Some myths persist -- among physicians and patients -- about managing cholesterol levels.

To overcome them, it helps to review the accumulated evidence from various large-scale treatment trials.

Coronary heart disease (CHD) is the leading killer of both men and women, accounting for 500 000 deaths per year in the United States. Its impact can be reduced by applying lessons learned from clinical trials. While 12 million to 13 million patients in the United States have CHD, millions more are at increased risk because of age, sex, BP, diabetes, obesity, smoking, sedentary lifestyle, and cholesterol levels.

Public health information has had only a mild influence on reducing mortality from CHD in recent years. Although cigarette use is slowly declining, the average American's weight is increasing -- along with the related problems of hypertension, diabetes mellitus, and hyperlipidemia.

The Adult Treatment Panel II of the National Cholesterol Education Program (NCEP) published guidelines in 1993 aimed at increasing physician and patient awareness to improve management of coronary risk factors. The panel based their recommendations for cholesterol goals, in large part, on epidemiologic studies from the previous 20 years, such as the Framingham Heart Study and the Multiple Risk Factor Intervention Trial (MRFIT) (see Table 1).

Table 1: NCEP Guidelines for Cholesterol Levels

Desirable total cholesterol:

<200 mg/dL

Desirable HDL-C:

>35 mg/dL

Desirable LDL-C:

-- If 0-1 risk factors present

<160 mg/dL

-- If 2 risk factors present

<130 mg/dL

-- Patients with evidence of CHD or other atherosclerotic disease

<100 mg/dL

Source: Summery of the second report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel II). JAMA. 1993;269:3015-3023.

Recommended LDL cholesterol (LDL-C) goals are based on a patient's cardiac risk profile. The NCEP recommendation is to reduce LDL-C levels below 100 mg/dL for secondary prevention of coronary events in patients with CHD and/or another atherosclerotic disease. Guidelines for patients without atherosclerotic disease are for more moderate LDL-C reduction -- depending on the number of coronary risk factors. HDL cholesterol (HDL-C) is a protective factor; patients whose HDL-C levels are less than 35 mg/dL are at increased risk for coronary events. A number of landmark cholesterol-reduction trials concluded since the NCEP report was issued validate most of its guidelines for lipid management. Still, most patients today aren't treated aggressively enough to reach NCEP goals.

Patients bear partial responsibility for their increased coronary risk -- especially if they don't comply with recommendations for lifestyle modification or medication. Health care providers may not make these recommendations to the patient, however, and may not give enough attention to counseling about diet, smoking cessation, exercise, or medical therapy. Hyperlipidemia is often a silent killer, and identification and appropriate management of the overall risk of affected patients is important to improving individual and societal outcomes.

Patients with CHD are at 5 to 7 times higher risk for coronary events and death than age- and sex-matched controls. These are the patients in whom cholesterol-reduction decreases mortality the most. Yet in a recent review of physician and hospital records, only 67% of patients with CHD had documented cholesterol levels. Fewer -- only 55% -- received any form of dietary counseling. Only 33% received medications to lower their cholesterol levels, and these medications were often not of the beneficial HMG-CoA reductase inhibitor (statin) group. Fewer than 1 in 7 CHD patients achieved the LDL-C target of 100 mg/dL first suggested by the NCEP guidelines, which have been validated by clinical trial data.1 The so-called treatment gap in hyperlipidemia and CHD results from lack of awareness and application of trial evidence and also from perpetuation of misconceptions or myths in clinical practice.

Awareness of Clinical Trial Evidence

The NCEP guidelines do not specify which agents to use in cholesterol reduction. Since the NCEP report was published, however, statins have emerged as the treatment of choice in both the prevention and treatment of CHD. This is partly because this class of drugs is very well-tolerated by patients, with few drug-related adverse events noted in large clinical trials.

The major reason to use statins is their demonstrated impact on reducing overall mortality and cardiovascular events.2 The Scandinavian Simvastatin Survival Study (4S), for example, demonstrated a 30% reduction in all-cause mortality in more than 4400 patients with hyperlipidemia and CHD, treated with simvastatin -- compared to placebo -- for just over 5 years.3 The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) study revealed a 24% improvement in mortality rates in patients with CHD who used pravastatin, 40 mg/d for 6 years.4 The patients in LIPID were 31 to 75 years old, with all age-groups and both sexes benefiting regardless of initial LDL-C levels. Even studying a high-risk population of primary prevention patients, the West of Scotland Coronary Prevention Study (WOSCOPS) demonstrated a 22% decrease in mortality in hyperlipidemic men using pravastatin for just less than 5 years.5

A recent meta-analysis of 29,000 patients in statin monotherapy trials found a 22% decrease in total mortality and a 29% decrease in stroke risk in treated patients. Meanwhile, no change was seen in non-cardiovascular mortality or cancer risk.2 Combined, these studies make a compelling case for using statins in a wide variety of clinical scenarios.

