Cardiovascular risk management in old age Ruijter, W. de

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(1)Cardiovascular risk management in old age Ruijter, W. de. Citation Ruijter, W. de. (2009, June 25). Cardiovascular risk management in old age. Retrieved from https://hdl.handle.net/1887/13869 Version:. Corrected Publisher’s Version. License:. Licence agreement concerning inclusion of doctoral thesis in the Institutional Repository of the University of Leiden. Downloaded from:. https://hdl.handle.net/1887/13869. Note: To cite this publication please use the final published version (if applicable)..

(2) 10 General discussion.

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(4) General discussion. General discussion This chapter describes the current situation with regard to cardiovascular risk management in old age, highlights and discusses the important themes that emerged from this thesis, and finishes with some reflections on and recommendations for future research. First, the rationales for the study are revisited, followed by a discussion of several aspects of secondary and primary prevention of cardiovascular disease in old age. Next, the role of various primary care givers, such as general practitioners, is reviewed, as well as the position of preventive health centers for seniors. Finally, suggestions are given for new avenues of research on cardiovascular risk management in old age. 10.1. Cardiovascular risk management in old age: rationales revisited 10.1a Why ‘cardiovascular disease’? When thinking about cardiovascular disease in general, many doctors intuitively think about acute myocardial infarctions, which are either immediately fatal, or ‘fully repaired’ through primary coronary interventions or thrombolysis. This latter intervention more and more also applies to ischemic strokes.1 However, in the general population at large, the vast majority of cardiovascular morbidity consists of chronic cardiovascular conditions in aging people due to earlier coronary, cerebral or peripheral vascular events. And although mortality from cardiovascular events is still closely related to increasing age, these events more and more become non-fatal over time: casefatality rates have decreased at all ages during the last two decades, also in old age.2;3 As a result of this, chronic heart failure and neurological defective states remain leading causes of loss of functional status and well being, not only for older patients themselves, but also for their close relatives. When objective evidence about ‘burden of disease’ is gathered, ischemic heart disease and stroke are in the lead at all ages from middle age onwards.4 In this context, it is remarkable that many patients and doctors still consider cancer as a synonym for a long, awkward and painful remainder of life, and cardiovascular disease as a synonym for a quick and painless death.5 In this line of argumentation, cardiovascular disease in old age (‘an easy way to go’) is not a disease one would want to prevent. As outlined above, in view of the large volume of cardiovascular morbidity in old age, there is however a strong case for such prevention. In the chapters of this thesis concerning risk prediction (primary prevention), however, cardiovascular mortality is the usual outcome of interest, as this permits head-to-head comparison with commonly used risk prediction models. Notwithstanding this seemingly focus on mortality, it should be noted that prevention of cardiovascular morbidity in old age, however, probably is even more important: not only adding ‘years to life’, but also ‘quality of life to years’.. 143.

(5) Chapter 10. 10.1b Why ‘risk management’? This thesis focuses on risk prediction and prevention: which individuals are at high risk of developing cardiovascular disease, and how can this be avoided. Once cardiovascular disease strikes, adequate treatments are of course important, and the effectiveness of certain treatments may also depend on age. Treatments of cardiovascular disease in old age, however, are not the focus of this thesis. On the other hand, in secondary prevention, it was already pointed out that the line between ‘treatment’ and ‘prevention’ is a thin one, since adequate preventive measures usually are an integral part of state-of-the-art treatment.6-10 Primary prevention of cardiovascular disease, however, is an essentially different concept than ‘treatment per se’, and, as was shown in this thesis, requires an age dependent approach. Of pivotal importance is the recognition that primary prevention starts with the selection of high risk individuals, irrespective of the subsequent preventive intervention. In other words: the intervention may not be aimed at altering the risk marker itself, because this risk marker may not be causally related to the outcome. These unique aspects of risk management of cardiovascular disease justify proper and separate attention beyond ‘treatment per se’. 10.1c Why ‘old age’? Worldwide, populations are ageing. In Europe, due to an improved survival of older persons and a low birth rate, societies have the oldest populations in the world. This will remain so in the 21st century, and by 2030 almost a fourth of the European population will be over 65 years of age.11 At the same time, within these older populations, the proportion of people over 85 years of age continues to rise. As cardiovascular disease typically comes with age, a large quantity of cardiovascular disease in old age lies ahead, with consequences as outlined sub 10.1a.12;13 Above all, this calls for a close-knit safety net for secondary prevention up to high ages. As for primary prevention of cardiovascular disease, one may argue that this, preferably, should start early in life, when the process of atherosclerosis can be slowed down or reversed. As true as this may be, it is a fact of life that people often do not act in accordance with primary preventive recommendations. Primary prevention of cardiovascular disease therefore probably stays a continuous process across all ages, including older people. And, given the high incidence of cardiovascular disease in old age, effective preventive interventions will result in a large number of prevented cardiovascular events, even if the relative risk reduction is only small. In short: although cardiovascular risk management is not confined to old age, it still is appropriate to study age-specific aspects of this management in old age. 10.1d ‘Ultimately, one has to die of something!’ In the end, everybody dies. It is, however, striking that this fundamental truth is never uttered in the context of preventive measures for young or middle aged people. Apparently, when prevention is considered in older age groups, patients and their doctors tend to trivialize the potential benefits of prevention and. 144.

