Aging and Antithrombotic Treatment

Abstract

Significance:

Several aging-related pathophysiological mechanisms have been described to contribute to increased thrombotic risk in the elderly, including oxidative stress, endothelial dysfunction, and platelet and coagulation cascade activation. Antithrombotic treatment in the elderly should be individualized.

Recent Advances:

Recent studies have clarified some pathophysiological mechanisms of enhanced oxidative stress and thrombotic alterations in older adults. In the last decade, randomized trials have evaluated different antithrombotic strategies to reduce the risk of cardiovascular events in these patients.

Critical Issues:

The proportion of elderly patients included in clinical trials is generally low, thus not reflecting the daily clinical practice. There is no consensus on the most appropriate antithrombotic treatment in the elderly, also considering that bleeding risk management may be challenging in this high-risk subgroup of patients. Routine antiplatelet treatment is not a valid strategy for the primary prevention of cardiovascular events given the associated high risk of bleeding. In elderly patients with acute coronary syndrome, low-dose prasugrel or clopidogrel, shorter dual antiplatelet therapy, and no pretreatment before stent placement should be considered. Advanced age should not be the only reason for the underuse of oral anticoagulation in patients with atrial fibrillation, with direct oral anticoagulants preferred over warfarin for stroke prevention. Instead, a case-by-case clinical evaluation is warranted based on patient's bleeding risk also.

Future Directions:

There is a need for a structured tailored approach to manage thrombotic risk in elderly patients. The choice of the most appropriate antithrombotic treatment should balance efficacy and safety to reduce the risk of bleeding.

Introduction

Globally, the population is aging and the World Health Organization predicts that by 2050, the population of individuals aged ≥60 years will double and those aged ≥80 years will be around 400 million (Singh and Bajorek, 2014). Despite aging being commonly measured by chronological age and, as a convention, a person aged ≥65 years is usually defined as ‘elderly,’ differences in genetics, lifestyle, and overall health have to be taken into account, mainly regarding the response to a specific treatment (Singh and Bajorek, 2014).

Several physiological mechanisms of vascular biology as well as thrombotic and hemostatic balance change during aging and are responsible for an increased risk of both thrombotic and hemorrhagic complications (Violi et al., 2017). The overproduction of reactive oxygen species (ROS) and downregulation of antioxidant enzymes during aging result in a pathologic imbalance that may affect clotting and platelet activation and impair endothelial function, further predisposing elderly patients to thrombosis (Violi et al., 2017).

From a clinical point of view, older individuals show higher odds of developing cardiovascular disease, and the prevalence of cardiovascular risk factors (i.e., arterial hypertension, diabetes mellitus, and dyslipidemia) was higher in individuals of advanced age, contributing to the aging-related cardiovascular burden (Violi et al., 2017) (Fig. 1). On the other hand, aging is often associated with inappropriate or reduced dosage and duration of antithrombotic therapy as elderly individuals may be considered at higher risk of drug toxicity or side effects and bleeding events than younger ones.

FIG. 1.

Imbalance between oxidative stress and antioxidant defenses in the aging process. Overproduction of ROS (e.g., increase in Nox activity and MPO activity and serum levels) and downregulation of antioxidant defenses in aging (e.g., reduction in SOD and GP serum activity, reduction in NOS levels) result in a pathologic imbalance that may contribute to endothelial dysfunction and platelet and clotting activation, which can predispose elderly patients to thrombosis. These events contribute to the onset of cardiovascular risk factors and age-related diseases such as cardiovascular disease. GP, glutathione peroxidase; MPO, myeloperoxidase; Nox, nicotinamide adenine dinucleotide phosphate oxidase; ROS, reactive oxygen species; SOD, superoxide dismutase.

Inappropriate low dosage of anticoagulants is indeed frequent in elderly patients and shorter treatment duration has been suggested in specific situations, mainly focusing on the safety profile (Lee et al., 2018; Moudallel et al., 2018). Finally, elderly patients may also be downrepresented in clinical trials and clinical decisions on this population are hampered by the lack of data.

The aims of this comprehensive review are to assess the pathogenetic mechanisms of aging-related atherothrombosis and to report available data on antithrombotic therapy during aging.

Pathogenetic Mechanisms Linking Aging with Atherothrombosis

Oxidative stress theory

Oxidative stress is the result of an imbalance between production and removal of ROS (Salisbury and Bronas, 2015; Violi et al., 2017). Even if the underlying mechanisms remain only partly understood, overproduction of ROS plays an important role in the aging-related cardiovascular burden, interacting with endothelial vascular cell homeostasis and functionality, platelet activation, and coagulation factor dysregulation (Liguori et al., 2018; Salisbury and Bronas, 2015; Violi et al., 2017).

The radical superoxide anion (O₂ ^•), hydrogen peroxide (H₂O₂), hydroxyl ion (OH^•), and hypochlorous acid are major endogenous ROS and their production is mainly mediated by the nicotinamide adenine dinucleotide phosphate oxidase (Nox), myeloperoxidase (MPO), lipoxygenase, and angiotensin II activity (Genestra, 2007; Violi et al., 2017).

Results of several experimental models have shown that the activity of some Nox isoforms (e.g., Nox4) as well as serum levels of myeloperoxidase (MPO) increased with age and that their inhibition through specific molecules may limit endothelial structural and functional dysfunction in vascular inflammation, reduce atherosclerotic mechanisms (e.g., endothelial activation, platelet adhesion and macrophage recruitment, and angiogenic mediator production), and promote atherosclerotic plaque stabilization (Fig. 1) (Azumi et al., 1999; Chen et al., 2022; Cheng et al., 2019; Douglas et al., 2012; Guzik et al., 2006; Hoy et al., 2001; Liu et al., 2013; Lozhkin et al., 2017; Ndrepepa, 2019; Quesada et al., 2015; Roth Flach et al., 2019; Scharnagl et al., 2014; Turgeon et al., 2012; Vendrov et al., 2015).

Low-density lipoprotein (LDL) retention and accumulation within the vessel wall (through neuraminidase-related desialylation) and oxidation (through lipoxygenase and MPO) are further critical steps in the oxidative stress-related atherogenic process of aging (Aureli et al., 2011; Demina et al., 2021; Dobrian et al., 2011; Funk et al., 2002; Iuliano et al., 2000; Mezentsev et al., 2021; Poznyak et al., 2020; Violi et al., 2017).

Damage in the vessel wall due to chronic accumulation and oxidation of LDL causes the migration of inflammatory cells (e.g., monocytes and macrophages) and formation of oxidative stress-related products (e.g., isoprostane and thromboxane production, expression of adhesion molecules) that exacerbate atherosclerotic lesions up to their erosion and rupture (Fogelstrand and Boren, 2012; Tabas, 2017; Violi et al., 2017). Dysregulation in tissue repair, clearance of inflammatory cells and necrotic materials, and vascular regeneration of aging further contribute to atherogenesis (Goldschmidt-Clermont et al., 2005; Karra et al., 2005; Tesauro et al., 2017) (Fig. 2).

FIG. 2.

Pro- and antioxidant enzymes during the process of aging. The migration of inflammatory cells, LDL retention and accumulation within the vessel, and their oxidation (ox-LDL) mediated by ROS (H₂O₂ and O₂ ^•) produced primarily by the Nox2 enzyme and angiotensin II activity are key events of the oxidative stress-related atherogenic process in aging. Moreover, the elderly are characterized by reduced activity of antioxidant pathways such as eNOS, SOD, CAT, and GPx that may lead to an increase in oxidative stress and impaired endothelium-dependent dilation through reduced bioavailability of NO. CAT, catalase; eNOS, endothelial nitric oxide synthase; GPx, glutathione peroxidase; H₂O₂, hydrogen peroxide; LDL, low-density lipoprotein; NO, nitric oxide; O₂ ^•−, superoxide anion; ox-LDL, oxidized low-density lipoprotein.

Along with increased systemic oxidative damage, aging seems to modulate the effects of both enzymatic (e.g., nitric oxide synthase [NOS], superoxide dismutase [SOD], glutathione peroxidase [GP]) and nonenzymatic (e.g., glutathione, α-tocopherol, ascorbic acid, and β-carotene) antioxidant pathways (Liguori et al., 2018; Violi et al., 2017).

