(Circulation. 1997;95:306-307.)
© 1997 American Heart Association, Inc.
Articles |
Clinical Reality of Lowering Total and LDL Cholesterol
the Mayo Clinic, Rochester, Minn.
Correspondence to Robert L. Frye, MD, Cardiovascular Diseases, Mayo Clinic, 200 First St SW, Rochester, MN 55905.
Key Words: Editorials • cholesterol • coronary disease
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Introduction |
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 Top Introduction References |
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I recall first learning of the importance of cholesterol from the work of Dr Ancel Keys, based on his landmark epidemiological studies subsequently identified as the Seven Countries Study.1 These population-based studies, in my own mind years ago, provided a general reference for judging the prevalence of coronary artery disease while providing a marker for risk of coronary artery disease over the long term. Most practitioners did not think of potential benefits to individual patients based on any short-term lowering of cholesterol levels, and treatment options were limited until the introduction of gemfibrozil and the statin drugs. The article by Andrews and colleagues2 in this issue of Circulation reflects how dramatically our understanding has changed regarding the consequences of elevated total and LDL cholesterol levels and the opportunities to intervene with effective treatment strategies. In this study, selected patients with documented coronary artery disease associated with myocardial ischemia on ambulatory ECG monitoring were randomized to an American Heart Association step 1 diet plus lovastatin or the diet plus a placebo. Four to 6 months after randomization, lower mean total and LDL cholesterol levels were found in those randomized to lovastatin therapy. The 25% reduction in LDL in the lovastatin group was associated with a "highly significant" reduction in myocardial ischemia compared with the control group, based on quantification of myocardial ischemia by 24-hour ECG monitoring. The authors appropriately conclude that "cholesterol lowering with lovastatin appears to be effective in eliminating myocardial ischemia during daily life in a significant proportion of patients."
Several themes came to mind as I read this excellent article.
1. This is a wonderful example of the power of clinical research to establish at the bedside the clinical reality of new knowledge derived from other basic studies. Simple in design and conducted with great care by an experienced group of clinical investigators, the Andrews study is characteristic of the fine work from this laboratory, led by Dr Andrew Selwyn. The reduction in myocardial ischemia observed in this study seems best explained by the new knowledge of the importance of LDL cholesterol, not only in the fundamental atherosclerotic process3 but also as influential in the response of the endothelium. Yla-Herttuala et al4 demonstrated a fundamental role of LDL in the development of the early lesion of atherosclerosis; thus the rationale for aggressive efforts to lower LDL cholesterol on a long-term basis. However, there is also great interest in the consequences of hypercholesterolemia on endothelial cell function in relation to vasoactivity of the coronary circulation. Harrison et al5 demonstrated a clear impairment of endothelial function in experimentally induced atherosclerosis with a reversal of this abnormality by dietary treatment in an animal model. Other investigators using a pig model also demonstrated a powerful effect of oxidized LDL in inhibiting endothelium-dependent relaxation of coronary arteries.6 Treasure and colleagues7 reported that cholesterol lowering with lovastatin improves endothelium-mediated responses and suggested that such improvement in the local regulation of coronary arterial tone could potentially relieve ischemic symptoms and signal the stabilization of the atherosclerotic plaque. The Andrews study2 confirms this hypothesis, and we now have a new clinical reality of the short-term benefits of cholesterol lowering to apply at the bedside well beyond the original long-term population-based studies of Keys and others.
2. Small, well-conceived, and well-performed clinical studies can provide important understanding of pathophysiological mechanisms that may explain outcomes observed in large randomized trials.
With the focus on LDL cholesterol noted above and the development of more powerful drugs, recent clinical trials have demonstrated a dramatic reduction not only in cardiac events but also in coronary heart disease deaths.9 10 In the 4S trial, total mortality was also reduced.10 The Andrews study suggests that relief of myocardial ischemia with effective lipid-lowering therapy may contribute to the beneficial outcomes observed in these and other clinical trials of primary and secondary prevention. Other "small" studies have contributed important insights into the mechanisms of benefit that might explain the long-term benefits in terms of mortality and subsequent cardiac events.11 12
3. The importance of "medical therapy" has new meaning in the management of patients with coronary artery disease.
The previous large trials13 14 15 (conducted in the 1970s) comparing an initial strategy of coronary artery bypass surgery with "medical therapy" need reconsideration in the light of the advances in our knowledge and the clinical reality of effective lowering of total and LDL cholesterol and other aspects of medical therapy provided today. It is interesting to review the description of medical therapy as reported in this article presenting 5-year survival data from CASS: "A standard protocol for medical treatment was developed by the CASS investigators and shared with physicians involved in the care of all of the randomly assigned patients. This included efforts to modify risk factors as well as the use of nitrates and ß-blocking drugs." The drugs were simply not available for more aggressive lipid lowering. Furthermore, all of these trials were conducted before the widespread use of thrombolytic drugs for acute myocardial infarction. We are thus faced with the challenge that much of our clinical decision making is based on conclusions from trials that include "medical therapy" that would be considered inappropriate in practice today. We hear a great deal about the new developments in technology that have advanced the invasive interventions for patients with coronary artery disease and how these may have improved outcomes in relation to old and current trials. We hear less about how the entire natural history of patients may be powerfully affected by the basic metabolic processes and new advances in medical therapy, particularly at a time when the growth in invasive procedures continues. It is also interesting to note that despite the limited medical therapy applied during the follow-up of patients randomized in the large trials comparing an initial strategy of coronary artery bypass graft surgery with medical therapy, it has not been possible to demonstrate that an invasive intervention prevented myocardial infarction. Contrast this conclusion with the striking reductions in rates of myocardial infarction demonstrated with use of aspirin15 and lowering of total and LDL cholesterol.9 Clearly, we need new randomized, controlled trials to determine the incremental value of current invasive strategies compared with aggressive medical therapy alone. Such trials should take into account not only lowering of total and LDL cholesterol but also the new antithrombotic and antioxidant therapies. It may be possible to stabilize even selected patients with what is currently labeled unstable angina, given the short-term effect of lipid lowering as noted in the Andrews study and the new antithrombotic interventions.
