Papers

Systematic underestimation of association between serum cholesterol concentration and ischaemic heart disease in observational studies: data from the BUPA study

BUPA Epidemiological Research Group, Department of Environmental and Preventive Medicine, Wolfson Institute of Preventive Medicine, St Bartholomew's Hospital Medical College, London EC1M 6BQ BUPA Health Services, London WC2R 3AU Correspondence to: Professor Wald.

Abstract

Objective : To estimate the size of the association between serum concentration of low density lipoprotein cholesterol and mortality from ischaemic heart disease.
Design : Prospective study of total serum cholesterol concentration and mortality from ischaemic heart disease in 21 515 men (538 deaths) and study of total cholesterol concentration measured on two occasions an average of three years apart in 5696 men in whom low density lipoprotein cholesterol concentration was also measured on the second occasion.
Subjects : Men who attended the medical centre of the British United Provident Association (BUPA) in London between 1975 and 1982.
Main outcome measure : The difference in mortality from ischaemic heart disease for a 0.6 mmol/1 difference in concentration of low density lipoprotein cholesterol after adjustment for, firstly, regression dilution bias, which arises from the random fluctuation of serum cholesterol concentration in people over time, and, secondly, the surrogate dilution effect, which arises because differences in total cholesterol concentration between people reflect smaller differences in low density lipoprotein cholesterol concentration.
Results : The observed difference in mortality from ischaemic heart disease associated with a difference of 0.6 mmol/1 in total serum cholesterol concentration was 17% but increased to 24% after correction for the regression dilution bias and to 27% (95% confidence interval 21% to 33%) after adjustment for both sources of underestimation, which provides an estimate of the difference in mortality for a true difference of 0.6 mmol/1 in low density lipoprotein cholesterol concentration. The association was greater at younger ages. The estimated decrease in mortality from all causes was 6% before and 10% (1% to 17%) after adjustment for the two sources of underestimation. There was no excess mortality from any cause associated with low cholesterol concentration.
Conclusions : The association between serum cholesterol concentration and ischaemic heart disease is materially stronger than directly inferred from prospective studies. This has important implications for the health benefit of achieving low cholesterol concentrations.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

Relevant Articles

"Polypill" to fight cardiovascular disease: Authors' reply

Nicholas Wald, Malcolm Law, Joan Morris, Alicja Rudnicka, and Rachel Jordan
BMJ 2003 327: 809-810. [Extract] [Full Text]

Ischaemic heart disease and cholesterol Safety of cholesterol reduction remains in doubt

M F Muldoon, S B Manuck, M R Law, N J Wald, T Wu, A Hackshaw, S G Thompson, and A Bailey
BMJ 1994 308: 1104-1105. [Extract] [Full Text]

Ischaemic heart disease and cholesterol There's more to heart disease than cholesterol

L Bonneux, J J Barendregt, U Ravnskov, L E Ramsay, W W Yeo, P R Jackson, T A Sheldon, F Song, J Millo, C L M Sudlow, M R Macleod, J A Heady, J N Morris, M F Oliver, D L Vine, G E Hastings, P N Durrington, A Dugdale, M R Law, T Wu, N J Wald, A Hackshaw, and A S G Thompson Bailey
BMJ 1994 308: 1038-1041. [Extract] [Full Text]

This article has been cited by other articles:

