Systematically missing confounders in individual participant data meta-analysis of observational cohort studies.

One difficulty in performing meta-analyses of observational cohort studies is that the availability of confounders may vary between cohorts, so that some cohorts provide fully adjusted analyses while others only provide partially adjusted analyses. Commonly, analyses of the association between an exposure and disease either are restricted to cohorts with full confounder information, or use all cohorts but do not fully adjust for confounding. We propose using a bivariate random-effects meta-analysis model to use information from all available cohorts while still adjusting for all the potential confounders. Our method uses both the fully adjusted and the partially adjusted estimated effects in the cohorts with full confounder information, together with an estimate of their within-cohort correlation. The method is applied to estimate the association between fibrinogen level and coronary heart disease incidence using data from 154,012 participants in 31 cohorts

Angina pectoris is a stronger indicator of diffuse vascular atherosclerosis than intermittent claudication: Framingham study.

OBJECTIVE: To compare implications of Angina Pectoris (AP) and Intermittent Claudication (IC) as indicators of clinical atherosclerosis in other vascular territories. STUDY DESIGN AND SETTING: Prospective cohort study of cardiovascular disease (CVD) in 5,209 men and women of Framingham, MA, aged 28-62 years at enrollment in 1948-1951, who received biennial examinations during the first 36 years of follow-up. Comparative 10-year incidence of subsequent atherosclerotic CVD in participants with IC and AP relative to a reference sample free of CVD was determined. RESULTS: On follow-up, 95 CVD events occurred in 186 participants with IC and 206 of 413 with AP. After age, sex, and risk-factor adjustment, the proportion acquiring other CVD was 34.0% for IC and 43.4% for AP. Relative to the reference sample, those with IC had a 2.73-fold higher age and sex-adjusted 10-year hazard of CVD (95% CI 2.21, 3.38) and for AP was 3.17 (95% CI 2.73, 3.69). CVD hazard ratios remained more elevated for AP and statistically significant after standard risk factor adjustment. Risk factors accounted for more of the excess CVD risk associated with IC (34.8%) than AP (9.5%). CONCLUSION: AP is as useful as IC as a hallmark of diffuse atherosclerotic CVD and an indication for comprehensive preventive measures.

Plasma fibrinogen level and the risk of major cardiovascular diseases and nonvascular mortality: an individual participant meta-analysis.

CONTEXT: Plasma fibrinogen levels may be associated with the risk of coronary heart disease (CHD) and stroke. OBJECTIVE: To assess the relationships of fibrinogen levels with risk of major vascular and with risk of nonvascular outcomes based on individual participant data. DATA SOURCES: Relevant studies were identified by computer-assisted searches, hand searches of reference lists, and personal communication with relevant investigators. STUDY SELECTION: All identified prospective studies were included with information available on baseline fibrinogen levels and details of subsequent major vascular morbidity and/or cause-specific mortality during at least 1 year of follow-up. Studies were excluded if they recruited participants on the basis of having had a previous history of cardiovascular disease; participants with known preexisting CHD or stroke were excluded. DATA EXTRACTION: Individual records were provided on each of 154,211 participants in 31 prospective studies. During 1.38 million person-years of follow-up, there were 6944 first nonfatal myocardial infarctions or stroke events and 13,210 deaths. Cause-specific mortality was generally available. Analyses involved proportional hazards modeling with adjustment for confounding by known cardiovascular risk factors and for regression dilution bias. DATA SYNTHESIS: Within each age group considered (40-59, 60-69, and > or =70 years), there was an approximately log-linear association with usual fibrinogen level for the risk of any CHD, any stroke, other vascular (eg, non-CHD, nonstroke) mortality, and nonvascular mortality. There was no evidence of a threshold within the range of usual fibrinogen level studied at any age. The age- and sex- adjusted hazard ratio per 1-g/L increase in usual fibrinogen level for CHD was 2.42 (95% confidence interval [CI], 2.24-2.60); stroke, 2.06 (95% CI, 1.83-2.33); other vascular mortality, 2.76 (95% CI, 2.28-3.35); and nonvascular mortality, 2.03 (95% CI, 1.90-2.18). The hazard ratios for CHD and stroke were reduced to about 1.8 after further adjustment for measured values of several established vascular risk factors. In a subset of 7011 participants with available C-reactive protein values, the findings for CHD were essentially unchanged following additional adjustment for C-reactive protein. The associations of fibrinogen level with CHD or stroke did not differ substantially according to sex, smoking, blood pressure, blood lipid levels, or several features of study design. CONCLUSIONS: In this large individual participant meta-analysis, moderately strong associations were found between usual plasma fibrinogen level and the risks of CHD, stroke, other vascular mortality, and nonvascular mortality in a wide range of circumstances in healthy middle-aged adults. Assessment of any causal relevance of elevated fibrinogen levels to disease requires additional research.