The serum activity of some SOD and GP isoforms, indeed, appeared to be reduced in older people, hampering their role in cell growth, leukocyte adhesion, and platelet aggregation inhibition (Fig. 1) (Pastori et al., 2016a; Rizvi et al., 2021; Sonkar et al., 2023). Similarly, the reduced levels of NOS identified in elderly patients may lead to impaired endothelium-dependent dilation through reduced bioavailability of nitric oxide (NO) (Kilic et al., 2015; Tesauro et al., 2017) (Fig. 2).

Even if studies with animal models have reported a relevant role and a positive effect of antioxidants in atherothrombosis, an interventional trial on antioxidant supplementation (e.g., vitamin C and vitamin E) provided inconclusive results and the heterogeneity of data did not allow any sound conclusions (Morelli et al., 2020; Violi et al., 2022).

The serum and urinary levels of some of the abovementioned molecules involved in aging-related oxidative stress are reported in Table 1.

Table 1.

Levels of Some Molecules Involved in Aging-Related Oxidative Stress from Available Human Studies

Molecules	Population	Number of patients	Age, years	Levels
Serum MPO (Scharnagl et al., 2014)	Patients undergoing PCI	3036	>70	35.4 (33.1–37.5) ng/mL
Serum Nox2 (Pastori et al., 2016a)	Patients with atrial fibrillation	909	73.5	10.0 (7.0–20.0) pg/mL
ox-LDL (Gradinaru et al., 2013)	Healthy individuals	88	67.0	20.3 ± 6.8 nmol/l
Serum F₂-isoprostane (LeLeiko et al., 2009)	Patients with acute coronary syndrome	108	66.1	151.2 ± 33.9 pg/mL
Urinary 11-deydro-thromboxane B₂ (Pastori et al., 2016a)	Patients with atrial fibrillation	909	73.5	120.0 (70.0–196.5) ng/mg creatinine
Serum glutathione peroxidase 3 (Pastori et al., 2016a)	Patients with atrial fibrillation	909	73.5	20.0 (10.0–34.0) U/mL
Serum superoxide dismutase (Pastori et al., 2016a)	Patients with atrial fibrillation	909	73.5	2.2 (1.4–3.2) U/mL
Serum eNOS (Kilic et al., 2015)	Healthy individuals	103	73.5	770.8 ± 12.2 pg/mL
Serum glutathione (van Lieshout and Peters, 1998)	Healthy individuals	44	60–80	12.3 ± 0.6 nmol/mg

MPO, myeloperoxidase; NOS, nitric oxide synthase; Nox, nicotinamide adenine dinucleotide phosphate oxidase; ox-LDL, oxidized low-density lipoprotein; PCI, percutaneous coronary intervention.

Other mechanisms involved in aging-related atherothrombosis

Considering that the integrity of the endothelium and maintenance of its functionality are essential to prevent atherogenesis, mechanisms other than oxidative stress may interfere with the vascular physiology and may enhance atherothrombosis (Bockus and Kim, 2022; Donato et al., 2018; Ungvari et al., 2018b).

Blood flow continuously generates mechanical forces on the vessel wall (radial, circumferential, and longitudinal forces) and on the endothelial surface (shear stress), alteration of which may lead to atherosclerotic plaque development (Kwak et al., 2014; Tesauro et al., 2017). For example, it has been demonstrated that high shear stress maintains the physiological properties of the endothelium and that aging-related reduction in shear stress is an independent predictor of atherogenesis (Carallo et al., 2016; Kwak et al., 2014; Zhang et al., 2017).

Aging is also associated with increase in luminal enlargement and wall stiffness, which are probably dependent on enhanced deposition of collagen fibrils, accelerated degradation of elastin, and calcification (Fig. 1) (Donato et al., 2018; Lakatta and Levy, 2003; Najjar et al., 2005).

In this setting, the intima–media thickness that represents a strong surrogate marker of arterial structural changes appeared to progressively increase with age even in populations at low risk of atherosclerosis and appeared to be strongly associated with future cardiovascular events (Li et al., 2003; Lorenz et al., 2007; Virmani et al., 1991). Similarly, pulse wave velocity that measures the velocity of pulse propagation through the arteries is considered a noninvasive index of vascular stiffness and appeared to increase during aging (Huveneers et al., 2015; Liao et al., 1999).

Several studies have shown that chronic, sterile low-grade inflammation characterizes aging, promoting arterial dysfunction and atherothrombosis (Kong et al., 2022; Ungvari et al., 2018a; Wolf and Ley, 2019). Atherosclerotic lesions are sites of immune inflammation in which several types of inflammatory cells (e.g., macrophage, T, dendritic, natural killer, and innate lymphoid cells) are present (Nilsson and Hansson, 2020).

However, LDL accumulation and oxidation within the vessel wall seemed to represent the main trigger for the proinflammatory response (e.g., cytokine production, in situ macrophage proliferation), while the release of other antigens by apoptotic cells seemed to maintain the atherogenic process (Miller et al., 2011; van der Valk et al., 2016).

Recent experimental studies have suggested that gut dysbiosis, possibly through the proatherogenic molecule lipopolysaccharide, may favor arterial inflammation and atherothrombosis (Violi et al., 2023). A pathogenetic gut microbiota, indeed, is more common in patients with symptomatic atherosclerotic lesions (Violi et al., 2023).

Platelet and coagulation cascade activation

Platelets play a relevant role in aging-related atherothrombosis (Montenont et al., 2019). However, several studies have shown that the platelet count may drop approximately by 10% after 70 years of age probably due to a reduction in the hematopoietic stem cell reserve or a shift in the hematopoietic stem cell population toward a megakaryocytic bias (Biino et al., 2013; Montenont et al., 2019; Rossi et al., 2007; Rundberg Nilsson et al., 2016; Segal and Moliterno, 2006; Troussard et al., 2014; Vazquez-Santiago et al., 2016).

The platelet-related increased thrombotic risk of aging, conversely, appeared to be associated with enhanced platelet activity, in which the response to common agonists (e.g., adenosine diphosphate) is higher than in a younger population (Mohebali et al., 2014; Sverdlov et al., 2014). Furthermore, the serum levels of platelet-mediated cytokines (e.g., β-thromboglobulin and platelet factor 4) and metabolites (e.g., thromboxane products) appeared to be higher in patients at risk or with overt atherosclerosis, as well as in older ones (Bastyr et al., 1990; Eikelboom et al., 2008; Pastori et al., 2016b; Reilly and FitzGerald, 1986; Zahavi et al., 1980).

Shorter bleeding time in older compared with younger patients confirms these data even if it should be acknowledged that this test represents both platelet activation and vascular reactivity in vivo (Franchini, 2006; Jorgensen et al., 1980) (Fig. 3).

FIG. 3.

Platelet and clotting activation during the process of aging. Platelet activation and coagulation activation are events that occur during aging as a result of damage to vessel walls. The rupture of atherosclerotic plaque causes coagulation cascade activation through exposition of TF and generation of thrombin, which promotes fibrin production and platelet activation. During aging is observed elevated concentration of some coagulation factors, such as thrombin, FVII, FVIII, and FX, and proaggregating molecules, such as 8-iso-PGF2a and TxB₂. 8-iso-PGF2a, 8-iso-prostaglandin F2 alpha; FVII, factor VII; FVIII, factor VIII; FX, factor X; TF, tissue factor; TxB₂, thromboxane B₂.

Growing evidence supports the role of the coagulation cascade in the atherothrombotic process. Rupture of atherosclerotic plaque is a major cause of coagulation cascade activation through exposition of tissue factor (TF) (Olie et al., 2018; Palmerini et al., 2013). Furthermore, coagulation activation and generation of thrombin not only promote fibrin production and platelet activation but also seem to be involved in atherogenesis, mainly through protease-activated receptor activation (Olie et al., 2018).

Aging may exacerbate these mechanisms as it is associated with increased concentration of some coagulation factors (e.g., factor V, factor VII, factor VIII, factor IX, and fibrinogen), reduction of natural anticoagulants (e.g., antithrombin III, proteins C and S, TF pathway inhibitor), and alterations in the fibrinolytic system activity (Franchini, 2006; Sakkinen et al., 1999) (Fig. 3).

