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(Circulation. 1998;97:946-952.)
© 1998 American Heart Association, Inc.

Clinical Investigation and Reports

Cholesterol Reduction Yields Clinical Benefit

Impact of Statin Trials

A. Lawrence Gould, PhD; Jacques E. Rossouw, MD; Nancy C. Santanello, MD, MSc; Joseph F. Heyse, PhD; ; Curt D. Furberg, MD

From Merch Research Laboratories, West Point, Pa (A.L.G., N.C.S., J.F.H.); NIH, Bethesda, Md (J.E.R.); and Bowman Gray School of Medicine, Winston-Salem, NC (C.D.F.).

Correspondence to A. Lawrence Gould, Merck Research Laboratories, BL3–2, West Point, PA 19486. E-mail goulda{at}merck.com

	Abstract

Top Abstract Introduction Methods Results Discussion Appendix 1 References

 
Background—We determined the effect of incorporating the results of eight recently published trials of Hmg CoA reductase inhibitors ("statins") on the conclusions from our previously published meta-analysis regarding the clinical benefit of cholesterol lowering.

Methods and Results—We used the same analytic approach as in our previous investigation, separating the specific effects of cholesterol lowering from the effects attributable to the different types of intervention studied. The reductions in coronary heart disease (CHD) and total mortality risk observed for the statins fell near the predictions from our earlier meta-analysis. Including the statin trial findings into the calculations led to a prediction that for every 10 percentage points of cholesterol lowering, CHD mortality risk would be reduced by 15% (P<.001), and total mortality risk would be reduced by 11% (P<.001), as opposed to the values of 13% and 10%, respectively, reported previously. Cholesterol lowering in general and by the statins in particular does not increase non-CHD mortality risk.

Conclusions—Adding the results from the statin trials confirmed our original conclusion that lowering cholesterol is clinically beneficial. The relationships (slope) between cholesterol lowering and reduction in CHD and total mortality risk became stronger, and the standard error of the estimated slopes decreased by about half. Use of statins does not increase non-CHD mortality risk. The effect of the statins on CHD and total mortality risk can be explained by their lipid-lowering ability and appears to be directly proportional to the degree to which they lower lipids.

Key Words: cholesterol • meta-analysis • mortality

	Introduction

Top Abstract Introduction Methods Results Discussion Appendix 1 References

 
Reports on the outcome of a number of trials of Hmg CoA reductase inhibitors ("statins") have appeared^{1 2 3 4 5 6 7 8} since the publication of our meta-analysis demonstrating that net decreases in total serum cholesterol attributable to an intervention translate linearly to net decreases in total mortality risk and coronary heart disease (CHD) mortality risk.⁹ The statins represent an especially effective class of lipid-lowering drugs that were not included in the meta-analysis. We report here (1) the consistency of findings from the statin trials with the predictions based on nonstatin interventions from our earlier meta-analysis and (2) updated estimates (and standard errors) of the effects of cholesterol reduction and therapy class incorporating this new information.

	Methods

Top Abstract Introduction Methods Results Discussion Appendix 1 References

 
We used the same methods as in our original meta-analysis,⁹ adding the results from eight trials of statins that were published since the meta-analysis appeared and considering additional models exploring the effect of the statin findings. Table 1 lists the findings from the studies included in the analyses, with the findings from the eight additional trials italicized. Tables 3 and 4 of the published meta-analysis inadvertently excluded the Scottish study¹⁰ ; the "original" findings presented here include that study and do not differ materially from the original results.

View this table: [in this window] [in a new window]   Table 1. Study Set

View this table: [in this window] [in a new window]   Table 3. CHD Mortality: Estimates of Effect of Cholesterol Reduction and Influential Interventions Using the Original Study Set and After Adding Published Statin Trial Findings

View this table: [in this window] [in a new window]   Table 4. Total Mortality: Estimates of Effect of Cholesterol Reduction and Influential Interventions Using the Original Study Set and After Adding Published Statin Trial Findings

The findings for the various causes of mortality were analyzed by use of a series of models (Table 2) involving separate intercepts for each of the intervention classes and either a common slope for all the interventions or separate slopes for the statins and nonstatins. The same approach was used in our earlier meta-analysis, although many fewer models were needed because fewer intervention classes were studied. These models provide a way to address such questions as, (1) Does the risk of CHD or total mortality decrease steadily as net cholesterol reduction improves, or is there even more (or less) risk reduction with large reductions in total cholesterol? (2) Is the reduction in CHD and total mortality risk realized with 2 or more years of statin therapy consistent with what might be expected from their ability to lower cholesterol, or is there some specific attribute of statins as a class that confers extra benefit? (3) Do the statins have any specific effects on non-CHD mortality?