Risk stratification of dyslipidemia: insights from the Framingham Study.

Dyslipidemia, fundamental to the atherosclerotic process, is now a readily correctable risk factor with established efficacy of treatment for reducing risk of CHD and strokes. The current focus on LDL-cholesterol for risk assessment needs to be broadened to accommodate the two-way traffic of cholesterol entering and leaving the arterial intima reflected by the LDL/HDL ratio or the Total/HDL ratio. The choice of lipid therapy should be individualized to take into account the presence of the metabolic syndrome and the lipid profile of the patient. The intensity of therapy and goals should be linked to multivariable risk, particularly in those with modest lipid values. Cardiovascular risk factor clustering is pronounced for each lipid, is promoted by adiposity and greatly influences its CHD hazard. Global risk assessment taking clustering into account is essential for efficient preventive management of lipids. More attention needs to be afforded the absolute risk reduction attainable and must recognize that the number needed to treat to prevent one event increases the lower the lipid value, the lower global risk and the healthier the subject.

An adaptation of the Framingham coronary heart disease risk function to European Mediterranean areas.

AIM: To determine whether the Framingham function accurately predicts the 10 year risk of coronary disease and to adapt this predictive method to the characteristics of a Spanish population. METHOD AND RESULTS: A Framingham function for predicting 10 year coronary deaths and non-fatal myocardial infarction was applied to the population of the province of Gerona, Spain, where the cumulated incidence rate of myocardial infarction has been determined since 1988 by a specific registry. The prevalence of cardiovascular risk factors in this region of Spain was established in 1995 by a cross sectional study on a representative sample of 1748 people. The number of cases estimated by the Framingham function for 10 year coronary deaths and non-fatal myocardial infarction was compared with that observed. The Framingham function estimated 2425 coronary heart disease cases in women and 1181 were observed. In men, 9919 were estimated and 3706 were observed. Recalibrating the Framingham equations to the event rate and the prevalence of the risk factors in Gerona led to estimates very close to the number of cases observed in Gerona men and women. CONCLUSIONS: The Framingham function estimates more than doubled the actual risk of coronary disease observed in north east Spain. After calibration, the Framingham function became an effective method of estimating the risk in this region with low coronary heart disease incidence.

Assessment of frequency of progression to hypertension in non-hypertensive participants in the Framingham Heart Study: a cohort study.