(6) General discussion. undervalue the gains with regard to mortality, morbidity and quality of life. Why should we accept that older persons die sooner from cardiovascular disease, or suffer from non-fatal strokes or myocardial infarctions, when evidence-based preventive interventions are available? In aging societies, proportions of fairly healthy (very) old individuals are increasing, and these persons often truly value their quality of life. In fact, in the Leiden 85-plus Study, the mean score on Cantril’s ladder (0-10) was 8.14 Not studying potentially beneficial preventive interventions in old age, referring to ‘ultimately everybody dies’, therefore is ageism in its purest form. 10.2 Reflections on prevention of cardiovascular disease in old age 10.2a Secondary prevention in old age: ‘Yes, unless’ Previous cardiovascular events and prevalent cardiovascular disease, such as a prior myocardial infarction or current atrial fibrillation, are powerful predictors of recurrent cardiovascular events and mortality up to the highest ages (chapter 4).15 Secondary prevention in old age therefore certainly stays an issue. The Dutch guideline on cardiovascular risk management refers to the Heart Protection Study and the PROSPER study (and in the next revision probably also the Hypertension in the Very Elderly Trial) as evidence for the effectiveness of secondary preventive measures in old age, provided a reasonable life-expectancy and a careful weighing of pros and cons when many co-morbidities are present.16-19 Indeed, evidence for the effectiveness of secondary prevention of cardiovascular disease in old age has grown over time, and this has already caused a growing number of elderly patients who receive full secondary preventive medication after a myocardial infarction, as described in chapter 2. However, in line with other studies, we also showed that secondary prevention still is increasingly substandard with rising age.20;21 When guidelines change, the first concern should be to make sure that relevant parties, such as general practitioners and specialists, are repeatedly informed, not only concerning the contents of the guidelines, but also about the evidence that underlies them. The latter is important, since we showed in chapter 3 that belief in evidence underlying (new) guidelines is crucial to motivate professionals to implement new guidelines in their handling of new cases. Barriers concerning time, support and financial compensation need to be explored and dealt with. In order to repair ‘overdue’ secondary prevention in pre-existing cases, regular screening of the medical records for cases that do not yet receive state-of-the-art secondary prevention is necessary. In old age, this is something that general practitioners, or practice nurses under their supervision, may very well do (chapter 5). Collaboration with pharmacies and specialists is warranted. In conclusion: at present, the onus of proof rests with treating physicians to indicate why a person is not receiving proper secondary prevention after a cardiovascular event, irrespective of age of the patient involved. At the same time, researchers need to pass on all available evidence to these physicians in daily practice, as this encourages them to implement the guidelines involved.. 145.

(7) Chapter 10. 10.2b Primary prevention in old age x ‘To screen or not to screen?’ Systematic screening for cardiovascular risk factors in the general population at large has so far not been implemented at any age. Such screening only occurs in subgroups of patients with an expected high prior risk of cardiovascular disease, for instance patients with diabetes mellitus. The latter may be considered secondary prevention, since diabetes is often regarded as vascular disease per se. Primary prevention otherwise is carried out by casefinding: either patients themselves have specific questions about their risk of developing cardiovascular disease, or physicians suspect an elevated risk, both resulting in a measurement of cardiovascular risk factors. The foremost message of this thesis is that measurement of classic risk factors in very old age does not lead to any valuable information concerning the actual risk of cardiovascular mortality (chapters 6 and 7). With regard to separate risk factors, systolic blood pressure is even inversely related to cardiovascular and all cause mortality from age 85 years onwards. The lack of predictive value of classic risk factors as weighed by the Framingham risk score was evident in our study, also when these risk factors were entered in a newly calibrated model based on the Leiden 85-plus Study data. The same is expected for the SCORE risk function, although this has so far not been studied. To date it is also unknown at what age the predictive characteristics of the classic risk factors, integrated in one risk function, disappear. Elaborating on the results of our study within the Rotterdam Study (chapter 7), this may be anywhere between the age of 75 and 85 years. The inevitable next question is which risk factors should be used in stead from this age onwards. One could hypothesize that from age 75 onwards the 10-year risk of cardiovascular mortality always is .

