Maddalena Lettino

Julia Mascherbauer

Matias Nordaby

André Ziegler

Jean-Philippe Collet

Geneviève Derumeaux

Stefan H Hohnloser

Christophe Leclercq

Deirdre E O'neill

Frank Visseren

Franz Weidinger

Isabelle Richard-Lordereau

Cardiovascular Disease in the Elderly: Proceedings of the European Society of Cardiology-Cardiovascular Round Table

Keywords: risk assessment, older people, primary prevention, antiplatelet, anticoagulant, coronary revascularization

ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

Introduction

Globally, the population is ageing, with older people becoming a proportionally larger share of the total population. [START_REF]Population on 1st January by age, sex and type of projection (code: proj_19NP)[END_REF][START_REF]Population on 1 January by age group and sex (code: demo_pjangroup[END_REF] In Europe in 2017, more than 20% of the population was age ≥60 years, and this is projected to increase to 35% by 2050. The incidence of cardiovascular disease (CVD) increases with age from about 40% in adults aged 40-59 years, to 75% in those 60-79 years, and 86% in those >80 years. [START_REF] Rodgers | Cardiovascular risks associated with gender and aging[END_REF] This has been linked to several factors such as increased oxidative stress, inflammation, apoptosis and overall vascular and myocardial deterioration associated with ageing, as well as to a higher risk for other morbid conditions including frailty, obesity, and diabetes. [START_REF] Rodgers | Cardiovascular risks associated with gender and aging[END_REF] While ageing is often measured chronologically (i.e., the number of years since birth), this does not reflect the distribution of functional capacities, health, and productivity within the older population. 4 5 Clinical trials have a need to "categorise" patient populations for analyses, and often use arbitrary cut-offs of over age 65 years, 70 years, 75 years, etc. However, a review of 20 guidelines found that all used the term elderly, but 17 did not define the term in anyway. [START_REF] Singh | Defining 'elderly' in clinical practice guidelines for pharmacotherapy[END_REF] The 2021 ESC Guidelines on CV prevention, and the Systemic Coronary Risk Estimation 2-Older Persons (SCORE2-OP) risk prediction tool used a cut-off of 70 years of age. [START_REF]Score2-OP working group and ESC Cardiovascular risk collaboration. SCORE2-OP risk prediction algorithms: estimating incident cardiovascular event risk in older persons in four geographical risk regions[END_REF][START_REF] Visseren | ESC Guidelines on cardiovascular disease prevention in clinical practice[END_REF] Clinically when making management decisions, elderly or older age should be based less on chronological age and more on defining the risk and outcomes for an individual patient. This article is the product of presentations and discussions during a virtual Cardiovascular Round Table (CRT) workshop organised in May 2021 by the European Society of Cardiology (ESC). It aims to demonstrate the need to continue primary prevention for cardiovascular risk factors, to summarise important factors when choosing treatments for older patients, and the need to consider quality of life and patient priorities when making decisions.

CV risk assessment in older people: Are we over treating or under treating?

Factors to consider when assessing risk of CVD in older people

In older people, the lifetime benefit from CVD risk-factor treatment should consider absolute CV risk, life expectancy, competing (non-CV) risks, and efficacy and safety data from randomised controlled trials (RCT) (Figure 1). [START_REF]Score2-OP working group and ESC Cardiovascular risk collaboration. SCORE2-OP risk prediction algorithms: estimating incident cardiovascular event risk in older persons in four geographical risk regions[END_REF][START_REF] Jaspers | Prediction of individualized lifetime benefit from cholesterol lowering, blood pressure lowering, antithrombotic therapy, and smoking cessation in apparently healthy people[END_REF] Moreover, management decisions should be patient-centric and consider patient preferences, frailty, comorbidities, and polypharmacy.

Risk assessment tools for older people

While age is a strong predictor of risk, the PROSPER trial demonstrated that age alone does not automatically put an individual at high risk, especially in the primary prevention setting. [START_REF] Mc | Personalized absolute benefit of statin treatment for primary or secondary prevention of vascular disease in individual elderly patients[END_REF] Therefore, risk prediction tools can help identify patients at higher CV risk who may potentially benefit from treatment. Tools designed for the general population can be inaccurate in older people. [START_REF]Score2-OP working group and ESC Cardiovascular risk collaboration. SCORE2-OP risk prediction algorithms: estimating incident cardiovascular event risk in older persons in four geographical risk regions[END_REF][START_REF] Cooney | Cardiovascular risk estimation in older persons: SCORE O.P[END_REF] The relationship between many risk factors and CVD decreases with age, and competing risks become increasingly important. [START_REF]Score2-OP working group and ESC Cardiovascular risk collaboration. SCORE2-OP risk prediction algorithms: estimating incident cardiovascular event risk in older persons in four geographical risk regions[END_REF] In addition, older patients are generally at higher risk of adverse drug events, so it is important to identify those individuals who benefit from preventive treatment.

In 2021, the SCORE2-OP tool was developed and validated to estimate 5-and 10-year CVD risks of both fatal and nonfatal CVD events (myocardial infarction, stroke), in adults aged ≥70 years. [START_REF]Score2-OP working group and ESC Cardiovascular risk collaboration. SCORE2-OP risk prediction algorithms: estimating incident cardiovascular event risk in older persons in four geographical risk regions[END_REF] The sex-specific scores include age, smoking status, systolic blood pressure, and high-density lipoprotein cholesterol and are adjusted for competing risks. Therefore, the threshold levels in different risk categories are higher in older age groups, in order to avoid overtreatment in older persons. The decision to initiate preventive therapy should consider that both benefits and risks of treatments are impacted by age, and therefore, should be made on an individual basis with the patient. [START_REF] Visseren | ESC Guidelines on cardiovascular disease prevention in clinical practice[END_REF] In older people the focus should be on the lifetime benefit of treating risk factors rather than 10-year CVD risk. [START_REF] Jaspers | Prediction of individualized lifetime benefit from cholesterol lowering, blood pressure lowering, antithrombotic therapy, and smoking cessation in apparently healthy people[END_REF] Risk calculators are available online at www.u-prevent.com. [START_REF] Rossello | Risk prediction tools in cardiovascular disease prevention: A report from the ESC Prevention of CVD Programme led by the European Association of Preventive Cardiology (EAPC) in collaboration with the Acute Cardiovascular Care Association (ACCA) and the Association of Cardiovascular Nursing and Allied Professions (ACNAP)[END_REF] Primary prevention strategies in older people: Is it ever too late?

Given that CVD begins at a young age, primordial and primary prevention strategies to address risk factors should start early to prevent CV events at older age. [START_REF] Gooding | Challenges and opportunities for the prevention and treatment of cardiovascular disease among young adults: Report from a National Heart, Lung, and Blood Institute Working Group[END_REF] While, data show that it is never too late to initiate risk factor management strategies, the goal of preventative medicine in older adults is somewhat different; focusing not only on reduction of morbidity and mortality, but more significantly on maintenance of function and preservation of quality of life. The 2021 ESC guidelines on CVD prevention include a section focused on older adults aged ≥70 years, acknowledging the importance of primary prevention throughout the lifespan. [START_REF] Visseren | ESC Guidelines on cardiovascular disease prevention in clinical practice[END_REF] This should be delivered in an individualized and patient-centred manner, focusing on outcomes important to the patient, and using interventions with the best evidence and least risk to their day-to-day function.

General considerations when using pharmacotherapy in older people: In general, when addressing primary prevention in older adults, the risk of CVD, which is higher by virtue of age, needs to be balanced with the evidence for potential benefit of a medication in an older population, as well as the potential risk of that medication in that individual patient. When doing so, it is important to keep in mind that a number of factors can all lead to well-intentioned, evidence-based medications being poorly tolerated by the older adult or even resulting in harm.

