (4.14 mmol/L), and the age-adjusted prevalence of LDL cholesterol above 130 mg/dL (3.37 mmol/L) has been estimated to be approximately 46%, with higher prevalence among men than women.³

Under current National Cholesterol Education Program (NCEP) guidelines, more than 65 million US adults qualify for therapeutic lifestyle change and more than 36 million qualify for lipid-lowering pharmacological therapy.⁵ Adoption of proposed modifications to these guidelines would extend pharmacological treatment to an even larger number of patients.⁶

Tools such as the Framingham Risk Score have been developed to evaluate the impact of multiple risk factors simultaneously.^{5 ,7 - 9} The Third NCEP Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (NCEP-ATP III) recommends counting the number of established risk factors to assess risk and determine the frequency of cholesterol screening and treatment goals. The risk factors considered by NCEP-ATP III are as follows: age at least 45 years for men or at least 55 years for women; family history of premature CHD (before age 55 years in a male first-degree relative or before age 65 years in a female first-degree relative); current cigarette smoking; hypertension; and an HDL cholesterol level of less than 40 mg/dL (1.04 mmol/L). The NCEP-ATP III guidelines recommend that patients with diabetes mellitus be treated as aggressively as patients with established CHD—a position supported by other recent guidelines.^{6 ,8 ,10 - 11} Ms T has one of the NCEP-identified risks, hypertension.

The NCEP-ATP III guidelines recommend that all adults aged 20 years and older should have a fasting lipoprotein profile, including total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides, measured every 5 years.⁵ For low-risk individuals (0-1 risk factors) like Ms T, a more convenient nonfasting blood sample may be used to measure total and HDL cholesterol and no further testing is needed if the HDL cholesterol level is 40 mg/dL (1.04 mmol/L) or higher and total cholesterol is less than 200 mg/dL (5.18 mmol/L). Annual full fasting lipoprotein assessment is recommended for patients at higher risk by virtue of having 2 or more risk factors or borderline results on previous testing. The guidelines do not recommend an upper age to discontinue screening. Because higher absolute benefit of treatment is likely to occur in patients at the highest baseline risk of cardiovascular events, treatment of dyslipidemia in elderly people is likely to be associated with a large absolute risk reduction.¹²

While there is a growing body of literature supporting the central role of vascular inflammation in the pathobiology of atherosclerosis and acute cardiovascular events,^{13 - 17} the value of routine populationwide screening for markers of inflammation has not been proven at this point.^{18 - 19} Although there is extensive evidence that an elevated C-reactive protein level is associated with an increased risk of cardiovascular events,^{20 - 29} the role of screening for novel or emerging risk factors is controversial.¹⁸ Based on a recent Scientific Statement from the Centers for Disease Control and Prevention and the American Heart Association,¹⁸ measuring Ms T's C-reactive protein is optional and I would not measure it at this time. Other novel markers that appear to predict risk and are important areas of current research but do not have sufficient data to support widespread screening include homocysteine,^{30 - 32} lipoprotein(a), apolipoprotein A-1, apolipoprotein B, LDL particle size and number, and computed tomographic evaluation for coronary calcium.^{5 ,19 ,33 - 34} On the other hand, elevated triglyceride levels are associated with increased cardiovascular risk, particularly among women.³⁵

Medical conditions that can lead to hypercholesterolemia include diabetes mellitus, hypothyroidism, obstructive liver disease, nephrotic syndrome, Cushing syndrome, anorexia nervosa, acute intermittent porphyria, and the use of certain drugs, including oral contraceptives. Conditions that are known to be associated with elevated triglyceride levels include diabetes mellitus, hypothyroidism, chronic renal failure, pancreatitis, bulimia, obesity, excessive alcohol intake, lipodystrophy, glycogen storage disease, ileal bypass surgery, pregnancy, systemic lupus erythematosus, monoclonal gammopathy, multiple myeloma, lymphoma, pregnancy, and certain drugs including estrogen, isotretinoin, β-blockers, glucocorticoids, bile acid–binding resins, thiazides, and protease inhibitors.³⁶

The evaluation for secondary causes of dyslipidemia consists primarily of a careful history taking, physical examination, and a few basic laboratory tests. Routine evaluation of patients like Ms T must include a careful examination for xanthelasmas and tendon xanthomata, potential signs of familial hypercholesterolemia, indicating an even higher CHD risk. Ms T's physical examination and laboratory testing did not reveal any familial or secondary causes of her hypercholesterolemia.