Myth: Diet is the appropriate initial cholesterol-lowering therapy in CHD.

The NCEP guidelines suggest that an American Heart Association (AHA) step II diet be used for 3 months toward an LDL-C goal of less than 100 mg/dL in CHD patients (see Table 2). Keep in mind, though, that the CHD prevention trials of statins showed benefit against a background of diet therapy. This means that both the treatment and placebo groups received dietary counseling throughout the trial.

As mortality rates for simvastatin versus placebo in the secondary prevention trials began to diverge in a matter of months, waiting to begin drug therapy in this setting leads to unjustified loss of life in the interim. The AHA, therefore, released a policy statement acknowledging that drugs and diet together should be initial therapy for patients with CHD whose LDL-C is greater than 130 mg/dL.6

Table 2: NCEP/AHA "Step" Diet

Nutrient

Step I

Step II

Total fat

</=30%

</=30%

Saturated fat

8%-10%

<7%

Polyunsaturated fat

</=10%

</=10%

Monounsaturated fat

</=15%

</=15%

Carbohydrates

</=55%

</=55%

Protein

15%

15%

Cholesterol

<300 mg/d

<200 mg/d

Note: This diet should be coupled with total caloric restriction, when appropriate, to achieve and maintain desirable weight.

Source: Summary of the second report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, end Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel 11). JAMA. 1993;269:3015-3023.

Myth: A patient with CHD whose cholesterol panel is normal doesn't have a problem.

The fact that the patient already has CHD means his or her cholesterol level is too high. Other factors also interact with cholesterol to promote atherosclerosis, including diabetes mellitus, smoking, hypertension, or other less easily quantifiable factors such as an adverse family history, an oxidative environment, and hypercoagulability.

The Cholesterol and Current Events (CARE) trial examined how often coronary events recurred in 4159 men and women with "normal" cholesterol levels who had previously suffered an MI. The patients were randomized to receive pravastatin, 40 mg, or placebo daily. Pravastatin treatment was associated with a 24% reduction in CHD death and nonfatal MI rates, but the trend toward decreased total mortality did not reach statistical significance.7 In 4S, patients with total cholesterol levels of 215 to 240 mg/dL at entry showed a mortality risk reduction from simvastatin similar to results for more hyperlipidemic patients. In the LIPID study, pravastatin's benefit was seen at all initial LDL-C levels.

As nearly all types of patients with CHD benefit from statin therapy, their disease -- not just their serum cholesterol level -- justifies treatment with a statin.

Statins' effectiveness in patients with coronary disease and relatively "normal" cholesterol levels may relate to how the medications improve endothelial function, provide anti-inflammatory effects that may lessen the likelihood of plaque rupture, inhibit platelet aggregation, contribute antithrombotic/fibrinolytic effects, and promote other factors contributing to plaque stabilization.8

Myth: Hormone replacement in postmenopausal women with CHD is an appropriate alternative to lipid-lowering medication.

Estrogen replacement has a number of advantages, including improvement in HDL-C levels, bone mineral density, and quality-of-life measures. Also, observational research suggests a decreased rate of MI associated with hormone replacement.9 Recent data from the Heart and Estrogen/progestin Replacement Study (HERS), however, suggest a 52% increased coronary event rate in the first year of treatment with a conjugated estrogen/medroxyprogesterone regimen in postmenopausal women. But the effect was balanced by a lower event rate in the ensuing 3 years of the trial, producing no net change in the CHD event rate.10

These findings contrast with beneficial effects of other forms of lipid-lowering treatments in a similar patient population. Women in both the CARE trial and the LIPID study were significantly less likely to die when treated with pravastatin rather than a placebo. Of course, hormone replacement should be discussed individually, noting the risks and benefits of treatment for each patient's clinical situation. As part of this discussion, women should understand that CHD is their leading cause of death. While the data (though certainly limited at present) do not yet support use of a combined estrogen/progestin regimen to decrease recurrent events in CHD, trial evidence is adequate to support statin therapy. Whether hormone replacement offers additional cardiovascular benefit to statin treatment remains to be seen.