Factors that should be considered include changes in pharmacokinetics and pharmacodynamics that occur with age, increased risk and susceptibility to disease-drug interactions, drug-drug interactions, and adverse events with polypharmacy in older adults, and varied and unexpected clinical response to medications. [START_REF] Arnett | ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines[END_REF][START_REF] Krishnaswami | Deprescribing in older adults with cardiovascular disease[END_REF] For example, the prescription of a statin for a high-risk individual could lead to myalgias that prevent performance of activities of daily living, or an antihypertensive medication in an individual with an untreated blood pressure of 160/90 mmHg, may result in orthostatic hypotension that can result in injurious falls. [START_REF] Arnett | ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines[END_REF][START_REF] Krishnaswami | Deprescribing in older adults with cardiovascular disease[END_REF] It is important to engage in shared decision-making and practice patient-centred care, providing the best estimate of risks and benefits based on the evidence and discussing the patient's values, preferences, and risk tolerance. Clinicians and patients may inadvertently have opposing goals, with patients being more concerned about symptoms, functional and cognitive status, and quality of life, and clinicians being more interested in preventing major cardiac adverse events or reducing mortality rate. [START_REF] Arnett | ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines[END_REF][START_REF] Krishnaswami | Deprescribing in older adults with cardiovascular disease[END_REF] Discussing an individual's values, and when in keeping with their preferences, addressing non-pharmacologic risk reduction, such smoking cessation, diet and exercise and when needed, starting pharmacotherapy at low doses and titrating slowly, can help ensure the best possible outcome in this vulnerable patient population.

In older people, the ability to follow lifestyle or pharmacological strategies can be impacted by cognitive and emotional factors. [START_REF] Visseren | ESC Guidelines on cardiovascular disease prevention in clinical practice[END_REF] Cognitive decline shares many risk factors with CVD, including high cholesterol, and high blood pressure, obesity, diabetes, physical inactivity, smoking, and poor diet. [START_REF] Rovio | Cognitive decline before and after incident coronary heart disease: Opportunity to intervene cognitive function trajectories[END_REF] In addition, higher levels of cardiac troponin T have been associated with cognitive decline in older adults independent of CVD. [START_REF] Wijsman | High-sensitivity cardiac troponin T is associated with cognitive decline in older adults at high cardiovascular risk[END_REF] The importance of primary prevention is underscored by the fact that CV events have been associated with accelerated cognitive decline over time. [START_REF] Xie | Cognitive decline before and after incident coronary events[END_REF] Hypertension: The prevalence of hypertension in older patients is very high, for example, in the U.S. the prevalence in individuals 20-44 years was reported to be 28%, increasing to 77% in those ≥65. [START_REF] Virani | SS. Heart disease and stroke statistics-2021 update: A report from the American Heart Association[END_REF] Multiple RCTs in older people have demonstrated the benefits of blood pressure lowering in both fit and frail people, with the greatest absolute benefit being seen in those 75-80 years of age (Table 1). [START_REF] Shep Cooperative | Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension. Final results of the Systolic Hypertension in the Elderly Program (SHEP)[END_REF][START_REF] Staessen | Randomised double-blind comparison of placebo and active treatment for older patients with isolated systolic hypertension. The Systolic Hypertension in Europe (Syst-Eur) Trial Investigators[END_REF][START_REF] Beckett | Treatment of hypertension in patients 80 years of age or older[END_REF][START_REF] Research Group | A randomized trial of intensive versus standard blood-pressure control[END_REF][START_REF] Warwick | No evidence that frailty modifies the positive impact of antihypertensive treatment in very elderly people: an investigation of the impact of frailty upon treatment effect in the HYpertension in the Very Elderly Trial (HYVET) study, a double-blind, placebo-controlled study of antihypertensives in people with hypertension aged 80 and over[END_REF][START_REF] Williamson | Intensive vs standard blood pressure control and cardiovascular disease outcomes in adults aged >/=75 years: A randomized clinical trial[END_REF] However, this benefit is not without some degree of risk, with estimations based on US population data suggesting intensive blood pressuring lowering, such as that in the SPRINT trial, would result in >56,000 episodes of hypotension, >34,000 episodes of syncope and nearly 89,000 episodes of acute kidney injury annually. [START_REF] Research Group | A randomized trial of intensive versus standard blood-pressure control[END_REF][START_REF] Bress | Potential deaths averted and serious adverse events incurred from adoption of the SPRINT (Systolic Blood Pressure Intervention Trial) intensive blood pressure regimen in the United States: Projections from NHANES (National Health and Nutrition Examination Survey)[END_REF] Therefore, universal implementation of intensive blood pressure lowering has great potential benefit, alongside potential detrimental consequences.

The older adult population is very heterogeneous, with large variation in function, frailty and independence, necessitating a person-centred, rather than a "one-size fits all" approach to balancing the risks and benefits. [START_REF] Benetos | Hypertension management in older and frail older patients[END_REF] While older adults with preserved function should often be treated similar to younger adults, those with advanced frailty and functional dependence should have their hypertension management reassessed, with consideration of deprescribing and blood pressure leniency to avoid further functional impairment from adverse effects. [START_REF] Krishnaswami | Deprescribing in older adults with cardiovascular disease[END_REF][START_REF] Kutner | Safety and benefit of discontinuing statin therapy in the setting of advanced, life-limiting illness: a randomized clinical trial[END_REF][START_REF] Kua | Health outcomes of deprescribing interventions among older residents in nursing homes: A systematic review and meta-analysis[END_REF][START_REF] Ibrahim | A systematic review of the evidence for deprescribing interventions among older people living with frailty[END_REF] Clinical decision making for older adults in between these two spectrums is most challenging, requiring a tailored approach considering comorbidities, life expectancy, function, frailty, as well as patient preferences in a process of shared decision-making. The 2018 ESC/European Society of Hypertension guidelines recommend offering antihypertensive treatment to older adults (>65 years, including individuals >80 years with very high systolic blood pressure), taking into account factors such as comorbidities, polypharmacy, frailty and dependence, and not viewing age alone as a barrier to the treatment of hypertension. [START_REF] Williams | 2018 ESC/ESH Guidelines for the management of arterial hypertension[END_REF] In addition, the ESC CVD prevention guidelines recommend lowering blood pressure to <140/90 mmHg, and to consider a lower systolic blood pressure target of 130 mmHg in those ≥70 years, if tolerated. 8

Hyperlipidaemia:

