Aging modifies some characteristics of atrial structure, facilitating the development of AF and increasing the risk of cardio-embolic events. Multi-slice CT imaging studies have shown that the end-systolic diameter of the left atrium progressively increases from 30 mm for ages ≤40 years to 48 mm in those over 80 years (Fig. 12.3) [6]. The thickness of the anterior left atrium also increases from 2 to 3.7 mm. The Framingham Heart Study has recently confirmed, in a longitudinal analysis, that the size of the left atrium increases progressively with age, in both sexes, by approximately 0.6 mm per decade [7]. These modifications can partially be attenuated through the control of some cardiovascular risk factors such as obesity and hypertension [7]. In uncontrolled hypertension, the atrial diameter increases with age by 50 %, at a rate of 0.9 mm per decade [7]. Aging changes both the geometry and structure of the atrial myocardium. In addition, biopsy samples obtained during cardiac surgery have shown an age-related increase of the connective-fibrous tissue, from 10 % of atrial mass in subjects <50 years to 17 % in subjects >70 years [8]. Tissue acetylcholinesterase, a marker of the autonomic nervous system activity, also decreases with age, in association with a decrease in number and extension of nerve fibers [9]. The ostium of the left atrium auricula and the diameter of the pulmonary veins become progressively larger, growing from 12 to 28 mm and from 10 to 24, respectively, between age 30 and 90 years [6].

In conclusion, the atria seem to encounter a real aging process (“wrinkles in the atrium”) that could justify the increased incident risk of AF in the elderly [10]. Whether age, increase in atrial size, degree of fibrosis, and presence of arrhythmia are causes, effect or epiphenomenon of extra-cardiac alterations still needs to be clarified [10].

Epidemiological studies have shown that, with AF, the incidence of cardio-embolic stroke increases exponentially with age [1, 11]. In a registry study conducted in Dijon, for example, the incidence of cardio-embolic stroke was 28 per 100,000 person-years in men aged 50–60 years and 216 per 100,000 person-years in men >80 years [11]. At advanced ages, the incidence of disease is higher in women [11]. A recent UK community survey showed that the incidence of cardio-embolic stroke was as high as 12.7 per 1000 per year in AF women ≥90 years [12] (Fig. 12.4). About 20 % of all ischemic strokes are AF related [11].

Furthermore, the incidence of cryptogenic stroke progressively increases with age, representing, in >75 years patients, the second cause of disease [13]. The use of loop recorders, allowing long EKG monitoring, demonstrated that 25.5 % of all cryptogenic strokes could be attributed to AF [14]. Asymptomatic forms of arrhythmia play an important role in the genesis of silent cerebrovascular disease in type 2 diabetic patients [15].

The European Community Stroke Project Study, which enrolled 4462 subjects, with a first ischemic stroke, demonstrated that patients with cardio-embolism had a more severe form of disease [16] with a greater incidence of delirium, coma, motor impairment, aphasia, dysphagia, and urinary incontinence [16] and higher in-hospital and short- (3 months, 32.8 vs. 19.9 %, p <0.001) and long-term (2 years, 57 vs. 31 %, p <0.001) mortality [11, 16].

Thus, survivors of AF-related strokes are at increased risk of disability and more frequently need assistance in basic activities of daily living and institutionalization in nursing homes [16]. AF-related disability-adjusted life years progressively increase with age [3]. The higher severity of cardio-embolic stroke can be explained by the more frequent involvement of the anterior portion of the circle of Willis [16]. All these reasons support the fact that age is one of the most important variables linked to AF-related stroke [17].

The incidence of systemic cardio-embolism (SE) was 0.24 per 100 patient-years (11.5 % of all cardio-embolic events), involving lower limbs and renal and mesenteric circulation. SE mortality was 25 %, while 20 % of survivors had some kind of residual disability [18].

The prevalence of chronic kidney disease increases with age, ranging from 20 % in subjects aged 60–69 years to over 45 % in subjects >70 years. In the Atherosclerosis Risk Communities Study (ARIC), a cohort of 10.328 subjects, after a 10-year follow-up, the risk of developing AF was independently associated with renal function [19]. When compared to those with a normal glomerular filtration rate (GFR), the relative risk of developing new arrhythmic events was 1.57 and 2.84 higher in those with a GFR of 30–59 and 15–29 ml, respectively [19].

The Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study showed that in 11,527 AF patients, followed up from 1996 to 2003, the incidence of cardio-embolism was directly related to the degree of chronic renal impairment, increasing from 1.63 to 4.22 events per 100 person-years for GFR values ranging from ≥60 to <45 ml/min/1.73 m² [20]. Recently, a large Danish cohort study has further clarified the relationship between AF, chronic kidney disease, and clinical outcomes in 132,732 patients, hospitalized between 1997 and 2008 with a diagnosis of AF [21]. The prevalence of non-end-stage and end-stage kidney failure was 2.7 % and 0.9 %, respectively. During follow-up, the incidence of ischemic stroke and cardio-embolic events was higher with impaired kidney function, with a relative risk of 1.49 and 1.83 in patients with non-end-stage disease and in those requiring dialysis. A similar trend was observed for risk of myocardial infarction and major bleeding [21]. Total mortality was higher in AF patients with impaired kidney function [21].

These evidences led the investigators of ROCKET AF trial to elaborate and validate the R₂CHADS₂ score, in which two additional points are assigned in subjects with chronic renal failure, defined by a GFR < 60 ml/min [22]. Even if this score presents some limitations (it was derived in a selected trial cohort that excluded patients with severe renal impairment or presenting some risk of stroke) [23], it reflects the awareness that AF patients with chronic renal failure have a higher risk of thromboembolism and major bleeding [23].

The prevalence of peripheral artery disease is high among AF patients [24], and, in a review of ten observational studies, it was found to be associated with a 1.3–2.5 times greater stroke risk [25].

Less is known about the mechanisms linking the condition to arrhythmia development. In the Framingham Heart Study, the incidence of AF on a median follow-up of 12 years was 13.1 % (N = 698/5331), and it was lower in those with a pulse pressure ≤40 mmHg than in those with a pulse pressure >61 mmHg (5.6 vs. 23.3 %). After multivariate adjustment, pulse pressure, but not mean arterial pressure, was associated with an increased risk of arrhythmia development [26]. The observational “Atrial Fibrillation Registry for Ankle-Brachial Index Prevalence Assessment-Collaborative Italian Study” (ARAPACIS), conducted on 2027 patients, analyzed the relation between peripheral arterial disease and non-valvular AF. The study showed that abnormal ankle-brachial index (ABI) values (≤0.90) are found in 21 % of AF patients and have a direct association with the arrhythmic burden [27]. A higher prevalence of a previous ischemic stroke was observed in patients with a pathologic ABI when compared to those with a normal one (17 vs. 10 %, p < 0.001) [27]. Later, the same study found that an ABI ≤ 0.90 was an independent predictor of vascular events, vascular death, and MI [28]. More recently, arterial stiffness was found to be an independent predictor of left atrium dimensions even after adjustment for interventricular septum thickness [29]. Hence, aortic mechanical characteristics, possibly through inflammation cascade, could play a role in promoting and maintaining AF [29, 30].

The incident risk of dementia is about twice higher in patients with AF. In a cohort of 6584 subjects, the Rotterdam Study investigators reported that AF prevalence increased with the severity of cognitive impairment, from 2.1 % in normal cognitive status to 6 and 13 % in mild cognitive impairment and dementia [31]. The Olmsted County Study confirmed this association [32].

More recently, the Cardiovascular Health Study evaluated in a longitudinal analysis the changes in cognitive profile of the 5150 participants enrolled between 1989 and 1993. During a mean follow-up of 7 years, cognitive performance test (assessed by a modified version of the Mini-Mental State Examination) decreased progressively with age. The presence of AF was associated with a higher score reduction in those older than 75 years [33] (Fig. 12.5). These data confirm the observations of “The Adult Changes in Thought Study,” where the incidence of dementia had a 38 % risk increase in arrhythmic patients, growing from 25 to 47.9 events per 1000 person-years [34].

A meta-analysis of observational studies showed an association between AF and dementia in the subgroup of patients with a previous stroke (OR = 2.4) [35]. In an extensive review of literature, eight out of 11 studies published between 1990 and 2012 (three cross-sectional, two case-control, and three prospective cohorts) were found to report a significant correlation between cognitive decline and the arrhythmia. Among cross-sectional studies, patients with AF had a 1.7 to a 3.3 greater risk of cognitive impairment, and a 2.3-fold increased risk of dementia, compared to those in sinus rhythm [36].

