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(Circulation. 1996;94:2381-2388.)
© 1996 American Heart Association, Inc.
Articles |
Serum Lipids and Incidence of Coronary Heart Disease
Findings From the Systolic Hypertension in the Elderly Program (SHEP)
the Cardiovascular Research Institute, University of California, San Francisco (P.H.F.); University of Texas School of Public Health, Houston (B.R.D.); Kaiser Permanente Medical Center, Sacramento, Calif (A.J.B.); University of Hawaii School of Medicine, Honolulu (J.D.C.); University of Kentucky College of Medicine, Lexington (G.P.G.); Christ Hospital, Cincinnati, Ohio (J.L.I.); Albert Einstein College of Medicine, Bronx, NY (S.W.-S.); Robert Wood Johnson Medical School, New Brunswick, NJ (A.C.W.); and Northwestern University Medical School, Chicago, Ill (J.S.).
Correspondence to Philip H. Frost, MD, University of California, San Francisco, 400 Parnassus Ave, #585, San Francisco, CA 94143-0326. E-mail phf@itsa.ucsf.edu.
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Abstract |
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Background The association of serum lipids with coronary heart disease has been studied extensively in middle-aged men and, to a lesser extent, in similar women. Less well defined are lipid variables predictive of CHD in individuals of age
60 years. Methods and Results The Systolic Hypertension in the Elderly Program recruited 4736 persons (mean age, 72 years; 14% were black; and 43% were men). Mean systolic and diastolic blood pressures were 170 and 77 mm Hg, respectively. Baseline mean total cholesterol was 6.11 mmol/L (236 mg/dL); HDL cholesterol, 1.39 mmol/L (54 mg/dL); and non-HDL cholesterol, 4.72 mmol/L (182 mg/dL). Triglyceride levels were 1.62 mmol/L (144 mg/dL) for fasting participants and 1.78 mmol/L for the total group. LDL cholesterol, estimated in fasting samples with triglycerides of <4.52 mmol/L, averaged 3.98 mmol/L (154 mg/dL). Mean follow-up was 4.5 years. In multivariate Cox regression analyses, baseline total, non-HDL, and LDL cholesterol levels and the ratios of total, non-HDL, and LDL to HDL cholesterol were significantly related to CHD incidence. HDL cholesterol and triglycerides were not significant in these analyses. In fasting participants with triglyceride levels of <4.52 mmol/L, a 1.03 mmol/L (40 mg/dL) higher baseline total, non-HDL, or LDL cholesterol was associated with a 30% to 35% higher CHD event rate.
Conclusions The results of this study support the concept that serum lipids are CHD risk factors in older Americans.
Key Words: cholesterol • coronary disease • risk factors • lipids • lipoproteins
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Introduction |
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The association of serum lipids with CHD has been studied extensively in middle-aged men and, to a lesser extent, in middle-aged women.1 2 3 4 5 In middle-aged populations, CHD risk is positively associated with total and LDL cholesterol and inversely associated with HDL cholesterol. Additional CHD risk factors include cigarette smoking, blood pressure above optimal, and diabetes mellitus.
Less well defined are lipid variables predictive of CHD in individuals 60 years old. Although results of studies support associations similar to those in younger individuals,6 7 8 9 10 11 12 these observations are more limited.13 The definition of CHD risk in persons age 60 has potential public health importance and may provide a basis for clinical intervention in those at higher risk. The demonstration that cholesterol reduction is accompanied by a decrease in coronary plaque progression and/or reduction in CHD incidence14 15 16 17 18 19 20 21 22 23 and the fact that the great majority of CHD events occur in men after the age of 60 and in women after the age of 70 indicate a potential role for risk factor reduction in those at jeopardy.
The SHEP provided an opportunity to examine CHD risk in a defined older cohort. SHEP recruited 4736 persons of age 60 years with SBP of 160 to 219 mm Hg and DBP of <90 mm Hg. Mean age was 72 years; 57% were women; and 14% were black. Data are presented for SHEP enrollees followed for a mean of 4.5 years after baseline laboratory and clinical assessment. These data support the association of serum total cholesterol, non-HDL cholesterol, and LDL cholesterol with CHD incidence in older men and women.
