Original Article
Changes in Risk Factors and the Decline in Mortality from Cardiovascular Disease — The Framingham Heart Study
N Engl J Med 1990; 322:1635-1641June 7, 1990
- Abstract
- Abstract
A decline in mortality from cardiovascular disease over the past 30 years has been well documented, but the reasons for the decline remain unclear. We analyzed the 10-year incidence of cardiovascular disease and death from cardiovascular disease in three groups of men who were 50 to 59 years old at base line in 1950, 1960, and 1970 (the 1950, 1960, and 1970 cohorts) in order to determine the contribution of secular trends in the incidence of cardiovascular disease, risk factors, and medical care to the decline in mortality.
The 10-year cumulative mortality from cardiovascular disease in the 1970 cohort was 43 percent less than that in the 1950 cohort and 37 percent less than that in the 1960 cohort (P = 0.04 by log-rank test). Among the men who were free of cardiovascular disease at base line, the 10-year cumulative incidence of cardiovascular disease declined approximately 19 percent, from 190 per 1000 in the 1950 cohort to 154 per 1000 in the 1970 cohort (0.10<P<0.20 by chi-square test), whereas the 10-year rate of death from cardiovascular disease declined 60 percent (relative risk for the 1950 cohort as compared with the 1970 cohort, 2.53; 95 percent confidence interval, 1.22 to 5.97).
Significant improvements were found in risk factors for cardiovascular disease among the men initially free of cardiovascular disease in the 1970 cohort as compared with those in the 1950 cohort, including a lower serum cholesterol level (mean ±SD, 5.72±0.98 mmol per liter [221±38 mg per deciliter], as compared with 5.90±1.03 mmol per liter [228±40 mg per deciliter]) and a lower systolic blood pressure (mean ±SD, 135±19 mm Hg, as compared with 139±25 mm Hg), better management of hypertension (22 percent vs. 0 percent were receiving antihypertensive medication), and reduced cigarette smoking (34 percent vs. 56 percent). We propose that these improvements may have had more pronounced effects on mortality from cardiovascular disease than on the incidence of cardiovascular disease in this population.
Our data suggest that the improvement in cardiovascular risk factors in the 1970 cohort may have been an important contributor to the 60 percent decline in mortality in that group as compared with the 1950 cohort, although a decline in the incidence of cardiovascular disease and improved medical interventions may also have contributed to the decline in mortality. (N Engl J Med 1990; 322: 1635–41.)
Media in This Article
Figure 1
Ten-Year Cardiovascular Disease Survival-Distribution Functions for Men Who Were 50 to 59 Years Old at Base Line.Figure 2
Ten-Year Cardiovascular Disease Survival-Distribution Functions for Men Who Were 50 to 59 Years Old and Free of Cardiovascular Disease at Base Line.Article Activity
- Article
A DRAMATIC reduction in mortality from cardiovascular disease over the past 30 years has been well documented1 2 3 4 5; over that period, age-adjusted mortality from cardiovascular disease has fallen by 40 percent in the United States.6 , 7 The causes of the decline are not well understood, however. Whether it has resulted from a reduced incidence of disease,8 , 9 an improved case-fatality rate,10 , 11 or a combination of primary and secondary prevention12 13 14 15 16 17 remains in dispute. Adequate data are not yet available to evaluate these possibilities. We undertook to examine the contribution of secular trends in risk factors, the incidence of disease, and the case-fatality rate to the reduction in mortality from cardiovascular disease in a study of subjects enrolled in the Framingham Heart Study, a well-defined, geographically circumscribed population that has been followed consistently for more than 40 years.
Methods
Information on risk factors for cardiovascular disease and disease end points was obtained by means of interviews, physical examinations, and laboratory tests in a cohort of 5209 people, then 28 to 62 years of age, that was assembled in Framingham, Massachusetts, between 1948 and 1951. This information has been continually updated through surveillance of hospital and death records and biennial examinations. Information on all cardiovascular disease events, hospitalizations, and deaths from any cause that occurred between examinations was recorded, and the medical records and death certificates were obtained and reviewed.
Study Population
Three male cohorts within the Framingham Heart Study were the subjects of the present study: 549 men who were 50 to 59 years of age on January 1, 1950 (the 1950 cohort), 541 men who were 50 to 59 years of age on January 1, 1960 (the 1960 cohort), and 613 men who were 50 to 59 years of age on January 1, 1970 (the 1970 cohort). Each cohort was followed for 10 years. Within each cohort, men who were free of cardiovascular disease at base line were identified, and their 10-year cardiovascular disease experience was analyzed. The sizes of these subgroups were 485 for the 1950 cohort, 464 for the 1960 cohort, and 512 for the 1970 cohort.