All these findings would suggest that the arrhythmia could produce cognitive changes not only through cardio-embolic events but also through the increased production of beta-amyloid [35]. Evidence shows a possible pathway linking vascular disease to reduced beta-amyloid clearance, which would determine a further worsening of vascular disease. This mechanism, sustained by protein tau hyper-phosphorylation, would result in white and gray matter reduction [37]. Furthermore, variation in the concentration of inflammatory mediators could help to explain the association between the arrhythmia and the risk of dementia. Beside a higher CPR level, AF patients show higher concentrations of pro- (e.g., interferon, interleukin-1, interleukin-6, tumor necrosis factor-α) and anti-inflammatory (e.g., transforming growth factor-β) cytokines. Similar changes can be also observed in dementia [38].

Oral anticoagulant therapy (OAT) with vitamin K antagonists proved to be extremely effective in reducing the incidence of cardio-embolism in patients with non-valvular AF. A meta-analysis of the original historical trials demonstrated that OAT, compared to placebo, reduces the risk of stroke by 62 % and all-cause mortality by 26 % [39, 40]. The benefit of OAT is also significantly higher compared to that of aspirin, with a 36 % additional risk reduction [39, 40].

The “Birmingham Atrial Fibrillation Treatment of the Aged Study” (BAFTA) first explored the effects of OAT, compared with aspirin, in the elderly (inclusion criteria, age ≥75 years). After a mean follow-up of 2.7 years, in the 973 patients enrolled (mean age 81.5 years), OAT significantly reduced the combined risk of stroke, cardio-embolism, and intracranial hemorrhage compared to aspirin (1.8 vs. 3.8 % per year, RR = 0.48; p = 0.003) [41].

Subsequently, a sub-analysis of ATRIA study analyzed in 13,559 patients the net clinical benefit (avoided ischemic stroke – provoked hemorrhagic strokes) of OAT by age group. Interestingly, the benefit of anticoagulation increased with age, reaching the statistical significance for those aged 75–84 and ≥85 years [42]. In the “Loire Valley Atrial Fibrillation Project,” which enrolled 4832 patients <75 years and 4130 patients ≥75 years, the benefit of warfarin vs. placebo to prevent stroke, thromboembolism, and mortality was maintained through all age strata, even in subjects older than 85 and 90 years [43] (Fig. 12.6).

As shown in a Swedish registry enrolling 182,678 subjects, the risk of cardio-embolism was progressively higher for increasing scores not only of CHA₂DS₂-VASc but also of the HAS-BLED, the instrument used to assess the bleeding risk [44].

In addition, the results of an Italian prospective multicenter registry enrolling 4093 elderly patients (mean age, 84 years) receiving anticoagulants for AF or deep vein thrombosis showed that bleeding could be minimized (1.87 events per 100 patient.years) by the adoption of tight monitoring protocols [45]. In multivariate analysis, the incidence of hemorrhagic events was associated with the presence of deep vein thrombosis, prior bleeding, an active cancer, and a history of falls [45].

Despite all these findings recommending the adoption of the OAT in elderly AF patients, anticoagulation is still largely underused at older ages. Data from the Euro Heart Survey on Atrial Fibrillation study showed that among 5329 enrolled patients, the use of vitamin K antagonists significantly decreased with age, going from 64 % in the < 65 years group to 56 % in the > 80 years group [46]. These findings were later confirmed by the results of the EURObservational Research Programme-Atrial Fibrillation General Pilot Registry [47]. Moreover, time in the therapeutic range (TTR) was found to be associated with cognitive performance, measured by the Mini-Mental State Examination [48]. Conversely, during follow-up of AF patient with normal cognitive status at baseline, incidence of dementia progressively increases with lower values of TTR [49].

Compared to warfarin, non-VKA oral anticoagulants (NOACs) are characterized by a more foreseeable biological effect, due to their pharmacokinetic and pharmacodynamic characteristics, a reduced interaction with drugs and food, as well as a better safety profile. All randomized controlled trials demonstrated a reduced incidence of intracranial hemorrhage [50–55]. The elderly (age > 75 years) subgroup in the RE-LY study (Randomized Evaluation of Long-Term Anticoagulation Therapy), in the ROCKET AF study (Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation), in the ARISTOTLE study (Apixaban for Reduction in Stroke and Other Events in Atrial ThromboemboLic Fibrillation) and in the ENGAGE AF-TIMI 48 trial (The Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48 trial) were, respectively, 40, 38, 31, and 40 % of all enrolled patients. The subgroup analysis showed no significant age-related differences in the primary efficacy outcome (new cases of stroke and cardio-embolism) compared to warfarin [50–55]. The incidence of major bleeding, with both rivaroxaban and apixaban, did not show any age-related differences [52–54]. Apixaban consistently reduced major bleeding across all age groups [56]. In older patients treated with dabigatran, the incidence of major hemorrhage was not different between dabigatran 110 and 150 mg twice a day, while intracranial hemorrhage was lower in dabigatran 110 mg twice a day, which represent the current recommended dose in the elderly [51, 54].

