Review Article

Frailty and Cardiovascular Risk

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Abstract

Frailty (the loss of physiological reserve to withstand a stressor response) is associated with an increase in vascular risk and cardiovascular disease, and exerts marked disease- and treatment-modifying effects on cardiovascular outcomes and treatments. Frailty is anticipated to rise as the global population ages, resulting in an increase in the burden of cardiovascular morbidity and mortality that will have clear implications for the demand on healthcare services. However, despite these challenges, frailty may also represent an opportunity as a therapeutic target to reduce cardiovascular disease, and consequently direct a strategy to promote healthy ageing. Conversely, frail individuals may benefit from less intervention and polypharmacy, through a more holistic, person-centred approach. This review will consider the role of frailty in vascular risk factors and their inter-relationships, the impact of frailty on vascular risk management and treatment and the implications for research and clinical care in order to meet and minimise the burden of cardiovascular disease in individuals with frailty.

Keywords

Frailty, cardiovascular disease, stroke, blood pressure, diabetes, atherosclerosis,

Received:

Accepted:

Published online:

DOI: https://doi.org/10.15420/ecr.2026.09

Disclosure: NRE has received travel support from the World Stroke Organisation and European Stroke Organisation. SB has received travel support from the European Stroke Organisation. All other authors have no conflicts of interest to declare.

Funding: NRE is supported by a Stroke Association Senior Clinical Lectureship [SA-SCL-MED-22\100006], Stroke Association grant funding [PG2S21\100018], and the National Institute for Health and Care Research (NIHR) Cambridge Biomedical Research Centre [NIHR203312]. SB is supported by a Research Training Fellowship from the Vivensa Foundation (formerly The Dunhill Medical Trust; JBGS22\20). OMT is funded by an NIHR Advanced Fellowship (NIHR303219). JH is funded by the Stroke Association and Health and Social Care Research Wales [PG2S21\100015].

Correspondence: Nicholas Evans, Department of Clinical Neurosciences, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK. E: ne214@cam.ac.uk

Copyright:

© The Author(s). This work is open access and is licensed under CC-BY-NC 4.0. Users may copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Despite improvements in vascular risk factor management in recent decades, the globally ageing population has resulted in an increasing burden of cardiovascular disease and stroke.1–3 This global health challenge has implications for health services across the world, and has prompted a renewed focus on healthy ageing strategies to improve healthspan (defined as the number of years a person lives in good health, free from chronic disease and disability), and to reduce cardiovascular morbidity and mortality specifically.

A key process involved in biological ageing, as distinct from chronological age, is frailty, the loss of homeostatic regulation that leaves an individual more vulnerable to illness, poorer recovery and increased mortality after a stressor event (Figure 1 ).4 Cardiovascular disease is no exception, given that frailty is an independent risk factor for coronary artery disease, peripheral artery disease and acute MI.5 Furthermore, in those presenting with acute coronary syndromes, frailty is associated with lower rates of cardiac investigation and poorer outcomes for individuals after MI.6 Frailty is also common in individuals with heart failure, with many of these individuals with concurrent frailty prescribed suboptimal medication regimens and/or not receiving guideline-directed therapy, resulting in poorer functional recovery and increased mortality.7 There is also an association between frailty and increased rates of valvular heart disease, and poorer recovery after valve surgery.8,9

Figure 1: Approaches to Evaluating Frailty

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In stroke, frailty has both disease- and treatment-modifying effects. Premorbid frailty is independently associated with increased mortality after both ischaemic and haemorrhagic strokes, and associated with attenuated responses to hyperacute reperfusion therapy.10–13 Identification of the exact mechanisms underlying this relationship is a research priority, but current evidence indicates that frailty is associated with both vascular and systemic inflammation that is associated with reduced penumbra (salvageable brain) in hyperacute stroke.14–17 The presence of vascular risk factors and inflammation in atherosclerosis (‘atheroinflammation’) is associated with increased neuroinflammation and structural changes in the brain, resulting in a brain that is more vulnerable to injury and more likely to have poorer functional and cognitive recovery after stroke.18–20 Reflecting this, frailty also has implications for all stages of the stroke pathway, including profound effects on rehabilitation trajectory and long-term recovery.21,22

Given the implications of frailty for the risk of developing cardiovascular disease and poorer outcomes, the role of frailty in vascular risk and primary and secondary prevention is a critical consideration.23

This review will consider the role of frailty in relation to the major conventional vascular risk factors and their management, as well as highlighting future directions for the field (Figure 2 ).

