Sex differences in lifetime risk and first manifestation of cardiovascular disease: prospective population based cohort studyBMJ 2014; 349 doi: https://doi.org/10.1136/bmj.g5992 (Published 17 November 2014) Cite this as: BMJ 2014;349:g5992
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Re: Sex differences in lifetime risk and first manifestation of cardiovascular disease: prospective population based cohort study
Should Men and Women be Guided Differently to Maintain Lifetime Healthy?
Leenign MJ, et al’s paper evaluated differences in first manifestations of cardiovascular disease (CVD) between men and women in a competing risks framework and reported that at age 55, though men and women have similar lifetime risks of CVD, there are considerable differences in the first manifestation. Men are more likely to develop coronary heart disease as a first event, while women are more likely to have cerebrovascular disease or heart failure as their first event, although these manifestations appear most often at older ages.1
CVD is a leading cause of death and disability to both men and women in developed countries.2,3 Previous studies have reported sex differences of CVD risk.4,5 However, no studies have compared multiple first manifestations of CVD between men and women in a competing risks framework. This analytic approach is important because cardiovascular risk factors also affects the risk of dying from non-cardiovascular causes before the development of CVD.6 Further, it is very important to find out a manifestation pattern of CVD to prevent CVD in both men and women during lifetime.
In the current study, although authors discussed some limitations such that the lifetime risks of CVD could be somewhat underestimated, some new and important observations are worthwhile to be discussed in detail. Several baseline characteristics differed in this study. Women were older than men and had lower levels of attained education. Cholesterol concentrations and BMI were generally higher in women, whereas men had higher diastolic blood pressure and were more often smokers. Cholesterol concentrations is a major risk factor of coronary heart disease and diastolic blood pressure a major risk factor of cerebrovascular disease. Nevertheless, of interest, men are more likely to develop coronary heart disease as a first event, while women are more likely to have cerebrovascular disease or heart failure as their first event.
In men, the cumulative incidence of coronary heart disease is higher than that of cerebrovascular disease and heart failure at all ages with the cumulative incidences of the latter two catching up until age 70 and all curves running about parallel thereafter. In women, the curves were steeper for cerebrovascular disease and heart failure than for coronary heart disease, especially at higher ages, indicating that most cases of cerebrovascular disease and heart failure occurred in the later part of the lifespan. These results underscore the importance of adequate control of risk factors for stroke and heart failure in middle aged women with a moderate to high burden of risk factors for the primary prevention of CVD. In the light of the current study, physicians should follow the recently released guidelines on primary prevention of CVD pointing out the importance of assessment of lifetime risk.7,8 And it should be noted that most current prevention guidelines have focused on the indications for lipid lowering treatment, but adequate control of the main modifiable causes of stroke such as hypertension, smoking, and therapeutic lifestyle changes should remain top priorities for clinicians to reduce the population burden of cerebrovascular disease.9
Funding: None, Disclosures: None
1. Leening MJ, Ferket BS, Steyerberg EW, Kavousi M, Deckers JW, Nieboer D, et al. Sex differences in lifetime risk and first manifestation of cardiovascular disease: prospective population based cohort study. BMJ 2014;349:g5992.
2. Wilkins JT, Ning H, Berry JD, Zhao L, Dyer AR, Lloyd-Jones DM. Lifetime risk and years
lived free of total cardiovascular disease. JAMA 2012;308:1795-801.
3. Go AS, Mozaffarian D, Roger VL, Benjamin EJ, Berry JD, Blaha MJ, et al. Heart disease
and stroke statistics—2014 update: a report from the American Heart Association.
4. Bleumink GS, Knetsch AM, Sturkenboom MCJM, Straus SMJM, Hofman A, Deckers JW,
et al. Quantifying the heart failure epidemic: prevalence, incidence rate, lifetime risk and
prognosis of heart failure: the Rotterdam Study. Eur Heart J 2004;25:1614-9.
