Supplementary Appendix This appendix has been provided by the authors to give readers additional information about their work. Supplement to: Berry JD, Dyer A, Cai X, et al. Lifetime risks of cardiovascular disease. N Engl J Med 2012;366:321-9.
Lifetime Risks for Cardiovascular Disease by Age and Risk Factor Burden Supplementary Appendix Table of Contents Cohorts Included in The Cardiovascular Lifetime Risk Pooling Project Page 2 Event Ascertainment and Definitions Page 2 Secondary Statistical Analyses Page 3 Supp. Table 1: Baseline Characteristics by Time of Initial Risk Factor Assessment Page 4 Supp. Table 2: Baseline Characteristics for Black and White Men in the MRFIT Cohort Page 5 Supp. Figure 1: Lifetime Risk for CVD Death According to Risk Factor Burden at Age 45 Page 6 Supp. Figure 2: Lifetime Risk for CVD Death for Black and White Men Page 8 Supp. Figure 3: 20-Year Risk for CVD Death by Birth Year Before or After 1920 Page 10 Supp. Figure 4: 20-Year Risk for CVD Death by NHANES Cohort Page 11 Supp. Figure 5: Kaplan-Meier Estimate Versus Competing-Risk Estimate of Lifetime Risk Page 12 Supplementary Appendix References Page 14 1
METHODS SUPPLEMENT Cohorts Included in the Cardiovascular Lifetime Risk Pooling Project The following cohorts were included: the Atherosclerosis Risk in Communities Study, 1 Framingham Heart Study, 2 Framingham Offspring Study, 3 Honolulu Heart Program, 4-5 and Puerto Rico Heart Health Project. 6 Data were also obtained from the First National Health and Nutrition Examination Survey Epidemiologic Follow-up Study, 7 the National Health and Nutrition Examination Survey II Mortality Study, 8 the National Health and Nutrition Examination Survey III Mortality Follow-up Study 9, the Established Populations for the Epidemiologic Studies of the Elderly, 10 the Hispanic Established Populations for the Epidemiologic Studies of the Elderly, 11-12 the Kaiser Permanente Study of the Oldest Old, 13 the Tecumseh Community Health Study 14, Cardiovascular Health Study, 15 the Women s Health Initiative Observational Study 16, the Chicago Heart Association Detection Project in Industry, 17-18 the People s Gas and Western Electric studies, 19-20 and the Multiple Risk Factor Intervention Trial (MRFIT) screenees (i.e. non-trial participants) 21. Event Ascertainment and Definitions Events were ascertained using several strategies selected by each cohort s investigator group. For death events, many cohorts used linkage to the National Death Index for underlying cause of death from death certificate data, whereas others used adjudicated cause of death by study investigators after review of all available medical records and/or autopsy data. For the present analyses, all-cause mortality and deaths due to cardiovascular disease (as adjudicated, or indicated by ICD 9 codes 390 to 458, or equivalent codes from ICD-8 or 10) or coronary heart disease (as adjudicated, or indicated by ICD 9 codes 410 to 414 or equivalent) were included. Non-fatal events of interest, including myocardial infarction and stroke, were obtained only from studies that adjudicated events, with two exceptions. Criteria for adjudication of myocardial infarction and stroke have been published for these cohorts: the Atherosclerosis Risk in Communities study, 1 the Cardiovascular Health Study, 15 the Framingham Heart Study and Framingham Offspring Study, 22-23 the Honolulu Heart Program, 24 and the Women s Health 2
Initiative 16. Diagnosis of myocardial infarction generally required at least two of the following criteria for diagnosis: typical chest discomfort, evolution of electrocardiographic abnormalities consistent with myocardial infarction, and serologic evidence of myocardial necrosis. Diagnosis of stroke generally required persistent central neurologic deficit(s) lasting longer than 24 hours and unexplained by other causes. Two cohorts (Kaiser Old 13 and First National Health and Nutrition Examination Survey I Epidemiologic Follow-up Study 7 ) ascertained incident myocardial infarction and stroke events from