Cardiovascular Risk Management in Elderly Patients

Elderly patients constitute the majority of patients encountered in clinical practice. These patients represent a high-risk subgroup of patients given their high cardiovascular burden and mortality rate. Cardiovascular disease still represents the main cause of death in elderly patients, accounting for ∼40% of all deaths (Fleg et al., 2011).

This increased cardiovascular risk observed in the elderly is likely the result of long-term exposure to some specific risk factors (i.e., raised cholesterol levels, smoking) and the consequence of accumulating comorbidities such as heart failure, hypertension, diabetes, and atrial fibrillation (AF). The latter is particularly important in elderly patients as its incidence rises sharply with age (Roth et al., 2020).

Cardiovascular risk stratification in older people should take into account some specific age-related factors such as life expectancy, quality of life, frailty, comorbidities, polypharmacy (with related drug–drug interactions and side effects), and competing (noncardiovascular) risks (Lettino et al., 2022).

In 2021, the SCORE2-OP tool was proposed to calculate the 5- and 10-year risks of fatal and nonfatal cardiovascular disease events (myocardial infarction and stroke) in adults older than 70 years.

Some previous studies, however, showed some differences in the prognostic role and management of cardiovascular risk factors according to age. As such, the therapeutic target for elderly patients may be different compared with younger ones.

For instance, the systolic blood pressure target for the elderly is set at <140, but not <130 mmHg (Williams et al., 2018). Elderly patients may be at higher risk of drug-induced hypotension with consequent risk of syncope and falls (Rutan et al., 1992), translating into worse quality of life and higher mortality risk (Wiersinga et al., 2022).

Regarding dyslipidemia, administration of statin therapy is recommended to prevent cardiovascular disease, but its benefit seems to be mitigated in elderly patients without evidence of occlusive disease (Cholesterol Treatment Trialists, 2019). A large study on 208,673 Korean participants without cardiovascular disease at baseline and aged ≥60 years found no predictive value for total cholesterol against mortality and cardiovascular events (Yang et al., 2021). However, recent data coming from stroke patients have shown that lack of statin therapy is associated with greater risk of cardiovascular events also in elderly patients (Lefeber et al., 2021).

In addition, for blood glucose control, recommendations from international societies differ between older and younger patients. In elderly patients, glycemic targets and drug regimens need to be adjusted to minimize the risk of hypoglycemic events that are associated with an increased mortality rate. In this context, it may be necessary to simplify complex therapeutic regimens for some patients.

The 2022 American Diabetes Association guidelines recommend a therapeutic goal according to the general health status of patients. Indeed, in healthy patients, a target of glycated hemoglobin (HbA1c) may be maintained, while a value <8% for older patients with complex medical issues is indicated (American Diabetes Association Professional Practice, 2022).

In more complex patients with limited life expectancy, HbA1c should not be considered for drug monitoring, but rather a blood glucose level of 100–200 mg/dL may be satisfactory with monitoring to avoid hypoglycemia (American Diabetes Association Professional Practice, 2022).

Elderly Patients in Cardiovascular Clinical Trials

Despite aging being considered a major risk factor for the incidence of different cardiovascular diseases (Violi et al., 2017), the proportion of elderly patients in major cardiovascular clinical trials performed in the last decade (testing antithrombotic strategies) is generally limited (Rodriguez and Harrington, 2021) (Table 2). These trials tested antiplatelet and anticoagulant drugs alone or in combination for reducing cardiovascular events. These drugs act synergistically by impairing platelet function and inhibiting clotting activation (Fig. 4).

FIG. 4.

Potential therapeutic targets. Platelet activation is amplified by 3 major pathways that are inhibited by oral agents: 1, the COX-1 pathway inhibited by ASA; 2, the ADP-P2Y12 pathway inhibited by clopidogrel, prasugrel, and ticagrelor; and 3, the thrombin pathway. Activity of the thrombin pathway can be inhibited by direct inhibition of thrombin (dabigatran), inhibition of thrombin generation by targeting FXa (apixaban, rivaroxaban, and edoxaban), and inhibition of the platelet protease-activated receptor (PAR)-1 by vorapaxar—a thrombin receptor. ADP, adenosine 5′-diphosphate; ASA, acetylsalicylic acid; FVIIa, factor VIIa; FXa, factor Xa; TxA₂, thromboxane A₂.

Table 2.

Proportion of Elderly Patients and Outcomes in Representative Major Cardiovascular Trials in the Last Decade, 2012–2022

Name of the trial/year	Setting	Mean/median age, years	Definition of elderly	Proportion of elderly (%)	Risk of ischemic/bleeding events in elderly patients
Primary prevention
ASCEND/2018 (Group et al., 2018)	Persons with diabetes. Aspirin versus placebo	63.2	≥70 years	324/7740 aspirin 339/7740 placebo	Rate ratio for cardiovascular events 0.95 (0.81–1.10)
ASPREE/2018 (McNeil et al., 2018a)	Effect of aspirin on all-cause mortality in the healthy elderly		≥74 years	404/9572349/9572	HR 1.15 (1.00–1.33)
ASPREE 2018 (McNeil et al., 2018b)	Effect of aspirin on cardiovascular events and bleeding in the healthy elderly		≥74 years	50%	HR for MACE 0.97 (0.81–1.17)HR for major hemorrhage 1.23 (1.01–1.49)
ARRIVE/2018 (Gaziano et al., 2018)	Aspirin for patients at moderate risk of cardiovascular disease	63.9	≥65 years	5517	HR 1.04 (0.84–1.30)
ACS/CAD
TRILOGY ACS/2012 (Roe et al., 2012)	Prasugrel versus clopidogrel for ACS without revascularization	62–63	≥75 years≥65 years	22.340.2	HR for patients aged ≥65 years for prasugrel versus clopidogrelCardiovascular death, MI, or stroke = 1.02 (0.84–1.24)
ATLAS ACS 2–TIMI 51/2012 (Mega et al., 2012)	Rivaroxaban in patients with recent ACS	61.5–61.8	≥75 years≥65 years	8.5–9.635.5–37.1	HR 0.84 (0.70–1.01) for rivaroxaban versus placebo
ACCOAST/2013 (Montalescot et al., 2013)	Pretreatment with prasugrel in non-ST-segment elevation ACS	63.6–63.8	≥75 years	17.7	HR for prasugrel, 30 mg:Cardiovascular death, MI, stroke, urgent revascularization, or glycoprotein IIb/IIIa inhibitor rescue therapy = 1.20 (0.76–1.88)Bleeding = 2.95 (1.08–8.05)
DAPT/2014 (Mauri et al., 2014)	12 or 30 Months of DAPT after drug-eluting stents	61.6–61.8	≥75 years	10.4	HR for continued thienopyridine versus placebo:Stent thrombosis = 0.23 (0.03–2.06)MACE = 0.95 (0.59–1.52)Bleeding = 1.03 (0.54–1.98)
ATLANTIC/2014 (Montalescot et al., 2014)	Prehospital versus in-hospital ticagrelor in STEMI	60.6–61	≥75 years	15.8–16.8	HR for ticagrelor 0.617 (0.269–1.418) for absence of ST-segment elevation resolution ≥70% pre-PCIBleeding: prehospital (1.3%) versus in hospital (0.8%), p = 0.3208
PEGASUS-TIMI 54/2015 (Bonaca et al., 2015)	Long-term use of ticagrelor in patients with prior MI	65.4	≥75 years	14.6	HR for cardiovascular death, MI, or stroke:Ticagrelor, 60 mg versus placebo = 0.77 (0.59–1.01)Ticagrelor, 90 mg versus placebo = 1.02 (0.80–1.30)For bleeding:Ticagrelor, 60 mg versus placebo = 2.50 (1.25–4.97)Ticagrelor, 90 mg versus placebo = 3.06 (1.56–5.99)
COMPASS/2017 (Eikelboom et al., 2017)	Rivaroxaban with or without aspirin in stable CAD	68.2	≥75 years	20.9	HR for rivaroxaban + aspirin versus aspirin 0.89 (0.69–1.14)
GLOBAL LEADERS/2018 (Vranckx et al., 2018)	Ticagrelor monotherapy for 23 months compared with DAPT after DES implantation	64.5–64.6	>75 years	16.1	HR 0.92 (0.77–1.11) for ticagrelor monotherapy versus DAPT
ISAR-REACT 5 Trial/2019 (Schupke et al., 2019)	Ticagrelor or prasugrel in patients with ACS	64.5	≥75 years	24.4	HR for ticagrelor versus prasugrel 1.19 (0.85–1.66)
TWILIGHT/2019 (Mehran et al., 2019)	Ticagrelor with or without aspirin in high-risk patients after PCI	65	≥65 years	52.2	HR for ticagrelor versus ticagrelor + aspirin 1.02 (0.75–1.40)
TICO/2020 (Kim et al., 2020)	Effect of ticagrelor monotherapy versus ticagrelor with aspirin on major bleeding and cardiovascular events in patients with ACS	61	≥65 years	38.8	HR 0.52 (0.33–0.82) for ticagrelor monotherapy after 3 months of DAPT
Stroke
SOCRATES/2016 (Johnston et al., 2016)	Ticagrelor versus aspirin in acute stroke or transient ischemic attack	65.8–65.9	>75 years	22.7	HR for ticagrelor versus aspirin:Stroke, MI, or death = 1.16 (0.90–1.50)Bleeding = not reported by age
RE-SPECT ESUS/2019 (Diener et al., 2019)	Dabigatran or aspirin for prevention of stroke after embolic stroke of undetermined source	63.9–64.5	≥75 years	19.1	HR for dabigatran versus aspirin:Recurrent stroke = 0.63 (0.43–0.94)Bleeding = 0.75 (0.42–1.35)
NAVIGATE ESUS/2018 (Hart et al., 2018)	Rivaroxaban for stroke prevention after embolic stroke of undetermined source	66.9	≥75 years	20.6	HR for rivaroxaban versus aspirin:First recurrence of ischemic or hemorrhagic stroke or systemic embolism = 0.97 (0.63–1.51)Bleeding = not reported by age
Atrial fibrillation and CAD
PIONEER AF-PCI/2016 (Gibson et al., 2016)	Prevention of bleeding in patients with AF undergoing PCI	70	≥75 years	32.6–35.8	HR for VKA + DAPT versus rivaroxaban 15 mg, + P₂Y₁₂ inhibitor:Bleeding = 0.62 (0.42–0.90)MACE = 1.65 (0.74–3.68)
AFIRE/2019 (Yasuda et al., 2019)	Antithrombotic therapy with rivaroxaban for AF with stable CAD	74.3	≥75 years	52.6	HR for rivaroxaban versus rivaroxaban plus an antiplatelet:Cardiovascular events or death = 0.64 (0.46–0.91)Bleeding = 0.62 (0.36–1.06)
RE-DUAL PCI/2017 (Cannon et al., 2017)	DAPT with dabigatran after PCI in AF	70.8	≥80 y (≥70 years in Japan)	16.8	No significant difference in ischemic or bleeding events.
AUGUSTUS/2019 (Lopes et al., 2019)	Antithrombotic therapy with apixaban after ACS or PCI in AF	70.7	65–80 years≥80 years	57.315.2	HR for apixaban versus VKA in patients ≥80 years:Death or ischemic events = 0.84 (0.53–1.31)Bleeding = 0.85 (0.59–1.21)
ENTRUST-AF PCI/2019 (Vranckx et al., 2019)	Edoxaban versus VKA after successful coronary stenting in patients with AF	69–70	≥75 years	33.6	Not reported by age group