• Armitage, J (2008). Commentary on NICE technology appraisal guidance on ezetimibe for the treatment of primary (heterozygous-familial and non-familial) hypercholesterolaemia. Heart 94: 643-645 [Full text]  
• Sritara, P., Patoomanunt, P., Woodward, M., Narksawat, K., Tulyadachanon, S., Ratanachaiwong, W., Sritara, C., Barzi, F., Yamwong, S., Tanomsup, S. (2008). Associations Between Serum Lipids and Causes of Mortality in a Cohort of 3499 Urban Thais: The Electricity Generating Authority of Thailand (EGAT) Study. ANGIOLOGY 58: 757-763 [Abstract]  
• Clarke, R., Emberson, J. R., Parish, S., Palmer, A., Shipley, M., Linksted, P., Sherliker, P., Clark, S., Armitage, J., Fletcher, A., Collins, R. (2007). Cholesterol Fractions and Apolipoproteins as Risk Factors for Heart Disease Mortality in Older Men. Arch Intern Med 167: 1373-1378 [Abstract] [Full text]  
• Boshuizen, H. C., Lanti, M., Menotti, A., Moschandreas, J., Tolonen, H., Nissinen, A., Nedeljkovic, S., Kafatos, A., Kromhout, D. (2007). Effects of Past and Recent Blood Pressure and Cholesterol Level on Coronary Heart Disease and Stroke Mortality, Accounting for Measurement Error. Am J Epidemiol 165: 398-409 [Abstract] [Full text]  
• Rippe, J. M., Angelopoulos, T. J., Zukley, L. (2007). The Rationale for Intervention to Reduce the Risk of Coronary Heart Disease. AMERICAN JOURNAL OF LIFESTYLE MEDICINE 1: 10-19 [Abstract]  
• The Fibrinogen Studies Collaboration, (2006). Regression dilution methods for meta-analysis: assessing long-term variability in plasma fibrinogen among 27 247 adults in 15 prospective studies. Int J Epidemiol 35: 1570-1578 [Abstract] [Full text]  
• McElduff, P, Lyratzopoulos, G, Edwards, R, Heller, R F, Shekelle, P, Roland, M (2004). Will changes in primary care improve health outcomes? Modelling the impact of financial incentives introduced to improve quality of care in the UK. Qual Saf Health Care 13: 191-197 [Abstract] [Full text]  
• Psomas, E. I., Fletouris, D. J., Litopoulou-Tzanetaki, E., Tzanetakis, N. (2003). Assimilation of Cholesterol by Yeast Strains Isolated from Infant Feces and Feta Cheese. J DAIRY SCI 86: 3416-3422 [Abstract] [Full text]  
• Wald, N., Law, M., Morris, J., Rudnicka, A., Jordan, R. (2003). "Polypill" to fight cardiovascular disease: Authors' reply. BMJ 327: 809-810 [Full text]  
• Wald, N. J, Morris, J. K (2003). Teleoanalysis: combining data from different types of study. BMJ 327: 616-618 [Full text]  
• Key, T. J, Appleby, P. N, Davey, G. K, Allen, N. E, Spencer, E. A, Travis, R. C (2003). Mortality in British vegetarians: review and preliminary results from EPIC-Oxford. Am. J. Clin. Nutr. 78: 533S-538 [Abstract] [Full text]  
• Shim, S. Y., Ahn, J., Kwak, H. S. (2003). Functional Properties of Cholesterol-Removed Whipping Cream Treated by {beta}-Cyclodextrin. J DAIRY SCI 86: 2767-2772 [Abstract] [Full text]  
• Hackam, D. G., Anand, S. S. (2003). Emerging Risk Factors for Atherosclerotic Vascular Disease: A Critical Review of the Evidence. JAMA 290: 932-940 [Abstract] [Full text]  
• Xiao, J. Z., Kondo, S., Takahashi, N., Miyaji, K., Oshida, K., Hiramatsu, A., Iwatsuki, K., Kokubo, S., Hosono, A. (2003). Effects of Milk Products Fermented by Bifidobacterium longum on Blood Lipids in Rats and Healthy Adult Male Volunteers. J DAIRY SCI 86: 2452-2461 [Abstract] [Full text]  
• Law, M R, Wald, N J, Rudnicka, A R (2003). Quantifying effect of statins on low density lipoprotein cholesterol, ischaemic heart disease, and stroke: systematic review and meta-analysis. BMJ 326: 1423- [Abstract] [Full text]  
• (2002). References. Circulation 106: 3373-3421 [Full text]  
• Mouradian, M. S., Majumdar, S. R., Senthilselvan, A., Khan, K., Shuaib, A. (2002). How Well Are Hypertension, Hyperlipidemia, Diabetes, and Smoking Managed After a Stroke or Transient Ischemic Attack?. Stroke 33: 1656-1659 [Abstract] [Full text]  