Figure 2: Cardiovascular Risk Factors and Frailty

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Blood Pressure

Frailty and hypertension frequently coexist. A meta-analysis found that 72% of individuals with frailty had hypertension, while the pooled prevalence of frailty among individuals with hypertension was 14%.24 The relationship between blood pressure (BP) and frailty appears to be U-shaped, with both hypotension and hypertension observed in frailty, reflecting impaired BP regulation.25

Frailty has complex disease- and treatment-modifying effects in hypertension, raising key questions about whether BP targets should differ by frailty status. In a meta-analysis of nine observational studies involving 21,906 participants, achieving a systolic BP <140 mmHg was associated with reduced all-cause mortality in non-frail individuals, but no benefit was observed among those with frailty.26

Observational studies in older adults with hypertension consistently show higher mortality among individuals with frailty compared with non-frail individuals regardless of BP control. Notably, individuals with frailty and uncontrolled systolic BP (≥140 mmHg) had lower mortality than those with frailty and controlled BP, suggesting potential harm from tighter BP control in frailer populations.27

These findings are supported by a large routine data study showing that although hypertension was associated with increased mortality overall, no such association was observed in adults aged over 85 years or in those aged 75–84 years with moderate or severe frailty. In the latter group, higher BP appeared protective: systolic BP 150–159 mmHg was associated with lower all-cause mortality than 130–139 mmHg (HR 0.84; 95% CI [0.77–0.92]).28 A similar frailty-related treatment-modifying effect was reported in a German cohort study.29

Interpretation of these observational findings must consider residual confounding and reverse causality. Low BP in individuals with high disease burden may reflect proximity to death due to multi-system failure, rather than harm from antihypertensive treatment itself.

In contrast, post-hoc analyses of randomised clinical trials yielded different conclusions. In SPRINT, 26.7% of participants were classified as frail. Frailty was associated with higher rates of major adverse cardiovascular events (MACE) in both intensive and standard BP groups. However, intensive BP lowering reduced MACE irrespective of frailty status, with a significant frailty interaction observed only for cardiovascular death, in which benefit was seen in non-frail but not frail participants.30

Similarly, a post hoc analysis of the SHEP trial demonstrated increasing risk of MACE with frailty, but no interaction between frailty and antihypertensive treatment, suggesting similar relative treatment effects in frail and non-frail individuals.31 In ESPRIT, which included a high proportion of moderately (46.7%) and severely frail (14.5%) participants, achieving systolic BP <120 mmHg reduced MACE regardless of frailty status, although serious adverse events (hypotension, syncope, falls with injury, electrolyte disturbance, acute kidney injury and end-stage renal failure) increased with increasing frailty.32

Several factors may explain discrepancies between observational and trial evidence. Trial populations are highly selected, often excluding older adults with multimorbidity. In ESPRIT, approximately half of the cohort had established cardiovascular disease, which may have contributed to frailty and amplified the benefits of intensive BP lowering compared with primary prevention populations.32 Trial outcomes prioritise cardiovascular endpoints, while adverse effects, such as hypotension-related syncope and falls, may be under-recorded. BP measurement and medication titration in trials may also not reflect routine clinical practice, and frailty subgroup analyses were retrospective and not statistically powered.

Frailty indices derived retrospectively in trials also warrant scrutiny. While some indices capture multidimensional frailty, many post hoc trial indices disproportionately include cardiovascular deficits.33 For example, in the SPRINT frailty index, 14 of 37 components were cardiovascular risk factors, nine reflected trial exclusion criteria and 11 were functional measures that may represent health behaviours rather than physical capability. As a result, frailty in SPRINT may reflect cardiovascular burden, potentially mediating associations between BP and cardiovascular outcomes.