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(13) 22 This would mean an unprecedented medicalization of a growing proportion of society, and this strategy does therefore not seem desirable by many, nor is its effectiveness at this point evidence-based. In other words, some kind of selection in order to assign primary preventive interventions to those with highest risks is necessary. As pointed out in chapter 6, homocysteine is a prime candidate as a stand-alone measurement of cardiovascular risk in old age, and also NT-proBNP is an excellent predictor of cardiovascular mortality (chapter 9). A head-to-head comparison of these candidates, probably alongside other promising risk markers, is still lacking. Unanswered from this thesis remains the issue of systematic screening as opposed to the case-finding strategy. In systematic screening policies, all screening criteria as formulated by Wilson and Jungner will have to be fulfilled, including a careful evaluation of costs and benefits.23 The major components regarding this issue in old age are: “How to efficiently select the patients with the highest risks?”, and, “Is a widely accepted and efficient intervention available?”. The first question has partly been answered by the studies involved in this thesis, but the second question is still open to answers. As proposed in chapter 6, it may be that interventions aimed at classic risk factors prove to be much more efficient if they are applied to a properly selected population (that is: by measuring homocysteine, and not. 146.

(14) General discussion. the classic risk factors). This parallels the concept from the JUPITER trial, in which patients were selected on the basis of an elevated hs-CRP (plus a normal LDL cholesterol level), and then treated with a statin.24 But not only statins should be considered, other possible candidates are beta-blockers, aspirin, and certain blood pressure lowering drugs such as ACE-inhibitors. Finally, the homocysteine-lowering hypothesis has not been definitely ruled out, as a large meta-analysis is still underway.25 More research is needed in older populations of varying ages to evaluate the effect of interventions in adequately selected high-risk individuals. Until then, it is too early to recommend primary prevention of cardiovascular disease in old age by programmatic screening. x ‘Towards age-specific risk scores in old age’ In the field of primary prevention of cardiovascular disease the use of risk prediction models (‘risk scores’), such as the Framingham risk score, is widely accepted and preferred over the use of individual components as triggers for preventive interventions (chapter 6). Remarkably, it was not until 2006 that the Dutch College of General Practitioners finally launched an integrated guideline on ‘Cardiovascular risk management’,16 at the same time abandoning the separate guidelines on ‘Hypertension’ and ‘Cholesterol’. In the mean time, the Framingham risk score had been validated in many populations, and it had become clear that it tended to overestimate risks in European populations.26 Elaborating on the concept of the Framingham risk score, a new risk score was developed for use in Europe: the Systematic COronary Risk Evaluation (SCORE), based on pooled data from 12 European cohort studies.22 This SCORE is also used in the Dutch guideline. While the general concept resembles that of the Framingham risk score, there are some striking differences (Table 1).. Regarding the use of each of the two risk scores in old age, Table 1 shows that the SCORE risk function allows for risk evaluation for people up to age 65-70 years, and the Framingham risk score for people up to age 70-75 years. This means that for people aged 75 years and over a validated risk prediction rule is nonexistent. Moreover, as it was shown in chapter 6 that the Framingham risk score, when applied to people aged 85 years and over, completely loses its. 147.