ACS, acute coronary syndrome; AF, atrial fibrillation; CAD, coronary artery disease; DAPT, dual antiplatelet therapy; HR, hazard ratio; MACE, major adverse cardiovascular events; MI, myocardial infarction; STEMI, ST-segment elevation myocardial infarction.

However, the benefit of combination therapy should be balanced against the increased risk of bleeding with this therapeutic approach, which may be particularly challenging in elderly patients. Thus, although antithrombotic therapy has been proven to provide a clear net clinical benefit in elderly patients with established cardiovascular disease, data from studies on primary prevention of cardiovascular events are controversial.

Primary prevention of cardiovascular events

The ASPREE trial randomized healthy elderly subjects to receive either aspirin (9525 subjects) or placebo (9589 subjects). The trial found an increased overall mortality rate in subjects on aspirin than controls, mainly due to cancer-related deaths. This result was evident in the subgroup of elderly subjects (Table 2). An analysis of the same trial showed no difference in the rate of major adverse cardiovascular events, but an increased risk of major bleeding (Table 2).

The ARRIVE trial randomized patients at moderate cardiovascular risk to receive either placebo or aspirin for prevention of a first vascular event. The aspirin treatment was not superior to placebo in the elderly patients (Table 2), but in the safety analysis, the risk of gastrointestinal bleeding was doubled in the group of patients treated with aspirin compared with placebo (HR 2.11, 95% CI: 1.36–3.28; p = 0.0007). No data on the subgroup of elderly patients were provided.

In the ASCEND trial, 15,480 patients with diabetes and no cardiovascular disease at baseline were randomized to receive either placebo or aspirin. In the overall population, aspirin lowered the risk of cardiovascular events, but increased the risk of bleeding (rate ratio 0.88; 95% CI: 0.79–0.97; p = 0.01; and 1.29; 95% CI: 1.09–1.52; p = 0.003). In the subgroup of elderly patients, the effect on cardiovascular events was not statistically significant (Table 2).

Altogether, these data do not indicate a clear benefit of routine antithrombotic treatment in elderly patients for primary prevention of cardiovascular events.

Acute coronary syndrome/coronary artery disease

In clinical trial on patients with acute coronary syndrome (ACS) testing different antiplatelet drugs or different lengths of combination therapy, the proportion of patients aged 75 years or older was generally low (Table 2).

In 2014, the dual antiplatelet therapy (DAPT) trial found no significant reduction in cardiovascular events in the subgroup of elderly patients assigned to prolonged DAPT with thienopyridines. The more recent TICO study (2020) found a reduction in bleeding events with ticagrelor monotherapy compared with ticagrelor plus aspirin after 3 months of DAPT in the subgroup of patients aged 65 years or older (Table 2).

Two studies, ATLANTIC and ACCOAST, evaluated pretreatment with ticagrelor and prasugrel in patients with ACS. No difference in reduction of ischemic endpoints was found in the group of elderly patients, but excess bleeding was found for prasugrel in non-ST-elevation myocardial infarction ACS (Table 2).

In general, studies comparing different antiplatelet drugs did not reveal a clear advantage in using any of them in terms of bleeding prevention or cardiovascular event reduction.

Based on this, the European Society of Cardiology Working Group on Thrombosis recommends that patients (aged ≥75 years) treated with percutaneous coronary intervention (PCI) for ACS should be given reduced doses of prasugrel (i.e., 5 mg daily) or clopidogrel. In addition, DAPT should be limited to 12 months and be reduced depending on the bleeding risk (Andreotti et al., 2023).

Furthermore, pretreatment with P₂Y₁₂ inhibitors (unless in cases of ST-elevation myocardial infarction) could be avoided, and the use of single antiplatelet therapy (e.g., aspirin, clopidogrel, ticagrelor) after 1–3 months of DAPT should be considered to reduce bleeding risk (Andreotti et al., 2023).

Stroke prevention in patients without AF

In the last decade, three major trials tested antiplatelet and anticoagulant drugs in patients with stroke (Table 2). The SOCRATES study randomized patients with acute non-severe ischemic stroke or high-risk transient ischemic attack to receive either high-potency ticagrelor or aspirin treatment. In the subgroup of elderly patients, the two antiplatelet regimens were similar regarding the risk of occurrence of stroke, myocardial infarction, or death (Table 2).

Two trials tested the anticoagulant therapy with direct oral anticoagulants (DOACs) for secondary prevention after embolic stroke of undetermined source. In the RE-SPECT ESUS trial, dabigatran was not superior to aspirin in the overall analysis in terms of recurrent stroke risk. However, the subgroup analysis of the elderly showed a favorable effect of dabigatran, with reduction in recurrent stroke and a similar bleeding risk (Table 2).

In the NAVIGATE ESUS trial, rivaroxaban was compared with aspirin in patients with embolic stroke of undetermined source. The study found that rivaroxaban was not superior to aspirin for stroke prevention in the overall analysis and also in the subgroup of elderly patients. The risk of bleeding was increased in the whole cohort, but no data on the subgroup of the elderly were reported (Table 2).