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Methods |
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SHEP was a randomized, placebo-controlled, double-blind multicenter clinical trial designed to determine whether pharmacological treatment of isolated systolic hypertension (average SBP,
160 mm Hg; average DBP, <90 mm Hg) among persons of age 60 years would reduce the incidence of fatal and nonfatal stroke.24 A secondary end point was major coronary heart disease events.
In 16 clinical centers, from among 447 921 persons age 60 who were screened, there were 4736 men and women found to be eligible, and they were randomized, in double-blind fashion, to receive either active therapy or matching placebo. Stratification at randomization was by clinical center and by whether the participant was on antihypertensive medication at the initial contact.
Criteria for SHEP enrollment have been reported.24 Blood pressure was determined with a Hawksley random zero manometer. Blood pressure eligibility for randomization was determined after four seated blood pressure measurements, two at each of two baseline visits. The average had to yield SBP of 160 to 219 mm Hg and a DBP of <90 mm Hg.
Trial exclusion criteria included the presence of major cardiovascular disease or other major disease such as cancer, alcoholic liver disease, renal dysfunction, or medical management problems. Participants eligible at end of second baseline visit were randomly allocated to receive either active drug or matching placebo in a double-blind fashion.
Each participant had a goal blood pressure established as follows: persons with SBP 180 mm Hg had a goal reduction to <160 mm Hg, whereas those with SBP of 160 to 179 had a goal reduction of 20 mm Hg, so that a patient with a baseline SBP of 165 mm Hg had a goal of 145 mm Hg. Drugs used were low-dose chlorthalidone (12.5 mg/d) (step 1). If step 1 medication did not achieve the goal, active drug (or matching placebo) dosage was doubled. If the goal was not achieved at this maximal dose of step 1 medication, then atenolol (25 mg/d) or matching placebo was added as the step 2 drug unless it was contraindicated; then, reserpine (0.05 mg/d) was substituted. If necessary, the dosage of the step 2 drug was doubled. Participants with serum potassium concentration of <3.5 mmol/L at two consecutive visits were administered a potassium supplement.
Monthly visits were required until participants reached goal SBP or until the maximum level of stepped care treatment was attained. If blood pressure rose above predefined escape levels despite maximal stepped-care therapy, known active drug therapy could be prescribed. These escape criteria were SBP of 250 mm Hg or DBP of 115 mm Hg at a single visit or sustained SBP of 220 mm Hg or sustained DBP of 90 mm Hg.
At quarterly visits for all participants, blood pressure, heart rate, body weight, medical history, and review of medication were obtained. Semiannual and annual visits were required, including questionnaires for depression and dementia. At annual visits, detailed medical history, comprehensive physical examination, laboratory tests, and behavioral assessments were done. Additional visits were scheduled when clinically indicated.
Blood Sampling and Laboratory Methods
Baseline blood samples were procured at the second baseline visit, immediately before randomization. Participants previously receiving antihypertensive medication had been off of these medications for 2 to 8 weeks before sample collection. A defined protocol for venipuncture was followed and included the participant in the seated position, minimal tourniquet time, and centrifugation of the sample 30 to 60 minutes after sample collection to harvest serum.25 Whenever feasible, samples were collected in the morning after an overnight fast. Sixty-four percent of all blood samples were collected from fasting participants. Serum samples were collected by courier and transported to the central laboratory (MetPath Laboratories, Teterboro, NJ) under refrigeration; all measurements were made within 2 days of sample collection. Lipids determined included total cholesterol, HDL cholesterol, and triglycerides. Non–HDL cholesterol, the difference between total and HDL cholesterol, was calculated. It includes cholesterol in atherogenic lipoproteins and is unchanged postprandially.26 LDL cholesterol was estimated in individuals fasting at baseline and with triglyceride levels of <4.52 mmol/L (400 mg/dL).27 Methods of analysis and external laboratory surveillance have been described previously.25
End Point Determination
End points included in this report are (1) nonfatal MI or CHD death (major CHD events) and (2) major CHD events, angioplasty (PTCA), or coronary artery bypass graft (CABG). A nonfatal MI was defined as typical symptoms of acute MI plus either typical ECG changes or significant enzyme elevations but not including silent MI. CHD death was defined as either sudden cardiac death (death within 1 hour of onset of severe cardiac symptoms) or rapid cardiac death (death from 1 to 24 hours of onset of severe cardiac symptoms) or fatal MI (diagnosis at autopsy or on death certificate from preterminal hospitalization data). Other end points are described in detail elsewhere.24 The occurrence of nonfatal and fatal events was confirmed by a panel of three physicians who were blinded to randomization status, including one cardiologist for cardiac events.