View this table: [in this window] [in a new window]   Table 2. Models Used to Analyze Mortality Findings

Models in Table 2 that set the intercept to zero for a particular class of interventions as, for example, model 3 does for "other/diet" say that the intervention has no specific effect on the degree of risk reduction. This means that if the intervention has the same effect on cholesterol reduction as a concurrent control, then it has the same effect on risk reduction. This would not be true, and the intercept would not be zero, if the intervention were inherently toxic, when there would be an excess of adverse events on the intervention, including mortality, even if the intervention and control reduced cholesterol equally. The "Appendix" describes the process for identifying appropriate models. The significance levels (probability values) reported in the "Results" section were determined by use of the hierarchical testing scheme. The "Appendix" also illustrates how these significance levels are calculated.

We report here the findings for CHD, non-CHD, and total mortality. As in the original analysis, statistical significance refers to two-sided tests with =0.05. The figures illustrate the analytic findings by plotting the observed log odds ratios for event occurrence in each trial on the y axis against the net reduction in cholesterol caused by the intervention on the x axis, with the predicted lines relating risk reduction to net cholesterol reduction for each type of intervention when appropriate. Larger studies, with many patients and many events, are represented with larger symbols on the figures because they estimate the log odds ratio more precisely than smaller studies and thus have a larger influence on the estimates of slope and intercepts; the symbol area is proportional to the variance of the log odds ratio.

	Results

Top Abstract Introduction Methods Results Discussion Appendix 1 References

 
CHD Mortality
The only significant factors affecting CHD mortality risk reduction are net cholesterol reduction, with the same slope for all interventions, and an intercept term for hormone interventions (model 8, P=.011 to .013) in all but the primary prevention trials, which did not include hormone interventions. Our previous meta-analysis gave the same result. The facts that the intercept for statins is zero in this model and that a common slope applies for all interventions implies that (1) there is no evidence to conclude that CHD mortality risk reduction is anything other than proportional to net reduction in total cholesterol even when the cholesterol reduction is large and (2) that statins as a class or individually do not appear to have any specific effects on CHD mortality risk.

Table 3 summarizes the computational results and gives the results from our original meta-analysis⁹ for comparison. Fig 1 displays the relationship between cholesterol reduction and CHD mortality risk reduction. The slope becomes slightly more pronounced when the statin trial results are included (slope=-0.0166 versus -0.0138, a nonsignificant difference). However, the results from the statin trials fall about where the original meta-analysis would have predicted. The trials whose findings deviate most from the prediction lines (ACAPS, MARS, and MAAS) are small atheroma trials with few deaths.

View larger version (24K): [in this window] [in a new window]   Figure 1. Observed log odds ratios and predicted lines relating log odds ratios for coronary heart disease (CHD) mortality to net improvement in percent total serum cholesterol reduction. Dashed lines present the relationships predicted from the data in our earlier meta-analysis9 ; solid line presents the relationship based on all the data included in the analysis reported here.

Total Mortality
The only significant factors affecting total mortality risk reduction are net cholesterol reduction, same slope for all interventions, and whether the intervention was a fibrate or a hormone (model 6, P<.01) when all trials and all unifactorial trials are considered, net cholesterol reduction and whether the intervention was a hormone (model 8, P<.01) when the unifactorial secondary prevention trials are considered, and net cholesterol reduction and whether the intervention was a fibrate for the primary prevention trials (model 9, P=.038) The fibrate effect loses significance (P<.05) when the WHO trial results are excluded. These findings are the same as for our previous meta-analysis, except for the primary prevention trials in which the original analysis did not reveal a significant effect of net cholesterol reduction. As with CHD mortality, there is no evidence for anything other than proportionality of total mortality risk reduction to net total cholesterol reduction, and statins as a class do not appear to have any specific effects on total mortality risk.

Table 4 summarizes the computational results and, for comparison, the results from the original meta-analysis. Fig 2 displays the relationship between cholesterol reduction and total mortality risk reduction. The statin trial results increase the slope slightly from what was reported in the original meta-analysis. As with CHD mortality, the results from the statin trials fall about where the original meta-analysis would have predicted.

View larger version (23K): [in this window] [in a new window]   Figure 2. Observed log odds ratios and predicted lines relating log odds ratios for total mortality to net improvement in percent total serum cholesterol reduction. Dashed lines present the relationships predicted from the data in our earlier meta-analysis9 ; solid line presents the relationship based on all the data included in the analysis reported here. CHD indicates coronary heart disease.

Non-CHD Mortality
There is no relationship between degree of cholesterol reduction and non-CHD mortality risk. As our earlier meta-analysis found, higher risk of non-CHD mortality is associated with the use of a fibrate or a hormone (model 10; all trials, all unifactorial trials, P=.022) or just the use of a hormone (model 12; unifactorial secondary prevention trials, P=.022) or a fibrate (model 11; primary prevention trials, P=.013). The fibrate effect loses significance (P>.05) when the WHO trial results are omitted. Table 5 summarizes the computational results and, for comparison, the results from our original meta-analysis. Fig 3 displays the results, including the findings from the statin trials.