BACKGROUND: Patients with optimum (<120/80 mm Hg), normal (120-129/80-84 mm Hg), and high normal (130-139/85-89 mm Hg) blood pressure (BP) may progress to hypertension (>140/90 mm Hg) over time. We aimed to establish the best frequency of BP screening by assessing the rates and determinants of progression to hypertension. METHODS: We assessed repeated BP measurements in individuals without hypertension (BP<140/90 mm Hg) from the Framingham Study (4200 men, 5645 women; mean age 52 years) who attended clinic examinations during 1978-94. The incidence of hypertension (or use of antihypertensive treatment) and its determinants were studied. FINDINGS: A stepwise increase in hypertension incidence occurred across the three non-hypertensive BP categories; 5.3% (95% CI 4.4-6.3%) of participants with optimum BP, 17.6% (15.2-20.3%) with normal, and 37.3% (33.3-41.5%) with high normal BP aged below age 65 years progressed to hypertension over 4 years. Corresponding 4-year rates of progression for patients 65 years and older were 16.0% (12.0-20.9), 25.5% (20.4-31.4), and 49.5% (42.6-56.4), respectively. Obesity and weight gain also contributed to progression; a 5% weight gain on follow-up was associated with 20-30% increased odds of hypertension. INTERPRETATION: High normal BP and normal BP frequently progress to hypertension over a period of 4 years, especially in older adults. These findings support recommendations for monitoring individuals with high normal BP once a year, and monitoring those with normal BP every 2 years, and they emphasise the importance of weight control as a measure for primary prevention of hypertension.

Elevated midlife blood pressure increases stroke risk in elderly persons: the Framingham Study.

BACKGROUND: Stroke risk predictions are traditionally based on current blood pressure (BP). The potential impact of a subject's past BP experience (antecedent BP) is unknown. We assessed the incremental impact of antecedent BP on the risk of ischemic stroke. METHODS: A total of 5197 stroke-free subjects (2330 men) in the community-based Framingham Study cohort were enrolled from September 29, 1948, to April 25, 1953, and followed up to December 31, 1998. We determined the 10-year risk of completed initial ischemic stroke for 60-, 70-, and 80-year-old subjects as a function of their current BP (at baseline), recent antecedent BP (average of readings at biennial examinations 1-9 years before baseline), and remote antecedent BP (average at biennial examinations 10-19 years earlier), with adjustment for smoking and diabetes mellitus. Models incorporating antecedent BP were also adjusted for baseline BP. The effect of each BP component (systolic BP, diastolic BP, and pulse pressure) was assessed separately. RESULTS: Four hundred ninety-one ischemic strokes (209 in men) were observed in eligible subjects. The antecedent BP influenced the 10-year stroke risk at the age of 60 years (relative risk per SD increment of recent antecedent systolic BP: women, 1.68 [95% confidence interval, 1.25-2.25]; and men, 1.92 [95% confidence interval, 1.39-2.66]) and at the age of 70 years (relative risk per SD increment of recent antecedent systolic BP: women, 1.66 [95% confidence interval, 1.28-2.14]; and men, 1.30 [95% confidence interval, 0.97-1.75]). This effect was evident for recent and remote antecedent BP, consistent in hypertensive and nonhypertensive subjects, and demonstrable for all BP components. CONCLUSIONS: Antecedent BP contributes to the future risk of ischemic stroke. Optimal prevention of late-life stroke will likely require control of midlife BP.

Does the relation of blood pressure to coronary heart disease risk change with aging? The Framingham Heart Study.

BACKGROUND: We examined the relative importance of diastolic (DBP), systolic (SBP) and pulse pressure (PP) as predictors of coronary heart disease (CHD) risk in different age groups of Framingham Heart Study participants. METHODS AND RESULTS: We studied 3060 men and 3479 women between 20 and 79 years of age who were free of CHD and were not on antihypertensive drug therapy at baseline. Cox regression adjusted for age, sex, and other risk factors was used to assess the relations of BP indexes to CHD risk over a 20-year follow-up. In the group <50 years of age, DBP was the strongest predictor of CHD risk (hazard ratio [HR] per 10 mm Hg increment, 1.34; 95% CI, 1.18 to 1.51) rather than SBP (HR, 1.14; 95% CI, 1.06 to 1.24) or PP (HR, 1.02; 95% CI, 0.89 to 1.17). In the group 50 to 59 years of age, risks were comparable for all 3 BP indexes. In the older age group, the strongest predictor of CHD risk was PP (HR, 1.24; 95% CI, 1.16 to 1.33). When both SBP and DBP were considered jointly, the former was directly and the latter was inversely related to CHD risk in the oldest age group CONCLUSIONS: With increasing age, there was a gradual shift from DBP to SBP and then to PP as predictors of CHD risk. In patients <50 years of age, DBP was the strongest predictor. Age 50 to 59 years was a transition period when all 3 BP indexes were comparable predictors, and from 60 years of age on, DBP was negatively related to CHD risk so that PP became superior to SBP.