(15) Chapter 10. predictive abilities, it has disqualified itself for use in this age group, and possibly also in ‘younger’ older persons from age 75 years onwards. These observations clearly call for age-specific risk scores that can be applied to older populations. Apart from this limitation with regard to age, there are several fundamental limitations with the use of risk scores in general that should be observed, including the issues of external validity, imprecision and heterogeneity of risk categories.27 ‘Blind’ application of risk scores, irrespective of a patient’s age, therefore does not seem good clinical practice. In recent years several new risk scores have been developed, all incorporating additional information of patients into the algorithm, such as area measure of social deprivation, ethnicity, treated hypertension, parental history of coronary heart disease, renal disease and hs-CRP.28-30 All these risk scores have in common that they are not validated in older populations, making their application in older people unfeasible. This thesis challenges researchers to develop agespecific risk scores for people over 75 years of age, and try to account for the abovementioned general and age-specific limitations. A remark should be made about the statistical evaluation of new risk markers or new risk prediction models (including multiple risk markers). By tradition in cardiovascular research, comparisons between risk markers are made by receiver-operating-characteristic (ROC) curves for both models, and, more specifically, the difference between the areas under the curves of both models: the difference between the proportion of pairs for which each model correctly assigns a higher probability to the person who will have the outcome than to the one who will not.31 In recent years this method of comparison has been criticised in medical and statistical literature, as new evaluation methods were introduced.32-35 One of the newly developed methods involves evaluation of reclassification: how many patients are reclassified into another clinically relevant risk category when using a new model, compared to the reference model. When calculated separately for all persons with the outcome of interest and those without, and when penalties are included for incorrect reclassification, the ‘net reclassification improvement’ for a prediction model can be calculated, allowing for sometimes surprising conclusions concerning the value of the new model compared to traditional ROC-curve comparison.35 This statistical method was also applied to the prediction models used in chapter 6 from this thesis. In conclusion: current risk scores are invalid in older persons from age 75 years onwards. Besides, all risk scores have intrinsic limitations that should be accounted for when they are used in clinical practice. When different risk prediction models are compared, multiple statistical methods should be applied, including evaluation of reclassification. Along this line of reasoning, age-specific risk scores for older persons from age 75 years onwards should be developed, then properly evaluated, and when put into practice, all mentioned general limitations must be observed.. 148.

(16) General discussion. x ‘Risk prediction in the light of causality: prediction versus etiology’ In this thesis risk prediction in old age is a key issue: prediction either by stand-alone risk factors such as systolic blood pressure (chapter 7 and 9), or prediction by risk scores that integrate multiple risk markers (chapter 6). It is essential to realise that risk markers used in risk prediction models do not necessarily inform us about the etiology of the outcome of interest. In fact, risk markers sometimes are obviously not in the causal pathway leading to the outcome: the simple fact that alcohol abuse is a risk marker for lung cancer does not mean that the use of alcohol causes lung cancer. Therefore, in studying the causal relation between alcohol and lung cancer, adjustments are made for all known factors that may confound this association, such as smoking habits and socio-economic status, which both may also be related to the determinant (alcohol consumption) and outcome (lung cancer) of interest. It may then appear that an existing unadjusted association indeed disappears, and the causal relationship is negated. Yet, from a risk prediction perspective, alcohol consumption could still be used to identify individuals at increased risk of lung cancer. It should be clear from this example that when risk prediction is the objective, adjusting for all possible confounders may erase an association that could be very suitable for screening purposes. Therefore, in risk prediction settings, adjustments are usually absent or minimal. However, in etiological studies, adjustments for all known confounders are essential, as they are fundamental to subsequent studies into effective interventions. Elaborating on this theme, it is obvious that interventions may not be aimed at the risk markers themselves. In chapter 6, gender-specific homocysteine levels were introduced as a robust risk marker of 5-year cardiovascular mortality in people with no history of cardiovascular disease aged 85 years and over. Since homocysteine lowering therapies have shown to be not effective so far, they cannot be recommended as effective intervention.36-38 Yet, homocysteine is very suitable to select the high-risk part of the population, as opposed to classic risk factors, and thus may be very useful for screening purposes. As stated above, this way of reasoning resembles the design of the JUPITER trial, in which participants with normal LDL cholesterol levels were randomised to statin treatment or placebo on the basis of their C-reactive protein levels.24 10.2c. Older persons’ own opinions with regard to prevention of cardiovascular disease In the survey amongst general practitioners in the Netherlands (chapter 3), less than 20% of general practitioners indicated that they felt that there is no demand for prevention of cardiovascular disease among older persons themselves. So far, no studies have been published about older persons’ own opinions about prevention of cardiovascular disease in old age. As evidencebased medicine is meant to integrate clinical expertise with the best available research evidence as well as patient values, a needs assessment for cardiovascular prevention among older persons themselves is warranted. This assessment should not only list older persons’ wishes and expectations on this. 149.