View this table: [in this window] [in a new window]   Table 5. Non-CHD Mortality: Estimates of Effect of Cholesterol Reduction and Influential Interventions Using the Original Study Set and After Adding Published Statin Trial Findings

View larger version (22K): [in this window] [in a new window]   Figure 3. Observed log odds ratios and predicted lines relating log odds ratios for non–coronary heart disease (CHD) mortality to net improvement in percent total serum cholesterol reduction. Dashed lines present the relationships predicted from the data in our earlier meta-analysis9 ; solid line presents the relationship based on all the data included in the analysis reported here.

Statin Slopes
The slope of the relationship between cholesterol reduction and mortality risk reduction is the same for statins and nonstatins. The computations for the models fitting separate slopes for statins and nonstatins that included all of the trials gave the same estimates and standard errors for the statin slopes as the computations including only the statin trials. The slopes for statins and nonstatins and their standard errors obtained by fitting models 7 (hormone intercept and separate slopes) and 8 (hormone intercept and common slope) to the unifactorial trials (without WHO) are given in Table 6. A simple test for a difference between the statin and nonstatin slopes—eg, (0.0125-0.0081)/ = 0.0044/0.0046 <1 —confirms the conclusion of the maximum likelihood analyses that the relationship of mortality risk reduction to cholesterol reduction can be explained adequately by a common slope for statins and nonstatins.

View this table: [in this window] [in a new window]   Table 6. Slope Relating Cholesterol Reduction and Mortality Risk Reduction

	Discussion

Top Abstract Introduction Methods Results Discussion Appendix 1 References

 
The cholesterol reductions produced by the statins studied in the trials listed in Table 1 lead to reductions in CHD and total mortality risk that are close to the predictions from our original meta-analysis for nonfibrate, nonhormone interventions.

Including the data from the statin trials in the analyses provides a clinically modest improvement in the slopes relating CHD and total mortality to net cholesterol reduction. A net reduction in total serum cholesterol of 10 percentage points translates to an expected 15% reduction in CHD mortality risk and an expected 11% reduction in total mortality risk when the statin trial data are included, as opposed to the 13% and 10% reductions, respectively, predicted by the original meta-analysis.

The estimated effects of fibrates and hormones remain essentially unchanged: Hormones and fibrates (at least clofibrate and gemfibrozil) remain significantly associated with increased total mortality risk when the analysis includes all the trials or all the unifactorial trials. Only hormones are associated with increased risk when the analysis includes just the secondary prevention trials (all unifactorial) or, as in our earlier analysis, when the WHO trial data are omitted from the calculations.

Statin Effects
The analyses summarized in Tables 3 through 5 establish clearly that the mortality risk reduction realized over periods of 2 years and longer in the statin trials is a consequence of the reduction in cholesterol. These analyses exclude trials of less than 2 years' duration and so cannot address possible shorter-term effects of statins on events such as plaque stabilization. The statins used in these trials do not increase non-CHD mortality risk. The rate of reduction in total or CHD mortality risk with increasing net decrease in serum cholesterol is the same for statins and nonstatins. Statins reduce CHD and total mortality risk more than other currently available therapies because they reduce cholesterol levels more effectively without increasing non-CHD mortality.

View this table: [in this window] [in a new window]   Table 7. Times Log Likelihoods for the Models Fitted to the Data

View this table: [in this window] [in a new window]   Table 8. Computation of Significance Levels for Models Presented in Tables 3 and 4 Applied to Unifactorial Trials

	Appendix 1

Top Abstract Introduction Methods Results Discussion Appendix 1 References

 
The models in Table 2 are naturally ordered in the sense that some models are special cases of others. For example, a model that includes a single slope for all interventions is a special case of a model that allows for separate slopes for statins and nonstatins because the separate slopes could be equal. Consequently, model 2 is a special case of model 1, model 4 is a special case of model 3, etc. Likewise, a model that includes some but not all of the intercept terms that another model includes is a special case of the model with more terms (the extra terms could be zero), so for example, models 3, 5, and 7 are special cases of model 1. This natural ordering of the models provides a way to identify appropriate models via conventional likelihood ratio tests. Table 7 contains values of -2 times the logarithm of the likelihood for various models. The tests reported in this article all concern whether a simpler model describes the observed outcomes as well as a more complex model of which the simpler model is a special case. The additional factors of the more complex model are unlikely to be important if a simpler model describes the observed outcomes as well. Tests proceed by taking the difference between the values in Table 7 corresponding to pairs of models differing only in the effects of interest and comparing the difference to a central ² table with degrees of freedom equal to the difference between the numbers of parameters in the models.

Table 8 illustrates the calculation of the significance levels reported in Tables 3 and 4 for the unifactorial trials. The resulting significance levels apply to the model as a whole relative to any simpler model. Separate evaluations of individual parameters can be carried out in the usual way in terms of the ratio estimate/standard error.