Antihypertensive medications are a key modifiable risk factor for falls.34 Hypotension can cause syncope, an under-recognised contributor to recurrent falls, particularly in frail older adults.35 Among individuals aged >85 years, lower systolic BP in those taking antihypertensive medications was associated with increased all-cause mortality (HR 1.29 per 10 mmHg lower systolic BP) and accelerated cognitive decline, particularly in those with reduced grip strength.36

Supporting this, an observational study of 3.8 million adults with hypertension in England found that initiation of antihypertensive therapy was associated with increased risk of falls, hypotension, syncope, acute kidney injury, electrolyte abnormalities and gout-related primary care visits, with risk rising with age and frailty.37 Estimates were broadly consistent with trial meta-analyses, except for hypotension and acute kidney injury.38

Concerns about over-treatment have driven interest in de-prescribing. The RETREAT-FRAIL trial randomised nursing home residents aged over 80 years (90% with Clinical Frailty Scale 4–8) who were taking at least two antihypertensives and had a systolic BP <130 mmHg, to usual care or medication reduction. No significant differences were observed in mortality, MACE or falls, although between-group systolic BP difference was modest (4.1 mmHg).39

Choices about antihypertensive medication are made more challenging as BP becomes more variable with age.40 Older adults are prone to both hypertensive and hypotensive episodes, making single BP readings unreliable. Binary classifications of frailty and BP targets inadequately capture this complexity. Ambulatory BP monitoring, increasingly feasible using wearable technology may be necessary to individualise treatment based on both cardiovascular and falls risk.41

Consensus guidance exists for managing hypertension in the presence of orthostatic hypotension, but further prospective research is needed.42 When randomised trials are not feasible, emulated trials using routine data and causal inference methods could help inform personalised treatment strategies for older adults living with both hypertension and frailty.43

Diabetes

The relationship between frailty and diabetes involves a complex bi-directional relationship. Diabetes can accelerate the development of a frailty phenotype, in particular sarcopenia (the loss of skeletal muscle), through inflammation.44,45 This may provoke a positive feedback cycle: glucose uptake by skeletal muscle accounts for approximately 80% of postprandial glucose uptake from the circulation, meaning that the reduced muscle mass in sarcopenia may result in lower skeletal muscle glucose uptake, higher serum glucose levels, insulin resistance and consequent β-cell failure.46

In turn, frailty may worsen pre-diabetes and diabetes through practical effects on medication administration or drug interactions with polypharmacy, as well as the impaired homeostasis that exacerbates dysglycaemia and increases the risk of complications. For example, in a study of 38,950 individuals with pre-diabetes in the UK Biobank, both pre-frailty and frailty were associated with an increased risk of microvascular complications and all-cause mortality, demonstrating a dose-dependent relationship according to frailty severity.47

It is important to consider dysglycaemia at either extreme, rather than solely hyperglycaemia. In older individuals, a U-shaped curve was observed with glycaemic control, with more harm than benefit seen with HbA1c >42 mmol/mol and >75 mmol/mol.48 Hypoglycaemia awareness may also be reduced in older individuals; and older individuals with hypoglycaemia typically present more with neuroglycopenic symptoms (visual disturbance, agitation, confusion) rather than adrenergic symptoms (palpitations, sweating, tremors), potentially making it harder to recognise hypoglycaemic episodes.49 Consequently, several guidelines have a more relaxed HbA1c target for individuals with frailty, although whether such guidance will change in the era of newer agents with a lower risk of hypoglycaemia remains to be seen.50

Linked to this, monitoring of glycaemic control in diabetes may also be more challenging in individuals with frailty versus more robust individuals. Comorbidities found frequently in frailty may alter red blood cell lifespan and reliability of HbA1c readings. For example, increased red blood cell turnover from haemolytic conditions and haemoglobinopathies will artificially reduce HbA1c, while anaemias (B12 deficiency, iron deficiency and anaemia of chronic disease) artificially increase HbA1c readings.51 Furthermore, the day-to-day monitoring of capillary glucose levels may be more challenging in individuals with frailty due to visual, motor and cognitive deficits.

