European Journal of Epidemiology 19: 409–410, 2004. 2004 Kluwer Academic Publishers. Printed in the Netherlands.
Once at risk – forever at risk? The long-term impact of cardiovascular risk factors on death Hans-Werner Hense Institute of Epidemiology and Social Medicine, University Mu¨nster, D 48129 Mu¨nster, Germany
Blood pressure, serum cholesterol and smoking are established risk factors, that is to say that in individuals with elevated levels of these factors the risk for the occurrence of atherosclerotic diseases in the heart, the brain and in the peripheral vessels is increased. There is ample evidence from numerous prospective observational and interventional studies to provide a sound basis for this statement [1]. Rarely, however, do we ask ourselves another question, namely, for how long does this predictive association hold – or in other words, is the relation of cardiovascular risk factors with subsequent disease essentially sustained, is it increasing or is it gradually attenuated and diminishing over time? The most likely reason why this question is rarely being asked may be found in the fact that most prospective studies have a limited time frame that is often restricted to only 5 or 10 years of follow-up. Only very few studies, such as, for example, the Framingham Heart Study, dispose of more than 30 years of followup with regard to both morbidity and mortality of their participants [2]. There are, however, also a few other studies that were started around the middle of the last century and that continue to periodically assess the vital status of their samples. In this issue of the Journal, Menotti et al. present the death rates due to all causes, coronary heart disease (CHD) and a group encompassing all atherosclerotic cardiovascular diseases (ACVD) in the US Railroad cohort of the Seven Countries Study and investigate their association with risk factor levels measured some 40 years ago [3]. The participants in this study were men, aged between 40 and 59 years at baseline and, by the end of the follow-up period, death had occurred in 83.4% of the initial study sample. More than half of the men had died from ACVD, and one out of three fatalities was due to CHD while cancers accounted for about one quarter of the deaths. Not surprisingly, the authors identified age at baseline as a prominent risk factor of subsequent death. However, baseline systolic blood pressure, serum cholesterol and smoking were also statistically significant, independent predictors of death although their impact was modest with hazard ratios per standard deviation ranging from 1.06 to 1.14 for death of any cause and from 1.12 to 1.26 for CHD and ACVD mortality.
The unacquainted reader may be amazed by this finding – especially when only reading the Medline abstract … – and tend to contest that a one-occasion measurement of risk factor levels in middle-aged men could realistically confer an elevation of risk that persisted over the next 40 years. In response, several general aspects of long-term mortality studies need to be clarified. These relate to the risk factor assessment, to the mortality outcome and its assessment, and to the time-dependency of the hazards. Customarily, risk factors are measured on only one occasion in epidemiological studies as opposed to the clinical situation where repeated measurements are the rule. If a risk factor shows high within-person variability, such as blood pressure, single measurements tend to misclassify individuals with regard to their usual levels, in particular at the extremes of the risk factor distribution. The resulting regression dilution bias can be accounted for by applying appropriate correction factors [2]. Of note, regression dilution ratios were also derived and applied in the study by Menotti et al. using data from the reexamination of survivors after 5 years of follow-up. Quite predictably, their application lead to a strengthening of the association of blood pressure and cholesterol with mortality risk. Nevertheless, detailed analyses by Clarke et al. [2, 4] have shown that corrections based on remeasurements made relatively soon after baseline may not allow properly for the effects of long-term variability [5]. Moreover, since the interval between the baseline and death is typically longer among those who suffer events at older age, underestimation may be greater in the elderly. Therefore it has been recommended to make appropriate time-dependent corrections employing data obtained by biennial examinations over more than 30 years in the Framingham Heart Study [2, 4, 5]. This was not done by Menotti et al. and may have contributed to the rather modest and, compared with earlier results of 25 years of follow-up, declining strengths of the associations reported. Related to this is a phenomenon known as risk factor tracking. Tracking refers to the phenomenon that individual risk factor levels tend to be stable over time, not necessarily in absolute terms which may change with age, but in relation to the position within the population distribution. Tracking is difficult to assess and many problems related to the evaluation of its
410 magnitude remain unresolved [6]. However, there is some evidence for risk factor tracking, and an example over a 40-year period has been described for blood pressure [7]. In the presence of tracking, single baseline measurements in middle-aged men may provide information that captures part of the longterm risk factor developments – at least on the group level which is of relevance here. Thus, the assumption of risk factor tracking together with the correction for regression dilution described above, can help to justify the use of single risk factor measurements even over longer periods of follow-up. The outcome in this study is the cumulative hazard of death. It has been shown for blood pressure that the age-specific hazard ratios decline with older age despite proper correction for time-dependent regression dilution [5]. On one hand, this is probably related to the longer time from baseline to death in long-term studies and, on the other hand, to the proportional increase of ACVD as a cause of death in an ageing cohort. The latter tends to reduce the hazard ratio due to increases of the absolute hazard in subjects with low risk factor levels. The longer the follow-up and the further ageing of the study sample has proceeded, the more pronounced will be this effect. It may therefore be of great value to assess the impact of baseline risk factors on hazard of death in different time windows to disentangle the present overall, averaged effect. This could well be dominated by higher hazard ratios during the early phase of follow-up which differ from those experienced after, say, 20 years and more. A recent report from the Seven Countries Study, also published in this Journal [8], showed very elegantly that the annual hazards of death, observed from baseline onwards, have been subject to very substantial changes, in particular in the US cohort. This report covered the first 25 years of follow-up and included in addition risk factor changes over 10 years in the analyses. The latter, in particular their secular declines, appeared to account for much of the parallel decline in annual hazards. One is eager to get to know if this decline was sustained and how it
affected the hazards and their ratios over the remaining period up to 40 years. References 1. Yusuf S, Fallen E, Gersh B, Camm J, Cairns JA. Evidence-based cardiology. 2nd edn. London: BMJ Books, 2002. 2. Clarke R, Shipley M, Lewington S, et al. Underestimation of risk associations due to regression dilution in long-term follow-up of prospective studies. Am J Epidemiol 1999; 150: 341–353. 3. Menotti A, Kromhout D, Blackburn H, Jacobs D, Lanti M. Forty-year mortality from cardiovascular diseases and all causes of death in the US Railroad cohort of the Seven Countries Study. Eur J Epidemiol 2004; 19: 417–424. 4. Clarke R, Lewington S, Youngman L, Sherliker P, Peto R, Collins R. Underestimation of the importance of blood pressure and cholesterol for coronary heart disease mortality in old age. Eur Heart J 2002; 23: 286– 293. 5. Lewington S, Clarke R, Qizilbash N, Peto R, Collins R. Age-specific relevance of usual blood pressure to vascular mortality: A meta-analysis of individual data for one million adults in 61 prospective studies. Lancet 2002; 360(9349): 1903–1913. 6. Twisk JW. The problem of evaluating the magnitude of tracking coefficients. Eur J Epidemiol 2003; 18: 1025– 1026. 7. Tate RB, Manfreda J, Krahn AD, Cuddy TE. Tracking of blood pressure over a 40-year period in the University of Manitoba Follow-Up Study, 1948–1988. Am J Epidemiol 1995; 142: 946–954. 8. Menotti A, Puddu PE, Lanti M, Kromhout D, Blackburn H, Nissinen A. Twenty-five-year coronary mortality trends in the Seven Countries Study using the accelerated failure time model. Eur J Epidemiol 2003; 18: 113–122.
Address for correspondence: Hans-Werner Hense, Institute of Epidemiology and Social Medicine, University Mu¨nster, D 48129 Mu¨nster, Germany Phone: +49-251-83-55399; Fax: +49-251-83-55300 E-mail:
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