Anticoagulant therapy in elderly patients with AF

Anticoagulant therapy is generally underused in elderly patients with AF, especially in very old ones or in those with previous stroke or major bleeding (Munir et al., 2023). Several studies have consistently demonstrated a net clinical benefit of DOACs compared with vitamin K antagonists (VKAs) in elderly patients (Shah et al., 2019), with apixaban being associated with a lower risk of major bleeding in elderly patients with AF (Rutherford et al., 2022). A more challenging clinical scenario is represented by patients with AF experiencing ACS undergoing PCI, for whom combination therapy with anticoagulant and antiplatelet drugs is needed.

Two studies tested the safety and efficacy of rivaroxaban in patients with AF and coronary artery disease (CAD). In the subgroup of patients aged ≥75 years included in the AFIRE trial, rivaroxaban reduced ischemic events with a similar bleeding risk (Table 2).

In the PIONEER-AF trial, patients with AF undergoing PCI were randomized to receive either VKAs plus DAPT or rivaroxaban (15 mg once daily) plus a P₂Y₁₂ inhibitor. The study found a similar risk of ischemic events with lower bleeding risk in the group of elderly patients receiving rivaroxaban (Table 2).

In addition, using dabigatran in the REDUAL-PCI trial and apixaban in the AUGUSTUS trial, a subgroup analysis on elderly patients reported similar bleeding and ischemic risks between DOACs and VKAs (Table 2).

Conclusions

Several pathophysiological mechanisms contribute to the age-related thrombotic risk, including oxidative stress, endothelial dysfunction, low-grade inflammation, and platelet activation. Routine antiplatelet treatment should not be prescribed for primary prevention of cardiovascular events.

In older patients with ACS/CAD and without AF, strategies to reduce bleeding risk may include the use of low-dose prasugrel or clopidogrel, reduction in the length of DAPT, and no pretreatment before PCI. In elderly patients with embolic stroke of undetermined source, dabigatran was associated with lower risk of recurrent stroke.

Advanced age should not be a reason for the underuse of oral anticoagulation in patients with AF, and DOACs are generally preferred over VKAs, also in patients undergoing PCI, in whom dual antithrombotic therapy with rivaroxaban reduced bleeding risk in the subgroup of elderly patients.

In conclusion, older adults are underrepresented in cardiovascular clinical trials, and antithrombotic therapy in elderly patients should be tailored to balance ischemic and bleeding risk.

Footnotes

Authors' Contributions

E.V., P.P., and D.P. were involved in conceptualization (lead), writing—original draft (lead), and writing—review and editing (lead); and S.B. was involved in writing—original draft (supporting), and writing—review and editing (lead).

Author Disclosure Statement

No competing financial interests exist.

Funding Information

No funding was received for this article.

Abbreviations Used

References

American Diabetes Association Professional Practice

. 13. Older Adults: Standards of Medical Care in Diabetes-2022. Diabetes care, 2022; 45(Suppl 1):S195–S207; doi: 10.2337/dc22-S013

Andreotti

, Geisler

, Collet

, et al. Acute, periprocedural and longterm antithrombotic therapy in older adults: 2022 Update by the ESC Working Group on Thrombosis. Eur Heart J, 2023; 44(4):262–279; doi: 10.1093/eurheartj/ehac515

Aureli

, Loberto

, Lanteri

, et al. Cell surface sphingolipid glycohydrolases in neuronal differentiation and aging in culture. J Neurochem, 2011; 116(5):891–899; doi: 10.1111/j.1471-4159.2010.07019.x

Azumi

, Inoue

, Takeshita

, et al. Expression of NADH/NADPH oxidase p22phox in human coronary arteries. Circulation, 1999; 100(14):1494–1498; doi: 10.1161/01.cir.100.14.1494

Bastyr

, 3rd, Kadrofske

, Vinik

. Platelet activity and phosphoinositide turnover increase with advancing age. Am J Med, 1990; 88(6):601–606; doi: 10.1016/0002-9343(90)90525-i

Biino

, Santimone

, Minelli

, et al. Age- and sex-related variations in platelet count in Italy: A proposal of reference ranges based on 40987 subjects' data. PLoS One, 2013; 8(1):e54289; doi: 10.1371/journal.pone.0054289

Bockus

, Kim

. Coronary endothelial dysfunction: From pathogenesis to clinical implications. Open Heart, 2022; 9(2):e002200; doi: 10.1136/openhrt-2022-002200

Bonaca

, Bhatt

, Cohen

, et al. Long-term use of ticagrelor in patients with prior myocardial infarction. N Engl J Med, 2015; 372(19):1791–1800; doi: 10.1056/NEJMoa1500857

Cannon

, Bhatt

, Oldgren

, et al. Dual antithrombotic therapy with dabigatran after PCI in atrial fibrillation. N Engl J Med, 2017; 377(16):1513–1524; doi: 10.1056/NEJMoa1708454

10.

Carallo

, Tripolino

, De Franceschi

, et al. Carotid endothelial shear stress reduction with aging is associated with plaque development in twelve years. Atherosclerosis, 2016; 251:63–69; doi: 10.1016/j.atherosclerosis.2016.05.048

11.

Chen

, Tumanov

, Kong

SMY

, et al. Therapeutic inhibition of MPO stabilizes pre-existing high risk atherosclerotic plaque. Redox Biol, 2022; 58:102532; doi: 10.1016/j.redox.2022.102532

12.

Cheng

, Talib

, Stanley

, et al. Inhibition of MPO (Myeloperoxidase) attenuates endothelial dysfunction in mouse models of vascular inflammation and atherosclerosis. Arterioscler Thromb Vasc Biol, 2019; 39(7):1448–1457; doi: 10.1161/ATVBAHA.119.312725

13.

Cholesterol Treatment Trialists

. Efficacy and safety of statin therapy in older people: A meta-analysis of individual participant data from 28 randomised controlled trials. Lancet, 2019; 393(10170):407–415; doi: 10.1016/S0140-6736(18)31942-1

14.

Demina

, Smutova

, Pan

, et al. Neuraminidases 1 and 3 trigger atherosclerosis by desialylating low-density lipoproteins and increasing their uptake by macrophages. J Am Heart Assoc, 2021; 10(4):e018756; doi: 10.1161/JAHA.120.018756

15.

Diener

, Sacco

, Easton

, et al. Dabigatran for prevention of stroke after embolic stroke of undetermined source. N Engl J Med, 2019; 380(20):1906–1917; doi: 10.1056/NEJMoa1813959

16.

Dobrian

, Lieb

, Cole

, et al. Functional and pathological roles of the 12- and 15-lipoxygenases. Prog Lipid Res, 2011; 50(1):115–131; doi: 10.1016/j.plipres.2010.10.005

17.

Donato

, Machin

, Lesniewski

. Mechanisms of dysfunction in the aging vasculature and role in age-related disease. Circ Res, 2018; 123(7):825–848; doi: 10.1161/CIRCRESAHA.118.312563

18.

Douglas

, Bendall

, Crabtree

, et al. Endothelial-specific Nox2 overexpression increases vascular superoxide and macrophage recruitment in ApoE(−)/(−) mice. Cardiovasc Res, 2012; 94(1):20–29; doi: 10.1093/cvr/cvs026

19.

Eikelboom

, Connolly

, Bosch

, et al. Rivaroxaban with or without Aspirin in stable cardiovascular disease. N Engl J Med, 2017; 377(14):1319–1330; doi: 10.1056/NEJMoa1709118

20.

Eikelboom

, Hankey

, Thom

, et al. Incomplete inhibition of thromboxane biosynthesis by acetylsalicylic acid: Determinants and effect on cardiovascular risk. Circulation, 2008; 118(17):1705–1712; doi: 10.1161/CIRCULATIONAHA.108.768283

21.

Fleg

, Aronow

, Frishman

. Cardiovascular drug therapy in the elderly: Benefits and challenges. Nat Rev Cardiol, 2011; 8(1):13–28; doi: 10.1038/nrcardio.2010.162

22.

Fogelstrand

, Boren

. Retention of atherogenic lipoproteins in the artery wall and its role in atherogenesis. Nutr Metab Cardiovasc Dis, 2012; 22(1):1–7; doi: 10.1016/j.numecd.2011.09.007

23.