Frailty may exert treatment-modifying effects in pharmacological therapy for diabetes. In the ADVANCE trial, intensive glucose management in type 2 diabetes reduced the risk of combined micro- and macrovascular complications for robust individuals (HR 0.84; 95% CI [0.74–0.94]), but the effect was attenuated for individuals with frailty (HR 1.03; 95% CI [0.90–1.19]). Furthermore, the risk of severe hypoglycaemia was significantly higher for individuals with frailty than for those without.52

Anti-hyperglycaemic agents may differ in their benefit and safety profiles when used in individuals with frailty, given that individuals with frailty appear to be more vulnerable to the effects of older anti-hyperglycaemic therapies compared with newer agents. Older individuals are at an increased risk of hypoglycaemia with sulfonylureas and insulin, while dipeptidyl peptidase-4 inhibitors had lower rates of hypoglycaemia compared with sulfonylureas in older individuals with frailty (although the risks of hyperglycaemia, MI, heart failure and combined MACE and heart failure were equivalent).53,54

In a pooled analysis, the long-term use of dapagliflozin (a sodium-glucose cotransporter 2 inhibitor [SGLT2I]) was well-tolerated and showed no difference in rates of hypoglycaemia in older (>65 years of age) individuals versus younger individuals.55 However, this did not consider physiological age. The impact of frailty on the use of another SGLT2I, canagliflozin, was considered in a post hoc patient-level analysis of the CANVAS Programme and CREDENCE Trial, finding similar efficacy in cardiovascular and mortality endpoints, as well as comparable side-effect profiles, between frail and non-frail participants.56

The impact of increasing age and frailty on diabetes management means that it is important that such individuals are reviewed regularly, and that de-escalation of pharmacological management is considered in instances when an individual is at increasing risk from hypoglycaemia. For example, in a large registry of 76,278 individuals with diabetes presenting to hospital with hypoglycaemia, less than half had their diabetes medication de-escalated, although the presence of frailty increased the likelihood of de-escalating the most intensive regimens of combined sulfonylurea and insulin therapy.57

Lipids

Frailty also shows a U-shaped association with total cholesterol concentration, with an association with both low levels and elevated levels of total cholesterol.58,59 A similar association is seen between frailty and non-HDL cholesterol concentration.60 While the mechanisms underlying the relationship between hypercholesterolaemia and frailty are likely to reflect the impact of cholesterol in promoting chronic systemic low-grade atheroinflammation, the mechanisms underlying the relationship with hypocholesterolaemia are less-well understood.61 One potential reason is that the low cholesterol levels reflect poor diet and/or reduced oral intake, themselves a marker of frailty. Another is more physiological, with impaired cholesterol absorption and synthesis found in older individuals, indicating that the low cholesterol levels are a product of frailty-associated gastrointestinal changes.62

The role of cholesterol-lowering therapy in individuals with concurrent hypercholesterolaemia and frailty remains debated. A meta-analysis of 14,324 individuals across five studies showed no benefit from statins for all-cause mortality in frail individuals.63 This may reflect the typical life expectancy of individuals with frailty: in the SPARCL study, the Kaplan–Meier curves for recurrent stroke began to diverge only at the 2-year mark, and hence it is possible that individuals with frailty died prior to any beneficial effects of statins being seen.64

In contrast, a large registry of 710,313 veterans in the US found that primary prevention with statins was associated with significantly decreased all-cause mortality and MACE over a mean follow-up period of 8 years, with no significant interaction to indicate a treatment-modifying effect from frailty.65 In terms of agent used, different preparations of statin appear to have similar efficacy.66

This discrepancy highlights the potential confounding effect when considering the efficacy and side-effect profiles of statins in frailty: there is frequently an under-representation of individuals with frailty in trials, and often the evidence is limited to observational studies or secondary analyses of randomised clinical trials. This highlights the need for specific randomised clinical trials in this specific population with frailty, particularly given the high prevalence of such individuals seen in clinical practice, but under-represented in existing clinical trials. An example of studies that are being developed to address this question is the SAFEST-RCT trial, which aims to guide this decision-making by evaluating the effects of statin versus no statin in individuals aged >70 years with frailty who have had a recent stroke or transient ischaemic attack.67

It is important to consider that statins may have important effects other than improved lipid levels, with non-lipid-mediated beneficial effects for secondary prevention. In strokes secondary to large artery atherosclerosis, statins may have pleiotropic effects on reducing atheroinflammation and stabilising the atherosclerotic plaque.68,69 Such effects typically occur quickly; hence, statins may be indicated for atherosclerotic plaque stabilisation early after stroke in individuals with frailty, even if the long-term effects on lipid level and outcome are less clear.

