**4. Nonagenarian patient with AF**

#### **4.1 Epidemiology**

Improvements in health systems and education in human care progressively lead to an increase in life expectancy, especially in developed countries.

The population census of Spain 2021 had a total of 47,394,223 inhabitants, with a record of 491,369 (1.03%) individuals ≥90 years old [50]. In Argentina, 45,808,747 people were projected for 2021, of whom 242,409 (0.53%) would be ultra-elderly people [51].

In Germany, according to population growth projection data in 2021, the total population of 83,450,000 and is expected by 2030 to be 82,857,000, with a slight population decrease of 593,000 people (0.71%). Paradoxically, the numerical count of residents will increase in the age group ≥90 years, from 878,000 to 1.40,300 (1.69%); and in this way, it is speculated that the number of very long-lived individuals will grow by 59.79% [52].

In the prospective longitudinal study in Gothenburg, Sweden, which initiated the enrolment of patients at 70 years and was then followed for 30 years; an AF prevalence of 16.8% at 90 years was recorded, with an incidence of approximately 47/1000/ year in both sexes; and in the 95–99-year group (n = 189) it had an almost double incidence of 93/1000/year; with an increase in men [53].

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

#### **4.2 Anticoagulated nonagenarian patient**

In the subanalysis of very elderly patients with NVAF, J-RHYTHM registry, 7406 consecutive individuals were enrolled who were divided into three age groups (<70 years; 70–84 years, and >85 years).

This elderly population of the third age group with the highest preponderance to polypathologies (n = 330) had an average age of 87.4 ± 2.8 (4.4%), with 58.8% permanent AF. The combination of thrombus embolism and major bleeding was lower in those who used warfarin at an International Normalized Ratio (INR) between 1.6 and 2.59 with a p < 0.001.

The registry compared the ultra-elders the use of warfarin with a TTR of 67.1 vs. the other group, those who did not use warfarin. It was postulated that it could be used in very long-lived, with a lower INR range than that used in large anticoagulation works [54].

Based on the National Registry of Taiwan 2012, T.-F. Chao et al. [55] investigated patients >90 years with NVAF in a total of n = 16,798 with an average age of 92.5 years.

N = 7362 were observed with different pre-existing diseases, such as chronic kidney disease, n = 3151 (CKD); intracerebral bleeding, n = 950 (ICH); and gastrointestinal bleeding, n = 5370 (GI).

About 67.3% of the patients studied, n = 4955, were not treated with anticoagulants (N-OACs), and 32.7%, n = 2407 were anticoagulated (OACs).

Of the OAC, DOACs was used in 23.6%; apixaban (n = 190), 2.6%; rivaroxaban (n = 927), 12.6%; dabigatran (n = 620), 8.4%; as a vitamin K antagonist, warfarin (n = 670), 9.1%.

Rivaroxaban was the most used DOACs in doses of 10 mg, 15 mg, and 20 mg once a day, with a preference of treating physicians with doses of rivaroxaban 15 mg/day at 41%. Regarding apixaban, the doses of 2.5 mg every 12 hours and dabigatran 110 mg twice a day were the most frequently chosen drug presentations (**Figure 6**) [55].

A total of 1750 patients with AF >90 years of age were identified from three regions of Spain, these enrolled individuals were divided into three groups; the nonanticoagulated n = 534; those anticoagulated with vitamin K antagonist (VKA), n = 500 with INR = 2–3. Those who were treated with DOACs, n = 716. Patients had a creatinine clearance close to 50 ml/min [56].

In a subanalysis of the FREFER-AF study, 6412 adult patients with AF were enrolled and followed for 12 months. In this European registry, they were divided into three age groups (<85 years old; >85 years old; and >90 years old), 505 patients were very old >85 years old and referred to the third group (16.6%), 84 of them were extremely elderly.

This segment of ultra-elderly people suffered a net clinical benefit when they were anticoagulated with DOACs, a balance given by a reduction in thromboembolic events of 43%, which is evident when treating 50 individuals to avoid an event.

A significant difference was established in favor of anticoagulantes of 4.6%; p < 0.48, with an increase in major bleeding similar to patients >75 years (younger), the comparison was made by age groups who took only anticoagulants, only anti-platelets, or the sum of the two, p < 0.025.

Regarding MB, it had only a 10% increase compared to the extremely elderly (>90) who were not anticoagulated.

The net clinical benefit is observed in the three groups, with greater intensity in those over 90 years of age, being 8.02% with a p < 0036 (**Figure 7**) [57].

#### **Figure 6.**

*Patients >90 with AF and history of previous illnesses.*

It was found among the best net benefit of reducing embolic phenomena and bleeding to anticoagulated patients >90 years old (6.1% use of DOACs).

Nonagenarian patients aged 90–100.1 years (n = 300) with an age average of 91 years who suffered from AF and were medicated with OACs were studied.

Extremely elderly individuals were divided into three groups; those who took DOACs (n = 93), those who took warfarin (n = 147), and a third group (N-OACs) n = 80 who were not medicated with anticoagulants.