Franchini

. Hemostasis and aging. Crit Rev Oncol Hematol, 2006; 60(2):144–151; doi: 10.1016/j.critrevonc.2006.06.004

24.

Funk

, Chen

, Johnson

, et al. Lipoxygenase genes and their targeted disruption. Prostaglandins Other Lipid Mediat, 2002; 68–69:303–312; doi: 10.1016/s0090-6980(02)00036-9

25.

Gaziano

, Brotons

, Coppolecchia

, et al. 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. Lancet, 2018; 392(10152):1036–1046; doi: 10.1016/S0140-6736(18)31924-X

26.

Genestra

. Oxyl radicals, redox-sensitive signalling cascades and antioxidants. Cell Signal, 2007; 19(9):1807–1819; doi: 10.1016/j.cellsig.2007.04.009

27.

Gibson

, Mehran

, Bode

, et al. Prevention of bleeding in patients with atrial fibrillation undergoing PCI. N Engl J Med, 2016; 375(25):2423–2434; doi: 10.1056/NEJMoa1611594

28.

Goldschmidt-Clermont

, Creager

, Losordo

, et al. Atherosclerosis 2005: Recent discoveries and novel hypotheses. Circulation, 2005; 112(21):3348–3353; doi: 10.1161/CIRCULATIONAHA.105.577460

29.

Gradinaru

, Borsa

, Ionescu

, et al. Advanced oxidative and glycoxidative protein damage markers in the elderly with type 2 diabetes. J Proteomics, 2013; 92:313–322; doi: 10.1016/j.jprot.2013.03.034

30.

Group

ASC

, Bowman

, Mafham

, et al. Effects of aspirin for primary prevention in persons with diabetes mellitus. N Engl J Med, 2018; 379(16):1529–1539; doi: 10.1056/NEJMoa1804988

31.

Guzik

, Sadowski

, Guzik

, et al. Coronary artery superoxide production and nox isoform expression in human coronary artery disease. Arterioscler Thromb Vasc Biol, 2006; 26(2):333–339; doi: 10.1161/01.ATV.0000196651.64776.51

32.

Hart

, Sharma

, Mundl

, et al. Rivaroxaban for stroke prevention after embolic stroke of undetermined source. N Engl J Med, 2018; 378(23):2191–2201; doi: 10.1056/NEJMoa1802686

33.

Hoy

, Tregouet

, Leininger-Muller

, et al. Serum myeloperoxidase concentration in a healthy population: Biological variations, familial resemblance and new genetic polymorphisms. Eur J Hum Genet, 2001; 9(10):780–786; doi: 10.1038/sj.ejhg.5200702

34.

Huveneers

, Daemen

, Hordijk

. Between Rho(k) and a hard place: The relation between vessel wall stiffness, endothelial contractility, and cardiovascular disease. Circ Res, 2015; 116(5):895–908; doi: 10.1161/CIRCRESAHA.116.305720

35.

Iuliano

, Mauriello

, Sbarigia

, et al. Radiolabeled native low-density lipoprotein injected into patients with carotid stenosis accumulates in macrophages of atherosclerotic plaque: Effect of vitamin E supplementation. Circulation, 2000; 101(11):1249–1254; doi: 10.1161/01.cir.101.11.1249

36.

Johnston

, Amarenco

, Albers

, et al. Ticagrelor versus aspirin in acute stroke or transient ischemic attack. N Engl J Med, 2016; 375(1):35–43; doi: 10.1056/NEJMoa1603060

37.

Jorgensen

, Dyerberg

, Olesen

, et al. Acetylsalicylic acid, bleeding time and age. Thromb Res, 1980; 19(6):799–805; doi: 10.1016/0049-3848(80)90007-9

38.

Karra

, Vemullapalli

, Dong

, et al. Molecular evidence for arterial repair in atherosclerosis. Proc Natl Acad Sci U S A, 2005; 102(46):16789–16794; doi: 10.1073/pnas.0507718102

39.

Kilic

, Gok

, Erenberk

, et al. A remarkable age-related increase in SIRT1 protein expression against oxidative stress in elderly: SIRT1 gene variants and longevity in human. PLoS One, 2015; 10(3):e0117954; doi: 10.1371/journal.pone.0117954

40.

Kim

, Hong

, Cho

, et al. Effect of ticagrelor monotherapy vs ticagrelor with aspirin on major bleeding and cardiovascular events in patients with acute coronary syndrome: The TICO Randomized Clinical Trial. JAMA, 2020; 323(23):2407–2416; doi: 10.1001/jama.2020.7580

41.

Kong

, Cui

, Huang

, et al. Inflammation and atherosclerosis: Signaling pathways and therapeutic intervention. Signal Transduct Target Ther, 2022; 7(1):131; doi: 10.1038/s41392-022-00955-7

42.

Kwak

, Back

, Bochaton-Piallat

, et al. Biomechanical factors in atherosclerosis: Mechanisms and clinical implications. Eur Heart J, 2014; 35(43):3013–3020, 3020a–3020d; doi: 10.1093/eurheartj/ehu353

43.

Lakatta

, Levy

. Arterial and cardiac aging: Major shareholders in cardiovascular disease enterprises: Part I: aging arteries: A “set up” for vascular disease. Circulation, 2003; 107(1):139–146; doi: 10.1161/01.cir.0000048892.83521.58

44.

Lee

, Hong

, Palmerini

, et al. Short-term versus long-term dual antiplatelet therapy after drug-eluting stent implantation in elderly patients: A meta-analysis of individual participant data from 6 randomized trials. JACC Cardiovasc Interv, 2018; 11(5):435–443; doi: 10.1016/j.jcin.2017.10.015

45.

Lefeber

, Knol

, Souverein

, et al. Statins after ischemic stroke in the oldest: A Cohort Study Using the Clinical Practice Research Datalink Database. Stroke, 2021; 52(4):1244–1252; doi: 10.1161/STROKEAHA.120.030755

46.

LeLeiko

, Vaccari

, Sola

, et al. Usefulness of elevations in serum choline and free F2)-isoprostane to predict 30-day cardiovascular outcomes in patients with acute coronary syndrome. Am J Cardiol, 2009; 104(5):638–643; doi: 10.1016/j.amjcard.2009.04.047

47.

Lettino

, Mascherbauer

, Nordaby

, et al. Cardiovascular disease in the elderly: Proceedings of the European Society of Cardiology-Cardiovascular Round Table. Eur J Prevent Cardiol, 2022; 29(10):1412–1424; doi: 10.1093/eurjpc/zwac033

48.

, Chen

, Srinivasan

, et al. Childhood cardiovascular risk factors and carotid vascular changes in adulthood: The Bogalusa Heart Study. JAMA, 2003; 290(17):2271–2276; doi: 10.1001/jama.290.17.2271

49.

Liao

, Arnett

, Tyroler

, et al. Arterial stiffness and the development of hypertension. The ARIC study. Hypertension, 1999; 34(2):201–206; doi: 10.1161/01.hyp.34.2.201

50.

Liguori

, Russo

, Curcio

, et al. Oxidative stress, aging, and diseases. Clin Interv Aging, 2018; 13:757–772; doi: 10.2147/CIA.S158513

51.

Liu

, Davidson

, Yue

, et al. Molecular imaging of inflammation and platelet adhesion in advanced atherosclerosis effects of antioxidant therapy with NADPH oxidase inhibition. Circ Cardiovasc Imaging, 2013; 6(1):74–82; doi: 10.1161/CIRCIMAGING.112.975193

52.

Lopes

, Heizer

, Aronson

, et al. Antithrombotic therapy after acute coronary syndrome or PCI in atrial fibrillation. N Engl J Med, 2019; 380(16):1509–1524; doi: 10.1056/NEJMoa1817083

53.

Lorenz

, Markus

, Bots

, et al. Prediction of clinical cardiovascular events with carotid intima-media thickness: A systematic review and meta-analysis. Circulation, 2007; 115(4):459–467; doi: 10.1161/CIRCULATIONAHA.106.628875

54.

Lozhkin

, Vendrov

, Pan

, et al. NADPH oxidase 4 regulates vascular inflammation in aging and atherosclerosis. J Mol Cell Cardiol, 2017; 102:10–21; doi: 10.1016/j.yjmcc.2016.12.004

55.