• Magnus, P., Beaglehole, R. (2001). The Real Contribution of the Major Risk Factors to the Coronary Epidemics: Time to End the "Only-50%" Myth. Arch Intern Med 161: 2657-2660 [Full text]  
• Yarnell, J.W.G., Patterson, C. C., Sweetnam, P. M., Thomas, H. F., Bainton, D., Elwood, P. C., Bolton, C. H., Miller, N. E. (2001). Do Total and High Density Lipoprotein Cholesterol and Triglycerides Act Independently in the Prediction of Ischemic Heart Disease?: Ten-Year Follow-Up of Caerphilly and Speedwell Cohorts. Arterioscler. Thromb. Vasc. Bio. 21: 1340-1345 [Abstract] [Full text]  
• Wald, D. S., Bishop, L., Wald, N. J., Law, M., Hennessy, E., Weir, D., McPartlin, J., Scott, J. (2001). Randomized Trial of Folic Acid Supplementation and Serum Homocysteine Levels. Arch Intern Med 161: 695-700 [Abstract] [Full text]  
• Eichholzer, M., Stahelin, H. B, Gutzwiller, F., Ludin, E., Bernasconi, F. (2000). Association of low plasma cholesterol with mortality for cancer at various sites in men: 17-y follow-up of the prospective Basel study1. Am. J. Clin. Nutr. 71: 569-574 [Abstract] [Full text]  
• Wasnich, R. D., Miller, P. D. (2000). Antifracture Efficacy of Antiresorptive Agents Are Related to Changes in Bone Density. J. Clin. Endocrinol. Metab. 85: 231-236 [Abstract] [Full text]  
• Nguyen, T. T. (1999). The Cholesterol-Lowering Action of Plant Stanol Esters. J. Nutr. 129: 2109-2112 [Abstract] [Full text]  
• Grundy, S. M., Pasternak, R., Greenland, P., Smith, S. Jr, Fuster, V. (1999). Assessment of cardiovascular risk by use of multiple-risk-factor assessment equations: A statement for healthcare professionals from the American Heart Association and the American College of Cardiology. J Am Coll Cardiol 34: 1348-1359 [Full text]  
• Grundy, S. M., Pasternak, R., Greenland, P., Smith, S. Jr, Fuster, V. (1999). Assessment of Cardiovascular Risk by Use of Multiple-Risk-Factor Assessment Equations : A Statement for Healthcare Professionals From the American Heart Association and the American College of Cardiology. Circulation 100: 1481-1492 [Full text]  
• Key, T. J, Fraser, G. E, Thorogood, M., Appleby, P. N, Beral, V., Reeves, G., Burr, M. L, Chang-Claude, J., Frentzel-Beyme, R., Kuzma, J. W, Mann, J., McPherson, K. (1999). Mortality in vegetarians and nonvegetarians: detailed findings from a collaborative analysis of 5 prospective studies. Am. J. Clin. Nutr. 70: 516S-524 [Abstract] [Full text]  
• Grundy, S. M. (1999). Primary Prevention of Coronary Heart Disease : Integrating Risk Assessment With Intervention. Circulation 100: 988-998 [Full text]  
• The Long-Term Intervention with Pravastatin in Isc, (1998). Prevention of Cardiovascular Events and Death with Pravastatin in Patients with Coronary Heart Disease and a Broad Range of Initial Cholesterol Levels. NEJM 339: 1349-1357 [Abstract] [Full text]  
• Rosengren, A (1998). Cholesterol: how low is low enough?. BMJ 317: 425-426 [Full text]  
• British Cardiac Society, , British Hyperlipidaemia Association, , British Hypertension Society, , endorsed by the British Diabetic Association, (1998). Joint British recommendations on prevention of coronary heart disease in clinical practice. Heart 80: 1S-29 [Full text]  
• Grundy, S. M., Balady, G. J., Criqui, M. H., Fletcher, G., Greenland, P., Hiratzka, L. F., Houston-Miller, N., Kris-Etherton, P., Krumholz, H. M., LaRosa, J., Ockene, I. S., Pearson, T. A., Reed, J., Washington, R., Smith, S. C. Jr (1998). Primary Prevention of Coronary Heart Disease: Guidance From Framingham : A Statement for Healthcare Professionals From the AHA Task Force on Risk Reduction. Circulation 97: 1876-1887 [Full text]  
• Jousilahti, P., Vartiainen, E., Pekkanen, J., Tuomilehto, J., Sundvall, J., Puska, P. (1998). Serum Cholesterol Distribution and Coronary Heart Disease Risk : Observations and Predictions Among Middle-aged Population in Eastern Finland. Circulation 97: 1087-1094 [Abstract] [Full text]  