hospitalization discharge code data. For these two cohorts, we only counted the first hospitalization for which myocardial infarction (ICD-9 code 410, or equivalent) or stroke (ICD-9 code 430 to 438, or equivalent) was the first-listed discharge diagnosis. For the present study, all participants were included for analyses of lifetime risks for cardiovascular disease death or coronary heart disease death; for analyses of composite endpoints that included incident non-fatal events (coronary heart disease death or non-fatal myocardial infarction, fatal or non-fatal stroke), we included only those participants who were free of prevalent myocardial infarction or stroke, respectively, at the index age (age at beginning of observation). Secondary Statistical Analyses In secondary analyses, we tested for the effect of secular trends in long-term CVD risk by stratifying our analyses across different birth cohorts. We stratified the pooled cohort into those individuals born prior to and after 1920 with risk factors measured at age 55 years. This stratification allowed us to compare lifetime risk estimates for CVD death to age 75 years across different birth cohorts with significant differences in risk factor levels. Similarly, we analyzed separately the association between risk factor burden measured at age 55 years and lifetime risk for CVD death across three nationally representative samples (NHANES I, II, and III) derived from different birth cohorts. Of note, because the younger birth cohorts have shorter follow-up periods, these secondary analyses for 55 year olds were restricted to 20 years of follow-up (i.e. thru age 75 years). Finally, additional secondary analyses were performed for blacks and whites separately in the pooled cohort and in MRFIT screenees. 3
Supplemental Table 1: Baseline characteristics for men and women at age 55 in the Cardiovascular Lifetime Risk Pooling Project according to time period of initial risk factor ascertainment (before and after 1975) and for participants in NHANES I, II, and III Men Risk Factors Measured Before 1975* N=17535 Risk Factors Measured After 1975* N=8061 NHANES I 1971-1975 N=510 NHANES II 1976-1980 N=688 NHANES III 1988-1994 N=699 Diabetes (%) 4.2% 8.8% 4.1% 4.1% 7.3% Current Smoking (%) 52.3% 29.5% 44.1% 43.3% 31.6% Mean Total Cholesterol (mg/dl) a 216.4 210.8 228.4 228.4 215.1 Mean Systolic Blood Pressure (mmhg) 136.5 124.3 136.9 135.8 130.7 All Optimal Risk Factors (%) 1.5% 5.7% 0.6% 0.7% 2.1% 1 Not Optimal Risk Factors (%) 6.5% 12.0% 4.1% 5.0% 11.0% 1 Elevated Risk Factors (%) 17.6% 21.2% 13.3% 16.4% 22.3% 1 Major Risk Factors (%) 48.5% 40.5% 42.9% 44.9% 43.4% 2 Major Risk Factors (%) 25.9% 20.6% 39.0% 33.0% 21.2% Women Before 1975 N=7076 1975 and after N=10148 NHANES I 1971-1975 N=462 NHANES II 1976-1980 N=791 NHANES III 1988-1994 N=839 Diabetes (%) 2.9% 8.6% 4.5% 2.8% 7.2% Current Smoking (%) 35.5% 24.7% 33.8% 30.2% 22.9% Mean Total Cholesterol (mg/dl) a 237.8 219.0 239.7 240.8 226.6 Mean Systolic Blood Pressure (mmhg) 139.9 122.3 138.9 135.5 129.3 All Optimal Risk Factors (%) 0.6% 5.6% 0.7% 0.4% 3.3% 1 Not Optimal Risk Factors (%) 4.4% 11.2% 2.0% 4.7% 9.8% 1 Elevated Risk Factors (%) 20.5% 22.2% 16.7% 17.7% 24.0% 1 Major Risk Factors (%) 44.0% 38.5% 40.5% 44.9% 39.9% 2 Major Risk Factors (%) 30.5% 22.5% 40.3% 32.3% 23.0% *Data from the 17 studies in the pooled analysis as described in the text (not including the data from MRFIT). a To calculate total cholesterol in mmol/l, multiply by 0.0259. 4
Supplemental Table 2: Baseline characteristics for black and white men with risk factors measured at Age 55 in the Multiple Risk Factor Intervention Trial screenee cohort Black Men N=4,669 White Men N=76,348 Diabetes (%) 6 2 Current Smoking (%) 45 30 Mean Total Cholesterol (mg/dl) a 214.0 218.5 Mean Systolic Blood Pressure (mmhg) 139.1 134.0 All Optimal Risk Factors (%) 1.1 1.9 1 Not Optimal Risk Factors (%) 7.7 11.6 1 Elevated Risk Factors (%) 21.8 30.8 1 Major Risk Factors (%) 44.9 41.2 2 Major Risk Factors (%) 24.6 14.5 a To calculate total cholesterol in mmol/l, multiply by 0.0259. 5