The prevalence of hyperlipidaemia is also more frequent in older people. In a European study, hyperlipidaemia was present in 76% in older people (mean age 69 years) compared to 41% in younger (mean age 29 years) people. [START_REF] Rosada | Hyperlipidemias in elderly patients: results from the Berlin Aging Study II (BASEII), a cross-sectional study[END_REF] While evidence supports the benefit of lipid-lowering therapy in older adults with known vascular disease, the evidence for primary prevention in older adults is less clear. [START_REF] Cholesterol | Efficacy and safety of statin therapy in older people: a meta-analysis of individual participant data from 28 randomised controlled trials[END_REF][START_REF] Gencer | Efficacy and safety of lowering LDL cholesterol in older patients: a systematic review and meta-analysis of randomised controlled trials[END_REF] A meta-analysis of 8 primary prevention trials in people ≥65 years, at high CV risk, found a significant reduction in the risk of MI and stroke (39.4% and 23.8%, respectively) with statins versus placebo (Table 1). [START_REF] Savarese | Benefits of statins in elderly subjects without established cardiovascular disease: a meta-analysis[END_REF] Primary prevention studies in people >75 years are more limited however, and it is difficult to extrapolate data from younger age groups to this population. [START_REF] Cholesterol | Efficacy and safety of statin therapy in older people: a meta-analysis of individual participant data from 28 randomised controlled trials[END_REF][START_REF] Savarese | Benefits of statins in elderly subjects without established cardiovascular disease: a meta-analysis[END_REF][START_REF] Shepherd | Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial[END_REF] A meta-analysis of 28 statin trials found a significant reduction in major cardiovascular events (MACE) in all age groups, with a 13% reduction in events per 1.0 mmol/L reduction in LDL cholesterol in patients over 75 years old, however only 8% of participants were in this age group. [START_REF] Cholesterol | Efficacy and safety of statin therapy in older people: a meta-analysis of individual participant data from 28 randomised controlled trials[END_REF] While older adults are intrinsically vulnerable to CVD, thereby increasing the potential benefit of statin, they are also susceptible to frailty, sarcopenia, polypharmacy, and multimorbidity, increasing the risk of statin-related adverse effects and compounding the functional burden of such adverse effects. Additionally, statins have a rather short time-to-harm, with a relatively long time-to-benefit of at least 2-2.5 years, making life expectancy very pertinent when prescribing primary prevention statin. [START_REF] Yourman | Evaluation of time to benefit of statins for the primary prevention of cardiovascular events in adults aged 50 to 75 years: A meta-analysis[END_REF][START_REF] Holmes | Rationalizing prescribing for older patients with multimorbidity: considering time to benefit[END_REF] It is unlikely that benefit would outweigh risk in those with a limited life expectancy, however many older adults have an anticipated prognosis of >2.5 years, making shared decision-making and consideration of individual patient's goals and values essential. Current data to inform decisions on primary prevention cholesterol management in older adults are limited, but two large randomized controlled trials are underway. STAREE and PREVENTABLE are both designed to assess the role of primary prevention statins in patients Downloaded from https://academic.oup.com/eurjpc/advance-article/doi/10.1093/eurjpc/zwac033/6529006 by Universite de Rennes 1 SCD Section sante user on 25 February 2022 ≥70-75 years and include outcome measures relevant to older adults, such as independence and disability. [START_REF]A clinical trial of statin therapy for reducing events in the elderly (STAREE)[END_REF][START_REF]Pragmatic Evaluation of Events And Benefits of Lipid-lowering in Older Adults (PREVENTABLE)[END_REF] The ESC CVD prevention guidelines provide a class IIb recommendation (may be considered) for initiation of statins for primary prevention in older adults aged ≥70 if at high 10year CVD risk, when assessed using SCORE2-OP, a risk score validated to estimate 5-and 10year CVD risk in older adults aged ≥70 years. [START_REF]Score2-OP working group and ESC Cardiovascular risk collaboration. SCORE2-OP risk prediction algorithms: estimating incident cardiovascular event risk in older persons in four geographical risk regions[END_REF][START_REF] Visseren | ESC Guidelines on cardiovascular disease prevention in clinical practice[END_REF] However, the decision to use statin therapy for primary prevention in older adults should be individualised, based on frailty, estimated life expectancy, time to benefit, comorbidities and patient preference.

Diabetes:

The prevalence of type 2 diabetes mellitus increases with age. [START_REF] Fazeli | Aging is a powerful risk factor for type 2 diabetes mellitus independent of body mass index[END_REF] Metformin has been shown to reduce the risks of MI, CV death, and stroke in overweight patients with diabetes compared to conventional therapy (Table 1), [START_REF] Uk Prospective | Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34)[END_REF] and the both the 2019 ESC guidelines on diabetes and 2021 ESC CVD prevention guidelines recommend it as first-line therapy for primary prevention in patients with diabetes. [START_REF] Visseren | ESC Guidelines on cardiovascular disease prevention in clinical practice[END_REF][START_REF] Cosentino | 2019 ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD[END_REF] Two newer classes of medications have been found to lower blood glucose and reduce CVD events in those at high risk: SGLT-2 inhibitors [START_REF] Monteiro | Efficacy and safety of empagliflozin in older patients in the EMPA-REG OUTCOME(R) trial[END_REF][START_REF] Cahn | Efficacy and safety of dapagliflozin in the elderly: Analysis from the DECLARE-TIMI 58 study[END_REF] and GLP-1 receptor agonists. [START_REF] Leiter | Cardiovascular risk reduction with once-weekly semaglutide in subjects with type 2 diabetes: a post hoc analysis of gender, age, and baseline CV risk profile in the SUSTAIN 6 trial[END_REF][START_REF] Riddle | Efficacy and safety of dulaglutide in older patients: A post hoc analysis of the REWIND trial[END_REF][START_REF] Gilbert | Effect of liraglutide on cardiovascular outcomes in elderly patients: A post hoc analysis of a randomized controlled trial [Letter][END_REF] Post hoc analyses of pivotal trials show that these agents have similar effect on CV outcomes across age categories including those ≥75 years (SGLT-2 inhibitors) [START_REF] Monteiro | Efficacy and safety of empagliflozin in older patients in the EMPA-REG OUTCOME(R) trial[END_REF][START_REF] Cahn | Efficacy and safety of dapagliflozin in the elderly: Analysis from the DECLARE-TIMI 58 study[END_REF] and those ≥65 years (GLP-1 receptor agonists). [START_REF] Leiter | Cardiovascular risk reduction with once-weekly semaglutide in subjects with type 2 diabetes: a post hoc analysis of gender, age, and baseline CV risk profile in the SUSTAIN 6 trial[END_REF][START_REF] Riddle | Efficacy and safety of dulaglutide in older patients: A post hoc analysis of the REWIND trial[END_REF][START_REF] Gilbert | Effect of liraglutide on cardiovascular outcomes in elderly patients: A post hoc analysis of a randomized controlled trial [Letter][END_REF] ESC guidelines recommend these agents for primary prevention in patients with DM and CKD, and consideration of their use in those at high or very high CV risk. [START_REF] Visseren | ESC Guidelines on cardiovascular disease prevention in clinical practice[END_REF][START_REF] Cosentino | 2019 ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD[END_REF] Aspirin: The evidence for use of aspirin in those with vascular disease (secondary prevention) is unequivocal. However, three more recent randomized controlled trials (ARRIVE, ASPREE and ASCEND) have led to contention about its role in primary prevention (Table 1). 