In a meta-analysis of RE-LY, ROCKET AF, and ARISTOTLE studies, NOACs compared to warfarin were associated with a lower incidence of intracranial hemorrhage (relative risk reduction, RRR −51 %), with similar incidence of systemic major bleeding [57]. Moreover the combined effect of the three molecules, on prevention of all cardio-embolic events, showed RRR of 22 %, compared to warfarin [57]. A meta-analysis of the ten major randomized controlled clinical trials on NOACs, including only over 75 years patients, found that the risk of major or clinically relevant bleeding did not differ between NOACs and conventional therapy (6.4 vs. 6.3 %, OR = 1.02, 95 % CI = 0.73–1.43). Importantly, the incidence of stroke and other thromboembolic events was significantly reduced (3.3 vs. 4.7 %, OR = 0.65, 95 % CI = 0.48–0.87), with a number needed to treat of 71 [58].

The use of NOACs in patients with kidney impairment is a matter of particular importance in elderly patients, considering the high prevalence of the condition [59], and the significantly increased risk associated with both cardio-embolism [20, 21] and hemorrhage [60]. The European Heart Rhythm Association (EHRA) recommendations suggest that NOACs are reasonable choice in patients with mild-to-moderate chronic kidney impairment [61]. Present EHRA guidelines do not recommend dabigatran, which is mainly excreted by kidneys, for GFR lower < 30 ml/min [61]. In ROCKET AF, 20.7 % of patients had a GFR between 30 and 49 ml/min; their mean age was higher (79 vs. 71 years). There was no interaction between degree of kidney impairment, efficacy, and safety of the drug. Fatal bleeding had a lower incidence in rivaroxaban-treated patients (0.28 vs. 0.74 per 100 patient.years; p = 0.047) [52, 62]. A sub-analysis of ARISTOTLE study confirmed that GFR ≤50 ml/min (17 % of the enrolled subjects, mean age 77.6 years) did not affect the efficacy of apixaban. The benefit in terms of major bleeding events was even found to be higher in the presence of kidney impaired function, with an RRR higher than 50 % when compared to the warfarin [53, 63]. Based on these evidences, EHRA therefore recommends the use of rivaroxaban and apixaban, at reduced doses, up to GFR of 15 ml/min [61].

In a real-world scenario, in 134,414 Medicare patients, dabigatran, when compared to warfarin, was associated with a reduction of stroke incidence (HR = 0.80, 95 % CI = 0.67–0.96), intracranial hemorrhages (HR = 0.34, 95 % CI = 0.26–0.46), and hence mortality (HR = 0.86, 95 % CI = 0.77–0.96). Only gastrointestinal bleeding had a higher incidence in women ≥75 years and in men >84 years [64]. Recent data seem to demonstrate that older patients treated with NOACs have greater psychological satisfaction, lower therapy-related burden, higher awareness of benefits, and lower psychological stress [65].

Real-world data from the EURObservational Research Programme-Atrial Fibrillation General Pilot Registry show that the use of rate-control strategy was more frequently adopted in the elderly, with lower proportions of electrical cardioversion, transcatheter ablation, and prescription of antiarrhythmic drugs. Among rate-control agents, while beta- blockers were prescribed regardless of age, digoxin and nondihydropyridine calcium channel blockers were more often used in older patients [47]. These findings are partially motivated by the results of a sub-analysis of the “Atrial Fibrillation Follow-Up Investigation of Rhythm Management Study” (AFFIRM) which, in patients between 70 and 80 years of age, showed that rate control, compared to rhythm control of AF, was associated with lower mortality and hospitalization rates [66]. However, the evidence is conflicting. In a sub-analysis, the AFFIRM investigators found that, in the follow-up, the presence of sinus rhythm was associated with a lower risk of death, as was warfarin use. Conversely, the use of antiarrhythmic drugs was linked to increased mortality [67].