	Footnotes

 
The opinions expressed in this manuscript are those of the authors and do not necessarily reflect the views of the National Institutes of Health.

Received August 15, 1997; revision received November 14, 1997; accepted November 18, 1997.

	References

Top Abstract Introduction Methods Results Discussion Appendix 1 References

 
1. 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;20:1301–1307.

2. 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.[Medline] [Order article via Infotrieve]

3. Sacks FM, Pfeffer MD, Moye LA, Rouleau JL, Rutherford JD, Cole TG, Brown L, Warnica JW, Arnold JMO, Wun C-C, Davis BR, Braunwald E. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med. 1996;334:1001–1009.

4. Furberg CD, Adams JP Jr, Applegate WB, Byington RP, Espeland MA, Hartwell T, Hunninghake DB, Lefkowitz DS, Probstfield J, Riley WA, Young B. Effect of lovastatin on early carotid atherosclerosis and cardiovascular events. Circulation. 1994;90:1679–1687.[Abstract/Free Full Text]

5. Blankenhorn DH, Azen SP, Kramsch DM, Mack WJ, Cashin-Hemphill L, Hodis HN, DeBoer WWV, Mahrer PR, Masteller MJ, Vailas LI, Alaupovic P, Hirsch LJ. Coronary angiographic changes with lovastatin therapy: the Monitored Atherosclerosis Regression Study (MARS). Ann Intern Med. 1993;119:969–976.[Abstract/Free Full Text]

6. Waters D, Higgison L, Gladstone P, Kimball B, Le May M, Bocuzzi SJ, Lesperance J. Effects of monotherapy with an HMB-CoA reductase inhibitor on the progression of coronary atherosclerosis as assessed by serial quantitative arteriography: the Canadian coronary atherosclerosis intervention trial (CCAIT). Circulation. 1994;89:959–968.[Abstract/Free Full Text]

7. MAAS Investigators. Effect of simvastatin on coronary atheroma: the Multicentre Anti-Atheroma Study (MAAS). Lancet. 1994;344:633–638.[Medline] [Order article via Infotrieve]

8. Byington RP, Jukema JW, Salonen JT, Pitt B, Bruschke AV, Hoen H, Furberg CD, Mancini J. Reduction in cardiovascular events during pravastatin therapy: pooled analysis of clinical events of the pravastatin atherosclerosis intervention program. Circulation. 1995;92:2419–2425.[Abstract/Free Full Text]

9. Gould AL, Rossouw JE, Santanello NC, Heyse JF, Furberg CD. Cholesterol reduction yields clinical benefit: a new look at old data. Circulation. 1995;91:2274–2282.[Abstract/Free Full Text]

10. Research Committee of the Scottish Society of Physicians. Ischaemic heart disease: a secondary prevention trial using clofibrate. BMJ. 1971;4:775–784.

11. Lipid Research Clinics Program. The Lipid Research Clinics Coronary Primary Prevention Trial results, I: reduction in incidence of coronary heart disease. JAMA. 1984;251:351–364.[Abstract/Free Full Text]

12. Frick MH, Elo O, Haapa K, Heinonen OP, Heinsalmi P, Helo P, Huttunen JK, Kaitaniemi P, Koskinen P, Manninen V, Maenpaa H, Malkonen M, Manttari M, Norola S, Pasternack A, Pikkarainen J, Romo M, Sjoblom T, Nikkila EA. Helsinki Heart Study: primary prevention trial with gemfibrozil in middle-aged men with dyslipidemia. N Engl J Med. 1987;317:1237–1245.[Abstract]

13. Committee of Principal Investigators. A cooperative trial in the primary prevention of ischaemic heart disease using clofibrate. Br Heart J. 1978;40:1069–1103.[Free Full Text]

14. Committee of Principal Investigators. WHO cooperative trial on primary prevention of ischaemic heart disease with clofibrate to lower serum cholesterol: final mortality follow-up. Lancet. 1984;2:600–604.[Medline] [Order article via Infotrieve]

15. Heady JA, Morris JN, Oliver MF. WHO clofibrate/cholesterol trial: clarifications. Lancet. 1992;340:1405–1406.[Medline] [Order article via Infotrieve]

16. Dorr AE, Gunderson K, Schneider JC, Spencer TW, Martin WB. Colestipol hydrochloride in hypercholesterolemic patients: effect on serum cholesterol and mortality. J Chronic Dis. 1978;31:5–14.[Medline] [Order article via Infotrieve]

17. Dayton S, Pearce ML, Hashimoto S, Dixon WJ, Tomiyasu UA. A controlled clinical trial of a diet high in unsaturated fat in preventing complications of atherosclerosis. Circulation. 1969;40(suppl II):II-1-II-63.

