**2. An elderly patient with AF**

#### **2.1 Epidemiology**

The elderly world population >65 years old in 2004 was 461 million, and it is estimated that it will grow 4.3 times by 2050 [5].

The challenge proposed by diagnosing a supraventricular arrhythmia, as frequent as atrial fibrillation (AF), is important to avoid future complications, such as systemic embolism (SEE) diseases, stroke, heart failure, tachycardiomyopathies, worsening cognitive disorders and dementia, increased fragility syndrome, and polypharmacy.

AF screening in the elderly population is of paramount importance. It is at 4.6% which positions it in a perfect cost-benefit balance (it takes only 70 elderly individuals to find a patient with AF) [6].

#### **2.2 Diagnosis of AF in the elderly**

AF can be detected in the patient in different medical areas, such as in an emergency service, in clinical consultation, in a pre-competitive check-up for sports, and in an immediate postoperative period.

Semiology should be used with the simple manual pulse socket or with different devices; electrical tensiometers, smartwatches, and in those who have some type of external monitoring the multi parameters, Holter, etc., or some instrument for internal monitoring are the loop recover, pacemakers, defibrillators, etc. In this way, it is about looking for, when interrogating these devices, the atrial high-frequency episodes (AHFE) characteristic of AF, which will then be corroborated with 12-lead electrocardiogram "Gold Standard" to be able to make the diagnosis of clinical AF and if it cannot be compared with ECG, it will be a subclinical AF.

In elderly patients, it is recommended to use the nominal classification of AF; previously undiagnosed AF, paroxysmal AF, persistent AF, long-term persistent AF, and permanent AF. All AF modalities must be anticoagulated or look for all the tools to be able to do so, except those that are contraindicated [6].

One term that falls into disuse is Non-Valvular Atrial Fibrillation (NVAF) [6, 7] which encompasses all AF except those for which anticoagulation with DOACs does not represent a benefit; moderate or severe mitral stenosis and those concomitant with mechanical heart valves.

In an elderly patient with NVAF, the thromboembolic probability he/she suffers must be weighted, by using the CHA2DS2VASc scale [8] where it is established that the elderly patient who is ≥75 years old, provides information to establish a crucial score

#### *Use of Non-Vitamin K-Dependent Oral Anticoagulants in Elderly and Fragile Patients… DOI: http://dx.doi.org/10.5772/intechopen.103033*

of 2, with an embolic probability of 4% per year, and if the patient is also female, 1 point with this sum of data, anticoagulation is a priority (Class I A) [9].

When the stroke prevention score is established, the probability of bleeding should be assessed with the HAS-BLED scale, which is a daily example of a 65-year-old patient with knee osteoarthritis, added to this a history of the previous stroke, who drinks wine daily and the use of nonsteroidal anti-inflammatory drugs (NSAIDs), gives a count of four with a probability of bleeding of 4.9–1.9% annually. But it is advisable to suppress alcohol consumption and change the type of painkillers to non-NSAIDs, the eventuality of future bleeding is reduced to 1.88–3.2% per year [10].

Glomerular Filtration Rate (GFR) is another important factor to be able to assess renal function with a calculation formula, "Crockoft Goul formula" (CG) estimated by the patient's serum creatinine, age, weight, and a constant numeric denominator. The result of this equation is corrected in the case of female patients [9, 11].

When studying healthy elderly people aged 70–101 years, a significant correlation between age and GFR measured with CG was observed, where it was concluded that GFR figures decrease by 1.01 ml/min per year [12].

An anticoagulation card was designed to be taken to each medical consultation and which includes useful tools to help decide on anticoagulation and to make dose corrections at each medical visit if the patient required it (**Figure 1**).

Once it is decided to treat with anticoagulant an elderly patient, the challenge is to choose the right anticoagulant for each patient. DOACs or Warfarin? If you choose the first one, the options are—dabigatran, rivaroxaban, apixaban, or edoxaban. An attempt will be made to bring the right option closer during this chapter.

#### **2.3 Elderly anticoagulated patient**

In the pivotal trials on anticoagulation in patients with NVAF, individuals with an average age of 70 years, small ethnic groups, with a lower percentage of women, and none with renal failure on dialysis enrolled.

The four large studies, such as ARISTOTLE included 3658 patients >75 (31%); in RE-LAY, n = 7258 (40%); in a subgroup of ROCKET-AF, N = 6259 (44%) and in the ENGAGE AF-TIMI 48 trial, n = 8474, (40.05%).

All this forceful but scarce information in relation to the elderly led to multiple analyses of real-life data.

In 2017, a group of patients (n = 110) who were between 66 and 100 years old (average age of 80.4 years) was studied, of which 45% were women. The use of apixaban at maximum doses of 5 mg every 12 hours or doses lower than 2.5 every 12 hours was observed when they met 2 of 3 criteria stipulated in the ARISTOTLE study (>80 years, weight < 60 kg, and plasma creatinine >1.5 mg/dl).

Patients who received the maximum recommended doses, approximately 10% had drug concentrations above the expected range, as did 2/3 of the patients who used apixaban 2.5 mg every 12 hours.

Differences in the proportion of apixaban concentrations within or outside the expected ranges were not significantly different. However, four patients had apixaban dosage above the expected range.

This increase in drug concentrations found in this small group of elderly people could allow the possibility of a blood dosage of the anticoagulant drug, to minimize inconveniences, since these patients, old as such, have not been taken into account in large randomized studies [13].