49- randomized nearly 20,000 patients aged 70 years and above, without known CVD, to aspirin or placebo. [START_REF] Mcneil | Effect of aspirin on cardiovascular events and bleeding in the healthy elderly[END_REF] After 4.7 years of follow up, the rate of CVD was unchanged (HR 0.95, 95% CI 0.83-1.08) but the rate of major bleeding was increased (HR 1.38, 95% CI 1.18-1.62) with aspirin compared to placebo in these older adults. A 2019 meta-analysis found no reduction in CV mortality with aspirin, but did show a lower risk of non-fatal myocardial infarction (RR 0.82, 95% CI 0.72-0.94) and stroke (RR 0.87, 95% CI 0.79-0.95), with a higher risk of major bleeding (RR 1.5, 95% CI 1.33 to 1.69), intracranial bleeding (RR 1.32, 95% CI 1.12-1.55) and major gastrointestinal bleeding (RR 1.52, 95% CI 1.34-1.73); with a number needed to harm of 222 for major bleeding and a number needed to treat of 357 to prevent one myocardial infarction. [START_REF] Abdelaziz | Aspirin for primary prevention of cardiovascular events[END_REF] The use of aspirin for primary prevention in selected patients at low bleeding risk and high or veryhigh CV risk remains controversial. However, overall, in the majority of older adults, the increased risk of bleeding appears to outweigh the CV primary prevention benefit, with many national and international guidelines downgrading or eliminating their recommendation for aspirin altogether in older adults. [START_REF] Arnett | ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines[END_REF][START_REF]By the American Geriatrics Society Beers Criteria Update Expert Panel. American Geriatrics Society 2019 updated AGS Beers Criteria(R) for potentially inappropriate medication use in older adults[END_REF][START_REF] Rabi | Hypertension Canada's 2020 comprehensive guidelines for the prevention, diagnosis, risk assessment, and treatment of hypertension in adults and children[END_REF] The 2021 ESC CVD prevention guidelines recommend making decisions in healthy individuals <70 years of age with (very) high CVD risk, on a caseby-case basis, with consideration of both ischaemic and bleeding risks. [START_REF] Visseren | ESC Guidelines on cardiovascular disease prevention in clinical practice[END_REF] The risk of bleeding may be even more important in older patients, and any consideration of use for primary prevention should be discussed with the patient. [START_REF] Hawk | The ASPREE trial: An unanticipated stimulus for greater precision in prevention?[END_REF][START_REF] Lewis | Aspirin use for primary prevention of cardiovascular disease in older patients: A review of clinical guidelines and updated evidence[END_REF] Smoking is a known major cause of CVD, with 1 in 10 CV deaths worldwide being attributable to smoking. [START_REF] Ezzati | Role of smoking in global and regional cardiovascular mortality[END_REF] Tobacco cessation has been shown to reduce CV risk even among people ≥60 years (Table 1). [START_REF] Mons | Impact of smoking and smoking cessation on cardiovascular events and mortality among older adults: metaanalysis of individual participant data from prospective cohort studies of the CHANCES consortium[END_REF] Excess CV risk decreases with time since tobacco cessation, with benefits accruing within <5 years of quitting. [START_REF] Mons | Impact of smoking and smoking cessation on cardiovascular events and mortality among older adults: metaanalysis of individual participant data from prospective cohort studies of the CHANCES consortium[END_REF][START_REF] Ahmed | Risk of heart failure and death after prolonged smoking cessation: Role of amount and duration of prior smoking[END_REF] The ESC CV prevention guidelines recommend that clinicians encourage all smokers to quit, including those ≥70 years. [START_REF] Visseren | ESC Guidelines on cardiovascular disease prevention in clinical practice[END_REF] Diet: Dietary modifications have been shown to lower the risk of CV events (Table 1). [START_REF] Estruch | Primary prevention of cardiovascular disease with a Mediterranean diet[END_REF][START_REF] Trichopoulou | Modified Mediterranean diet and survival: EPIC-elderly prospective cohort study[END_REF] In the PREDIMED RCT in people 55-80 years at high CV risk, a modified Mediterranean diet was associated with a 28-30% reduction in MACE over a median 5-year follow-up. [START_REF] Estruch | Primary prevention of cardiovascular disease with a Mediterranean diet[END_REF] Similarly, in the EPIC, multicentre cohort study in people ≥60 years without CVD, a modified Mediterranean diet was associated with a significantly longer life expectancy, with benefits increasing with increasing adherence to the diet. [START_REF] Trichopoulou | Modified Mediterranean diet and survival: EPIC-elderly prospective cohort study[END_REF] The ESC CVD prevention guidelines focus on the importance of maintaining a more plant-based diet, low in saturated fat, high in whole grains, fruit, vegetables, nuts and fish, while reducing red meat, alcohol and sugar-sweetened beverages. [START_REF] Visseren | ESC Guidelines on cardiovascular disease prevention in clinical practice[END_REF] These lifestyle recommendations are applicable to all age groups. Currently, there is insufficient evidence of benefit of vitamin C, D, or E in prevention of CVD. [START_REF] Al-Khudairy | Vitamin C supplementation for the primary prevention of cardiovascular disease[END_REF][START_REF] Barbarawi | Vitamin D supplementation and cardiovascular disease risks in more than 83000 individuals in 21 randomized clinical trials: A metaanalysis[END_REF][START_REF] Sesso | Vitamins E and C in the prevention of cardiovascular disease in men: the Physicians' Health Study II randomized controlled trial[END_REF][START_REF] Manson | Vitamin D supplements and prevention of cancer and cardiovascular disease[END_REF] Evidence for omega-3 fatty acid supplementation is conflicting. A 2020 Cochrane review suggested little to no effect of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) on mortality or CV health. [START_REF] Abdelhamid | Omega-3 fatty acids for the primary and secondary prevention of cardiovascular disease[END_REF] In a more recent meta-analysis (2021), EPA monotherapy was associated with a reduction in cardiovascular mortality, non-fatal myocardial infarction, coronary heart disease events, MACE, and revascularization. [START_REF] Khan | Effect of omega-3 fatty acids on cardiovascular outcomes: A systematic review and meta-analysis[END_REF] While this evidence is not specific to older patients, it suggests that omega-3 fatty acid supplementation, specifically EPA, may be useful for prevention of CVD, however, there was an increased risk of AF and total bleeding events.