18. Wilhelmsen L, Berglund G, Elmfeldt D, Tibblin G, Wedel H, Pennert K, Vedin A, Wilhelmsson C, Werko L. The multifactor primary prevention trial in Goteborg, Sweden. Eur Heart J. 1986;7:279–288.[Abstract/Free Full Text]

19. Multiple Risk factor Intervention Trial Research Group. Multiple Risk Factor Intervention Trial: risk factor changes and mortality results. JAMA. 1982;248:1465–1477.[Abstract/Free Full Text]

20. Miettinen TA, Huttunen JK, Naukkarinen V. Multifactorial primary prevention of cardiovascular diseases in middle-aged men: risk factor changes, incidence, and mortality. JAMA. 1985;254:2097–2102.[Abstract/Free Full Text]

21. Hjerman I, Byre KV, Holme I, Leren P. Effect of diet and smoking on the incidence of coronary heart disease: report from the Oslo Study Group of a randomized trial of healthy men. Lancet. 1981;2:1303–1310.[Medline] [Order article via Infotrieve]

22. Buchwald H, Varco RL, Matts JP, Long JM, Fitch LL, Campbell GS, Pearce MB, Yellin AE, Edmiston WA, Smink RD, Sawin HS, Campos CT, Hansen BJ, Tuna N, Karnegis JN, Sanmarco ME, Amplatz K, Castaneda-Zuniga WR, Hunter DW, Bissett JK, Weber FJ, Stevenson JW, Leon AS, Chalmers TC, for the POSCH group. Report of the Program on the Surgical Control of Hyperlipidemias (POSCH): effect of partial ilial bypass surgery on mortality and morbidity from coronary heart disease in patients with hypercholesterolemia. N Engl J Med. 1990;323:946–955.[Abstract]

23. Carlson LA, Rosenhamer G. Reduction of mortality in the Stockholm Ischemic Heart Disease Secondary Prevention Study by combined treatment with clofibrate and nicotinic acid. Acta Med Scand. 1988;223:405–418.[Medline] [Order article via Infotrieve]

24. Coronary Drug Project Research Group. The findings leading to further modifications of its protocol with respect to dextrothyroxine. JAMA. 1972;220:996–1008.[Abstract/Free Full Text]

25. Schoch HK. The US Veterans Administration cardiology drug-lipid study: an interim report. In: Holmes WL, Carlson LA, Paoletti R, eds. Drugs Affecting Lipid Metabolism. New York, NY: Plenum Press; 1969:405–420.

26. Frick MH, Heinonen OP, Huttunen JK, Koskinen P, Manttari M, Manninen V. Efficacy of gemfibrozil in dyslipidaemic subjects with suspected heart disease: an ancillary study in the Helsinki Heart Study frame population. Ann Intern Med. 1993;25:41–45.

27. Coronary Drug Project Research Group. The Coronary Drug Project: clofibrate and niacin in coronary heart disease. JAMA. 1975;231:360–381.[Abstract/Free Full Text]

28. Canner PL, Berge KG, Wenger NK, Stamler J, Friedman L, Prineas RJ, Friedewald W. Fifteen year mortality in coronary drug project patients: long-term benefit with niacin. J Am Coll Cardiol. 1986;8:1245–1255.[Abstract]

29. Acheson J, Hutchinson EC. Controlled trial of clofibrate in cerebral vascular disease. Atherosclerosis. 1972;15:177–183.[Medline] [Order article via Infotrieve]

30. Group of Physicians of the Newcastle upon Tyne Region. Trial of clofibrate in the treatment of ischaemic heart disease: five year study by a group of physicians of the Newcastle Upon Tyne region. BMJ. 1971;4:767–775.

31. Oliver MF, Boyd GS. Influence of reduction of serum lipids on prognosis of coronary heart disease: a five year study using oestrogen. Lancet. 1961;2:499–505.[Medline] [Order article via Infotrieve]

32. Burr ML, Fehily AM, Gilbert JF, Rogers S, Holliday RM, Sweetnam PM, Elwood PC, Deadman NM. Effects of changes in fat, fish, and fibre intakes on death and myocardial infarction: Diet and Reinfarction Trial (DART). Lancet. 1989;2:757–761.[Medline] [Order article via Infotrieve]

33. Woodhill JM, Palmer AJ, Leelarthaepin B, McGilchrist CRB. Low fat, low cholesterol diet in secondary prevention of coronary heart disease. Adv Exp Med Biol. 1978;109:317–330.[Medline] [Order article via Infotrieve]

34. Research Committee. Low-fat diet in myocardial infarction: a controlled trial. Lancet. 1965;2:501–504.[Medline] [Order article via Infotrieve]

35. Rose GA, Thompson WB, Williams RT. Corn oil in treatment of ischemic heart disease. BMJ. 1965;1:1531–1533.

36. Research Committee to the Medical Research Council. Controlled trial of soyabean oil in myocardial infarction. Lancet. 1968;2:693–700.[Medline] [Order article via Infotrieve]

37. Leren P. The effect of plasma cholesterol lowering diet in male survivors of myocardial infarction: a controlled clinical trial. Acta Med Scand. 1966;466(suppl):1–92.