Impact of high-normal blood pressure on the risk of cardiovascular disease.

BACKGROUND: Information is limited regarding the absolute and relative risk of cardiovascular disease in persons with high-normal blood pressure (systolic pressure of 130 to 139 mm Hg, diastolic pressure of 85 to 89 mm Hg, or both). METHODS: We investigated the association between blood-pressure category at base line and the incidence of cardiovascular disease on follow-up among 6859 participants in the Framingham Heart Study who were initially free of hypertension and cardiovascular disease. RESULTS: A stepwise increase in cardiovascular event rates was noted in persons with higher baseline blood-pressure categories. The 10-year cumulative incidence of cardiovascular disease in subjects 35 to 64 years of age who had high-normal blood pressure was 4 percent (95 percent confidence interval, 2 to 5 percent) for women and 8 percent (95 percent confidence interval, 6 to 10 percent) for men; in older subjects (those 65 to 90 years old), the incidence was 18 percent (95 percent confidence interval, 12 to 23 percent) for women and 25 percent (95 percent confidence interval, 17 to 34 percent) for men. As compared with optimal blood pressure, high-normal blood pressure was associated with a risk-factor-adjusted hazard ratio for cardiovascular disease of 2.5 (95 percent confidence interval, 1.6 to 4.1) in women and 1.6 (95 percent confidence interval, 1.1 to 2.2) in men. CONCLUSIONS: High-normal blood pressure is associated with an increased risk of cardiovascular disease. Our findings emphasize the need to determine whether lowering high-normal blood pressure can reduce the risk of cardiovascular disease.

Elevated systolic blood pressure as a cardiovascular risk factor.

This paper reviews the evolution of attitudes toward the treatment and diagnosis of hypertension. In particular, there is a growing realization that elevated systolic pressure may be a more valuable measurement in evaluating and controlling hypertension than is generally acknowledged. A large number of epidemiologic studies in a wide variety of populations have revealed that systolic blood pressure exerts a stronger influence than diastolic blood pressure. The largest of these, the Framingham Heart Study, showed that in subjects with systolic hypertension, diastolic blood pressure was only weakly related to the risk of cardiovascular events, but in those with diastolic hypertension, the risk of these events was strongly influenced by the level of systolic pressure. Furthermore, cardiovascular event rates were found to increase steeply with systolic pressure and were higher in cases of isolated systolic hypertension than diastolic hypertension. Clinical trials produced similar results, again suggesting that a greater reliance should be placed on systolic pressure in evaluating the risk of cardiovascular problems. This review concludes that the health community needs to be reeducated to consider the importance of systolic and diastolic blood pressure in assessing appropriate management strategies for hypertensive patients.

Proteinuria as a risk factor for cardiovascular disease and mortality in older people: a prospective study.