Statistical Analysis
Lipids examined were total cholesterol, HDL cholesterol, non–HDL cholesterol, LDL cholesterol, triglycerides, total-to-HDL cholesterol ratio, non–HDL-to-HDL cholesterol ratio, and LDL-to-HDL cholesterol ratio. Descriptive statistics for these lipid measures and several other baseline characteristics are presented. Cox regressions and univariate relative risks (and 95% confidence intervals) for these baseline factors were calculated for the two CHD end points.28 Relative risk is e(coefficientxinterval tested) (ie, antilogarithm to e [base for natural logarithm]): eg, coefficient for the relation of the total cholesterol to CHD risk=.167834-interval of interest 1.03 mmol/L higher-RR=e(.167834x1.03).
Multivariate Cox regressions were calculated with the following other variables: randomization group, age, sex, race, history of CHD, serum uric acid, diabetes, smoking, DBP, alcohol use, angina (by Rose questionnaire), and presence of carotid bruit. Each lipid measure was included as a separate variable in each model. Finally, independent contribution to risk was assessed by including selected lipids together in the regression model.
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Results |
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Baseline Descriptive Statistics
Previous reports have presented detailed data on baseline findings for SHEP participants, both overall and for various subgroups.24 25 29 Table 1
presents data on baseline characteristics used in this report. Baseline lipid levels are presented in Table 2. Mean values for total and HDL cholesterol obtained through fasting did not differ from those in all participants. Correlations of lipid variables for the fasting cohort with triglycerides of <4.52 mmol/L (400 mg/dL) are presented in Table 3. Correlations in the all-participants cohort were similar.
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CHD Events: Univariate Analyses
SHEP participants experienced 245 definite nonfatal MIs or fatal CHD events and underwent 79 CABG or PTCA procedures in the average 4.5 years of follow-up.24 Table 4 presents the results of univariate Cox regression analyses, with nonfatal MI or CHD death as the outcome, for each of the baseline lipid variables. All cholesterol measures were significantly related to CHD outcome with total, non–HDL, and LDL cholesterol, and their ratios to HDL cholesterol positively related and HDL cholesterol negatively related to CHD. Fasting triglycerides were positively related to CHD as well.
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Table 5 presents results of univariate Cox regressions with nonfatal MI, CHD death, PTCA, or CABG as the outcome for the same lipid variables. In comparison with Table 4
, relative risks were similar except those for triglycerides, which were smaller.
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CHD Events: Multivariate Analyses
Tables 6 and 7 present results for single lipid variables in multivariate analyses with control for randomization group, age, race, sex, history of CHD, DBP, smoking, diabetes, alcohol use, Rose Questionnaire angina, presence of carotid bruit, and uric acid for the end point nonfatal MI or CHD death (Table 6) and for the end point nonfatal MI, CHD death, PTCA, or CABG (Table 7). For both end points, coefficients were significant for total cholesterol, non–HDL cholesterol, and LDL cholesterol and the ratios of these to HDL cholesterol. The coefficients were significant for triglycerides in fasting participants with triglycerides of <4.52 mmol/L for the nonfatal MI or CHD death end point. HDL cholesterol was not significant in these analyses. Total and non–HDL cholesterol higher by 1.03 mmol/L (40 mg/dL) (
1 SD) were associated with an event rate higher by 19% to 22% and by 22% to 26%, respectively. For the subcohort of people fasting at baseline and with triglycerides of <4.52 mmol/L, a 1.03 mmol/L higher total, non–HDL, or LDL cholesterol was associated with a 30% to 35% higher major CHD or combined event rate. In this subcohort, for nonfatal MI and CHD death, serum triglycerides were also significantly related to risk, with relative risks of 1.19 and 1.26 for levels of triglycerides and ln triglycerides higher by 1 SD. In separate analyses across treatment groups (data not shown), relative risks for the lipid measurements were similar in placebo and active treatment groups. In multivariate analyses by sex (data not shown), similar findings were observed for both sexes. Relative risks were larger for women than for men.