The current NCEP-ATP III guidelines recommend that patients be divided into 3 categories of risk that modify the threshold to begin treatment and the target levels of LDL cholesterol. Low-risk patients are those with 0 or 1 risk factor and an estimated 10-year risk of CHD of less than 10% based on the Framingham Risk Score. Patients with 2 or more major risk factors or an estimated 10-year risk of 10% to 20% are at intermediate risk. Patients with established CHD, other clinical atherosclerotic disease (including peripheral arterial disease, abdominal aortic aneurysm, carotid artery disease, transient ischemic attack, stroke, and other forms of clinical atherosclerotic disease), diabetes mellitus, and those with multiple risk factors and an estimated 10-year risk of CHD of more than 20% are all considered at high risk.⁵

Based on Ms T's history of hypertension, age, and other risk factors, she is at low risk with an estimated 10-year risk of developing CHD of approximately 1% to 2% based on the Framingham Risk Score. However, this is likely an underestimate of her true risk for several reasons. First, the Framingham Risk Score does not directly take family history into account.⁵ Although there are no definitive data on its importance as a risk factor, I am concerned by her brother's history of stroke in his 30s. Second, the model was not developed using much data from African American women, who are known to have higher average risk than European American women.³ For example, the Framingham Risk Score substantially underestimated the relative risk (RR) associated with hypertension among African American women enrolled in the Atherosclerosis Risk in Communities (ARIC) study.³⁷

In addition to assessing her 10-year risk, it is important to consider Ms T's longer-term risk of developing heart disease. Based on the Framingham Heart Study, an average 40-year-old woman with a total cholesterol level greater than 240 mg/dL (6.22 mmol/L) has an approximate 1 in 3 chance of developing CHD in her lifetime,³⁸ and African American women appear to have an even higher risk.³

Treatment Goals for High-Risk Patients. Until recently, the standard for lipid-lowering therapy for high-risk patients has been to treat to an LDL cholesterol goal of 100 mg/dL (2.59 mmol/L), beginning drug therapy only after a trial of diet and behavioral change. However, based on recent clinical trials^{5 - 6 ,39 - 43} shown in the Table, an update to the NCEP-ATP III guidelines recommends that all high-risk patients with LDL cholesterol levels above 100 mg/dL (2.59 mmol/L) begin with LDL-lowering therapy⁵ and have a target LDL cholesterol level of 70 mg/dL (1.81 mmol/L).^{5 - 6 ,39 - 43} Patients with elevated triglyceride or low HDL cholesterol levels should have medications that target these levels added to their regimen.

Treatment Goals for Intermediate-Risk Patients. For patients with multiple risk factors but a 10-year risk below 10%, the NCEP-ATP III guidelines recommend that drug therapy be added if the LDL level remains above 160 mg/dL (4.14 mmol/L) despite dietary therapy. The NCEP-ATP III update notes that an LDL cholesterol goal below 100 mg/dL (2.59 mmol/L) is optional for intermediate-risk patients.⁶

Treatment Goals for Low-Risk Patients.The recommendation for low-risk patients is to begin dietary and lifestyle changes when the LDL cholesterol level is 160 mg/dL (4.14 mmol/L) or higher, with a goal of reducing LDL to this level. The panel recommended that cholesterol-lowering drug therapy should be considered if the LDL cholesterol level remains at least 190 mg/dL (4.92 mmol/L) after an adequate trial of dietary therapy. A cholesterol-lowering drug is considered optional when LDL cholesterol is 160 to 189 mg/dL (4.14-4.90 mmol/L).⁵ Ms T has attempted to follow dietary recommendations for several months, yet her LDL cholesterol level remains elevated; the guidelines recommend intensification of therapeutic lifestyle changes and initiation of pharmacological therapy at this point.⁵

Based on extensive epidemiological and clinical trial evidence, the risk of CHD appears to have a log-linear relationship with LDL cholesterol level.^{6 ,42 ,44 - 46} For every 30 mg/dL (0.78 mmol/L) decrement in LDL cholesterol, there is an expected approximate 30% lower risk of CHD events.^{6 ,41 ,44} When counseling individual patients, it is important to consider patient concerns and preferences together with evidence from clinical trials, the patient's absolute risk, and the expected absolute potential benefit or harm of any specific treatment.