Although the risk associated with other less proven vitamin supplementation is low, it is important to remember that many older adults already struggle with polypharmacy and pill burden. Therefore, taking pills which are unlikely to provide benefit can result in worsening lack of appetite due to the number of pills ingested, as well as potential for medication non-adherence related to increased pill burden.

Exercise: Multiple observational studies have demonstrated the benefits of exercise for primary prevention of CVD (Table 1). [START_REF] Hakim | Effects of walking on coronary heart disease in elderly men: The Honolulu Heart Program[END_REF][START_REF] Bijnen | Physical activity and 10-year mortality from cardiovascular diseases and all causes: The Zutphen Elderly Study[END_REF][START_REF] Kim | Changes in exercise frequency and cardiovascular outcomes in older adults[END_REF][START_REF] Lachman | Impact of physical activity on the risk of cardiovascular disease in middleaged and older adults: EPIC Norfolk prospective population study[END_REF] The Honolulu Heart Program, a cohort study in men aged 71-93 years, found that those who walked ≥1.5 miles/day had a 50% lower risk of CVD versus those who walked <0.25 miles/day (p<0.01). [START_REF] Hakim | Effects of walking on coronary heart disease in elderly men: The Honolulu Heart Program[END_REF] In the Zutphen Elderly Study in men aged 64-84 years, self-reported physical activity proportionally decreased the risk of all cause (23%) and CVD (30%) mortality with increasing levels of activity. [START_REF] Bijnen | Physical activity and 10-year mortality from cardiovascular diseases and all causes: The Zutphen Elderly Study[END_REF] Furthermore, maintaining activity levels, or engaging in small increases in the frequency of physical activity (even 1-2 times/week) have been associated with significantly reduced risk for total CVD among older people aged ≥60 years. [START_REF] Kim | Changes in exercise frequency and cardiovascular outcomes in older adults[END_REF] Individuals of all ages can benefit from implementation of a safe, tailored exercise routine. [START_REF] Arnett | ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines[END_REF][START_REF] Cheng | Physical activity and risk of cardiovascular disease among older adults[END_REF] While moderate-to-vigorous activity is advised in the ESC CVD prevention guidelines, baseline fitness should be considered. [START_REF] Visseren | ESC Guidelines on cardiovascular disease prevention in clinical practice[END_REF] Even frail older adults can benefit by moving from an inactive state to performing any physical activity. Therefore, although 150-300 minutes/week of moderate intensity, or 75-150 minutes/week of vigorous intensity aerobic exercise is preferred, it is recommended that even those who cannot achieve these levels be encouraged to stay as active as their abilities and health conditions allow, while reducing sedentary time to reduce CV risk. [START_REF] Visseren | ESC Guidelines on cardiovascular disease prevention in clinical practice[END_REF] The guidelines also recommend exercise-based cardiac rehabilitation programs for patients for secondary prevention and for patients with HF. [START_REF] Visseren | ESC Guidelines on cardiovascular disease prevention in clinical practice[END_REF] Programs should be medically Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia in adults, and the prevalence is expected to double by 2060. [START_REF] Hindricks | ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS): The Task Force for the diagnosis and management of atrial fibrillation of the European Society of Cardiology (ESC) Developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC[END_REF] Increasing age is an important risk factor, and approximately 70% of patients are 65-85 years old. [START_REF] Feinberg | Prevalence, age distribution, and gender of patients with atrial fibrillation. Analysis and implications[END_REF] However, these patients are also at increased risk of bleeding, which makes the use of antithrombotic therapies one of the most challenging management decisions in older people. [START_REF] Karamichalakis | Efficacy and safety of novel anticoagulants in the elderly[END_REF][START_REF] Schafer | Anticoagulants for stroke prevention in atrial fibrillation in elderly patients[END_REF] Non-vitamin K antagonist oral anticoagulants (NOACs) have demonstrated improved efficacy and safety compared to warfarin in older people. [START_REF] Ruff | Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials[END_REF] A meta-analysis of RCTs included 71,683 older people with AF, of whom 30-40% of were ≥75 years. [START_REF] Ruff | Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials[END_REF] NOACs significantly reduced stroke or systemic embolic events by 19% (relative risk 0.81, 95% CI 0.73-0.91; p<0.0001) compared with warfarin. Although there was a greater risk of gastrointestinal bleeding, NOACs significantly reduced all-cause mortality and intracranial haemorrhage, with a similar risk of major bleeding compared to warfarin. Results were consistent in patients <75 and ≥75 years. [START_REF] Ruff | Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials[END_REF] Low-dose NOAC regimens yielded similar benefits, with a better safety profile than warfarin, and thus, might be useful for patients who have a high bleeding risk. [START_REF] Ruff | Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials[END_REF] Bleeding risk is also a major concern in older patients with AF and concomitant coronary artery disease (CAD) who need both anticoagulant (e.g., NOAC or vitamin K antagonist [VKA]) and antiplatelet therapy (e.g., aspirin or a P2Y12 inhibitor). [START_REF] Martin | Management of atrial fibrillation and concomitant coronary artery disease[END_REF][START_REF] Yasuda | Antithrombotic therapy for atrial fibrillation with stable coronary disease[END_REF] Dual therapy has been associated with increased bleeding, and increased mortality, [START_REF] Yasuda | Antithrombotic therapy for atrial fibrillation with stable coronary disease[END_REF][START_REF] Eikelboom | Risk of bleeding with 2 doses of dabigatran compared with warfarin in older and younger patients with atrial fibrillation: an analysis of the randomized evaluation of long-term anticoagulant therapy (RE-LY) trial[END_REF] and triple therapy (e.g., NOAC, aspirin, and clopidogrel), has been associated with higher risks compared to dual therapy or monotherapy. [START_REF] Eikelboom | Risk of bleeding with 2 doses of dabigatran compared with warfarin in older and younger patients with atrial fibrillation: an analysis of the randomized evaluation of long-term anticoagulant therapy (RE-LY) trial[END_REF][START_REF] Lopes | Antithrombotic therapy after acute coronary syndrome or PCI in atrial fibrillation[END_REF] The 2021 European guidelines recommend restricting the use of concomitant anticoagulant and antiplatelet therapy to patients with a clear indication for both (e.g., AF plus PAD, CAD or cerebrovascular disease, particularly if treated with percutaneous revascularization and stent implantation). Further, a NOAC is preferred over a VKA, dual therapy should be continued for only 6-12 months, and duration of use of triple therapy including aspirin should be minimized. [START_REF] Hindricks | ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS): The Task Force for the diagnosis and management of atrial fibrillation of the European Society of Cardiology (ESC) Developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC[END_REF][START_REF] Lettino | Antiplatelet and antithrombotic treatment for secondary prevention in ischaemic heart disease[END_REF] However, the guidelines state that an elevated risk of bleeding is not a reason to withhold anticoagulants or to automatically use lower doses, even for older patients. [START_REF] Hindricks | ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS): The Task Force for the diagnosis and management of atrial fibrillation of the European Society of Cardiology (ESC) Developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC[END_REF] Rather, therapy should be individualised, modifiable risk factors addressed, and patients should be followed-up more frequently. Similarly, frailty, risk of falls, and cognitive issues are not reasons to withhold therapy. [START_REF] Hindricks | ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS): The Task Force for the diagnosis and management of atrial fibrillation of the European Society of Cardiology (ESC) Developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC[END_REF] Shared-decision making, with benefit/risk discussions can help in determining the best strategy for an individual.

Decision-making for invasive procedures in older people

Historically there has been a reluctance to perform complex percutaneous coronary intervention (PCI) in older patients. Older people may have more extensive or more severe CAD and be at higher CV risk, and may have a higher risk of post-procedure complications. [START_REF] Guo | Percutaneous coronary intervention in elderly patients with coronary chronic total occlusions: Current evidence and future perspectives[END_REF] However, improvements in equipment and techniques have led to high success rates and low complications rates among older patients. [START_REF] Guo | Percutaneous coronary intervention in elderly patients with coronary chronic total occlusions: Current evidence and future perspectives[END_REF] Treatment with revascularization and medical devices, such as transcatheter aortic-valve implantation (TAVI) and transcatheter mitral-valve repair (TMVR) can be highly effective in reducing the risk of MACE. [START_REF] Stone | Transcatheter mitral-valve repair in patients with heart failure[END_REF][START_REF] Leon | Transcatheter aortic-valve implantation for aortic stenosis in patients who cannot undergo surgery[END_REF] In addition, TAVI and TMVR have not been associated with the risk of major bleeding, even in older patients, compared to that seen with surgical treatment. [START_REF] Stone | Transcatheter mitral-valve repair in patients with heart failure[END_REF][START_REF] Leon | Transcatheter aortic-valve implantation for aortic stenosis in patients who cannot undergo surgery[END_REF] Similarly, even among patients ≥75 years, observational studies and RCTs have shown lower rates of MACE and mortality with revascularization (coronary artery bypass graft [CABG] or PCI) compared with medical treatment. [START_REF] Flores-Umanzor | Impact of revascularization versus medical therapy alone for chronic total occlusion management in older patients[END_REF][START_REF] Investigators | Trial of invasive versus medical therapy in elderly patients with chronic symptomatic coronary-artery disease (TIME): a randomised trial[END_REF] In addition, patients experienced improvements in angina severity and quality of life. [START_REF] Investigators | Trial of invasive versus medical therapy in elderly patients with chronic symptomatic coronary-artery disease (TIME): a randomised trial[END_REF]

When, who, and how to perform revascularization

Myocardial revascularization should be performed to improve prognosis or symptoms as recommended in the 2018 European guidelines on myocardial revascularization (Table 2). [START_REF] Neumann | ESC/EACTS guidelines on myocardial revascularization[END_REF] Shared-decision-making should include consultation with a heart team, thoroughly informing the patient of the benefits and risks, and consideration of patient preferences.