Mauri

, Kereiakes

, Yeh

, et al. Twelve or 30 months of dual antiplatelet therapy after drug-eluting stents. N Engl J Med, 2014; 371(23):2155–2166; doi: 10.1056/NEJMoa1409312

56.

McNeil

, Nelson

, Woods

, et al. Effect of aspirin on all-cause mortality in the healthy elderly. N Engl J Med, 2018a;379(16):1519–1528; doi: 10.1056/NEJMoa1803955

57.

McNeil

, Wolfe

, Woods

, et al. Effect of aspirin on cardiovascular events and bleeding in the healthy elderly. N Engl J Med, 2018b;379(16):1509–1518; doi: 10.1056/NEJMoa1805819

58.

Mega

, Braunwald

, Wiviott

, et al. Rivaroxaban in patients with a recent acute coronary syndrome. N Engl J Med, 2012; 366(1):9–19; doi: 10.1056/NEJMoa1112277.

59.

Mehran

, Baber

, Sharma

, et al. Ticagrelor with or without Aspirin in high-risk patients after PCI. N Engl J Med, 2019; 381(21):2032–2042; doi: 10.1056/NEJMoa1908419

60.

Mezentsev

, Bezsonov

, Kashirskikh

, et al. Proatherogenic sialidases and desialylated lipoproteins: 35 years of research and current state from bench to bedside. Biomedicines, 2021; 9(6):600; doi: 10.3390/biomedicines9060600

61.

Miller

, Choi

, Wiesner

, et al. Oxidation-specific epitopes are danger-associated molecular patterns recognized by pattern recognition receptors of innate immunity. Circ Res, 2011; 108(2):235–248; doi: 10.1161/CIRCRESAHA.110.223875

62.

Mohebali

, Kaplan

, Carlisle

, et al. Alterations in platelet function during aging: Clinical correlations with thromboinflammatory disease in older adults. J Am Geriatr Soc, 2014; 62(3):529–535; doi: 10.1111/jgs.12700

63.

Montalescot

, Bolognese

, Dudek

, et al. Pretreatment with prasugrel in non-ST-segment elevation acute coronary syndromes. N Engl J Med, 2013; 369(11):999–1010; doi: 10.1056/NEJMoa1308075

64.

Montalescot

, van ‘t Hof

, Lapostolle

, et al. Prehospital ticagrelor in ST-segment elevation myocardial infarction. N Engl J Med, 2014; 371(11):1016–1027; doi: 10.1056/NEJMoa1407024

65.

Montenont

, Rondina

, Campbell

. Altered functions of platelets during aging. Curr Opin Hematol, 2019; 26(5):336–342; doi: 10.1097/MOH.0000000000000526

66.

Morelli

, Gambardella

, Castellanos

, et al. Vitamin C and cardiovascular disease: An Update. Antioxidants (Basel), 2020; 9(12):1227; doi: 10.3390/antiox9121227

67.

Moudallel

, Steurbaut

, Cornu

, et al. Appropriateness of DOAC prescribing before and during hospital admission and analysis of determinants for inappropriate prescribing. Front Pharmacol, 2018; 9:1220; doi: 10.3389/fphar.2018.01220

68.

Munir

, Hlavacek

, Keshishian

, et al. Oral anticoagulant underutilization among elderly patients with atrial fibrillation: Insights from the United States Medicare database. J Interv Card Electrophysiol, 2023; 66(3):771–782; doi: 10.1007/s10840-022-01274-1

69.

Najjar

, Scuteri

, Lakatta

. Arterial aging: Is it an immutable cardiovascular risk factor?. Hypertension, 2005; 46(3):454–462; doi: 10.1161/01.HYP.0000177474.06749.98

70.

Ndrepepa

. Myeloperoxidase-A bridge linking inflammation and oxidative stress with cardiovascular disease. Clin Chim Acta, 2019; 493:36–51; doi: 10.1016/j.cca.2019.02.022

71.

Nilsson

, Hansson

. Vaccination strategies and immune modulation of atherosclerosis. Circ Res, 2020; 126(9):1281–1296; doi: 10.1161/CIRCRESAHA.120.315942

72.

Olie

, van der Meijden

PEJ

, Ten Cate

. The coagulation system in atherothrombosis: Implications for new therapeutic strategies. Res Pract Thromb Haemost, 2018; 2(2):188–198; doi: 10.1002/rth2.12080

73.

Palmerini

, Tomasi

, Barozzi

, et al. Detection of tissue factor antigen and coagulation activity in coronary artery thrombi isolated from patients with ST-segment elevation acute myocardial infarction. PLoS One, 2013; 8(12):e81501; doi: 10.1371/journal.pone.0081501

74.

Pastori

, Pignatelli

, Farcomeni

, et al. Aging-related decline of glutathione peroxidase 3 and risk of cardiovascular events in patients with atrial fibrillation. J Am Heart Assoc, 2016a;5(9):e003682; doi: 10.1161/JAHA.116.003682

75.

Pastori

, Pignatelli

, Farcomeni

, et al. Age-related increase of thromboxane B2 and risk of cardiovascular disease in atrial fibrillation. Oncotarget, 2016b;7(26):39143–39147; doi: 10.18632/oncotarget.9826

76.

Poznyak

, Nikiforov

, Markin

, et al. Overview of OxLDL and its impact on cardiovascular health: Focus on atherosclerosis. Front Pharmacol, 2020; 11:613780; doi: 10.3389/fphar.2020.613780

77.

Quesada

, Lucero

, Amaya

, et al. Selective inactivation of NADPH oxidase 2 causes regression of vascularization and the size and stability of atherosclerotic plaques. Atherosclerosis, 2015; 242(2):469–475; doi: 10.1016/j.atherosclerosis.2015.08.011

78.

Reilly

, FitzGerald

. Eicosenoid biosynthesis and platelet function with advancing age. Thromb Res, 1986; 41(4):545–554; doi: 10.1016/0049-3848(86)91700-7

79.

Rizvi

, Preston

, Emelyanova

, et al. Effects of aging on cardiac oxidative stress and transcriptional changes in pathways of reactive oxygen species generation and clearance. J Am Heart Assoc, 2021; 10(16):e019948; doi: 10.1161/JAHA.120.019948

80.

Rodriguez

, Harrington

. Management of antithrombotic therapy after acute coronary syndromes. N Engl J Med, 2021; 384(5):452–460; doi: 10.1056/NEJMra1607714

81.

Roe

, Armstrong

, Fox

, et al. Prasugrel versus clopidogrel for acute coronary syndromes without revascularization. N Engl J Med, 2012; 367(14):1297–1309; doi: 10.1056/NEJMoa1205512

82.

Rossi

, Bryder

, Seita

, et al. Deficiencies in DNA damage repair limit the function of haematopoietic stem cells with age. Nature, 2007; 447(7145):725–729; doi: 10.1038/nature05862

83.

Roth Flach

, Su

, Bollinger

, et al. Myeloperoxidase inhibition in mice alters atherosclerotic lesion composition. PLoS One, 2019; 14(3):e0214150; doi: 10.1371/journal.pone.0214150

84.

Roth

, Mensah

, Johnson

, et al. Global Burden of Cardiovascular Diseases and Risk Factors, 1990–2019: Update From the GBD 2019 Study. J Am Coll Cardiol, 2020; 76(25):2982–3021; doi: 10.1016/j.jacc.2020.11.010

85.

Rundberg Nilsson

, Soneji

, Adolfsson

, et al. Human and murine hematopoietic stem cell aging is associated with functional impairments and intrinsic megakaryocytic/erythroid bias. PLoS One, 2016; 11(7):e0158369; doi: 10.1371/journal.pone.0158369

86.

Rutan

, Hermanson

, Bild

, et al. Orthostatic hypotension in older adults. The Cardiovascular Health Study. CHS Collaborative Research Group. Hypertension, 1992; 19(6 Pt 1):508–519; doi: 10.1161/01.hyp.19.6.508

87.

Rutherford

, Jonasson

, Ghanima

, et al. Effectiveness and safety of oral anticoagulants in elderly patients with atrial fibrillation. Heart, 2022; 108(5):345–352; doi: 10.1136/heartjnl-2020-318753

88.