There are several approaches that have been shown to lower LDL cholesterol effectively and have other beneficial effects on the overall lipid panel, such as increased physical activity^{5 ,47 - 49} and specific dietary interventions.^{5 ,48} In the absence of weight loss, frequent high-intensity physical activity may increase HDL cholesterol by an average of 10%. However, the effect on LDL cholesterol is much more modest, an average of less than a 3% decline.⁴⁷ The cornerstones of the dietary recommendations include limiting saturated and trans fats and, to a lesser extent, dietary cholesterol, and increasing plant stanols and sterols and soluble fiber.^{5 ,48 - 49} Consumption of unsaturated fats from nuts and other vegetable sources can lower LDL cholesterol.⁵ Weight reduction in overweight men and women can lower LDL cholesterol.^{5 ,50} Ms T's body mass index is in the desirable range; thus, significant weight loss may not be medically indicated. Ms T has tried to follow a low-fat diet, although we do not know how much instruction she was given. However, data from the recently published Women's Health Initiative showed that compared with usual care, dietary advice similar to that given to Ms T was associated with only an average 3% reduction in LDL cholesterol after 3 years and did not significantly affect the risk of CHD in postmenopausal women.⁵¹

Although there is a lack of primary prevention trials conclusively proving that dietary changes and regular exercise can prevent cardiovascular disease, epidemiological evidence suggests that this is the case.^{5 ,48 - 49} In addition, there is direct experimental evidence of the beneficial effects on intermediate end points including favorable effects on the lipid profile, blood pressure, and weight reduction.^{5 ,48} Some clinical trial evidence also suggests the benefit of lifestyle changes in the secondary prevention setting, which may or may not generalize to primary prevention.^{52 - 53}

In terms of pharmacological therapy for LDL reduction, statins are the most widely used.⁶ In 2003, statin drugs already accounted for the largest expenditure of any prescription drug class, with $12.5 billion per year in the United States.⁵⁴ Their popularity stems from their relatively high potency at lowering LDL cholesterol and the extensive clinical trial evidence showing a reduction in clinical end points.^{5 - 6 ,8 ,39 - 40 ,42 - 44 ,48 ,55 - 58} Other drug treatments that lower LDL cholesterol and reduce cardiovascular end points include the bile acid–binding resins^{5 ,59} and niacin,^{5 ,60} which also reduces triglyceride and raises HDL levels. Ezetimibe is a Food and Drug Administration–approved treatment for lowering LDL cholesterol that has modest effects when used alone but synergestic effects when combined with a statin.⁶¹ However, to date, there are no long-term clinical trials evaluating the effect of this treatment on the incidence of cardiovascular events. Fibric acid derivatives reduced cardiovascular events in some^{62 - 63} but not all^{60 ,64} studies. The primary effect of the fibric acid derivatives is on lowering triglyceride levels and moderately raising HDL rather than potently lowering LDL cholesterol.^{5 ,62}

LDL-Lowering Pharmacological Therapy in Women. Although clinical trial data supports the efficacy of LDL-lowering therapy, particularly with statins, in reducing cardiovascular disease events in both primary and secondary prevention settings, there are relatively fewer data in women than in men.⁵⁷ However, there is little indication of gender-specific variation in the effect of these drugs.⁵⁶ Walsh and Pignone conducted a meta-analysis of drug treatment of hyperlipidemia in women.⁵⁷ They found that LDL-lowering therapy in women with prevalent heart disease was associated with no overall effect on total mortality (RR, 1.00; 95% confidence interval [CI], 0.77-1.29), a statistically significant reduction in CHD mortality (RR, 0.74; 95% CI, 0.55-1.00), nonfatal myocardial infarction (RR, 0.73; 95% CI, 0.59-0.90), and need for coronary revascularization (RR, 0.70; 95% CI, 0.55-0.89), and an overall 20% relative reduction in CHD events among women randomized to receive statin therapy compared with placebo (RR, 0.80; 95% CI, 0.71-0.91). In the setting of primary prevention there were relatively few outcome events among women in the examined trials, resulting in imprecise effect estimates with wide confidence limits. They found no significant overall effect of treatment on total mortality (RR, 0.95; 95% CI, 0.62-1.46) or CHD mortality (RR, 1.07; 95% CI, 0.47-2.40). The risks of nonfatal myocardial infarction and need for coronary revascularization were lower in the groups treated with statins, although these effects did not reach statistical significance (RR, 0.61; 95% CI, 0.22-1.68 and RR, 0.87; 95% CI, 0.33-2.31, respectively). Overall, there was a non–statistically significant 13% relative reduction in CHD events among women randomized to receive statin therapy compared with placebo (RR, 0.87; 95% CI, 0.69-1.09). In interpreting these data, it is interesting to note that the magnitude of the observed protective effect was similar to that reported among men enrolled in these trials. In the setting of an overall significant effect, the finding that a subgroup representing a minority of the participants does not reach statistical significance, despite a similar effect size as the majority of the participants, does not prove a lack of effect of treatment in that subgroup.⁶⁵ Based on this estimate, approximately 150 women with a 10-year risk of 5% would need to be treated for 10 years to prevent 1 event. However, that number would increase to more than 750 for women with an estimated 10-year risk of approximately 1%.