(17) Chapter 10. issue, but also study whether older persons are basically willing to adhere to life style changes and pharmacotherapeutical interventions, if proven effective. 10.3. Cardiovascular risk management in old age: who takes the lead? 10.3a General practitioners In chapter 3 it was shown that general practitioners consider prevention of cardiovascular disease in old age as part of their task. This is in line with the results from a recent survey amongst general practitioners in the Netherlands on prevention in general.39 Yet, less than 40% of all general practitioners in the Netherlands actively provide primary prevention to older patients from age 75 years onwards, and only little over 60% of all general practitioners actively offers secondary prevention to these older patients. It should be noted that, in the Netherlands, general practitioners by tradition were hesitant, if not reluctant, to comply with requests for general check-ups and other screening activities, unless integrated in nationwide evidence-based screening programs such as cervical smears and influenza vaccinations. Overtaken by current developments, general practitioners have now consented with the development of so-called ‘prevention consultations’, in which patients and general practitioners systematically evaluate patients’ risk profiles and screen accordingly. These preventive consultations are due to be implemented in the coming years. Primary care, by all means, is perfectly equipped for preventive care for older patients from the general population: it is close-to-home and lowthreshold care, by general practitioners who have longstanding relationships with patients and usually enjoy their trust. Besides, the patients’ medical history is carefully kept in medical records. Finally, expenses for primary care are fully covered by medical insurance companies. These circumstances create a perfect infrastructure for systematic prevention of cardiovascular disease in old age, both secondary and primary. If necessary, computer-software should be developed to support general practitioners in making selections of patients, inviting appropriate groups of older patients to come to the practice (or to agree to a home visit), and bring about preventive care. In the Netherlands this approach has led to very good responses by patients, when compared to inviting patients by, for patients, relatively unknown ‘third parties’ such as Municipal Health Services. This will consume valuable time of general practitioners, and, where possible, tasks should be delegated to well-trained practice nurses or nurse practitioners. General practitioners, needless to say, must be compensated for efforts, intellectual input and time when supervising their activities. In doing so, the most important self-reported barriers will be leveled (chapter 3). 10.3b Preventive health centers for seniors Preventive health centers for seniors in the Netherlands are booming.40 Time is obviously ready for it, as there is not only political focus on (and budget for) aging issues, but also a growing demand among elderly people themselves.. 150.

(18) General discussion. Third parties, such as home care organisations, health insurance companies and municipal health services, have gratefully jumped into this niche in the market, and have started preventive health centers for seniors in almost all districts in the Netherlands. Regrettably, little evidence is available for the main part of all their screening activities in older persons, and study results in younger age groups are often simply translated to older age groups. Another concern involves selection bias of seniors who visit these preventive health centers, since they are usually selected by adds in local newspapers, home-tohome flyers or written invitations from the centers themselves. The seniors who show up may not be the ones who may need it most. All in all, it appears that efforts and resources may better be spent at incorporating cardiovascular prevention in old age within primary care. If, however, senior health centers wish to continue their cardiovascular preventive actions, it is important that screening activities are along the lines of comparable activities in primary care. It may even turn out that prevention of cardiovascular disease in old age is best implemented when offered in cooperation by general practitioners and senior health centers. It is the cause that matters, and thinking out of the box may be necessary. However, certain minimal requirements apply to prevention of cardiovascular disease in older persons: it should be easily accessible, it should incorporate data on cardiovascular history from the general practitioner, it is executed by well trained staff according to latest evidence and guidelines, and communication and referral are efficiently organised. A proactive attitude from general practitioners, their (scientific) umbrella organisations and policy makers, as well as political input is indispensable in this respect. Since health care centers for seniors are moving forward, general practitioners should loose no time by retreating into the trenches. 10.4. Cardiovascular risk management in old age: where do we stand, where are we heading for, and what research is needed to get there? 10.4a Where do we stand? In part 1 of this thesis it was shown that current cardiovascular secondary prevention in old age has improved over time, especially in the very old, but that there is still much room for improvement, increasingly with age. General practitioners are committed to the cause of cardiovascular prevention in old age, both secondary as well as primary, but need to be assisted by well-trained staff, and compensated for time and costs. Apart from these practical issues, all evidence in this field needs to be passed on to them, in order to convince them of the effectiveness of such prevention in old age. In part 2 we showed that medical records of general practitioners contain most valuable information and should be kept carefully. Additional. 151.