Sakkinen

, Cushman

, Psaty

, et al. Relationship of plasmin generation to cardiovascular disease risk factors in elderly men and women. Arterioscler Thromb Vasc Biol, 1999; 19(3):499–504; doi: 10.1161/01.atv.19.3.499

89.

Salisbury

, Bronas

. Reactive oxygen and nitrogen species: Impact on endothelial dysfunction. Nurs Res, 2015; 64(1):53–66; doi: 10.1097/NNR.0000000000000068

90.

Scharnagl

, Kleber

, Genser

, et al. Association of myeloperoxidase with total and cardiovascular mortality in individuals undergoing coronary angiography—the LURIC study. Int J Cardiol, 2014; 174(1):96–105; doi: 10.1016/j.ijcard.2014.03.168

91.

Schupke

, Neumann

, Menichelli

, et al. Ticagrelor or prasugrel in patients with acute coronary syndromes. N Engl J Med, 2019; 381(16):1524–1534; doi: 10.1056/NEJMoa1908973

92.

Segal

, Moliterno

. Platelet counts differ by sex, ethnicity, and age in the United States. Ann Epidemiol, 2006; 16(2):123–130; doi: 10.1016/j.annepidem.2005.06.052

93.

Shah

, Singer

, Fang

, et al. Net clinical benefit of oral anticoagulation among older adults with atrial fibrillation. Circ Cardiovasc Qual Outcomes, 2019; 12(11):e006212; doi: 10.1161/CIRCOUTCOMES.119.006212

94.

Singh

, Bajorek

. Defining ‘elderly’ in clinical practice guidelines for pharmacotherapy. Pharm Pract (Granada), 2014; 12(4):489; doi: 10.4321/s1886-36552014000400007

95.

Sonkar

, Eustes

, Ahmed

, et al. Endogenous SOD2 (Superoxide Dismutase) regulates platelet-dependent thrombin generation and thrombosis during aging. Arterioscler Thromb Vasc Biol, 2023; 43(1):79–91; doi: 10.1161/ATVBAHA.121.317735

96.

Sverdlov

, Ngo

, Chan

, et al. Aging of the nitric oxide system: Are we as old as our NO?. J Am Heart Assoc, 2014; 3(4):e000973; doi: 10.1161/JAHA.114.000973

97.

Tabas

. 2016 Russell ross memorial lecture in vascular biology: Molecular-cellular mechanisms in the progression of atherosclerosis. Arterioscler Thromb Vasc Biol, 2017; 37(2):183–189; doi: 10.1161/ATVBAHA.116.308036

98.

Tesauro

, Mauriello

, Rovella

, et al. Arterial ageing: From endothelial dysfunction to vascular calcification. J Intern Med, 2017; 281(5):471–482; doi: 10.1111/joim.12605

99.

Troussard

, Vol

, Cornet

, et al. Full blood count normal reference values for adults in France. J Clin Pathol, 2014; 67(4):341–344; doi: 10.1136/jclinpath-2013-201687

100.

Turgeon

, Haddad

, Dussault

, et al. Protection against vascular aging in Nox2-deficient mice: Impact on endothelial progenitor cells and reparative neovascularization. Atherosclerosis, 2012; 223(1):122–129; doi: 10.1016/j.atherosclerosis.2012.05.003

101.

Ungvari

, Tarantini

, Donato

, et al. Mechanisms of vascular aging. Circ Res, 2018a;123(7):849–867; doi: 10.1161/CIRCRESAHA.118.311378

102.

Ungvari

, Tarantini

, Kiss

, et al. Endothelial dysfunction and angiogenesis impairment in the ageing vasculature. Nat Rev Cardiol, 2018b;15(9):555–565; doi: 10.1038/s41569-018-0030-z

103.

van der Valk

, Bekkering

, Kroon

, et al. Oxidized phospholipids on lipoprotein(a) elicit arterial wall inflammation and an inflammatory monocyte response in humans. Circulation, 2016; 134(8):611–624; doi: 10.1161/CIRCULATIONAHA.116.020838

104.

van Lieshout

, Peters

. Age and gender dependent levels of glutathione and glutathione S-transferases in human lymphocytes. Carcinogenesis, 1998; 19(10):1873–1875; doi: 10.1093/carcin/19.10.1873

105.

Vazquez-Santiago

, Ziyatdinov

, Pujol-Moix

, et al. Age and gender effects on 15 platelet phenotypes in a Spanish population. Comput Biol Med, 2016; 69:226–233; doi: 10.1016/j.compbiomed.2015.12.023

106.

Vendrov

, Vendrov

, Smith

, et al. NOX4 NADPH oxidase-dependent mitochondrial oxidative stress in aging-associated cardiovascular disease. Antioxid Redox Signal, 2015; 23(18):1389–1409; doi: 10.1089/ars.2014.6221

107.

Violi

, Cammisotto

, Bartimoccia

, et al. Gut-derived low-grade endotoxaemia, atherothrombosis and cardiovascular disease. Nat Rev Cardiol, 2023; 20(1):24–37; doi: 10.1038/s41569-022-00737-2

108.

Violi

, Loffredo

, Carnevale

, et al. Atherothrombosis and oxidative stress: Mechanisms and management in elderly. Antioxid Redox Signal, 2017; 27(14):1083–1124; doi: 10.1089/ars.2016.6963

109.

Violi

, Nocella

, Loffredo

, et al. Interventional study with vitamin E in cardiovascular disease and meta-analysis. Free Radic Biol Med, 2022; 178:26–41; doi: 10.1016/j.freeradbiomed.2021.11.027

110.

Virmani

, Avolio

, Mergner

, et al. Effect of aging on aortic morphology in populations with high and low prevalence of hypertension and atherosclerosis. Comparison between occidental and Chinese communities. Am J Pathol, 1991; 139(5):1119–1129.

111.

Vranckx

, Valgimigli

, Eckardt

, et al. Edoxaban-based versus vitamin K antagonist-based antithrombotic regimen after successful coronary stenting in patients with atrial fibrillation (ENTRUST-AF PCI): A randomised, open-label, phase 3b trial. Lancet, 2019; 394(10206):1335–1343; doi: 10.1016/S0140-6736(19)31872-0.

112.

Vranckx

, Valgimigli

, Juni

, et al. Ticagrelor plus aspirin for 1 month, followed by ticagrelor monotherapy for 23 months vs aspirin plus clopidogrel or ticagrelor for 12 months, followed by aspirin monotherapy for 12 months after implantation of a drug-eluting stent: A multicentre, open-label, randomised superiority trial. Lancet, 2018; 392(10151):940–949; doi: 10.1016/S0140-6736(18)31858-0

113.

Wiersinga

JHI

, Muller

, Rhodius-Meester

HFM

, et al. Orthostatic hypotension and mortality risk in geriatric outpatients: The impact of duration and magnitude of the blood pressure drop. J Hypertens, 2022; 40(6):1107–1114; doi: 10.1097/HJH.0000000000003097

114.

Williams

, Mancia

, Spiering

, et al. 2018 ESC/ESH Guidelines for the management of arterial hypertension. Eur Heart J, 2018; 39(33):3021–3104; doi: 10.1093/eurheartj/ehy339

115.

Wolf

, Ley

. Immunity and inflammation in atherosclerosis. Circ Res, 2019; 124(2):315–327; doi: 10.1161/CIRCRESAHA.118.313591

116.

Yang

, Jang

, Yu

, et al. Changes in cardiovascular risk factors and cardiovascular events in the elderly population. J Am Heart Assoc, 2021; 10(11):e019482; doi: 10.1161/JAHA.120.019482

117.

Yasuda

, Kaikita

, Akao

, et al. Antithrombotic therapy for atrial fibrillation with stable coronary disease. N Engl J Med, 2019; 381(12):1103–1113; doi: 10.1056/NEJMoa1904143

118.

Zahavi

, Jones

, Leyton

, et al. Enhanced in vivo platelet “release reaction” in old healthy individuals. Thromb Res, 1980; 17(3–4):329–336; doi: 10.1016/0049-3848(80)90067-5

119.

Zhang

, Gu

, Qian

, et al. Correlation between quantitative analysis of wall shear stress and intima-media thickness in atherosclerosis development in carotid arteries. Biomed Eng Online, 2017; 16(1):137; doi: 10.1186/s12938-017-0425-9