Safety of Lipid-Lowering Therapy. The safety of statins has been extensively and thoroughly reviewed elsewhere.^{10 ,44 ,66 - 68} Data from randomized trials and postmarketing studies accumulating since the late 1980s indicates that this class of medications is generally safe.^{10 ,40 - 43 ,55 ,69} Although the rate of discontinuation of statins in clinical trials has been approximately 15%, it has been consistently similar to placebo. In recent large randomized trials, the incidence of elevation of muscle or liver enzymes did not differ significantly from those in the placebo groups.^{40 - 43 ,55} In the Heart Protection Study,⁴⁰ 1.8% of patients randomized to receive simvastatin and 1.6% of patients receiving placebo had alanine transaminase elevations above twice the upper limit of normal. The frequency of creatine kinase (CK) elevation was similarly low at 0.3% and 0.2% for the statin and placebo groups, respectively. There appears to be a higher risk of adverse effects with higher-intensity statin treatment. Waters⁶⁹ reported that among 11 878 patients randomized to receive atorvastatin (80 mg daily), aspartate transaminase or alanine transaminase levels were elevated above 3 times the upper limit of normal in 0.5% to 3.3% of patients compared with 0% to 1.6% of patients randomized to lower-intensity lipid-lowering treatments.⁶⁹ Similarly, the risk of significantly elevated transaminases was low for patients treated with high-intensity simvastatin treatment ranging from 0.09% to 1%. There is a rare risk of rhabdomyolysis, for which cerivastatin was withdrawn from the market and cases have been reported with other, currently marketed statins, particularly when used at higher doses.⁶⁹ A recent clinical practice guideline from the American College of Physicians recommended that “routine monitoring of liver or muscle enzymes is probably not warranted except in patients with symptoms, patients who have liver enzyme abnormalities at baseline, or patients taking drugs that interact with statins to increase the risk for adverse events.”¹⁰ Such drugs include fibrates and inhibitors of the CYP3A4 pathway (eg, azole antifungals, macrolides, protease inhibitors, and grapefruit juice) for statins metabolized through this pathway, including atorvastatin, lovastatin, simvastatin, and to a lesser extent fluvastatin. Pravastatin and rosuvastatin are not metabolized through this pathway.

Ms T has a family history of breast cancer, which she cites as a greater health concern than her cholesterol levels. In 1996, the Cholesterol and Recurrent Events (CARE) study reported that breast cancer occurred in 1 patient in the placebo group and 12 in the pravastatin group.⁵⁸ This finding has not been replicated in subsequent large randomized trials of pravastatin or other statins.^{40 - 43 ,55} Recent meta-analyses of clinical trial data involving approximately 90 000 patients treated for an average of 2 to 10 years have found no association of statin therapy with breast cancer or for all cancers combined.^{70 - 71}

In advising Ms T, it is crucial that she be informed about the risks and potential benefits of treatment alternatives, including the lack of large-scale clinical trial evidence derived from patients with her clinical characteristics (African American women with hypertension and LDL cholesterol >190 mg/dL [4.92 mmol/L]). Ms T should be made aware of the risk of cardiovascular disease in African American women in general and counseled specifically regarding her individual risk. Once she is fully informed, Ms T should be an active participant in determining the most appropriate preventive strategy. Ms T's concern regarding breast cancer must be addressed and she should be given recommendations regarding appropriate breast cancer screening and prevention.

Given Ms T's history of hypertension, family history, and degree of elevation of her LDL cholesterol, I would recommend treatment to lower her LDL cholesterol level to 160 mg/dL (4.14 mmol/L) or lower. She has already had a trial of dietary intervention that did not succeed in lowering her LDL cholesterol to goal. Although Ms T describes an attempt to cut down on her saturated fat intake, she may benefit from more intensive, personalized counseling by a dietician. I would reinforce the importance of diet and exercise not only to control her hypercholesterolemia, but for overall health benefits including blood pressure control. The dietary supplement that Ms T obtained is unlikely to significantly reduce her LDL cholesterol and it may have significant cost.