5. Petrea RE, Beiser AS, Seshadri S, Kelly-Hayes M, Kase CS, Wolf PA. Gender differences
in stroke incidence and poststroke disability in the Framingham Heart Study. Stroke
6. Lloyd-Jones DM, Dyer AR, Wang R, Daviglus ML, Greenland P. Risk factor burden in
middle age and lifetime risks for cardiovascular and non-cardiovascular death (Chicago
Heart Association Detection Project in Industry). Am J Cardiol 2007;99:535-40.
7. JBS3 Board. Joint British Societies’ consensus recommendations for the prevention of
cardiovascular disease (JBS3). Heart 2014;100(suppl 2):ii1-ii67.
8. Goff DC Jr, Lloyd-Jones DM, Bennett G, Coady S, D’Agostino RB Sr, Gibbons R, et al.
2013 ACC/AHA guideline on the assessment of cardiovascular risk: a report of the
American College of Cardiology/American Heart Association Task Force on Practice
Guidelines. Circulation 2014;129(25 suppl 2):S49-73.
9. Bos MJ, Koudstaal PJ, Hofman A, Ikram MA. Modifiable etiological factors and the burden of stroke from the Rotterdam Study: a population-based cohort study. PLoS Med
Competing interests: No competing interests
Generalizability of cardiovascular risk from the population-based Rotterdam Study to the general population
We would like to thank Dr Hippisley-Cox and colleagues for their interest in our study. They noticed a nearly 2-fold higher lifetime risk of cardiovascular disease in the Rotterdam Study  as compared to results from the QResearch database. In this letter we would like to discuss how these differences might be explained and why we disagree with their conclusion that the Rotterdam Study consists of a high-risk population.
As acknowledged by Dr Hippisley-Cox and colleagues, part of the discrepancies in results may arise from the difference in cardiovascular disease definitions used in the two studies. Other differences in study design should also be highlighted. As pointed out by Dr Hippisley-Cox and colleagues, population-based cohort studies are generally smaller than administrative databases and will inevitably lack information on invitees unwilling or unable to participate. However, cohort studies collect baseline information on risk factors (e.g. smoking and cholesterol levels) in a standardised way for every participant, whereas availability of information in administrative databases depends on healthcare-seeking behaviour of patients and not all important risk factors are assessed and registered in every patient. Moreover, due to the use of multiple data sources, follow-up in prospective cohort studies is more detailed and may include more outcomes as compared to studies solely relying on administrative data.
The Rotterdam Study is a prospective population-based cohort study of an unselected sample of the population of the city of Rotterdam, the Netherlands. Population-based cohort studies, including in the Rotterdam Study , have repeatedly been shown to represent a lower risk population than the underlying eligible source population due to selective non-participation of individuals with a poorer health status. This results in somewhat lower event rates rather than an overestimation of cardiovascular risk and thus does not explain the difference observed by Dr Hippisley-Cox and colleagues. Besides, the Netherlands is considered a low risk country by the European Society of Cardiology. Recent work from the Rotterdam Study has shown that established cardiovascular risk calculators, including the SCORE calculator for low risk countries, overestimate risk in the Rotterdam Study.[6, 7] This indicates that the Rotterdam Study population is not a particular high-risk population. Finally, as discussed in our paper , lifetime risks of cardiovascular disease in the Rotterdam Study are comparable to those found in a recent meta-analysis on 5 prospective population-based cohort studies from the U.S.
What then may explain the observed difference in results? For one, the comparison of crude incidence rates over the studies are hampered by differences in age distribution. Mean (SD) age was 67.6 (8.9) in the Rotterdam Study  and 48.1 (14.3) in QResearch. The comparison of prevalence of diabetes mellitus is similarly flawed, since glucose levels were measured in all Rotterdam Study participants at baseline, whereas these were missing for many individuals in QResearch.