CABG has been associated with lower rates of mortality compared to PCI in RCTs in patients with left main disease or triple vessel disease. [START_REF] Hlatky | Coronary artery bypass surgery compared with percutaneous coronary interventions for multivessel disease: a collaborative analysis of individual patient data from ten randomised trials[END_REF] However, frail patients, especially those with left main disease were excluded from these trials. [START_REF] Guo | Percutaneous coronary intervention in elderly patients with coronary chronic total occlusions: Current evidence and future perspectives[END_REF][START_REF] Sabatine | Percutaneous coronary intervention with drug-eluting stents versus coronary artery bypass grafting in left main coronary artery disease: an individual patient data meta-analysis[END_REF] The guidelines on myocardial revascularization recommend using the SYNTAX score to help guide decisions on whether to perform PCI or CABG. [START_REF] Neumann | ESC/EACTS guidelines on myocardial revascularization[END_REF][START_REF] Windecker | Considerations for the choice between coronary artery bypass grafting and percutaneous coronary intervention as revascularization strategies in major categories of patients with stable multivessel coronary artery disease: an accompanying article of the task force of the 2018 ESC/EACTS guidelines on myocardial revascularization[END_REF] PCI is generally recommended in patients with low SYNTAX scores, mainly because of convenience and cost. CABG is recommended in patients with intermediate or high SYNTAX scores because of with the potential for lower mortality rates. [START_REF] Windecker | Considerations for the choice between coronary artery bypass grafting and percutaneous coronary intervention as revascularization strategies in major categories of patients with stable multivessel coronary artery disease: an accompanying article of the task force of the 2018 ESC/EACTS guidelines on myocardial revascularization[END_REF] However, the choice should also consider the presence of severe co-morbidities, advanced age (e.g., frailty or reduced life expectancy), and conditions that may affect rehabilitation (e.g., restricted mobility) favour PCI. [START_REF] Neumann | ESC/EACTS guidelines on myocardial revascularization[END_REF][START_REF] Windecker | Considerations for the choice between coronary artery bypass grafting and percutaneous coronary intervention as revascularization strategies in major categories of patients with stable multivessel coronary artery disease: an accompanying article of the task force of the 2018 ESC/EACTS guidelines on myocardial revascularization[END_REF]

When, who, and how to perform aortic or percutaneous mitral valve interventions

Updated European guidelines on valvular heart disease were published in 2021, and a summary of recommendations for the use of interventions in patients with aortic stenosis and mitral regurgitation is shown in Table 3. [START_REF] Vahanian | ESC/EACTS Guidelines for the management of valvular heart disease[END_REF] In addition, the Aortic Valve ReplAcemenT versus Conservative Treatment in Asymptomatic SeveRe Aortic Stenosis (AVATAR) study suggested that surgical aortic valve replacement (SAVR) is beneficial when stenosis becomes severe regardless of symptoms. [START_REF] Banovic | Aortic Valve ReplAcemenT versus Conservative Treatment in Asymptomatic SeveRe Aortic Stenosis: The AVATAR trial[END_REF] TAVI has been associated with reduced rates of all-cause mortality and stroke compared with SAVR, regardless of baseline surgical risk. [START_REF] Siontis | Transcatheter aortic valve implantation vs. surgical aortic valve replacement for treatment of symptomatic severe aortic stenosis: an updated meta-analysis[END_REF] Stroke may be an important outcome for older people because of the impact on quality of life.

Certain clinical, anatomical, and technical factors should be considered in the decision to perform SAVR or TAVI, and risks and benefits should be discussed with a heart team and an informed patient. [START_REF] Vahanian | ESC/EACTS Guidelines for the management of valvular heart disease[END_REF][START_REF] Baumgartner | ESC/EACTS Guidelines for the management of valvular heart disease[END_REF][START_REF] Capodanno | Antithrombotic therapy after transcatheter aortic valve replacement[END_REF] SAVR is favoured in patients with complex anatomy, concomitant conditions that require surgery such as significant CAD, or those with endocarditis. Life expectancy, potential quality of life in terms of comorbid conditions or frailty, together with well-informed patient preferences are critical in determining the best management strategy.

Delirium can be an important complication after TAVI, especially in older people, who may benefit from early recognition and interventions. [START_REF] Van Der Wulp | Delirium after TAVR: Crosspassing the limit of resilience[END_REF]

Adding years to life or life to years (making decisions to withhold or discontinue treatment)

The main goals of CV treatments should be to prevent or manage CVD, and to improve the quality and duration of life (healthy active life). [START_REF] Krishnaswami | Deprescribing in older adults with cardiovascular disease[END_REF] Patient preference becomes a primary factor in chronic, incurable, or highly disabling conditions such as advanced HF. [START_REF] Krishnaswami | Deprescribing in older adults with cardiovascular disease[END_REF][START_REF] Kilic | The importance of palliative care in cardiology: Differences between countries[END_REF] Individuals have different beliefs, values, and goals regarding their health care, and these may change over time. [START_REF] Krishnaswami | Deprescribing in older adults with cardiovascular disease[END_REF] Improved treatments and longer survival in patients with HF is associated with more hospitalizations and an increasingly unmanageable symptom burden. [START_REF] Kilic | The importance of palliative care in cardiology: Differences between countries[END_REF] CV risk factors alone should not determine therapy, rather risk minimization strategies should be preferred. Patients may benefit from proactive strategies to address side effects, or from discontinuation of some medications. Studies suggest that reducing the number of drugs in older patients on polypharmacy (including CV and/or non-CV medications) can be done safely, and has the potential to reduce falls, improve quality of life, reduce medication burden, and reduce medication costs. [START_REF] Krishnaswami | Deprescribing in older adults with cardiovascular disease[END_REF][START_REF] Kutner | Safety and benefit of discontinuing statin therapy in the setting of advanced, life-limiting illness: a randomized clinical trial[END_REF][START_REF] Kua | Health outcomes of deprescribing interventions among older residents in nursing homes: A systematic review and meta-analysis[END_REF][START_REF] Ibrahim | A systematic review of the evidence for deprescribing interventions among older people living with frailty[END_REF] In patients with cancer, palliative care has significantly improved quality of life and survival. 100 In cardiology, palliative care becomes especially important in patients with HF. HF is a progressive, chronic, life-threatening condition that significantly impacts quality of life. In addition, HF is often the end stage of most chronic CV conditions. In a RCT in patients with advanced HF, an interdisciplinary palliative care intervention was associated with significant improvements in quality of life measures, and depression and anxiety scores compared with usual care alone. 101 This illustrates that the risk is actionable and can be influenced. ESC HF guidelines suggest healthcare providers focus on the quality of life and the symptom burden of patients with advanced heart failure, as well as a timely plan for palliative care based on the patient's needs and beliefs (Table 4). 102 Patients with HF can benefit from palliative care not only to help manage their symptoms, but also to achieve a better understanding of their disease. With the patient's permission collateral information should be obtained from the family (e.g., in patients with cognitive impairment), and relatives should be included in discussions.

Despite favourable scientific evidence, palliative care has not been well integrated into cardiology. [START_REF] Kilic | The importance of palliative care in cardiology: Differences between countries[END_REF] Communication requires time, therefore, pathways should be in place for referral to palliative care, incorporating a shared-care strategy. 102 Palliative care should be discussed early in the disease trajectory, and end-of-life discussions should include advance care planning, disease understanding, and the patients' goals of care, with the goal of helping patients understand their disease status, prognosis, treatment options, and facilitate decision-making. [START_REF] Kilic | The importance of palliative care in cardiology: Differences between countries[END_REF]102 In patients with HF who are very debilitated and frail, palliative care can provide psychosocial support in making complex decisions such as device deactivation and place of death preferences. [START_REF] Kilic | The importance of palliative care in cardiology: Differences between countries[END_REF]102 A close collaboration between the palliative care team and the cardiologists is definitively needed, especially with mobile palliative care teams, and should improve the management of elderly patients requiring palliative care. Understanding and expanding the role of palliative care in cardiology is a much needed area for further investigation.

Summary

The growing elderly population worldwide represents a major responsibility, but also a challenge for caregivers, healthcare providers, and society. The life-long exposure to CV risk factors, as well as age-related comorbidities, promote a high prevalence of frequently complicated CVD in older patients. While prevention and management strategies have been shown to be effective in older people, there continues to be a paucity of robust evidence from dedicated clinical trials. The narrow therapeutic window of some recommended pharmacotherapies, frailty and cognitive impairments, and patients' re-assessment of important outcomes (e.g., quality of life versus mortality), can present management challenges.

With the increasing burden of ageing, the time has come to revisit CV research, including increasing use of real-world studies to assess longer-term outcomes. Use of pharmacological and interventional strategies in older patients should focus on quality of life and patient's preferences, with the optimal strategy being determined by a multidisciplinary team who involves the individual patient into the decision-making process.