(19) Chapter 10. screening by routine-ECGs in very old patients will not add relevant information concerning prognosis, but may reveal previously unknown major cardiovascular morbidities such as prior myocardial infarction or atrial fibrillation, deemed to have clinical consequences for individual patients. In part 3 it was shown that in persons with no history of cardiovascular disease, from age 85 years onwards, classic risk factors do not predict cardiovascular mortality anymore, whereas a single homocysteine measurement does very well. Also, systolic blood pressure is inversely associated with all cause and cardiovascular mortality from age 85 years onwards, and between age 75 and 85 years relative mortality risks reach unity. Thus, classic risk factors, either integrated in a risk score or as stand-alone risk factor, fail to predict (cardiovascular) mortality at very high age. Finally, NTpro-BNP was shown to have accurate predictive qualities regarding all cause and cardiovascular mortality in nonagenarians, even in those without known specific cardiac morbidities. This biomarker therefore also qualifies as a risk marker for cardiovascular mortality in very old age, also in primary preventive perspective. 10.4b Where are we heading for? In the years to come, secondary prevention in old age will probably show a catch up effect, because changes in guidelines always take some time before they are implemented in clinical practice. Screening of medical records, kept by general practitioners, for previous cardiovascular disease, preferably at regular intervals, may be a good way to bring about this catch up effect, and reach as many patients as possible for secondary prevention, irrespective of age. General practitioners and health centers for seniors may complement each other well. This will not only postpone mortality, but also reduce recurrent cardiovascular morbidity, and thus improve quality of life. Regarding primary prevention, it is likely that more and more older persons will be screened for risk markers that have demonstrated their validity in this specific age category. This could be homocysteine or NT-proBNP, but other biomarkers may also qualify. Age-specific guidelines for primary preventive risk prediction of cardiovascular disease in old age will be developed and used in appropriate patient groups. This will take place in primary care and under supervision of general practitioners, or in health centers for seniors, who will probably account for the initial ‘large-volume’ screening process. Communication and fine-tuning between both parties must be well organised. After adequate selection of older persons with high cardiovascular risks, effective age-specific interventions are offered, which may or may not resemble classic interventions in middle-aged persons. In doing so, cardiovascular disease is averted or postponed, and older persons may therefore enjoy more years without cardiovascular disease. This will not only improve their own quality of life, but also their spouses’.. 152.

(20) General discussion. 10.4c What research is needed to get there? Regarding secondary prevention of cardiovascular disease in old age, research questions that lie ahead concern the fine-tuning of secondary preventive regimens in old age. In case of previous myocardial infarctions in old age, for instance, there is no doubt whether or not to prescribe various drugs such as beta blockers, statins, ACE inhibitors and aspirin, but: how low should target values of LDL cholesterol and systolic blood pressure be? It is likely from many observational studies so far that these values may also be higher in (very) old age than in middle-aged persons.41-47 In this respect, fixed-dose administration of all components is also worth to be considered and evaluated.48 The majority of research questions apply to primary prevention in old age. With the observed inadequacy of classic risk factors to predict cardiovascular mortality after age 85 years, and parallel to our study on blood pressure in chapter 7, other classic risk factors should be individually evaluated to determine the ‘break-even point’ of their association with (cardiovascular) mortality. And parallel to chapter 6, classic risk factors must also be evaluated in old age when applied within an integrated SCORE risk function, preferably in various cohorts with several age categories. Elaborating on our work with homocysteine and other new biomarkers (chapter 6), the search for the best predictor of cardiovascular disease in old age must continue, as even better biomarkers may emerge. Many candidatebiomarkers are available.49 Preferably, head-to-head comparisons should be made. Finally, as the search for the ultimate risk marker for cardiovascular disease in old age goes on, etiological considerations should be kept in mind: do these risk markers also offer an opportunity for causal intervention, and how can this be explained from an etiological perspective? Many research questions still lie ahead of us concerning effective interventions in old age. When classic risk factors are not predictive anymore, does this mean that intervening on these risk factors is also ineffective? A Finnish randomised controlled trial in people aged 75 years and over with either previous cardiovascular disease or ‘high-risk’ as defined by classic risk factors, yielded no effect of complex interventions on all classic risk factors: yet these factors improved in the intervention group, but this did not result in a difference in primary endpoints in both groups.50 There is, however, a possibility that if risk selection had been performed based on homocysteine levels, the complex interventions would have been effective. Different cohorts from different studies in elderly patients may provide possibilities to study this hypothesis.19;50;51 In conclusion: when it comes to cardiovascular risk management in old age, important age-specific evidence has been established, and further implementation into daily practice is awaited. At the same time, many questions are yet to be answered, calling for continuous attention of all parties involved. Cardiovascular disease is not an inevitable, let alone desirable, perspective for the growing group of older persons in many societies, but may be substantially prevented or postponed by adequate, age-specific risk selection and subsequent interventions.. 153.

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