BACKGROUND: The prognostic significance of proteinuria in older people is not well defined. We examined the associations between proteinuria and incident coronary heart disease, cardiovascular mortality, and all-cause mortality in older people. SUBJECTS AND METHODS: Casual dipstick proteinuria was determined in 1,045 men (mean [+/- SD] age 68 +/- 7 years) and 1,541 women (mean age 69 +/- 7 years) attending the 15th biennial examination of the Framingham Heart Study. Participants were divided by grade of proteinuria: none (85.3%), trace (10.2%), and greater-than-trace (4.5%). Cox proportional hazards analyses were used to determine the relations of baseline proteinuria to the specified outcomes, adjusting for other risk factors, including serum creatinine level. RESULTS: During 17 years of follow-up, there were 455 coronary heart disease events, 412 cardiovascular disease deaths, and 1,214 deaths. In men, baseline proteinuria was associated with all-cause mortality (hazards ratio [HR] = 1.3, 95% confidence interval [CI] 1.0 to 1.7 for trace proteinuria; HR = 1.3, 95% CI 1.0 to 1.8 for greater-than-trace proteinuria; P for trend = 0.02). In women, trace proteinuria was associated with cardiovascular disease death (HR = 1. 6, 95% CI 1.1 to 2.4), and all-cause mortality (HR = 1.4, 95% CI 1.1 to 1.7). CONCLUSION: Proteinuria is a significant, although relatively weak, risk factor for all-cause mortality in men and women, and for cardiovascular disease mortality in women.

The Framingham Study: ITS 50-year legacy and future promise.

The Framingham Study was initiated in 1948 to investigate an epidemic of coronary disease in the USA, using a prospective epidemiological approach. Insights were provided into the prevalence, incidence, full clinical spectrum and predisposing factors. The major "risk factors" (a term coined by the Framingham Study) for coronary disease, stroke, peripheral artery disease and heart failure were identified and clinical misconceptions dispelled about isolated systolic hypertension, left ventricular hypertrophy, dyslipidemia, atrial fibrillation and glucose intolerance. Average values for blood lipids, blood pressure, body weight, glucose and fibrinogen were shown to be dangerously suboptimal and to have a continuous graded relationship to cardiovascular disease without critical values. Dyslipidemia, glucose intolerance and elevated fibrinogen were shown to have smaller hazard ratios in the elderly, but this was offset by a higher absolute risk. Diabetes was shown to operate more strongly in women, eliminating their advantage over men. Serum total cholesterol was shown to derive its atherogenic potential from its LDL component and also to reflect cholesterol being removed in the HDL fraction. The total/HDL-cholesterol ratio was demonstrated to be the most efficient lipid profile for predicting coronary disease. LDL was shown to be correlated with hemostatic factors, suggesting that there would be additional benefits to lowering LDL. High triglyceride associated with reduced HDL, indicating insulin resistance and small dense LDL, was shown to be associated with excess coronary disease. All the risk factors tended to cluster, and this was shown to be promoted by insulin resistance induced by weight gain. Multivariate risk profiles were produced to facilitate risk stratification of candidates for coronary disease, stroke, peripheral artery disease and heart failure. The Framingham Study is now engaged in quantifying the independent contributions of homocysteine Lp(a), insulin resistance, small dense LDL, C reactive protein, clotting factors and genetic determinants of cardiovascular disease. We are now able to estimate the lifetime risk of all the atherosclerotic cardiovascular disease outcomes.

Vital epidemiologic clues in heart failure.

The epidemiologic investigation of heart failure evolution by the Framingham Heart Study has provided vital clues concerning the pathogenesis, predisposing conditions, other predictive risk factors, and indicators of deteriorating ventricular function related to the disease. This information is important in the early detection of those susceptible to heart failure who are candidates for preventive measures-of importance because the prevalence of the disease has not declined despite the recent therapeutic advances. Epidemiologic investigation has identified useful indicators for the disease including a low or falling vital capacity suggesting diastolic dysfunction, a rapid resting heart rate in compensation for a decreased stroke volume, and cardiomegaly indicating myocardial hypertrophy or dilatation. Hypertension and coronary disease remain the leading causes of the disease, and heart failure due to myocardial infarction has increased in prevalence. Hypertension and coronary disease often coexist in individuals who develop heart failure so that correction and prevention of these conditions deserve a high priority. Early detection and correction of insulin resistance is important because a threefold increase in the prevalence of diabetes in the general population has serious implications for the incidence of heart failure. In patients with hypertension, the occurrence of a myocardial infarction increases the risk of developing heart failure five to sixfold, whereas angina increases it less than twofold. In these patients, the presence of left ventricular hypertrophy increases the risk of developing heart failure two- to threefold. Heart failure-related mortality remains unacceptably high, despite improvements in treatment, indicating a need for early detection and treatment of predisposing conditions.