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Tables 8 and 9 present independent contributions of selected serum lipid variables to risk of nonfatal MI or CHD death (Table 8) or nonfatal MI, CHD death, PTCA, or CABG (Table 9). In all participants, relative risks for total and non–HDL cholesterol but not HDL cholesterol were significant. In the subcohort of fasting participants with triglycerides of <4.52, coefficients for serum total cholesterol, non–HDL cholesterol, and LDL cholesterol were consistently significant in all analyses. For levels higher by 1.03 mmol/L, relative risks were greater by 26% to 34%. In contrast, HDL cholesterol was not significantly and independently related to CHD risk in any of these multivariate analyses. HDL cholesterol, included with one or more other serum lipid variables, was positively (albeit nonsignificantly) related to CHD risk in 7 (of 12) analyses rather than inversely (as expected). Triglycerides and ln triglycerides were significantly related to risk in 2 (of 8) analyses, with relative risks of 1.23 and 1.30, respectively, for levels higher by 1 SD for the end point nonfatal MI or CHD death. In analyses by sex for both end points (data not shown), similar findings were observed for both sexes but with relative risks nonsignificantly larger for women than for men.
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Discussion |
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In the SHEP cohort, total cholesterol, non–HDL cholesterol, LDL cholesterol, and the ratios of these three to HDL cholesterol are significant independent predictors of major CHD events. In separate analyses by sex, similar findings were observed in both sex subgroups. These observations extend the study of defined CHD risk factors to a mixed-race (but predominantly white) cohort of men and women age
60 with isolated systolic hypertension who were recruited to participate in the SHEP. Cholesterol is a constituent of all plasma lipoprotein classes (chylomicrons, VLDL, IDL, LDL, and HDL). Higher concentrations of LDL, IDL, and VLDL cholesterol (the apolipoprotein B-100–containing lipoproteins) and lower concentrations of HDL cholesterol are generally considered to be important lipid CHD risk factors.
For clinical assessment, measurement of lipoprotein cholesterol is arduous and therefore not well suited for routine use; estimates of LDL cholesterol require measured fasting triglycerides and, furthermore, are not valid with triglycerides of >4.52 mmol/L. As an assessment tool, non–HDL cholesterol (the difference between total and HDL cholesterol) includes the cholesterol in the apolipoprotein B-100–containing lipoproteins and can be measured satisfactorily in nonfasting plasma. Our results support the extension of the tenets of the lipid CHD risk concept to older men and women and the inclusion of non–HDL cholesterol with total cholesterol as a measure of CHD risk. These results in comparison with other observations are discussed in the following paragraphs.
Total Cholesterol
In the SHEP cohort, we found that total cholesterol concentration was a significant predictor of CHD events in univariate and multivariate analyses. In multivariate analysis, a 1.03 mmol/L higher total cholesterol (40 mg/dL) (1 SD above the cohort mean) was associated with an estimated 19% to 33% increase in major CHD events. A 10% higher total cholesterol (0.61 mmol/L) was associated with an 11% to 18% higher CHD event rate. Our results, with those of others,6 7 8 9 10 11 12 13 confirm that total cholesterol concentration, previously established as a CHD risk factor based mainly on research in middle-aged men,1 3 5 is an independent CHD risk factor in older men and women.
Lipoprotein Cholesterol
Lipoprotein cholesterol is described here in terms of non–HDL cholesterol and HDL cholesterol (total SHEP cohort) and LDL cholesterol (participants fasting and with triglycerides of <4.52 mmol/L). Also defined are the ratio of total to HDL cholesterol, non–HDL to HDL cholesterol, and LDL to HDL cholesterol.
Lipoprotein cholesterol abnormalities are well-described CHD risk factors in middle-aged men and women.1 2 4 30 We extend these conclusions to older individuals. In the SHEP cohort, in multivariate analyses, a 1.03 mmol/L higher non–HDL or LDL cholesterol level is associated with a significant 22% to 35% increase in CHD events, and a 10% (0.472 mmol/L for non–HDL and 0.398 for LDL) higher non–HDL or LDL cholesterol level is associated with a 9% to 13% higher CHD event rate. These findings are concordant with reports from the Framingham Study7 12 but not others.31
HDL cholesterol is not a CHD risk factor in SHEP. Our findings are supported by other13 but not all32 observations in older adults. At an NHLBI-sponsored workshop that reviewed studies that met specified criteria,13 unadjusted relative risk estimates for CHD mortality were presented separately for men and women. For men and women 65 years old, relative risks were significantly associated with HDL cholesterol in one of eight studies and two of seven studies, respectively. Taken together, our results suggest an emphasis on non–HDL cholesterol as the primary CHD lipoprotein cholesterol risk factor in older adults.