Table 1: Summary of important clinical trials of primary prevention strategies in older people

Risk factor/ interventions

Clinical trials Findings

Hypertension SHEP, [START_REF] Shep Cooperative | Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension. Final results of the Systolic Hypertension in the Elderly Program (SHEP)[END_REF] Syst-Eur, [START_REF] Staessen | Randomised double-blind comparison of placebo and active treatment for older patients with isolated systolic hypertension. The Systolic Hypertension in Europe (Syst-Eur) Trial Investigators[END_REF] HYVET, [START_REF] Beckett | Treatment of hypertension in patients 80 years of age or older[END_REF] SPRINT [START_REF] Research Group | A randomized trial of intensive versus standard blood-pressure control[END_REF][START_REF] Bress | Potential deaths averted and serious adverse events incurred from adoption of the SPRINT (Systolic Blood Pressure Intervention Trial) intensive blood pressure regimen in the United States: Projections from NHANES (National Health and Nutrition Examination Survey)[END_REF] Intensive SBP targets could prevent ~107,500 deaths/y, at the expense of episodes of hypotension (~56,000), syncope (~34,000), serious electrolyte disturbances (~43,000), and acute kidney injury (~88,000) [START_REF] Bress | Potential deaths averted and serious adverse events incurred from adoption of the SPRINT (Systolic Blood Pressure Intervention Trial) intensive blood pressure regimen in the United States: Projections from NHANES (National Health and Nutrition Examination Survey)[END_REF]  Proven benefit in older people (fit and frail). [START_REF] Warwick | No evidence that frailty modifies the positive impact of antihypertensive treatment in very elderly people: an investigation of the impact of frailty upon treatment effect in the HYpertension in the Very Elderly Trial (HYVET) study, a double-blind, placebo-controlled study of antihypertensives in people with hypertension aged 80 and over[END_REF][START_REF] Williamson | Intensive vs standard blood pressure control and cardiovascular disease outcomes in adults aged >/=75 years: A randomized clinical trial[END_REF] Maximum benefits in >75-80 y. [START_REF] Williamson | Intensive vs standard blood pressure control and cardiovascular disease outcomes in adults aged >/=75 years: A randomized clinical trial[END_REF]  Benefits of antihypertensive therapy need to be weighed with risks; increased susceptibility to adverse events in older adults  Treatment targets need to be individualised based on function, frailty, independence to minimise harms [START_REF] Benetos | Hypertension management in older and frail older patients[END_REF][START_REF] Williams | 2018 ESC/ESH Guidelines for the management of arterial hypertension[END_REF] Dyslipidemia Age ≥65 y: Meta-analyses suggest benefits [START_REF] Cholesterol | Efficacy and safety of statin therapy in older people: a meta-analysis of individual participant data from 28 randomised controlled trials[END_REF][START_REF] Savarese | Benefits of statins in elderly subjects without established cardiovascular disease: a meta-analysis[END_REF] Limited data >75 y: PROSPER (age 70-82 y), benefits driven by secondary prevention benefit [START_REF] Shepherd | Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial[END_REF]  Statins appropriate for most healthy older people for prevention of MI/stroke, less evidence of mortality benefit [START_REF] Cholesterol | Efficacy and safety of statin therapy in older people: a meta-analysis of individual participant data from 28 randomised controlled trials[END_REF][START_REF] Savarese | Benefits of statins in elderly subjects without established cardiovascular disease: a meta-analysis[END_REF]  Consider longer time-to-benefit with statins (~2-2.5 years), as well as patient's anticipated life expectancy [START_REF] Yourman | Evaluation of time to benefit of statins for the primary prevention of cardiovascular events in adults aged 50 to 75 years: A meta-analysis[END_REF][START_REF] Holmes | Rationalizing prescribing for older patients with multimorbidity: considering time to benefit[END_REF]  Older people more susceptible to adverse events, and more likely to have co-existing frailty, sarcopenia, polypharmacy; all of which increase potential for harm if adverse effect occurs; thus risk assessment and shared decision making are essential 14  Minimal or no net clinical benefit in older people (risk of bleeding vs. MACE/mortality) [START_REF] Gaziano | Use of aspirin to reduce risk of initial vascular events in patients at moderate risk of cardiovascular disease (ARRIVE): a randomised, double-blind, placebo-controlled trial[END_REF][START_REF] Study | Effects of aspirin for primary prevention in persons with diabetes mellitus[END_REF][START_REF] Mcneil | Effect of aspirin on all-cause mortality in the healthy elderly[END_REF]  Not recommended for primary prevention [START_REF] Arnett | ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines[END_REF][START_REF]By the American Geriatrics Society Beers Criteria Update Expert Panel. American Geriatrics Society 2019 updated AGS Beers Criteria(R) for potentially inappropriate medication use in older adults[END_REF][START_REF] Rabi | Hypertension Canada's 2020 comprehensive guidelines for the prevention, diagnosis, risk assessment, and treatment of hypertension in adults and children[END_REF]  Beers Criteria recommends additional caution when using ASA in older adults, due to risk of bleeding 54

Smoking

Meta-analyses Zutphen Elderly Study [START_REF] Bijnen | Physical activity and 10-year mortality from cardiovascular diseases and all causes: The Zutphen Elderly Study[END_REF]  Reduction in CVD risk [START_REF] Arnett | ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines[END_REF][START_REF] Hakim | Effects of walking on coronary heart disease in elderly men: The Honolulu Heart Program[END_REF][START_REF] Bijnen | Physical activity and 10-year mortality from cardiovascular diseases and all causes: The Zutphen Elderly Study[END_REF][START_REF] Cheng | Physical activity and risk of cardiovascular disease among older adults[END_REF]  Tailor to individual's needs and ability [START_REF] Arnett | ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines[END_REF][START_REF] Cheng | Physical activity and risk of cardiovascular disease among older adults[END_REF] CVD; cardiovascular disease; EPO; eicosapentaenoic acid; MACE, major cardiovascular events; SBP, systolic blood pressure. Note abbreviations for trials can be found in the references. o In selected symptomatic patients, TEER considered in those not eligible for surgery with a high likelihood of response o In selected high-risk symptomatic patients not eligible for surgery and unlikely to respond to TEER, consider a TEER procedure or other trans-catheter valve therapy, after evaluation for ventricular assist device or heart transplant by heart team Adapted from reference. [START_REF] Vahanian | ESC/EACTS Guidelines for the management of valvular heart disease[END_REF] BNP, B-type natriuretic peptide; CABG, coronary artery bypass grafting; LVEF, left ventricular ejection fraction; PCI, percutaneous coronary intervention; SAVR, surgical aortic valve replacement; SMR, secondary mitral regurgitation; TAVI, transcatheter aortic valve implantation; TEER, transcatheter edge-to-edge repair; Vmax, peak transvalvular velocity European guidelines for the management of acute and chronic heart failure Indications (despite optimal therapy)  Progressive functional decline and loss of independence  Severe HF symptoms and poor quality of life despite optimal therapy  Frequent episodes of serious decompensation or hospital admissions despite optimal therapy  Not suitable for heart transplantation or mechanical circulatory support  Cardiac cachexia  Close to end of life (clinical assessment)  Key components  Focus on optimising quality of life of the patient and family until death  Frequently assess symptoms (including dyspnoea and pain) and focus on symptom relief  Facilitate access for the patient and family to psychological/spiritual support as needed  Assist with advanced care planning, including preferences around death and resuscitation (may require multidisciplinary team decisions)

Adapted from reference. 102

  supervised, multidisciplinary, and comprehensive, and home-based interventions can be considered. Exercise-based cardiac rehabilitation should include both aerobic and muscular resistance exercise, address all recognized CV risk factors, and should be individualised. Treatment decisions: When should we use aggressive interventions vs. medication vs. no treatment? Decision making for antithrombotic treatments in older people (antiplatelet, anticoagulant, and combination therapy)