Myth: A patient with high triglycerides and/or low HDL-C is a more appropriate candidate for gemfibrozil or niacin.

Basing the choice of lipid-lowering medication on "phenotypes" of lipid disorders makes intuitive sense, but it isn't supported by available data. Fibrates may be used to treat severe hypertriglyceridemia (serum TG greater than 700-1000 mg/dL) to reduce the likelihood of pancreatitis and its devastating impact. Agents such as gemfibrozil, however, should be used with caution to reduce the risk of death when a patient has hyperlipidemia. When assessed as part of a meta-analysis, fibrates were associated with a higher mortality rate. Noncoronary mortality increased by 30% with fibrate use -- contributing to a 17% increase in total mortality.11 One trial was stopped early because of increased mortality associated with clofibrate use.12

For treating more modest hypertriglyceridemia, therefore, a safer option appears to be reducing dietary fat and body weight -- perhaps in concert with statin therapy.

The management of patients with low HDL-C is more uncertain. The most recent data from another study, involving treatment of men with CHD and low-normal HDL-C, showed a 22% reduction in the combined end point of CHD death and nonfatal MI with gemfibrozil, with no significant change in serum LDL-C levels.13 This suggests a small role for fibrates in selected CHD patients. Until there is demonstrated improvement in total mortality in a population treated with fibrates, however, better and safer treatment options are available.

Traditionally used as a therapy to boost HDL-C levels, niacin has a small impact on reducing mortality in the treatment of hyperlipidemia. In one study, mortality was reduced by 11%, but it took nearly 15 years of follow-up for this to be demonstrated.14 In contrast, statins achieve a much greater impact on mortality -- within months to years -- both in patients with established CHD and in selected ones with hyperlipidemia. In the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS), about a one-third reduction in coronary events (with no significant change in mortality) was seen in a low-risk primary prevention population with low-normal HDL-C treated with lovastatin.15 In general, lipid profiles from the lab should guide the intensity-but not the choice-of cholesterol-lowering therapy.

Myth: Achieving an LDL-C of 100 mg/dL in CHD treatment, as suggested by the NCEP guidelines, is not necessary.

While the NCEP panel arrived at this recommendation in large part by looking at observational data, prospective trials have since validated treating to a target LDL-C of 100 mg/dL in patients with established CHD. The best one to assess this so far is the Post-CABG trial, in which coronary bypass patients were treated for either "moderate" or "aggressive" LDL-G reduction. The trial used lovastatin, with cholestyramine added as necessary, to achieve LDL-C levels of 132 to 136 mg/dL, or 93 to 97 mg/dL, respectively. Patients receiving "aggressive" treatment were one third less likely to experience progression in their graft coronary disease and 30% less likely to undergo revascularization than were patients given placebo.

A comparison of cardiac event rates in placebo and treatment groups in the primary and secondary prevention statin studies strongly suggests that events decrease as the LDL-C level decreases, approaching 100 mg/dL. The recent Atorvastatin Versus Revascularization Treatments (AVERT) study examined even more aggressive lipid reduction in patients with mild CHD referred for angioplasty. The patients, 71% of whom were already taking lipid-lowering medication, were randomized either to undergo angioplasty with usual medical care, or to take atorvastatin, 80 mg/d.

Angioplasty/usual therapy patients achieved an LDL-C level of 119 mg/dL, which some physicians might feel is sufficient. But patients treated with high-dose atorvastatin -- without angioplasty -- achieved an LDL-C level of 77 mg/dL, which was associated with a 36% reduction in the combined end point of CHD death, MI, and any ischemic event. As patients in the study had a low ischemic event rate (approximately 13%) and mortality rate (just 2 deaths), despite their referral for angioplasty, they were at relatively low-risk in contrast to those in other CHD studies.16

Myth: A patient with no symptoms is at low risk for coronary events.

Approximately half of patients who suffer their first MI have had no antecedent symptoms of angina. Because roughly one third of MIs are fatal, identifying patients at risk for CHD is important. It would be ideal to diagnose asymptomatic early CHD and target these high-risk patients for therapy. Traditional stress testing is inadequate for this purpose, in that it detects only flow-limiting coronary lesions that would cause ischemia. Angiographic studies make clear, however, that nearly two thirds of MIs occur when vulnerable plaques of less than 50% stenosis rupture.17 These areas would be silent on most stress tests because they are unlikely to cause ischemia.