An analysis of prescribing patterns for primary prevention indicated that there was no significant difference between older individuals (aged >75 years) versus younger individuals being prescribed a statin, but they were less likely to report adverse events. In contrast, in secondary prevention, older individuals were slightly less likely to receive statins and much less likely to receive high-dose statin therapy.70

For individuals aged >75 years who had been taking statins for over 5 years, observational studies have found that subsequent discontinuation of a statin (in both primary or secondary prevention) was associated with an increased rate of MACE.71 Similar results were seen in a French study, in which discontinuation of a statin medication in individuals >75 years of age taking statins for primary prevention was associated with a 33% increased risk of a cardiovascular event over the subsequent 2.4 years.72

The use of proprotein convertase subtilisin/kexin type 9 (PCSK9) monoclonal antibodies has been shown to have similar efficacy for those aged over 70 years as for those aged under, although the role of frailty has not been considered and it is likely that studies had a selection bias for more robust individuals in the older age cohort.73

Smoking

Smoking accelerates frailty, either when considered as a cumulative deficit model or as a frailty phenotype.74,75 This association has been confirmed through Mendelian randomisation studies, with a dose-dependent relationship with lifetime smoking associated with a 46% higher risk of frailty.76 Although time since smoking cessation reduces the risk of frailty, former smokers continue to have a higher risk of frailty compared with never smokers.77 Similar results have been seen among non-smokers with passive smoke exposure, in that those with higher levels of serum cotinine were at an increased risk of developing frailty.78 The mechanisms by which smoking exacerbates frailty are likely to be multifactorial, but a major component is likely to be the inflammatory response that is a potent driver of frailty.79,80 Furthermore, in addition to the increased risk of developing frailty with smoking, frailty also increases the susceptibility of individuals to smoking-related mortality.81

Lifestyle

Lifestyle factors, such as alcohol consumption, dietary patterns and physical activity, have important associations with both frailty and cardiovascular disease. High alcohol consumption in mid-life is associated with both pre-frailty and frailty in older age, as well as increased risk of adverse cardiovascular outcomes.82,83 Healthy dietary patterns, i.e. those rich in fruit, vegetables and whole grains, are associated with a lower risk of frailty, while suboptimal nutritional status, i.e. diets high in saturated fatty acids, sugar-sweetened beverages, red or processed meat, and high salt intake, has been associated with an increased risk of cardiovascular disease.84,85 As such, dietary interventions represent an important component of rehabilitation strategies.86 Finally, higher levels of physical activity are associated with a lower risk of frailty, a better cardiovascular risk profile (lower BP, higher insulin sensitivity and reduced plasma lipoprotein levels) and a lower rate of MACE.87,88 With regard to frailty being a dynamic state, as well as frailty and cardiovascular disease sharing underlying biological mechanisms, physical activity interventions have been shown to reverse frailty and improve cardiovascular outcomes.89,90

Body Composition

Further to the aforementioned reduced quantity and quality of skeletal muscle seen in frailty-associated sarcopenia, frailty is associated with other changes in body composition that have been implicated in cardiovascular risk. Although frailty is often associated with being underweight, cases involving concurrent sarcopenia and increased abdominal visceral fat highlight the existence of ‘sarcopenic obesity’. In a study of community-dwelling individuals aged over 60 years, being either over- or underweight (BMI ≥30 kg/m2 or <18.5 kg/m2, respectively) was associated with an increased risk of frailty, as was the presence of abdominal obesity.91

Despite these associations, the impact on cardiovascular outcomes remains unclear. In one study, men with sarcopenic obesity were twice as likely to be frail and had a 58% and 36% increased risk of disability in activities of daily living and instrumental activities of daily living, respectively (although there was no independent association between sarcopenic obesity and mortality).92 The same study reported that obesity in isolation was protective for institutionalisation, as well as a trend towards reduced mortality.