#### **Figure 1.**

 *Anticoagulation card. Anticoagulation card to be used by the patient at each medical visit.* 

 In a Canadian meta-analysis of three cohorts (n = 227,579) in which different DOACs were compared (rivaroxaban vs. dabigatran, apixaban vs. dabigatran, and apixaban vs. rivaroxaban). It served to assess each other's effectiveness and safety.

 The follow-up period was approximately 5 years, with an average participation age close to 75 years, with a low percentage of women, CHA2SD2VASC = 2.5. These patients were treated with high doses and reduced doses of non-vitamin K antagonist oral anticoagulants (NOACs).

 The meta-analysis concludes that apixaban in these elderly patients was associated with fewer ischemic stroke events and systemic embolic (ES). When compared to rivaroxaban, a 15% decrease was found, and with respect to major bleeding (MB) the data obtained in favor of apixaban was 39% [ 14 ].

 Regarding dabigatran in the RE-LAY study compared to warfarin when segmented by age in over 75 years of age (n = 7258), it significantly reduced stroke and intracerebral hemorrhage (ICH) and was also shown that at a dose of 110 mg every 12 hours it is a safe option for patients >80 years old when it comes to reducing the slight increase in extracranial bleeding [ 15 ].

 Based on the ROCKET-AF study, where 44% of patients were >75 years old, rivaroxaban prevented stroke and reduced bleeding in life-threatening critical anatomical areas and bleeding from all causes. The reduction of the hemorrhagic stroke was 41%, with a p < 0.02). This group of patients was more polymorphic and they benefit from the use of rivaroxaban if they had the previous stroke as history, both young and elderly patients [ 16 ].

 In 2015, 30,655 patients >75 years old were recruited in eight studies published as a meta-analysis. The different DOACs vs. warfarin (two studies for apixaban, n = 2850; one study for dabigatran, n = 2466; two studies for edoxaban, n = 2838; three studies for rivaroxaban, n = 3082) were compared with a follow-up of 3 months to 2.8 years.

 This meta-analysis evaluated the efficacy of each drug in elderly people with stroke events and systemic embolisms (ES), also MB and clinically nonrelevant mayor bleeding (CNRMB).

*Use of Non-Vitamin K-Dependent Oral Anticoagulants in Elderly and Fragile Patients… DOI: http://dx.doi.org/10.5772/intechopen.103033*

 All DOACs compared to warfarin were significantly better, by an average of 29%. Regarding safety, edoxaban and apixaban turned out to be more beneficial in this group of elderly. Dabigatran in doses of 150 mg and 110 mg, both in two daily doses, had a higher number of gastrointestinal (GI) bleeding, along with rivaroxaban, which also had a lower safety profile ( **Figures 2** and **3** ) [ 17 ].

 Based on data collected in the Norwegian patient registry and the database of the same country, from 2012 to 2017, where the use of NOACs (standard dose and reduced doses) vs. warfarin is compared, it was observed.

 The total population studied was 31,041 of >75 years (average 82 years), 52% women with an average of CHA 2DS 2VASC = 4.5.

 The use of DOACs in standard and reduced doses decreased stroke and systemic embolism like warfarin, but the administration of low doses of DOACs is either similar or reduces bleeding complications. A door could be opened for future randomized subdose studies [ 18 ].

 Three prespecified groups of edoxaban vs. warfarin were studied, with a follow-up of approximately 2.8 years, in patients with NVAF. The third group, >75 years old, had 52% permanent AF. The direct oral factor Xa inhibitor was used in the standard and reduced doses, the latter by 41%.

 About 2.3% stroke and SEE were observed, 4.8% of MB with significant data. Embolisms were reduced by 17% and the same percentage of reduction was achieved in bleeding, so a safety tool is provided in the elderly when compared to younger patient groups [ 19 ].

 START T Register 2, studied in people over 85 years of age, showed that using DOACs there was low mortality, similar bleeding when compared to warfarin treatment. In addition, a small increase was observed in very elderly patients with embolic events with the use of direct oral anticoagulants [ 20 ].

 The use of warfarin has its disadvantages in long-lived patients; such as the need for frequent measurements of the International Normalized Ratio (INR), which is not always in a standardized window, and therefore has the difficulty in entering the Time in Therapeutic Range (TTR).


#### **Figure 2.**

 *Stroke and systemic embolism in subjects older than 75 years with DOACs.* 


#### **Figure 3.**

 *Major bleeding and clinically nonrelevant bleeding in patients over 75 years of age with DOACs.* 

 Warfarin interrupts the necessary recycling of vitamin K, which is an essential cofactor for the carboxylation of glutamic residues responsible for producing proteins indispensable for clotting. An example of this is the decrease in protein C levels, which can favor calcium deposits in the skin and other organs; as well as, this vitamin is required in the primary phases of bone matrix formation, effects of paramount importance in this advanced age group [ 21 , 22 ].

 In a database, a retrospective cohort of the city of Taiwan was observed (n = 17,008), an average of 28% reduction in osteoporosis was observed when comparing DOACs vs. warfarin.

 DOACs, especially the use of apixaban, minimize osteoporosis by 62% and rivaroxaban also does so by 32%, a decrease that is not statistically significant in those compared to dabigatran [ 23 ].

 DOACs do not deteriorate the γ-carboxylation of osteoclastine and do not disfavor the formation of the bone matrix, a very interesting topic for good "bone health."