Regarding the stroke/TIA/SEE the DOACs were statistically significant reduction (**Figure 8**) and it was observed on the bleeding events the DOACs had twice the percentage of bleeding—5%/year vs. 2.5% from warfarin use (p < 0.o48) (**Figure 9**) [58].

As already observed, in the subanalysis of the START-T Register, done in Italy, patients enrolled from 2012 to 2013, elderly people with NVAF, who were mostly treated with warfarin as an anticoagulant since the spread of the use of DOACs was beginning in this country. Two-thirds of the elderly were observed to have moderate or severe kidney disease [20].

In the START-T Registry 2 subanalysis, elderly people enrolled with VNAF, with average age 88.4 ± 2.8, compared DOACs (41.3%) vs. warfarin in the range 2–3 (58.7%).

The study was divided into two groups, <85 years and >85 years (n = 3209), in the second group, >90 years out of age 55 patients (1.7%).

In very elderly patients it was obtained; a mortality rate and a lower risk of sacred with a small thromboembolic increase [59].

In the Swedish design of 30 years of follow-up of patients with and without AF, separated by sex, it was observed that among survivors, the cumulative incidence of AF was more than 50%. Patients with AF had twice the chance of death [60].

In a geriatric institute, 77 geriatric patients with an average age of 80 ± 7 years, anticoagulated with warfarin and DOACs, were retrospectively enrolled after a

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

**Figure 7.** *Net clinical benefit adjusted for the mortality risk, of OAC vs. no OAC (adapted).*

fall from their own height or less. After admission to the hospital, he/she had a brain CT scan where the tomography image was accepted as positive if an ICH was observed.

The first brain CT had 20.8% positivity, then in an average control of 8 hours, in those patients with images that were negative, 9.8% HIC was found not detected previously.

**Figure 9.** *Annual major bleeding events.*

In the group of patients who took warfarin, there was 30% HIC vs. 14% of those who took DOACs. Patients who used DOACs had a higher rate of use of aspirin and clopidogrel [61].

In the Japanese study on anticoagulated elderly people, SAKURA-AF Registry, three groups of elderly people were enrolled, the third group, of very elderly with an average age of 87.3 years ± 2.5 (>85 years of age and under <97 years of age) where the use of DOACs and warfarin were compared.

About 45.8% DOACs were used and of these, 79% were in low doses. The study described those embolic events increase, in proportion, more than hemorrhagic events, and suggested the effective use of DOACs in very old people [62].

In a larger prevalence study of nonagenarian patients with anticoagulated AF made in the city of Madrid, published 2019, 10,077 nonagenarians (17%) had a high prevalence of comorbidities, 67.2% were anticoagulated; they used 11.6% DOACs [63].

The Berlin Registry ≥89 years studied by Wutzler et al., with an average age of 92-year-old patients who received anticoagulants by 26.5%; they used 21.1% vitamin K antagonist, and 5.4% used DOACs [64].

Regarding the falls, very frequently in nonagenarian, with the classic analysis of the Markov model, it was shown that to suffer from a dreaded subdural hematoma in anticoagulated patients with warfarin over 1 year, a hypothetical number of 295 falls is needed, to overcome the benefit of said anticoagulation [65].

When studied in patients aged 90 years old vs. <60 years old, fall mortality increases considerably (5.5% vs. 0.9%).

In a 10-year retrospective cohort study, which included 5088 traumatized patients, young and nonagenarian patients were compared.

It was observed that the <60 years had an early home discharge of 73.7% vs. 18.2% (p < 0.001). Patients who used aspirin had greater intracerebral bleeding (p = 0.001).

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

As for mortality caused by all injuries caused by trauma, added to death from cerebral hemorrhage, aspirin (p = 0.046) and warfarin (p = <0.001) show worse rates [66].

In the population analyzed in Spain in patients over 90 years of age in acute renal failure, the functional decline was the most frequent cause, presenting with 71% of hypertensive patients, 43% chronic kidney disease, 26% with AF among others [67].

A Korean database under review (n = 20,575) was used, where the use of DOACs and warfarin in elderly people with AF was compared.

In the total group of patients over 80 years of age, a positive benefit was observed on the outcomes of the clinical combination (ischemia, stroke and major bleeding), but there were no significant differences in people over 90 years of age; however, the largest East Asian study showed that extremely elderly patients (≥ 90 years (n=2142)), who were anticoagulated with NOACs, had benefits over the use of Warfarin.

Treatment with NOACs was preferred (83.3%), and warfarin was also used (almost 16%); of the total number of patients taking NOACs, 80% used low doses of anticoagulants [68].

GFR is extremely important in nonagenarians and we must keep in mind the Crockroft-Gaul formula for anticoagulation, it is of the simple and practical equation that contemplates a wide age range (25–100 years) [11].

Taking into account that renal function declines in elderly people, especially GFR and effective glomerular flow, with a 10% drop in the latter per milliliter/minute/ body surface [69].