In the British Regional Heart Study of men aged 60–79 years, both sarcopenia and obesity in isolation were associated with all-cause and cardiovascular mortality, while the highest risk of all-cause mortality (but not cardiovascular mortality) occurred with them in combination.93 In a subsample of the National Health and Nutrition Examination Survey III, the prevalence of sarcopenic obesity was 42.9% in men and 18.1% in women, but only women had an increased risk of all-cause mortality with sarcopenic obesity (although this narrowly missed statistical significance if mobility limitations were added to the regression analysis).94

Possibly associated with the risk of morbidity (but having an inconsistent effect on mortality), sarcopenic obesity has been associated with increased risk of adverse cardiovascular events. Sarcopenic obesity is associated with an increased risk of cardiovascular disease, heart disease and stroke.95 Sarcopenic obesity is associated with increased disability after stroke, and reduced cardiorespiratory fitness in heart failure with reduced ejection fraction; and a disease-modifying interaction has been reported between a high BMI and frailty in relation to increased heart failure events in both pre-frail (HR 1.42) and frail individuals (HR 3.33).96–98

Atherosclerosis

Although the association between frailty and vascular risk may explain the higher prevalence and severity of atherosclerosis found in individuals with frailty, frailty remains an independent risk factor for the development of coronary and carotid artery atherosclerosis.99 Frailty is associated with an increased risk of subclinical coronary atherosclerotic disease, and early pilot work indicates that for those with coronary artery atherosclerosis, individuals with concurrent frailty are more likely to have a higher prevalence of high-risk vulnerable atherosclerotic plaques.100,101

In the carotid arteries, the Beijing Longitudinal Study of Aging reported that frailty (as measured by a frailty index) was positively associated with the presence of carotid artery intima–media thickening and carotid artery atherosclerotic plaques, and that individuals with the highest severity of frailty were more likely to develop atherosclerotic-related cardiovascular events in the subsequent 5 years.102 Supporting this, and analogous to the morphological phenotypes seen in coronary artery disease for individuals with frailty, frailty was found to be associated with more inflamed (and consequently more high-risk) carotid atherosclerotic plaques on PET.17

The management of carotid atherosclerosis also demonstrates the importance of discriminating between chronological and physiological age. Leung et al. found only a modest increase in perioperative risk for carotid endarterectomy in older individuals for symptomatic disease (each 5-year increase after 65 years was associated with an increased perioperative risk of stroke of 0.14%, MI of 0.23% and death of 0.19%), whereas frailty demonstrated more marked perioperative complications (a 66% increase in the odds of periprocedural stroke and a 59% increase in the odds of death in those with frailty).103–105

Atrial Fibrillation

In a pooled analysis of 1,187,651 individuals with AF across 33 studies, the prevalence of frailty was 40%.106 Furthermore, longitudinal data suggest that the presence of AF accelerates the development of a frailty phenotype.107 Frailty is particularly accelerated in the event of stroke (due to the consequent accumulation of deficits) both during the stroke event and sustained in the post-stroke period.108 Furthermore, AF-related strokes tend to be more severe (with more consequent deficits), in part due to AF-associated fibrin-rich thrombi tending to be less responsive to reperfusion therapy, and the link between frailty and AF may account for the more severe strokes typically observed in individuals with frailty.109–111 Additionally, similar to atherosclerosis, the mechanisms underlying the link between AF and frailty may include chronic low-grade inflammation, as well as reduced cardiac output and tissue perfusion in AF.112,113

Frailty exerts a disease-modifying effect in AF. Individuals with concurrent AF and frailty are approximately twice as likely to be admitted to hospital compared with robust individuals with AF, and the presence of AF is associated with an increased length of hospital stay.114,115 Frailty is also associated in a near threefold increase in all-cause mortality in AF compared with non-frail individuals.116

Some of these findings, as well as the increased incidence of stroke secondary to AF in individuals with frailty, may be due to the observed differences in anticoagulation prescribing according to frailty status. In a cohort of hospitalised individuals with AF, individuals with frailty were 23% less likely to be prescribed anticoagulation than robust individuals.117 In a systematic review and meta-analysis of anticoagulation-prescribing patterns in AF, Wilkinson et al. found that individuals with frailty were approximately half as likely to be prescribed anticoagulation at hospital admission (aOR 0.45; 95% CI [0.22–0.93]), but there was no significant difference at hospital discharge.118 This difference may reflect study heterogeneity, the impact of the event prompting admission on clinical decision-making or the setting (given that the same systematic review also reported a single study in which community-dwelling individuals with frailty were more likely to be prescribed anticoagulation for AF than those who were robust).