• Turner, R C, Millns, H, Neil, H A W, Stratton, I M, Manley, S E, Matthews, D R, Holman, R R (1998). Risk factors for coronary artery disease in non-insulin dependent diabetes mellitus: United Kingdom prospective diabetes study (UKPDS: 23). BMJ 316: 823-828 [Abstract] [Full text]  
• Mann, J. I, Appleby, P. N, Key, T. J, Thorogood, M. (1997). Dietary determinants of ischaemic heart disease in health conscious individuals. Heart 78: 450-455 [Abstract] [Full text]  
• Cullen, P., Schulte, H., Assmann, G. (1997). The Munster Heart Study (PROCAM) : Total Mortality in Middle-Aged Men Is Increased at Low Total and LDL Cholesterol Concentrations in Smokers but Not in Nonsmokers. Circulation 96: 2128-2136 [Abstract] [Full text]  
• Cleeman, J. I., Grundy, S. M. (1997). National Cholesterol Education Program Recommendations for Cholesterol Testing in Young Adults : A Science-Based Approach. Circulation 95: 1646-1650 [Full text]  
• Frost, P. H., Davis, B. R., Burlando, A. J., Curb, J. D., Guthrie, G. P., Isaacsohn, J. L., Wassertheil-Smoller, S., Wilson, A. C., Stamler, J. (1996). Serum Lipids and Incidence of Coronary Heart Disease: Findings From the Systolic Hypertension in the Elderly Program (SHEP). Circulation 94: 2381-2388 [Abstract] [Full text]  
• Key, T. J A, Thorogood, M., Appleby, P. N, Burr, M. L (1996). Dietary habits and mortality in 11 000 vegetarians and health conscious people: results of a 17 year follow up. BMJ 313: 775-779 [Abstract] [Full text]  
• Cattaneo, M., Martinelli, I., Mannucci, P. M., Jacobson, M. W., den Heijer, M., Blom, H. J., Rosendaal, F. R. (1996). Hyperhomocysteinemia as a Risk Factor for Deep-Vein Thrombosis. NEJM 335: 974-976 [Full text]  
• Verschuren, W M M., Kromhout, D. (1995). Total cholesterol concentration and mortality at a relatively young age: Do men and women differ?. BMJ 311: 779-783 [Abstract] [Full text]  
• Thiery, J., Nebendahl, K., Rapp, K., Kluge, R., Teupser, D., Seidel, D. (1995). Low Atherosclerotic Response of a Strain of Rabbits to Diet-Induced Hypercholesterolemia. Arterioscler. Thromb. Vasc. Bio. 15: 1181-1188 [Abstract] [Full text]  
• Gotto, A. M. Jr (1995). Lipid Lowering, Regression, and Coronary Events : A Review of the Interdisciplinary Council on Lipids and Cardiovascular Risk Intervention, Seventh Council Meeting. Circulation 92: 646-656 [Full text]  
• Tobias, J S (1995). Hospital doctor's role in the Health of the Nation. BMJ 310: 889-889 [Full text]  
• Bhopal, R. S., Tonks, A. (1994). The role of letters in reviewing research. BMJ 308: 1582-1583 [Full text]  
• Muldoon, M F, Manuck, S B, Law, M R, Wald, N J, Wu, T, Hackshaw, A, Thompson, S G, Bailey, A (1994). Ischaemic heart disease and cholesterol Safety of cholesterol reduction remains in doubt. BMJ 308: 1104-1105 [Full text]  
• Smith, G D, Egger, M (1994). Commentary: Statistical problems. BMJ 308: 1025-1027 [Full text]  
• Law, M R, Wald, N J (1994). Commentary: Disagreements are not substantial. BMJ 308: 1027-1029 [Full text]  
• Bonneux, L, Barendregt, J J, Ravnskov, U, Ramsay, L E, Yeo, W W, Jackson, P R, Sheldon, T A, Song, F, Millo, J, Sudlow, C L M, Macleod, M R, Heady, J A, Morris, J N, Oliver, M F, Vine, D L, Hastings, G E, Durrington, P N, Dugdale, A, Law, M R, Wu, T, Wald, N J, Hackshaw, A, Bailey, A S G T. (1994). Ischaemic heart disease and cholesterol There's more to heart disease than cholesterol. BMJ 308: 1038-1041 [Full text]  
• Marmot, M (1994). The cholesterol papers. BMJ 308: 351-352 [Full text]  
• Law, M R, Wald, N J, Thompson, S G (1994). By how much and how quickly does reduction in serum cholesterol concentration lower risk of ischaemic heart disease?. BMJ 308: 367-372 [Abstract] [Full text]