In some analyses, fasting triglycerides were predictors of CHD risk. In analyses with other lipid variables, triglycerides were significant independent contributors in analyses including LDL and HDL cholesterol but not in analyses with non–HDL and HDL cholesterol. These results are consistent with the fact that triglycerides are primarily a constituent of VLDL and not LDL or HDL (non–HDL cholesterol includes the cholesterol in VLDL).
Our data suggest that intervention to achieve an optimal concentration of non–HDL cholesterol (<3.36 mmol/L, <130 mg/dL) in a population comparable to the SHEP cohort would be followed by a 23% to 30% reduction in CHD (antilogarithm of the product of 1.36 mmol/L reduction in non–HDL cholesterolxCox coefficients [Table 6]). In the SHEP placebo group, this would translate to a reduction of 32 to 42 CHD events from a total of 141 and, in the active treatment group, an additional reduction of 23 to 31 from the total 101. Additional reduction would accrue from smoking cessation.
We have taken the opportunity afforded by the SHEP to test elements of the risk factor concept in a large cohort of men and women 60 years old. SHEP was advantageous for study in that a large heterogeneous group of age eligible individuals was followed under a standard protocol with baseline measurements and systematic recording of cardiovascular and noncardiovascular events. Although the large sample size, its racial heterogeneity, and multiple clinical center organization was advantageous for this purpose, this study was not a population study in that individuals recruited as volunteers had established isolated systolic hypertension and on that basis alone were defined to be at increased risk for a cardiovascular event. Also, SHEP recruited a relatively healthy older cohort, based on their perceived interest in general health maintenance and the study selection process.
The results of this study support the inference that serum lipids are CHD risk factors in older American men and women. The lipid concept was developed based mainly on data on middle-aged white men and now is extended to the older population of men and women with isolated systolic hypertension. We suggest that serum lipids are predictors of CHD not only in older adults at higher risk on the basis of systolic hypertension, but also in the more broad-based larger elderly population. This latter statement is based on the comparison of SHEP data presented here not only with data collected in younger adults but also with findings available for older population samples. The strength of associations reported here is similar to those in other reports.11 13 32 33 34
Of practical importance is the unanswered question of whether risk factor reduction in older men and women will be followed by clinical benefit. In support of a positive answer are the primary SHEP results. In SHEP, the question was asked of whether treatment of isolated systolic hypertension would reduce the incidence of stroke. The result was a definite "yes,"24 and of additional importance was the concomitant significant (27%) reduction in major CHD events experienced by the active treatment group. Other supporting evidence for clinical benefit in this age group comes from evident success in reduction in CHD mortality with smoking cessation.35 More directly to the point of this report are individual data within trials of intensive lipid lowering17 and lifestyle modification20 that suggest that lipid modification is advantageous to older men and women. Additional support for the benefit of intervention in older adults comes from the Scandinavian Simvastatin Survival Study (4S) with participants ages 50 to 70 at baseline and followed for a mean of 5.4 years.22 In 4S, the benefit of treatment was observed in study strata regardless of age.36 Not answered conclusively is whether there is a benefit of lipid modification for primary CHD prevention in adults older than 65 years; for that we must await the results of carefully conducted clinical trials.
In conclusion, we used the SHEP database to assess the strength of association of serum total lipids and lipoprotein cholesterol with CHD in men and women age 60 years and older. We have found that as a group, plasma cholesterol, non–HDL cholesterol, LDL cholesterol, and the ratios of these three to HDL cholesterol were significantly related to CHD events. Based on the likelihood that modification of lipid risk factors will be beneficial to those at higher risk for CHD, we suggest that screening for these abnormalities be followed by active treatment for primary and secondary prevention.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This study was supported by contracts with the National Heart, Lung, and Blood Institute and the National Institute on Aging. A complete listing of the SHEP research group has been published.18
Received January 9, 1996; revision received June 5, 1996; accepted June 10, 1996.
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References |
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