In a subsequent large national study with a high population prevalence of frailty (approximately 80%), anticoagulation prescribing rose with the degree of frailty and was associated with a reduction in death, stroke and systemic emboli across all degrees of frailty.119

Outcomes with anticoagulation for older individuals with AF may be compounded by different coagulation profiles among individuals with frailty. Frailty is independently associated with increased factor VIII and D-dimer, with a concurrent rise in C-reactive protein suggesting an interplay between frailty, inflammation and coagulation pathways.120

The risk of bleeding with anticoagulation in individuals with frailty remains unclear. He et al. reported a significant risk of major bleeding from anticoagulation in individuals with frailty, with a relative risk of 1.83 (95% CI [1.24–2.71]).116 However, other studies have found no difference in the rates of haemorrhagic adverse events according to frailty status.121 In particular, the results of the recent large EUROSAF study indicate the superior efficacy of direct oral anticoagulants compared with warfarin, with a beneficial effect on mortality with no significant treatment-modifying effect from frailty, and with no significant increase in the risk of haemorrhage among individuals with frailty.122 Similar findings were seen in a large registry dataset from South Korea, in which anticoagulation use in individuals >65 years with frailty was associated with significantly lower rates of ischaemic stroke and cardiovascular death compared with those not taking anticoagulation, with no significant difference in the rates of major bleeding.123 Hence, some of the conflicting findings of efficacy and adverse effects from anticoagulation according to frailty status may depend on the agent used, with more modern direct oral anticoagulants being preferable for use in frailty based on efficacy, with no apparent additional risk of haemorrhage when used in frailty.

Holistic Treatment Approaches

Frailty and older age are independent of each other but clearly synonymous. Hence, many frail people will be approaching the final stages of their lives. Or for others, they may simply choose a reduction in a medicalised approach to their care, through a more holistic patient-centred care model. Additionally, much of the trial evidence and guideline provisions for both primary and secondary prevention of cardiovascular disease were gathered from younger and less frail populations, often using poor indices of frailty, making the generalisability of these findings and recommendations to these populations less reliable.124

Examples of when a more tailored strategy of cardiovascular risk factor management may be appropriate include withholding or stopping a statin, adopting a symptom-based management strategy for the management of AF, or prioritising quality of life in people with hypertension and frailty.125–127

Implications and Future Directions

Improving cardiovascular health across the lifespan is associated with a reduced risk of frailty, and hence optimising these vascular risk factors has important implications for promoting healthy ageing, not only by reducing cardiovascular events, but also by reducing the development of frailty.128 In addition to informing our understanding of why individuals with frailty may be at increased risk of cardiovascular events and poorer outcomes, an appreciation of the impact of frailty on cardiovascular disease may represent a novel therapeutic target. Frailty is dynamic, and recognition that someone is developing frailty at a sufficiently early stage may enable interventions to reverse this trajectory and reduce its impact on risk factors and disease. Hence, assessment and intervention for frailty should be considered during all healthcare encounters, including annual reviews for those with chronic conditions.

Interventions for reversing frailty should be multidimensional and multidisciplinary. Intervention strategies to reduce the accumulation of deficits and/or frailty phenotype characteristics include physical, pharmacotherapeutic, nutritional, cognitive and social domains.129 Rehabilitation strategies in cardiac disease and stroke recovery for individuals with concurrent frailty need to be tailored to accommodate and address both conditions, and further research is essential to help identify what interventions work or need adapting for those with frailty.

Most studies considering the impact of frailty on vascular risk modification have focused on community-dwelling individuals and primary prevention. In contrast, the impact of frailty on the efficacy of secondary prevention strategies after cardiovascular events has received less attention. Although some studies have attempted to analyse the effect of frailty in secondary analyses, such efforts are often limited by the lack of contemporaneous frailty measures during the study and limited recruitment of individuals with moderate-to-severe frailty (due to such individuals often being excluded from randomised clinical trials). As such, there are often limitations in the frailty measure used and significant selection bias. An important future direction will be to develop studies (in particular randomised clinical trials) that address these uncertainties specifically in a population of individuals with frailty.

Conclusion

The effects of the globally ageing population are already apparent on the incidence and outcomes of cardiovascular disease. The concomitant rise in frailty offers both a challenge and an opportunity to reduce the impact of vascular risk factors in order to promote healthy ageing. In order to address this, dedicated research (including robust randomised clinical trials) needs to be prioritised for these groups. Importantly, ensuring that primary and secondary prevention strategies are tailored to the needs of an older population with frailty will need refinements to clinical guidelines, care pathways and clinician expertise.

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