Supplemental Figure 1a (Men) 2 Major Risk Factors 1 Major Risk Factor 1 Elevated Risk Factor 1 Not Optimal Risk Factor All Optimal Risk Factors Supplemental Figure 1a: Lifetime risk for CVD death adjusted for the competing risk of death for men according to aggregate risk factor burden at 45 years of age. Data from the pooled analysis of 17 studies (excluding MRFIT screenees). 6
Supplemental Figure 1b (Women) 2 Major Risk Factors 1 Major Risk Factor 1 Elevated Risk Factor 1 Not Optimal Risk Factor All Optimal Risk Factors Supplemental Figure 1b: Lifetime risk for CVD death adjusted for the competing risk of death for women according to aggregate risk factor burden at 45 years of age. Data from the pooled analysis of 17 studies (excluding MRFIT screenees). 7
Supplemental Figure 2a (White Men) 2 Major Risk Factors 1 Major Risk Factor 1 Elevated Risk Factor 1 Not Optimal Risk Factor All Optimal Risk Factors Supplemental Figure 2a: Lifetime risk for CVD death adjusted for the competing risk of death for white men screenees in the Multiple Risk Factor Intervention Trial according to aggregate risk factor burden measured at age 55 years. 8
Supplemental Figure 2b (Black Men) 2 Major Risk Factors 1 Major Risk Factor 1 Elevated Risk Factor 1 Not Optimal Risk Factor All Optimal Risk Factors Supplemental Figure 2b: Lifetime risk for CVD death adjusted for the competing risk of death for black men screenees in the Multiple Risk Factor Intervention Trial according to aggregate risk factor burden measured at age 55 years. 9
Supplemental Figure 3a Supplemental Figure 3b Supplemental Figure 3c After 1920 Before 1920 After 1920 Before 1920 After 1920 Before 1920 Supplemental Figure 3d Supplemental Figure 3e Supplemental Figure 3f After 1920 Before 1920 After 1920 Before 1920 After 1920 Before 1920 Supplemental Figure 3: 20-year risk for CVD death adjusted for the competing risk of death for men and women born prior to and after 1920 according to aggregate risk factor burden at 55 years of age; (2a) Men, 1 elevated risk factor; (2b) Men, 1 major risk factor; (2c) Men, 2 major risk factors; (2d) Women, 1 elevated risk factor; (2e) Women, 1 major risk factor; (2f) Women, 2 major risk factors. Data from the pooled analysis of 17 studies (excluding MRFIT screenees). 10
Supplemental Figure 4a Supplemental Figure 4b NHANES I NHANES II NHANES III NHANES I NHANES II NHANES III Supplemental Figure 4c Supplemental Figure 4d NHANES I NHANES II NHANES III NHANES I NHANES II NHANES III Supplemental Figure 4: 20-year risk for CVD death adjusted for the competing risk of death for men and women according to aggregate risk factor burden at 55 years of age for participants in NHANES I, II, and III; (3a) Men, 1 major risk factor; (3b) Men, 2 major risk factors; (3c) Women, 1 major risk factor; (3d) Women, 2 major risk factors. 11
Figure 5a (Men) 80 70 60 Kaplan-Meier estimate (unadjusted for competing risk) Lifetime Risk estimate (adjusted for competing risk) 50 40 30 20 10 0 55 60 65 70 75 80 85 90 Supplemental Figure 5a: Comparison of cumulative incidence of CVD death adjusted for competing risk (Lifetime Risk estimate) with cumulative incidence of CVD death unadusted for competing risk (Kaplan-Meier estimate) in men with 2 risk factors. Data from the pooled analysis of 17 studies (excluding MRFIT screenees). 12
Figure 5b (Women) 80 70 60 Kaplan-Meier estimate (unadjusted for competing risk) Lifetime Risk estimate (adjusted for competing risk) 50 40 30 20 10 0 55 60 65 70 75 80 85 90 Supplemental Figure 5b: Comparison of cumulative incidence of CVD death adjusted for competing risk (Lifetime Risk estimate) with cumulative incidence of CVD death unadusted for competing risk (Kaplan-Meier estimate) in women with 2 risk factors. Data from the pooled analysis of 17 studies (excluding MRFIT screenees). 13