Statins also have anti-ischemic effects, as they decrease claudication symptoms, the incidence of carotid bruits,18,19 and silent ischemia on ST-segment monitoring. It is unlikely that this is why they have proven to be so beneficial, however. Other therapies targeting ischemic symptoms -- such as angioplasty for stable angina, nitrates, and calcium channel blockers -- have failed to reduce overall mortality.

We need to recognize patients with a known coronary history when treating them for other problems, such as sinusitis, back pain, and headaches. As most visits focus on symptoms, the asymptomatic CHD patient can be missed. Patients don't always ask what can be done about their mortality risk in relation to hyperlipidemia and/or CHD. We need to appropriately screen patients in histories and lab evaluations for CHD evidence or risk and then counsel them. Patients at particularly high risk include those with diabetes, many of whom may have silent, incipient CHD. Symptoms, therefore, should not be the main basis for assessing risk.

Myth: Society cannot bear the high cost of lipid-reduction therapy.

Presently, medical hyperlipidemic treatment, especially with statins, is costly. Statins vary significantly in price, but all will likely become less expensive when generic lovastatin becomes available in 2001. Several cost analyses of 4S show that in a high-risk CHD population, simvastatin cost is nearly or completely offset by savings in hospitalizations, procedures, and bypass surgery. These analyses do not factor in the costs to society of morbidity and mortality from not treating CHD patients with a statin. Statin treatment compares very favorably to other CHD treatments or procedures we readily offer.

In primary prevention, drug treatment is costly-likely to be offset only partially by savings from averted coronary events. Careful patient selection and continued reinforcement of lifestyle principles, therefore, are both critical.

One strategy is to reserve the medications for patients with multiple risk factors, as suggested by the NCEP. Another option is to use a recently published coronary risk assessment formula, based on data from the Framingham Heart Study, which is easily employed in an office visit.* The formula yields a likelihood of a CHD event within the next 10 years.20 The European community has adopted a strategy of primary prevention drug therapy when CHD event risk exceeds 2% per year, although some lipid experts suggest a threshold of 1.5%.

My strategy is often to attempt to prove or disprove the presence of CHD in hyperlipidemic patients for whom treatment appears of borderline benefit or who are reluctant to begin it. Finding ways to identify early, asymptomatic CHD in this way, which includes the use of ultra-fast CT, MRI, and positron emission tomography, is an active area of study.

Some suggest finding evidence for atherosclerotic disease in other areas of the circulation via B-mode carotid duplex scanning or ankle-brachial index measurement. If atherosclerotic disease is identified, patients should be treated to achieve an LDL-C level of 100 mg/dL or less. In patients who have moderately elevated cholesterol levels, and in whom noninvasive testing does not suggest incipient coronary disease, therapy can be reasonably deferred. This saves resources for higher-risk patients.

Other proposed "soft" risk factors, which might aid treatment decisions, include levels of homocysteine, lipoprotein(a), small, dense LDL-C, certain thrombotic markers, antibodies to Chlamydia pneumoniae, and ultrasensitive measurements of C-reactive protein. These tests cannot be recommended at this time, however, until further study supports their consistent value. Appropriate risk stratification when selecting patients for the primary prevention of CHD with lipid-lowering therapy helps make such therapy significantly more cost-effective.

The Future

Future research in lipid management and cardiovascular disease prevention will help physicians assess risk and guide treatment decisions for different populations with unhealthy lipid levels. Further studies are in progress regarding outcomes with more aggressive LDL-C reduction with statins, HDL-C improvement with niacin, and the use of hormone replacement therapy.

Based on current evidence, all patients with any form of atherosclerosis, regardless of cholesterol levels, should be considered candidates for statin therapy. Treatment to reduce LDL-C levels is a cost-effective way to save and improve lives. This therapy should be coupled with aspirin, beta-blockers, and angiotension-converting enzyme inhibitors, where indicated, as these therapies also help save the lives of patients with CHD.

References

1. McBride P, Schrott HG. Plane MD, at al Primary care practice adherence to National Cholesterol Education Program guidelines for patients with coronary heart disease. Arch Intern Med. 1998:158:1238-1244.

2. Hebert PR, Gaziano JM, Chan KS, et at Cholesterol lowering with statin drugs, risk of stroke, and total mortality: an overview of randomized trails. JAMA. 1997;278:313-321.