Risk-Factor Data
Base-line data on risk factors for the 1950, 1960, and 1970 cohorts were obtained from the 2nd examination of subjects enrolled in the Framingham Heart Study (conducted from 1951 to 1954), the 7th examination (1961 to 1963), and the 12th examination (1970 to 1972). Definitions of the risk factors assessed during the 1st through the 10th examinations are described elsewhere18; similar definitions were used in subsequent examinations. If information on risk factors was missing from the records of the base-line examination, data from the previous or subsequent examination were used. This method provided complete risk-factor data for all the subjects but 20 men in the 1970 cohort, for whom serum cholesterol values were not available.
Ascertainment of Morbidity and Mortality
Cardiovascular disease, the end point of interest in this study, included coronary heart disease (myocardial infarction, angina pectoris, coronary insufficiency, and sudden death), cerebrovascular disease (stroke and transient ischemic attack), intermittent claudication, and congestive heart failure. Events were assigned a diagnosis and date according to standard criteria19 by a panel of physicians who met regularly throughout the 34 years of the Framingham Heart Study that are covered in this report. Complete information on cardiovascular and vital status was available for all members of the three cohorts.
Acute myocardial infarction was considered confirmed when changes on serial electrocardiograms indicated the evolution of an infarction. Beginning in 1956, a hospital record showing an increase in the serum aspartate aminotransferase level to at least 60 U per liter, along with a history of prolonged ischemic chest pain, was accepted as evidence of myocardial infarction. In 1962, an elevated level of lactate dehydrogenase (>500 U per liter) was included in the criteria for a diagnosis of myocardial infarction. Later, as laboratory methods became standardized, the aspartate aminotransferase level was considered abnormal at 50 U per liter, and the lactate dehydrogenase level at 200 U per liter.19 "Unrecognized" infarctions in the Framingham Heart Study were defined as those that were not diagnosed by a physician at the time of the event. A completely asymptomatic event was classified as unrecognized and silent, whereas an undiagnosed event with symptoms reported by the patient was classified as unrecognized but not silent.19
Statistical Analysis
Life-table survival analysis was used to evaluate the distribution of new disease and deaths over time for the three cohorts. Estimates of survival-distribution functions were derived for each cohort with use of the LIFETEST procedure.20 Plots of the three cohorts were superimposed and compared. The log-rank test (the MantelHaenszel test21) was used to test the equality of the survival-distribution functions among the cohorts. Ten-year risk ratios (with 95 percent confidence intervals) and the chi-square statistic were calculated according to standard methods.22 Risk ratios (relative risks) were computed and used as an index of the change in morbidity and mortality from cardiovascular disease between two cohorts according to the following formula: percent change = (risk ratio − 1)/risk ratio. The MantelHaenszel test22 was used to test for overall association in stratified analyses. Risk-factor data recorded in the form of continuous variables were tested for significant differences among the base-line examinations by means of the general-linear-models procedure.23 Bonferroni t-tests24 were used for pairwise comparisons of the mean values at the examinations. All tests of significance were two-tailed.
Results
Mortality and Morbidity from Cardiovascular Disease
The cardiovascular disease survival-distribution functions for the three cohorts were significantly different, with a pronounced increase in survival in the 1970 cohort (P<0.04 by log-rank test; Fig. 1Figure 1
Ten-Year Cardiovascular Disease Survival-Distribution Functions for Men Who Were 50 to 59 Years Old at Base Line.). In this and subsequent analyses, trends in the 1960 cohort were found to resemble closely those in the 1950 cohort. Therefore, results are presented for the 1950 and 1970 cohorts. The 10-year cumulative risk of death from cardiovascular disease for the 1950 cohort as compared with the 1970 cohort was 1.75 (95 percent confidence interval, 1.12 to 2.73), indicating a 43 percent reduction in mortality from cardiovascular disease in the 1970 cohort.This reduction in mortality from cardiovascular disease was not due to a corresponding reduction in the prevalence of cardiovascular disease at base line (Table 1Table 1
Mortality from Cardiovascular Disease and Base-Line (Point) Prevalence of Cardiovascular Disease among Men Who Were 50 to 59 Years Old at Base Line.*). In fact, the base-line prevalence of cardiovascular disease increased from the 1950 to the 1970 cohort (risk ratio for the 1950 cohort as compared with the 1970 cohort, 0.71 [95 percent confidence interval, 0.53 to 0.95]). In addition, among men who were free of cardiovascular disease at base line, the cumulative incidence of cardiovascular disease did not decrease significantly (0.10<P<0.20 by chi-square test), although a decline was observed (Table 2Table 2