38. Brown G, Albers JJ, Fisher LD, Schaefer SM, Lin J, Kaplan C, Zhao X, Besson 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]

39. Watts GF, Lewis B, Brunt JNH, Lewis ES, Coltart DJ, Smith LR, Mann JL, Swan AV. Effects on coronary artery disease of lipid-lowering diet, or diet plus cholestyramine, in the St Thomas Atherosclerosis Regression Study (STARS). Lancet. 1992;339:563–569.[Medline] [Order article via Infotrieve]

40. Brensike JF, Levy RI, Kelsy SF, Passamani ER, Richardson JM, Loh IK, Stone NJ, Aldrich RF, Battaglini JW, Moriarity KJ, Fisher MR, Friedman L, Friedewald W, Detre KM, Epstein SE. Effects of therapy with cholestyramine on progression of coronary arteriosclerosis: results of the NHLBI Type II Coronary Intervention Study. Circulation. 1984;69:313–324.[Abstract/Free Full Text]

41. Blankenhorn DH, Nessim SA, Johnson RI, Sanmarco ME, Azen SP, Cashin-Hemphill L. Beneficial effects of combined colestipol-niacin therapy on coronary atherosclerosis and coronary venous bypass grafts. JAMA. 1987;257:3233–3240.[Abstract/Free Full Text]

42. Sahni R, Maniet AR, Voci G, Banka VS. The long-term clinical efficacy of lovastatin therapy following successful coronary angioplasty. Am Heart J. 1991;121:1600–1608.[Medline] [Order article via Infotrieve]

43. Fail PS, Sahni RS, Maniett AR, Voci G, Banka VS. The long-term clinical efficacy of lovastatin therapy following successful coronary angioplasty. Clin Res. 1992;40:400A. Abstract.

44. Law MR, Thompson SG, Wald NJ. Assessing possible hazards of reducing serum cholesterol. BMJ. 1994;308:373–379.[Abstract/Free Full Text]

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				D. Steinberg Thematic review series: The Pathogenesis of Atherosclerosis. An interpretive history of the cholesterol controversy, part IV: The 1984 Coronary Primary Prevention Trial ends it--almost J. Lipid Res., January 1, 2006; 47(1): 1 - 14. [Abstract] [Full Text] [PDF]

				T. R. Pedersen, O. Faergeman, J. J. P. Kastelein, A. G. Olsson, M. J. Tikkanen, I. Holme, M. L. Larsen, F. S. Bendiksen, C. Lindahl, M. Szarek, et al. High-Dose Atorvastatin vs Usual-Dose Simvastatin for Secondary Prevention After Myocardial Infarction: The IDEAL Study: A Randomized Controlled Trial JAMA, November 16, 2005; 294(19): 2437 - 2445. [Abstract] [Full Text] [PDF]

				P.J. Barter Cardioprotective Effects of High-Density Lipoproteins: The Evidence Strengthens Arterioscler Thromb Vasc Biol, July 1, 2005; 25(7): 1305 - 1306. [Full Text] [PDF]

				R. Sugano, H. Matsuoka, N. Haramaki, H. Umei, E. Murase, K. Fukami, S. Iida, H. Ikeda, and T. Imaizumi Polymorphonuclear Leukocytes May Impair Endothelial Function: Results of Crossover Randomized Study of Lipid-Lowering Therapies Arterioscler Thromb Vasc Biol, June 1, 2005; 25(6): 1262 - 1267. [Abstract] [Full Text] [PDF]

				V. Snow, P. Barry, S. D. Fihn, R. J. Gibbons, D. K. Owens, S. V. Williams, C. Mottur-Pilson, K. B. Weiss, and for the American College of Physicians/American Co Primary Care Management of Chronic Stable Angina and Asymptomatic Suspected or Known Coronary Artery Disease: A Clinical Practice Guideline from the American College of Physicians Ann Intern Med, October 5, 2004; 141(7): 562 - 567. [Abstract] [Full Text] [PDF]

				M. H. Criqui and B. A. Golomb Low and lowered cholesterol and total mortality J. Am. Coll. Cardiol., September 1, 2004; 44(5): 1009 - 1010. [Full Text] [PDF]

				N. L. Fox, B. J. Hoogwerf, S. Czajkowski, R. Lindquist, G. Dupuis, J. A. Herd, L. Campeau, A. Hickey, F. B. Barton, and M. L. Terrin Quality of Life After Coronary Artery Bypass Graft: Results From the POST CABG Trial Chest, August 1, 2004; 126(2): 487 - 495. [Abstract] [Full Text] [PDF]

				R. Corti, J. I. Osende, J. T. Fallon, V. Fuster, G. Mizsei, H. Jneid, S. D. Wright, W. F. Chaplin, and J. J. Badimon The selective peroxisomal proliferator-activated receptor-gamma agonist has an additive effect on plaque regression in combination with simvastatin in experimental atherosclerosis: in vivo study by high-resolution magnetic resonance imaging J. Am. Coll. Cardiol., February 4, 2004; 43(3): 464 - 473. [Abstract] [Full Text] [PDF]