Risk stratification in hypertension: new insights from the Framingham Study.

Five decades of epidemiologic research have established that blood pressure elevation is a common and powerful contributor to all of the major cardiovascular diseases, including coronary disease, stroke, peripheral artery disease, renal disease, and heart failure. The common variety of hypertension designated benign essential hypertension was not shown to be either benign or essential. Although clinicians favor the diagnosis and treatment of hypertension in terms of diastolic blood pressure elevation and categoric cut points, epidemiologic data show a more important influence of systolic blood pressure, and a continuous, graded influence of blood pressure even within what is regarded as the normotensive range. An important revelation in epidemiologic hypertension research is that hypertension usually occurs in conjunction with other metabolically linked risk factors; therefore, less than 20% occurs in isolation. The other risk factors that tend to accompany hypertension include glucose intolerance, obesity, left ventricular hypertrophy, and dislipidemia (elevated total, LDL, and small dense LDL cholesterol levels, raised triglyceride, and reduced HDL cholesterol levels). Clusters of three or more of these additional risk factors occur at four times the rate expected by chance. This clustering is attributed to an insulin resistance syndrome promoted by abdominal obesity. The amount of risk factor clustering accompanying elevated blood pressure was observed to increase with weight gain. Based on Framingham Study data the prevalence of insulin resistance syndrome in the general population could be as high as 22% in men and 27% in women. Risk of coronary disease, the most common and most lethal sequel to hypertension, increased stepwise with the extent of risk factor clustering. Among persons with hypertension, about 40% of coronary events in men and 68% in women are attributable to the presence of two or more additional risk factors. Only 14% of coronary events in hypertensive men and 5% of those in hypertensive women occurred in the absence of additional risk factors. Other important features of risk stratification of hypertension are the presence of an elevated heart rate and left ventricular hypertrophy, and an elevated fibrinogen that often accompany hypertension. Recent population-based data reported suggest that elevated renin accompanying hypertension may independently enhance the risk of coronary events. Because clustering of other major risk factors with hypertension is the rule, the prudent physician should routinely screen for the presence of these other factors. Multivariate risk assessment profiles are now available for coronary disease, stroke, peripheral artery disease, and heart failure, to enable physicians to pool all the relevant risk factor information so as to arrive at a composite risk estimate. Hypertensive patients are more appropriately targeted for therapy by such risk stratification and the goal of the therapy should be to improve the multivariate risk profile.

Fifty years of Framingham Study contributions to understanding hypertension.

The Framingham Study established hypertension as a major cardiovascular risk factor and quantified its atherogenic cardiovascular disease potential. An historical perspective is presented on the epidemiological insights about hypertension derived from 50 years of Framingham Study research into the prevalence, incidence, determinants and hazards of hypertension. Existing misconceptions about the presence of critical levels of blood pressure, the impact of the systolic and diastolic components of blood pressure, the hazard 'mild' hypertension, the impact in advanced age and the hazard of left ventricular hypertrophy. The importance of isolated systolic hypertension and the pulse pressure were demonstrated. It has been demonstrated that hypertension seldom occurs in isolation of other atherogenic risk factors, with which it tends to cluster. This clustering with other metabolically linked risk factors has been shown to reflect insulin resistance promoted by weight gain and abdominal obesity. Obesity was shown to be one of the major determinants of hypertension in the general population. Left ventricular hypertrophy was shown to be an ominous harbinger of cardiovascular disease rather than an incidental compensatory phenomenon. Multivariate risk profiles for coronary disease, stroke, peripheral artery disease and heart failure have been devised to facilitate incorporation of elevated blood pressure in a global, multivariate cardiovascular risk assessment.