Cumulative Incidence of Cardiovascular Disease and Mortality from Cardiovascular Disease among Men Who Were 50 to 59 Years Old and Free of Cardiovascular Disease at Base Line.*). The 10-year cumulative risk of cardiovascular disease was 1.23 for the 1950 cohort as compared with the 1970 cohort (95 percent confidence interval, 0.93 to 1.62).In contrast, a marked decrease in the case-fatality rate was found (P<0.05 by chi-square test) (Table 2). The 10-year risk of death from cardiovascular disease in the 1950 cohort as compared with the 1970 cohort was 2.53 (95 percent confidence interval, 1.22 to 5.97), indicating a 60 percent decline in mortality from cardiovascular disease. Comparison of the 10-year cardiovascular disease survival-distribution functions for these populations (Fig. 2Figure 2
Ten-Year Cardiovascular Disease Survival-Distribution Functions for Men Who Were 50 to 59 Years Old and Free of Cardiovascular Disease at Base Line.) revealed significant differences; 98 percent of the 1970 cohort had not died of cardiovascular disease 10 years after the base-line studies, as compared with approximately 95 percent of the 1950 and 1960 cohorts (P = 0.02 by log-rank test).Severity of Disease
No shift in the distribution of categories of cardiovascular disease toward less severe diagnoses was found (P = 0.77 by MantelHaenszel test) (Table 3Table 3
Diagnoses among Men Who Were 50 to 59 Years Old at Base Line Who Had Incident Cases of Cardiovascular Disease.*). Coronary heart disease, as the first manifestation of cardiovascular disease, accounted for 65 percent of the outcome events in the 1950 cohort, 71 percent in the 1960 cohort, and 67 percent in the 1970 cohort. Cerebrovascular disease was the first manifestation of cardiovascular disease in 12 percent of the cases of cardiovascular disease in the 1950 cohort, 11 percent of the cases in the 1960 cohort, and 12 percent in the 1970 cohort.There was no significant change in the distribution of specific diagnoses among the cohorts to indicate a change in the severity of the initial manifestations of cardiovascular disease (P = 0.78 by MantelHaenszel test). Myocardial infarction was confirmed in 28 percent, 36 percent, and 28 percent of the cases of cardiovascular disease in the 1950, 1960, and 1970 cohorts, respectively. Atherothrombotic brain infarction was confirmed in 8 percent, 4 percent, and 6 percent of the cases in the 1950, 1960, and 1970 cohorts, respectively.
Detection of Disease
Cases of myocardial infarction were reviewed in order to test whether the decline in mortality was due to changes in diagnostic techniques, resulting in the detection of less severe disease. There was a shift from reliance on electrocardiography alone (used in 70 percent of the cases) to diagnose myocardial infarction in the 1950 cohort to the use of both electrocardiography (53 percent) and measurements of cardiac enzymes or the medical history (14 percent) in the 1970 cohort (P<0.02 by chi-square test) (Table 4Table 4
Types of Myocardial Infarction, According to Diagnostic Method, in Men Who Were 50 to 59 Years Old at Base Line.*). However, the rate of unrecognized or undetected myocardial infarction in the population remained stable at 25 to 30 percent.New Treatments
Indirect evidence was used to test the contribution of the availability of the emergency-medical-service system and the coronary care unit to the reduction in mortality. In this population, there was no reduction in the rate of sudden death after the advent of the emergency-medical-service system (Table 5Table 5
Mortality from Sudden Death and Myocardial Infarction among Men Who Were 50 to 59 Years Old at Base Line.*). Out-of-hospital sudden death made up 4 percent of all cardiovascular events in the 1950 cohort, 3 percent of the events in the 1960 cohort, and 6 percent of the events in the 1970 cohort (0.50<P<0.70 by chi-square test for the comparison between the 1960 and 1970 cohorts). Neither did the case-fatality rate for myocardial infarction improve significantly after the advent of the coronary care unit (Table 5). Mortality through the seventh day after the event was 0 percent in the 1950 cohort, 14 percent in the 1960 cohort, and 5 percent in the 1970 cohort (0.20<P<0.30 by chi-square test for the comparison between the 1960 and 1970 cohorts). The 21-day case-fatality rates followed similar trends.Risk Factors
In order to test differences in cardiovascular health among the cohorts, risk factors for cardiovascular disease, evaluated for each subject at his base-line examination, were analyzed. MantelHaenszel and general-linear-model analysis of individual risk factors showed significant differences among the cohorts, with the 1970 cohort having a much healthier profile than either of the earlier cohorts. Table 6Table 6