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Figure legend

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Figure 1 :

 1 Figure 1: Individualised decisions on lifestyle changes and risk factor treatment will benefit from a thorough risk analysis and patient involvement

  3 m/s/year  Markedly elevated BNP levels by repeated measurements, without another cause Recommended mode of intervention (SAVR, TAVI) in patients with aortic stenosis  Heart team should assess risks and benefits based on evaluation of clinical, anatomical, and procedural factors, in consultation with informed patient  SAVR recommended in younger patients (<75 years) at low surgical risk, or patients unsuitable for transfemoral TAVI  TAVI recommended in older patients (≥75 years), or in those at high surgical risk  SAVR or TAVI recommended for remaining patients based on clinical, anatomical and procedural factors  Non-transfemoral TAVI considered in patients who are unsuitable for SAVR or transfemoral TAVI Indications for mitral valve intervention (SAVR, TAVI, TEER) in chronic severe secondary mitral regurgitation (SMR)  Surgery/intervention recommended in patients with severe SMR who are symptomatic despite optimal therapy in consultation with heart team  Patients with concomitant CAD or other cardiac disease requiring treatment o In symptomatic patients. PCI (and/or TAVI) possibly followed by TEER (if persistent severe SMR) considered in those not appropriate for surgery based on assessment by heart team o Valve surgery recommended in patients undergoing CABG or other cardiac surgery  Patients without concomitant CAD or other cardiac disease requiring treatment

Table 1

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	Aspirin	ARRIVE, 49 ASCEND, 50 ASPREE 51,
		52

Table 2 :

 2 Summary of extent of disease indicating a need for revascularization in patients with stable CAD and documented ischaemia or a haemodynamically relevant lesion from the 2018 Haemodynamically significant stenosis in patients with limiting angina on optimised medical therapyAdapted from reference.[START_REF] Neumann | ESC/EACTS guidelines on myocardial revascularization[END_REF] CAD, coronary artery disease, LVEF, left ventricular ejection fraction

	European guidelines on myocardial revascularization
	Goal of improving prognosis
	 >50% stenosis in
	o Left main CAD
	o Proximal left anterior descending CAD
	o 2-or 3-vessel disease with LVEF ≤35%
	o Sole remaining patent coronary artery
	 Extensive ischaemia on functional testing (>10% LV) or abnormal invasive fractional flow reserve
	Goal of improving symptoms
	

Table 2

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	ESC CRT on CVD in the elderly
	1
	ACCEPTED MANUSCRIPT -CLEAN COPY

Table 3 :

 3 Summary of interventional strategies for patients with aortic stenosis or chronic severe secondary mitral regurgitation from the 2021 European guidelines for valvular heart disease

	Recommended indications for intervention in aortic stenosis
	 Symptomatic
	o Intervention recommended if severe, high-gradient aortic stenosis (mean gradient ≥40 mmHg, Vmax ≥4.0
	m/s and valve area ≤1.0 cm 2 )
	 Asymptomatic
	o Intervention considered if severe and LVEF <55%, without another cause
	o Intervention considered if LVEF >55% with a normal exercise test and any of the following:
	 Very severe (mean gradient ≥60 mmHg or Vmax ≥5 m/s)
	 Severe valve calcification and Vmax progression ≥0.3 m/s/year
	 Markedly elevated BNP levels by repeated measurements, without another cause
	Recommended

mode of intervention (SAVR, TAVI) in patients with aortic stenosis

   Heart team should assess risks and benefits based on evaluation of clinical, anatomical, and procedural factors, in consultation with informed patient  SAVR recommended in younger patients (<75 years) at low surgical risk, or patients unsuitable for transfemoral TAVI  TAVI recommended in older patients (≥75 years), or in those at high surgical risk  SAVR or TAVI recommended for remaining patients based on clinical, anatomical and procedural factors  Non-transfemoral TAVI considered in patients who are unsuitable for SAVR or transfemoral TAVI Indications

for mitral valve intervention (SAVR, TAVI, TEER) in chronic severe secondary mitral regurgitation (SMR)

   Surgery/intervention recommended in patients with severe SMR who are symptomatic despite optimal therapy in consultation with heart team  Patients with concomitant CAD or other cardiac disease requiring treatment o In symptomatic patients. PCI (and/or TAVI) possibly followed by TEER (if persistent severe SMR) considered in those not appropriate for surgery based on assessment by heart team o Valve surgery recommended in patients undergoing CABG or other cardiac surgery  Patients without concomitant CAD or other cardiac disease requiring treatment o In selected symptomatic patients, TEER considered in those not eligible for surgery with a high likelihood of response o In selected high-risk symptomatic patients not eligible for surgery and unlikely to respond to TEER, consider a TEER procedure or other trans-catheter valve therapy, after evaluation for ventricular assist device or heart transplant by heart team

	Adapted from reference. 93
	BNP, B-type natriuretic peptide; CABG, coronary artery bypass grafting; LVEF, left ventricular ejection fraction;
	PCI, percutaneous coronary intervention; SAVR, surgical aortic valve replacement; SMR, secondary mitral
	regurgitation; TAVI, transcatheter aortic valve implantation; TEER, transcatheter edge-to-edge repair; Vmax, peak
	transvalvular velocity

Table 3 -

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	ESC CRT on CVD in the elderly
	1
	ACCEPTED MANUSCRIPT -CLEAN COPY

Table 3 :

 3 Summary of interventional strategies for patients with aortic stenosis or chronic severe secondary mitral regurgitation from the 2021 European guidelines for valvular heart disease Intervention considered if severe and LVEF <55%, without another cause o Intervention considered if LVEF >55% with a normal exercise test and any of the following:  Very severe (mean gradient ≥60 mmHg or Vmax ≥5 m/s)  Severe valve calcification and Vmax progression ≥0.

	Recommended indications for intervention in aortic stenosis
	 Symptomatic
	o Intervention recommended if severe, high-gradient aortic stenosis (mean gradient ≥40 mmHg, Vmax ≥4.0
	m/s and valve area ≤1.0 cm 2 )
	 Asymptomatic
	o

Table 3 -

 3 marked Downloaded from https://academic.oup.com/eurjpc/advance-article/doi/10.1093/eurjpc/zwac033/6529006 by Universite de Rennes 1 SCD Section sante user on 25 February 2022 ACCEPTED MANUSCRIPT -CLEAN COPY ESC CRT on CVD in the elderly 1

Table 4 :

 4 Considerations for palliative care in patients with advanced HF from the 2021

Table 4

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Downloaded from https://academic.oup.com/eurjpc/advance-article/doi/10.1093/eurjpc/zwac033/6529006 by Universite de Rennes 1 SCD Section sante user on 25 February 2022

While two of these trials were not specific to an older adult population, the ASPREE trial Downloaded from https://academic.oup.com/eurjpc/advance-article/doi/10.1093/eurjpc/zwac033/6529006 by Universite de Rennes 1 SCD Section sante user on 25 February 2022

Acknowledgements

This article was generated from discussions during a virtual Cardiovascular Round Table (CRT) workshop organised in May 2021 by the European Society of Cardiology (ESC). The ESC CRT is a strategic forum for high-level dialogue between 20 industry companies (pharmaceutical, devices and diagnostics) and the ESC leadership to identify and discuss key strategic issues for the future of cardiovascular health in Europe. The authors would like to thank Pauline Lavigne and Steven Portelance (unaffiliated, supported by the ESC) for contributions to writing, and editing the manuscript.

Author contributions

All CRT members that were included as authors contributed to design of the CRT meeting and to selection of the topics; ML and IR-L drafted the initial manuscript. All authors critically revised the manuscript, gave final approval, and agreed to be accountable for all aspects of work ensuring integrity and accuracy.