Based on the Framingham Risk Score, her 10-year risk of CHD is relatively low, certainly less than 5% and probably close to 2%.^{5 ,7} However, I am also concerned about her longer-term risk. It is important to remember that, in the United States, approximately 40% of African American women die of cardiovascular disease, which is about twice as many as who die from all cancers combined.³ Given her history of hypertension and because Ms T has already had a trial of lifestyle changes and her LDL cholesterol remains elevated at 197 mg/dL (5.10 mmol/L), I would obtain baseline liver function tests and CK values and recommend beginning treatment with a low dose of a statin. I would advise her on the risks of adverse events and would recheck her lipid profile after 4 to 6 weeks and again after 12 weeks of treatment. The statin package inserts recommend that liver function tests and CK be checked, but the need for monitoring in the absence of symptoms or potential drug interactions is not clear.⁶⁹ Long term, I would have her follow up every 6 to 12 months depending on how she responds to therapy.

A question to consider is whether it is reasonable to delay treatment until Ms T manifests clinical cardiovascular disease or until she is at substantially higher short-term risk for an event. However, this approach is not consistent with our current understanding of the progression of atherosclerosis over a lifetime. While it is true that patients with existing cardiovascular disease have a baseline risk of sustaining a recurrent event that is higher than for an individual currently free of clinical coronary disease, the relative risk reduction associated with preventive treatment is similar, leading to a lower net absolute risk reduction in the setting of primary prevention. Unfortunately, our risk prediction tools are not good enough to adopt a strategy of waiting until an event is about to occur and beginning preventive therapy at that point. On the other hand, the societal and direct patient costs of a primary prevention pharmacological intervention strategy, which may be quite large and is controversial from a cost-effectiveness viewpoint, must be considered.⁷²

Finally, although the evidence regarding LDL-lowering therapy in the primary prevention setting among women is sparse, it appears to indicate that such therapy may reduce the incidence of CHD events but not total mortality. An important role of prevention is not only to increase longevity, but also to help patients maintain a high quality of life by preventing potentially debilitating illnesses such as myocardial infarction and the need for revascularization procedures.

QUESTION: You recommended starting a 40-year-old woman on statins. That means she's likely to have to take a drug all her life, which inhibits a major enzyme in human metabolism. What do we know about the long, long, long term safety of statins?

DR MITTLEMAN: Statins have been approved and marketed in the United States since the late 1980s, with growing numbers of patients being treated in more recent years. At this time, there is no consistent evidence of unexpected long-term adverse effects based on postmarketing surveillance studies or from completed randomized trials.¹⁰ As for all drug classes, continued pharmacovigilance is essential to detect any unexpected long-term adverse effects.

QUESTION: If you recommend a statin for a 39-year-old woman, you have to think about the benefit and the risk. You took us through a calculation at the beginning that, according to Framingham numbers, her risk is about 1% to 2% of developing any coronary disease in the next 10 years. You extrapolated from AFCAPS/TexCAPS [Air Force/Texas Coronary Atherosclerosis Prevention Study] to say that maybe her risk reduction with treatment could be as much as 37%. However, the ALLHAT-LLT [Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack] study, which was a much larger study and included many more women, showed no benefits whatsoever to lowering lipids in asymptomatic people. Even if you could achieve that degree of benefit, you take her from a 1% risk to a 0.6% risk in the next 10 years, without considering potential harms. If she's 39, is she thinking about establishing a pregnancy? Statins are contraindicated in women who may potentially get pregnant. How do all those questions make it into your benefit and risk equation that would lead you to give this woman a statin?

DR MITTLEMAN: It is important to remember that the Framingham Risk Score does not take all of Ms T's attributes into account. For example, the family history of premature cardiovascular disease is not incorporated. Furthermore, the Framingham prediction likely underestimates risk in African Americans. It is also important to consider that the increase in cardiovascular risk with age appears to be steeper in African Americans than in European Americans.³ While the ALLHAT-LLT study did not reach statistical significance, there was a trend toward a reduction in major adverse cardiovascular events, of a magnitude that was consistent with other studies based on the relatively small difference in achieved LDL cholesterol.⁴² Statin use is contraindicated during pregnancy and Ms T should be counseled appropriately.