Selected Risk Factors at Base-Line Examinations of Men Who Were 50 to 59 Years Old at Base Line.* shows the degree and prevalence of selected risk factors for the three cohorts. The mean serum cholesterol levels at base line decreased by 0.57 mmol per liter (22 mg per deciliter) from a high of 6.28 mmol per liter (243 mg per deciliter) in the 1960 cohort to a low of 5.72 mmol per liter (221 mg per deciliter) in the 1970 cohort. An intermediate value of 5.90 mmol per liter (228 mg per deciliter) was observed in the 1950 cohort. The percentage of the men who smoked declined from 56 to 34 percent and the percentage with definite hypertension decreased from 21 to 15 percent between the 1950 and 1970 cohorts. The latter finding reflects the advent of antihypertensive drugs and their use in the 1960 and 1970 cohorts. In the 1960 cohort, 11 percent of men with hypertension were receiving medication; of these, only 30 percent had their hypertension controlled. In the 1970 cohort, these numbers were doubled: 22 percent of all men with hypertension were taking antihypertensive drugs, and of these, almost 60 percent had their hypertension controlled (P<0.02 by chi-square test).Although the men who later had cardiovascular events had higher average base-line risk-factor levels than the average for their cohorts, those in the 1970 cohort had significantly lower risk-factor levels than their counterparts in the 1950 and 1960 cohorts (Table 6). The mean serum cholesterol level decreased by 0.31 mmol per liter (12 mg per deciliter) from the 1950 to the 1970 cohort. In the area of hypertension control, the prevalence of definite hypertension decreased from 36 to 20 percent between the 1950 and 1970 cohorts. Both the mean systolic blood pressure and the mean diastolic blood pressure fell. Although there was no significant difference in the prevalence of the use of antihypertensive medication at base line among those who subsequently had a cardiovascular disease event in the 1960 and 1970 cohorts (11 percent vs. 15 percent), 75 percent of those receiving medication in the 1970 cohort had their blood pressure controlled, as compared with 22 percent in the 1960 cohort (P<0.01 by chi-square test).
Discussion
In the present study, we found a 43 percent reduction in the 10-year risk of death from cardiovascular disease among men who were 50 to 59 years old in 1970 (the 1970 cohort) who were enrolled in the Framingham Heart Study, as compared with similar men who were 50 to 59 years old in 1950 (the 1950 cohort). A 60 percent reduction in the 10-year mortality rate was found among men in the 1970 cohort who were initially free of cardiovascular disease, as compared with their counterparts in the 1950 cohort. Approximately 96 percent of the decline in mortality occurred between the 1960 and 1970 cohorts (the 1960:1970 risk ratio divided by the 1950:1970 risk ratio). These results are consistent with the beginning of the regional decline in cardiovascular mortality, reported by the literature to be 1968.25 , 26
Many factors must be taken into account when one assesses the cause of this decline in mortality. Improved medical interventions, changes in lifestyle and accompanying cardiovascular-risk profiles, and preventive measures may all be important.3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 A multifactorial explanation of the decline in the death rate is consistent with the nature of the disease and with recent studies, which found geographic variation in both the beginning of the decline in mortality25 and the rate of decline.26 The finding by Davis et al.26 that the rate of the decline in the death rate from acute ischemic heart disease differed from that for chronic disease points to the potential existence of a number of causal elements that affect types of cardiovascular disease differentially.
Although improved treatment methods and better prevention may have contributed individually to the decline in mortality, our study and others suggest that risk-factor modification has played an important part.27 , 28 Major improvements were found in risk factors for cardiovascular disease in the 1970 cohort as compared with the 1950 and 1960 cohorts. This was true both when the entire cohorts were compared and when only men who later had cardiovascular events were compared. Evidence from the Framingham Heart Study suggests that an improved cardiovascular-risk profile leads to a reduced risk both of cardiovascular disease and of death.27 However, our data do not prove that the improvement in risk factors caused the decline in cardiovascular mortality. We can conclude only that risk factors and mortality improved concurrently.
Our data indicate that the decline in mortality was primarily the result of improved survival among persons with new cases of cardiovascular disease, rather than the result of a substantial decrease in the incidence of the disease. Little is known about the delay between changes in risk-factor status in a population and changes in the incidence of disease and death. It is likely, however, that changes in risk-factor status would have to begin at an early age in order to produce major reductions in the incidence of disease among 50-to-59-year-olds. It seems reasonable that a shorter time would be necessary for changes in risk factors in a population to lead to reduced mortality.
Two potential sources of bias exist in this study: changes in the severity of disease over time and the limited sample size.