Finally, the implications are clear for practitioners and those who pay for care. Lowering of total and LDL cholesterol not only is established therapy for long-term benefits in reduction of mortality and other cardiac events but also may play an important role in relief of myocardial ischemia within a relatively short period of time after initiation of such therapy. Ensuring access to these drugs for patients with documented coronary artery disease is essential, and motivation of the patients to continue lipid-lowering efforts is a real challenge not only for physicians but for all of those engaged in the care of individual patients.
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Footnotes |
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The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
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References |
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TopIntroductionReferences |
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1. Keys AC. Seven Countries: A Multivariate Analysis of Death and Coronary Heart Disease. Boston, Mass: Harvard University Press; 1980:362-371.
2.
Andrews TC, Raby K, Barry J, Naimi CL, Allred E, Ganz P, Selweyn AP. The effect of cholesterol on myocardial ischemia in patients with coronary heart disease. Circulation. 1997;95:324-328.
3. Ross R. The pathogenesis of atherosclerosis: an update. N Engl J Med. 1986;314:488-500.[Medline] [Order article via Infotrieve]
4. Yla-Herttuala S, Palinski W, Rosenfeld ME, Parthasarathy S, Carew TE, Butler S, Witztum JL, Steinberg D. Evidence for the presence of oxidatively modified low density lipoprotein in atherosclerotic lesions of rabbit and man. J Clin Invest. 1989;84:1086-1095.
5. Harrison DG, Armstrong ML, Freiman PC, Heistad DD. Restoration of endothelium-dependent relaxation by dietary treatment of atherosclerosis. J Clin Invest. 1987;80:1808-1811.
6. Simon BC, Cunningham LC, Cohen RA. Oxidized low density lipoproteins cause contraction and inhibit endothelium-dependent relaxation in the pig coronary artery. J Clin Invest. 1990;86:75-79.
7.
Treasure CB, Klein JL, Weintraub WS, Talley JD, Stillabower ME, Kosinski AS, Zhang J, Boccuzzi SJ, Cedarholm C, Alendander RW. Beneficial effects of cholesterol-lowering therapy on the coronary endothelium in patients with coronary artery disease. N Engl J Med. 1995;332:481-487.
8.
Shepherd J, Cobbe SM, Ford I, Isles CG, Lorimer AR, MacFarlane PW, McKillop JH, Packard CJ. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N Engl J Med. 1995;333:1301-1307.
9. Scandinavian Simvastatin Survival Study Group. Randomized trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet. 1994;344:1383-1389.[Medline] [Order article via Infotrieve]
10. Brown G, Albers JJ, Fisher LD, Sheafer SM, Lin JT, Kaplan C, Zhao XQ, Bisson BD, Fitzpatrick VF, Dodge HT. Regression of coronary artery disease as a result of intensive lipid lowering therapy in men with high levels of apolipoprotein B. N Engl J Med. 1990;323:1289-1298.[Abstract]
11. Pitt B, Mancini GB, Ellis SG, Rosman HS, Park JS, McGovern ME. Pravastatin limitation of atherosclerosis in the coronary arteries (PLAC I): reduction in atherosclerosis progression and clinical events: PLAC I investigation. J Am Coll Cardiol. 1995;26:1133-1139.[Abstract]
12. The Veterans Administration Coronary Artery Bypass Surgery Cooperative Study Group. Eleven-year survival in the Veterans Administration randomized trial of coronary bypass surgery for stable angina. N Engl J Med. 1984;311:1333.[Abstract]
13. European Coronary Surgery Study Group. Prospective randomized study of coronary artery bypass surgery in stable angina pectoris. Lancet. 1980;2:491.[Medline] [Order article via Infotrieve]
14. Alderman EL, Bourassa MG, Cohen LS, Davis KB, Kaiser GG, Mock MB, Robertson TF, and the CASS Investigators. Ten-year follow-up of Coronary Artery Surgery Study (CASS) randomized patients. Circulation. 1988;78(suppl II):II-636. Abstract.
15. Theroux P, Ouimet H, McCans J, Latour JG, Joly P, Levy G, Pelletier E, Juneau M, Stasiak J, deGuise P, Pelletier GB, Rinsler D, Waters DD. Aspirin, heparin, or both to treat acute unstable angina. N Engl J Med. 1988;319:1105-1111.[Abstract]
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