				A. R. Folsom, E. S. Ford, A. H. Mokdad, W. H. Giles, and G. A. Mensah Serum Total Cholesterol Concentrations and Awareness, Treatment, and Control of Hypercholesterolemia Among US Adults * Response Circulation, November 25, 2003; 108 (21): e152 - e152. [Full Text] [PDF]

				S. S. Prichard Impact of Dyslipidemia in End-Stage Renal Disease J. Am. Soc. Nephrol., September 1, 2003; 14(90004): S315 - 320. [Abstract] [Full Text]

				M R Law, N J Wald, and A R Rudnicka Quantifying effect of statins on low density lipoprotein cholesterol, ischaemic heart disease, and stroke: systematic review and meta-analysis BMJ, June 25, 2003; 326(7404): 1423. [Abstract] [Full Text] [PDF]

				M. A. W. Umans-Eckenhausen, J. C. Defesche, M. J. van Dam, and J. J. P. Kastelein Long-term Compliance With Lipid-Lowering Medication After Genetic Screening for Familial Hypercholesterolemia Arch Intern Med, January 13, 2003; 163(1): 65 - 68. [Abstract] [Full Text] [PDF]

				References Circulation, December 17, 2002; 106(25): 3373 - 3421. [Full Text]

				B. F. Asztalos, K. V. Horvath, J. R. McNamara, P. S. Roheim, J. J. Rubinstein, and E. J. Schaefer Effects of atorvastatin on the HDL subpopulation profile of coronary heart disease patients J. Lipid Res., October 1, 2002; 43(10): 1701 - 1707. [Abstract] [Full Text] [PDF]

				M A W Umans-Eckenhausen, F J Oort, K C M P Ferenschild, J C Defesche, J J P Kastelein, and J C J M de Haes Parental attitude towards genetic testing for familial hypercholesterolaemia in children J. Med. Genet., September 1, 2002; 39(9): e49 - 49. [Full Text] [PDF]

				K. Foo and A. D Timmis Review: Managing the diabetic patient with angina The British Journal of Diabetes & Vascular Disease, May 1, 2002; 2(3): 169 - 175. [Abstract] [PDF]

				K. E. Ferrier, M. H. Muhlmann, J.-P. Baguet, J. D. Cameron, G. L. Jennings, A. M. Dart, and B. A. Kingwell Intensive cholesterol reduction lowers blood pressure and large artery stiffness in isolated systolic hypertension J. Am. Coll. Cardiol., March 20, 2002; 39(6): 1020 - 1025. [Abstract] [Full Text] [PDF]

				I. N M Day and D. I Wilson Science, medicine, and the future: Genetics and cardiovascular risk BMJ, December 15, 2001; 323(7326): 1409 - 1412. [Full Text] [PDF]

				J.C. Kaski Treatment of stable angina pectoris: is there a role for dipyridamole? Eur. Heart J., October 1, 2001; 22(19): 1762 - 1764. [PDF]

				S. W.E. van de Poll, T. J. Romer, O. L. Volger, D. J.M. Delsing, T. C. Bakker Schut, H. M.G. Princen, L. M. Havekes, J. W. Jukema, A. van der Laarse, and G. J. Puppels Raman Spectroscopic Evaluation of the Effects of Diet and Lipid-Lowering Therapy on Atherosclerotic Plaque Development in Mice Arterioscler Thromb Vasc Biol, October 1, 2001; 21(10): 1630 - 1635. [Abstract] [Full Text] [PDF]

				J. B. Braunstein, A. Cheng, G. Cohn, M. Aggarwal, C. M. Nass, and R. S. Blumenthal Lipid Disorders : Justification of Methods and Goals of Treatment Chest, September 1, 2001; 120(3): 979 - 988. [Abstract] [Full Text] [PDF]

				W. B. Parsons Jr., D. Waters, and R. R. Azar Niacin After Coronary Bypass Grafting and for Coronary Disease Prevention Circulation, July 10, 2001; 104 (2): e7 - e7. [Full Text] [PDF]

				U. Rauch, J. I. Osende, V. Fuster, J. J. Badimon, Z. Fayad, and J. H. Chesebro Thrombus Formation on Atherosclerotic Plaques: Pathogenesis and Clinical Consequences Ann Intern Med, February 6, 2001; 134(3): 224 - 238. [Abstract] [Full Text] [PDF]

				A. von Eckardstein, J.-R. Nofer, and G. Assmann High Density Lipoproteins and Arteriosclerosis : Role of Cholesterol Efflux and Reverse Cholesterol Transport Arterioscler Thromb Vasc Biol, January 1, 2001; 21(1): 13 - 27. [Abstract] [Full Text] [PDF]