Lifetime risk of death from cardiovascular causes is a uniform way to compare cardiovascular risk between populations. A greater burden of cardiovascular disease will be reflected by a greater proportion of deaths attributable to cardiovascular disease. We calculated lifetime risk of death due to cardiovascular disease using the data described in our paper. When applying a broad definition that also included non-atherosclerotic end points and sudden deaths , lifetime risk of death due to cardiovascular disease was 34.3% (95% CI 32.6 to 35.8); using a stricter definition based on ICD-10 (codes I00-I99), we estimated this to be 28.7% (95% CI 27.2 to 30.2). These results are in line with nationwide data from Statistics Netherlands (Centraal Bureau voor de Statistiek) on the second decade of our study period (2003-2010; 31% for ages 18 and over)[10, 11], as well as the data presented in the 2012 statistics report from the British Heart Foundation (33% for ages 55 and over).
In this context it is remarkable that the lifetime risks at age 55 in QResearch (37% in men and 28% in women for fatal and non-fatal cardiovascular disease combined) are similar to or lower than the 33% probability of dying from cardiovascular disease according the British Heart Foundation. This makes us wonder whether the striking difference in results might be due to an underestimation of lifetime risks in QResearch rather than an overestimation in the Rotterdam Study.
Mortality from cardiovascular disease is declining in Western societies. Yet the prospect that two out of three healthy adults at age 55 will face some form of cardiovascular disease during their lifespan should reinforce efforts to motivate people to adopt a healthy lifestyle and underscores the importance of primordial and primary prevention.
1. Leening MJG, Ferket BS, Steyerberg EW, et al. Sex differences in lifetime risk and first manifestation of cardiovascular disease: prospective population based cohort study. BMJ. 2014;349:g5992.
2. Hippisley-Cox J, Coupland C, Robson J, Brindle P. Derivation, validation, and evaluation of a new QRISK model to estimate lifetime risk of cardiovascular disease: cohort study using QResearch database. BMJ. 2010;341:c6624.
3. Hofman A, Darwish Murad S, van Duijn CM, et al. The Rotterdam Study: 2014 objectives and design update. Eur J Epidemiol. 2013;28:889-926.
4. Leening MJG, Heeringa J, Deckers JW, et al. Healthy volunteer effect and cardiovascular risk. Epidemiology. 2014;25:470-1.
5. Perk J, De Backer G, Gohlke H, et al. European guidelines on cardiovascular disease prevention in clinical practice (version 2012): The Fifth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of nine societies and by invited experts). Developed with the special contribution of the European Association for Cardiovascular Prevention & Rehabilitation (EACPR). Eur Heart J. 2012;33:1635-701.
6. Kavousi M, Leening MJG, Nanchen D, et al. Comparison of application of the ACC/AHA guidelines, Adult Treatment Panel III guidelines, and European Society of Cardiology guidelines for cardiovascular disease prevention in a European cohort. JAMA. 2014;311:1416-23.
7. Koller MT, Leening MJG, Wolbers M, et al. Development and validation of a coronary risk prediction model for older U.S. and European persons in the Cardiovascular Health Study and the Rotterdam Study. Ann Intern Med. 2012;157:389-97.
8. Wilkins JT, Ning H, Berry J, Zhao L, Dyer AR, Lloyd-Jones DM. Lifetime risk and years lived free of total cardiovascular disease. JAMA. 2012;308:1795-801.
9. Leening MJG, Kavousi M, Heeringa J, et al. Methods of data collection and definitions of cardiac outcomes in the Rotterdam Study. Eur J Epidemiol. 2012;27:173-85.
10. Vaartjes I, Koopman C, van Dis I, Visseren FLJ, Bots ML. Hart- en vaatziekten in Nederland 2013, cijfers over leefstijl, risicofactoren, ziekte en sterfte. The Hague: Dutch Heart Foundation; 2013.
11. Leening MJG, Siregar S, Vaartjes I, et al. Heart disease in the Netherlands: a quantitative update. Neth Heart J. 2014;22:3-10. Erratum in: Neth Heart J 2014;22:131-2.
12. Townsend N, Wickramasinghe K, Bhatnagar P, et al. Coronary heart disease statistics 2012 edition (p19; table 1.2). London: British Heart Foundation; 2012.