3. Pedersen TR, Kjekshus J. Berg K. et al and the Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet. 1994:344:1383-1389.

4. Tonkin A. Late-breaking clinical trials. Paper presented at: 70th Scientific Sessions. American Heart Association, November 12,1997; Orlando, Fla.

5. Packard CJ, Shepherd J, Cobbe SM. et al and the West of Scotland Coronary Prevention Study Group. Influence of pravastatin and plasma lipids on clinical events in the West of Scotland Coronary Prevention Study (WOSCOPS). Circulation. 1998;97:1440-1445.

6. Grundy SM, Balady GJ. Criqui MH. et al. When to start cholesterol-lowering therapy in patients with coronary heart disease: a statement For healthcare professionals host the American Heart Association Task Force on Risk Reduction. Circulation. 1997;95:1683-1685.

7. Sacks FM, Pieffer MA. Moye LA. at al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels: Cholesterol and Recurrent Events Trial investigators. N Engl J Med. 1996:335:1001-1009.

8. Rosenson RS. Tangney CC. Antiatherothrombotic properties of statins: implications for cardiovascular event reduction. JAMA. 1998;279:1643-1650.

9. Grodstein F. Stampfer M.J. Manson JE, et al. Postmenopausal estrogen and progestin use and the risk of cardiovascular disease. N Engl J Med. 1996;335:453-461.

10. Hulley S. Grady P. Bush T, et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women: Heart and Estrogen/progestin Replacement Study (HERS) Research Group. JAMA. 998:260:605-613.

11. Gould AL, Rossouw JE. Santanello NC. et al. Cholesterol reduction yields clinical benefit: a new look at old data. Circulation. 1995:91:2274-2282.

12. WHO cooperative trial on primary prevention of ischaemic heart disease with clofibrate to lower serum cholesterol: final mortality follow-up Report of the Committee of Principal Investigators. Lancet. 1984:2:600-604.

13. Robins HB. Paper presented at: 71st Scientific Sessions, American Heart Association; November 11, 1998; Dallas, Tex.

14. Canner PL. Bergs KG. Wenger NK et al. Fifteen year mortality in Coronary Drug Project patients: long-term benefit with niacin, J Am Coll Cardiol 1966:8:1245-1255.

15. Downs JR, Clearfield M, Weis S, et al. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS: Air Force/Texas Coronary Atherosclerosis Prevention Study. JAMA. 1998:279:1615-1622.

16. Pitt B. Waters D, Brown WV, et al. Results of the Atorvastatin VErsus Revascularization Treatments (AVERT) Study: an 18-month study of aggressive lipid lowering in patients with stable coronary artery disease indicated for a catheter-based revascularization (CR). Paper presented at: 71st Scientific Sessions. American Heart Association: November 11, 1996: Dallas, Tex.

17. Falk E. Shah PK Fuster V. Coronary plaque disruption Circulation, 1995:92:657-671.

18. Pedersen TR. Kjekshus J, Pyorala K, et al. Effect of simvastatin on ischemic signs and symptoms in the Scandinavian simvastatin survival study (4S). Am J Cardiol. 1998:81:333-335.

19. van Boven AJ. Jukema JW, Zwinderwan AH, et al. Reduction of transient myocardial ischemia with pravastatin in addition to the conventional treatment of patients with angina pectoris: REGRESS Study Group. Circulation. 1996:94:1503-1505.

20. Wilson PW. D'Agostino RB. Levy D, et al. Prediction of coronary heart disease using risk factor categories. Circulation 1998:97:1837-1847.

Drugs Mentioned in This Article

Atorvastatin (Lipitor)

Cholestyramine (Prevalite, Questran, Questran Light,)

Clofibrate (Atromid-S)

Conjugated estrogens/medroxyprogesterone (Premphase, Prempro)

Gemfibrozil (Lopid)

Lovastatin (Mevacor)

Niacin

Pravastatin (Pravachol)

Simvastatin (Zocor)

Article Contributor

Benjamin J. Ansell, MD, is Assistant Professor of Clinical Medicine, Division of General Internal Medicine and Health Services Research, University of California, Los Angeles, School of Medicine.

*See "Assessing CHD risk in men" and "Assessing CHD risk in women" in "Current strategies for the primary prevention of CAD," Patient Care November 30, 1998, pages 24 and 25.

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