				R. B. Weinberg, B. W. Geissinger, K. Kasala, K. J. Hockey, J. G. Terry, L. Easter, and J. R. Crouse Effect of apolipoprotein A-IV genotype and dietary fat on cholesterol absorption in humans J. Lipid Res., December 1, 2000; 41(12): 2035 - 2041. [Abstract] [Full Text]

				L. A Simons, J. Simons, P. McManus, and J. Dudley Discontinuation rates for use of statins are high BMJ, October 28, 2000; 321(7268): 1084 - 1084. [Full Text]

				C.G. Isles and J.R. Paterson Identifying patients at risk for coronary heart disease: implications from trials of lipid-lowering drug therapy QJM, September 1, 2000; 93(9): 567 - 574. [Abstract] [Full Text] [PDF]

				L. Mosca The Role of Hormone Replacement Therapy in the Prevention of Postmenopausal Heart Disease Arch Intern Med, August 14, 2000; 160(15): 2263 - 2272. [Abstract] [Full Text] [PDF]

				S. G. Worthley, G. Helft, V. Fuster, Z. A. Fayad, O. J. Rodriguez, A. G. Zaman, J. T. Fallon, and J. J. Badimon Noninvasive In Vivo Magnetic Resonance Imaging of Experimental Coronary Artery Lesions in a Porcine Model Circulation, June 27, 2000; 101(25): 2956 - 2961. [Abstract] [Full Text] [PDF]

				S. Ulrich, A. D Hingorani, J. Martin, and P. Vallance What is the optimal age for starting lipid lowering treatment? A mathematical model BMJ, April 22, 2000; 320(7242): 1134 - 1140. [Full Text]

				M. Law Plant sterol and stanol margarines and health BMJ, March 25, 2000; 320(7238): 861 - 864. [Full Text]

				B J Hunt The endothelium in atherogenesis Lupus, March 1, 2000; 9(3): 189 - 193. [Abstract] [PDF]

				J. C. LaRosa, J. He, and S. Vupputuri Effect of Statins on Risk of Coronary Disease: A Meta-analysis of Randomized Controlled Trials JAMA, December 22, 1999; 282(24): 2340 - 2346. [Abstract] [Full Text] [PDF]

				S. H. Woolf The Need for Perspective in Evidence-Based Medicine JAMA, December 22, 1999; 282(24): 2358 - 2365. [Abstract] [Full Text] [PDF]

				L. Goldman, P. Coxson, M. G. M. Hunink, P. A. Goldman, A. N. A. Tosteson, M. Mittleman, L. Williams, and M. C. Weinstein The relative influence of secondary versus primary prevention using the National Cholesterol Education Program Adult Treatment Panel II guidelines J. Am. Coll. Cardiol., September 1, 1999; 34(3): 768 - 776. [Abstract] [Full Text] [PDF]

				B. M. Psaty, C. D. Furberg, L. H. Kuller, D. E. Bild, P. M. Rautaharju, J. F. Polak, E. Bovill, and J. S. Gottdiener Traditional Risk Factors and Subclinical Disease Measures as Predictors of First Myocardial Infarction in Older Adults: The Cardiovascular Health Study Arch Intern Med, June 28, 1999; 159(12): 1339 - 1347. [Abstract] [Full Text] [PDF]

				R. J. Gibbons, K. Chatterjee, J. Daley, J. S. Douglas, S. D. Fihn, J. M. Gardin, M. A. Grunwald, D. Levy, B. W. Lytle, R. A. O'Rourke, et al. ACC/AHA/ACP-ASIM guidelines for the management of patients with chronic stable angina: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Management of Patients With Chronic Stable Angina) J. Am. Coll. Cardiol., June 1, 1999; 33(7): 2092 - 2197. [Full Text] [PDF]

				A. Zambanini, M. R Smith, M. D Feher, F. Gueyffier, J.-P. Boissel, A. D Hingorani, and P. Vallance Prediction of cardiovascular risk BMJ, May 22, 1999; 318(7195): 1418 - 1418. [Full Text]

				C. D. Furberg Natural Statins and Stroke Risk Circulation, January 19, 1999; 99(2): 185 - 188. [Full Text] [PDF]

				A. D Hingorani and P. Vallance A simple computer program for guiding management of cardiovascular risk factors and prescribing BMJ, January 9, 1999; 318(7176): 101 - 105. [Abstract] [Full Text]

				T. R. Pedersen, A. G. Olsson, O. Færgeman, J. Kjekshus, H. Wedel, K. Berg, L. Wilhelmsen, T. Haghfelt, G. Thorgeirsson, K. Pyorala, et al. Lipoprotein Changes and Reduction in the Incidence of Major Coronary Heart Disease Events in the Scandinavian Simvastatin Survival Study (4S) Circulation, April 21, 1998; 97(15): 1453 - 1460. [Abstract] [Full Text] [PDF]

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