Competing interests: Since publication of their article, the authors report no further potential conflict of interest.
Comparison of sex differences in lifetime risk of CVD in Rotterdam study with previously published BMJ paper on CVD lifetime risks in the UK
Comparison of sex differences in lifetime risk of CVD Rotterdam study vs QRISK Lifetime UK
We were interested to read the paper by Leening et al reporting on lifetime cardiovascular risks in a competing risks framework for men and women in Rotterdam1 . The key findings were that “Men and women of middle age have similar overall lifetime risks of cardiovascular disease, with two out of three facing some form of cardiovascular disease during their life”. At age 55, the overall lifetime risk for men was 67.1% and for women was 66.4%.
We noticed the findings of this study are at odds with our own study published in the BMJ (not cited by the authors) describing lifetime cardiovascular risk assessment in men and women using a competing risk framework, based on a large UK population2. We found that, at age 55 years, men had substantially higher lifetime risks of CVD than women. Using the 50th centile values presented in Fig3 of our paper2, the lifetime risk at age 55 was 37% for men and 28% for women. Also the overall lifetime risk estimates at age 55 years were twice as high in the Rotterdam study compared with our UK study, and correspondingly the incidence of CVD events in patients aged 55 years and older in the Rotterdam study was 35.5 per 1000 person years) was twice as high as the incidence for patients aged 55 years and older in UK study (17.7 per 1000 person years). We were interested to highlight these differences and explore the potential reasons.
The Rotterdam study appears to have a much higher risk population than the UK study on nearly all measures which might explain their higher lifetime risks. For example 26.2% of participants in the Rotterdam study were treated for hypertension compared with 13.7% of patients aged 55 and older the UK study, and 9.9% had diabetes compared with 4%.
The UK study was a very large study (2.3 million patients not on statins) drawn from across England and Wales whereas the Rotterdam study is a small cohort (8,419 patients) drawn from a particular suburb in Rotterdam which might introduce a bias towards a higher CVD risk if the population was deprived. Also approximately 75% of eligible patients were recruited in the Rotterdam study with a further 10% failing to attend for assessments, whereas the UK study included all eligible patients. This would tend to result in a more selected population and make the findings less generalisable outside Rotterdam.
Higher risks in the Rotterdam study might in part reflect the use of a broader definition of cardiovacular disease. Unlike the UK study, the Rotterdam study included carotid vascularisations and congestive cardiac failure in the definition of cardiovascular disease outcome although this only accounted for approximately one third of cases.
Whilst we think these differences between the two study are of interest, we remain unconvinced of the clinical utility of lifetime risk estimates of cardiovascular disease over the use of 10 year risk scores. Higher lifetime risks of cardiovascular disease can reflect increased life expectancy through reduced risks of dying from other causes such as cancer, and so their interpretation and applicability is complex.
• 1. Leening MJG, Ferket BS, Steyerberg EW, et al. Sex differences in lifetime risk and first manifestation of cardiovascular disease: prospective population based cohort study, 2014.
• 2. Hippisley-Cox J, Coupland C, Robson J, et al. Derivation, validation, and evaluation of a new QRISK model to estimate lifetime risk of cardiovascular disease: Cohort study using QResearch database. BMJ 2011;342(7788):93.
Competing interests: JHC is professor of clinical epidemiology at the University of Nottingham and co-director of QResearch® – a not-for-profit organisation which is a joint partnership between the University of Nottingham and EMIS (leading commercial supplier of IT for 60% of general practices in the UK). JHC is also director of ClinRisk Ltd which produces open and closed source software to ensure the reliable and updatable implementation of clinical risk algorithms within clinical computer systems to help improve patient care. CC is associate professor of Medical Statistics at the University of Nottingham and a consultant statistician for ClinRisk Ltd. . JR and PB were previously members of the NICE Guideline Development Group for Lipid Modification of which JR was chair. This work and any views expressed within it are solely those of the co-authors and not of any affiliated bodies or organisations. There are no other relationships or activities that could appear to have influenced the submitted work.