Supplementary Appendix References 1. The ARIC Investigators. The Atherosclerosis Risk in Communities (ARIC) Study: design and objectives.. Am J Epidemiol.1989;129(4):687 702. 2. Dawber TR, Kannel WB, Lyell LP. An approach to longitudinal studies in a community: the Framingham study. Ann NY Acad Sci.1963:539 556. 3. Kannel WB, Manning F, McNamara P, R.J. G, Castelli WP. An investigation of coronary heart disease in families. The Framingham Offspring Study. Am J Epidemiol.1979;110(3):281 290. 4. Kagan A, Harris BR, Winkelstein W, Jr., et al. Epidemiologic studies of coronary heart disease and stroke in Japanese men living in Japan, Hawaii and California: demographic, physical, dietary and biochemical characteristics. J Chronic Dis.1974;27(7 8):345 364. 5. Worth RM, Kagan A. Ascertainment of men of Japanese ancestry in Hawaii through World War II Selective Service registration. J Chronic Dis.1970;23(5):389 397. 6. Garcia Palmieri MR, Costas R, Jr., Cruz Vidal M, et al. Risk factors and prevalence of coronary heart disease in Puerto Rico. Circulation.1970;42(3):541 549. 7. Cohen BB, Barbano HE, Cox CS, et al. Plan and operation of the NHANES I Epidemiologic Followup Study: 1982 84. Vital Health Stat.1987;22:1 142. 8. Loria CM, Sempos CT, Vuong C. Plan and operation of the NHANES II Mortality Study, 1992. Vital Health Stat.1999;I(38):1 16. 9. Nelson KM, Boyko EJ, Koepsell T. All cause mortality risk among a national sample of individuals with diabetes. Diabetes Care.2010. 10. Cornoni Huntley J, Ostfeld AM, Taylor JO, et al. Established populations for epidemiologic studies of the elderly:study and design and methodology. Aging Clin Exp Res.1993;5:27 37. 11. Delgado JL, Johnson CL, Roy I, Trevino FM. Hispanic Health and Nutrition Examination Survey: methodological considerations. Am J Public Health.1990;80 Suppl:6 10. 12. Markides KS, Stroup Benham CA, Goodwin JS, Perkowski LC, Lichtenstein M, Ray LA. The effect of medical conditions on the functional limitations of Mexican American elderly. Ann Epidemiol.1996;6(5):386 391. 13. Haan MN, Selby JV, Rice DP, et al. Trends in cardiovascular disease incidence and survival in the elderly. Ann Epidemiol.1996;6(4):348 356. 14. Carman WJ, Barrett Connor E, Sowers M, Khaw KT. Higher risk of cardiovascular mortality among lean hypertensive individuals in Tecumseh, Michigan. Circulation.1994;89(2):703 711. 15. Fried LP, Borhani NO, Enright P, et al. The Cardiovascular Health Study: design and rationale. Ann Epidemiol.1991;1(3):263 276. 16. The Women's Health Initiative Study Group. Design of the Women's Health Inititiatve clinical trial and observational study. Control Clin Trials.1998;19:61 109. 17. Stamler J, Rhomberg P, Schoenberger JA, et al. Multivariate analysis of the relationship of seven variables to blood pressure: findings of the Chicago Heart Association Detection Project in Industry, 1967 1972. J Chronic Dis.1975;28(10):527 548. 18. Stamler J, Dyer AR, Shekelle RB, Neaton J, Stamler R. Relationship of baseline major risk factors to coronary and all cause mortality, and to longevity: findings from long term follow up of Chicago cohorts. Cardiology.1993;82(2 3):191 222. 19. Dyer AR, Persky V, Stamler J, et al. Heart rate as a prognostic factor for coronary heart disease and mortality: findings in three Chicago epidemiologic studies. Am J Epidemiol.1980;112(6):736 749. 20. Paul O, Lepper MH, Phelan WH, et al. A longitudinal study of coronary heart disease. Circulation.1963;28:20 31. 14
21. Neaton JD, Kuller LH, Wentworth D, Borhani NO. Total and cardiovascular mortality in relation to cigarette smoking, serum cholesterol concentration, and diastolic blood pressure among black and white males followed up for five years. Am Heart J.1984;108(3 Pt 2):759 769. 22. Lloyd Jones DM, Larson MG, Beiser A, Levy D. Lifetime risk of developing coronary heart disease. The Lancet.1999;353(9147):89 92. 23. Seshadri S, Beiser A, Kelly Hayes M, et al. The Lifetime Risk of Stroke: Estimates From the Framingham Study. Stroke.2006;37(2):345 350. 24. Yano K, Grove JS, Reed DM, Chun HM. Determinants of the prognosis after a first myocardial infarction in a migrant Japanese population. The Honolulu Heart Program. Circulation.1993;88:2582 2595. 15