Severity of Disease
Bias in the study of secular trends or period effects can result if diagnostic categories shift over time as a result of improvements in clinical skills, diagnostic techniques, or both. Increased detection of less severe disease can result in increased incidence and lower case-fatality rates (the Will Rogers phenomenon).29 , 30
We evaluated the possibility of bias toward the identification of less severe disease by a review of the criteria for the events we analyzed. An important shift in diagnostic criteria to reliance on measurements of aspartate aminotransferase and lactate dehydrogenase and the medical history to diagnose myocardial infarction was evident in the 1970 cohort. (Measurements of creatine kinase or its MB fraction were not used in the Framingham study at the time.) Although the sensitivity of these enzyme measurements probably did improve the diagnosis of myocardial infarction, it is uncertain to what extent they improved the detection of small, less severe infarctions.31
Another issue concerns the changing information base available to support a diagnosis—i.e., the issue of a change in the quality or quantity of information available to make a diagnosis, regardless of the diagnostic criteria. Although early diagnosis of cardiac disease is now assisted by noninvasive techniques such as echocardiography, nuclear magnetic resonance imaging, and radionuclide scanning, these techniques were not generally available during the period covered in this study. Other studies have confirmed that these techniques were not used to a substantial degree until after 1979 through 1981,32 , 33 the end of our follow-up period.
Sample Size
The samples were restricted in this study in order to control for effects of age and cohort that could have confounded the analysis of period effects. However, these restrictions may have limited the statistical power of the study to detect important changes in incidence and in treatment effects.
Incidence
The 10-year cumulative risk of cardiovascular disease was 1.23 in the 1950 cohort as compared with the 1970 cohort (95 percent confidence interval, 0.93 to 1.62). The 95 percent confidence interval indicates a range of values from an 8 percent increase in disease to a 38 percent decline. The sample had an 80 percent power of detecting a decline in incidence of 25 percent or more, but there would have had to be 724 men in each cohort for this study to have had an 80 percent power of detecting a 19 percent decline, given a Type I error of 0.05.34 Thus, it cannot be determined from the sample whether the 19 percent decrease in the calculated risk reflects a true decline in the incidence of disease. If it is real, given a stable case-fatality rate of 26 percent (as in the 1950 cohort), it would account for a 19 percent reduction in mortality — according to the formula (case-fatality rate × 1950 incidence) — (case-fatality rate × 1970 incidence)/(case-fatality rate × 1950 incidence) — or 31 percent of the observed decline. The improved risk-factor status of the 1970 cohort is consistent with a decline in incidence of this magnitude.
Treatment Effects
The small numbers of men who had specific events may mean that the study had limited power to detect important treatment effects in the 1970 cohort. During the period we studied, the major new interventions were the emergency-medical-service system and the coronary care unit, since the 1970 cohort did not yet benefit from such new treatments as thrombolysis or angioplasty.28 , 32 Although the results presented here are consistent with those of other investigators who have evaluated these interventions,35 36 37 38 39 the small samples in our study argue against excluding the medical treatment of coronary events as a contributor to the 50 percent improvement we found in case-fatality rates in the 1970 cohort as compared with the 1950 cohort.40 We did not specifically assess the potential benefits of beta-adrenergic—blocking agents, antiarrhythmic or antiplatelet drugs, or coronary-artery bypass surgery, any or all of which could have improved survival if they had been available.
Using meta-analysis, Goldman and Cook17 estimated that 54 percent of the decline in the rate of death from ischemic heart disease was related to changes in lifestyle, whereas 40 percent could be attributed to medical interventions. In the cohort analyses presented here, we attempted to provide more direct evidence of the contribution of secular trends to the decline in mortality from cardiovascular disease. The weight of the evidence in this study suggests that the improved risk-factor status of the 1970 cohort may have been an important contributor to the 60 percent decline in deaths from cardiovascular disease in this population as compared with the 1950 cohort. A possible 19 percent reduction in the incidence of cardiovascular disease, which is consistent with the improvements in risk factors noted in the 1970 cohort, may account for as much as 31 percent of the decline in mortality.
Supported by grants (HL-32301 [to Dr. Sytkowski] and HL-40423 (to Dr. D'Agostino]) from the National Institutes of Health.
Source Information
From the New England Research Institute, Watertown, Mass. (P.A.S., W.B.K., R.B.D.); the Epidemiology and Preventive Medicine Section, Department of Medicine, Boston University School of Medicine, Boston (W.B.K.); and the Department of Mathematics, Boston University, Boston (R.B.D.). Address reprint requests to Dr. Sytkowski at the New England Research Institute, 9 Galen St., Watertown, MA 02172.
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