European Journal of Internal Medicine 71 (2020) 32–38

Contents lists available at ScienceDirect

European Journal of Internal Medicine

journal homepage: www.elsevier.com/locate/ejim

Review Article

Practical use of Direct Oral Anti Coagulants (DOACs) in the older persons T
with atrial fibrillation.
Mario Bo (MD, PhD)a,1, , Niccolò Marchionni (MD, PhD)b,1,2
⁎

a
Section of Geriatric, Department of Medical Sciences, AOU Città della Salute e della Scienza, Molinette, Turin, Italy
b
University of Florence, Head, Division of General Cardiology, Director, Cardiothoracovascular Department, AOU Careggi, Florence, Italy

ARTICLE INFO ABSTRACT

Keywords: Direct Oral Anticoagulants (DOACs) consistently demonstrated a greater net clinical benefit compared to
Aged Vitamin K Antagonists (VKAs) also in persons aged 75 years and over, who account for the largest proportion of
Atrial fibrillation AF patients; however, major uncertainties in DOACs prescription have to do with this age group. In this review,
Direct oral anticoagulants persistent uncertainties and implications of frailty and geriatric syndromes on DOACs prescription, and practical
Frail elderly
use of DOACs in real-world older persons, and will be discussed.

1. Introduction embolism and, with the exception of rivaroxaban, with a significant

reduction of intracranial bleeding events, with apixaban showing the
Current European guidelines recommend oral anticoagulant therapy best combination of efficacy and safety in these older patients [5].
(OAT) with direct oral anticoagulants (DOACs) over vitamin K an- However, despite consistent evidence of clinical benefit and in-
tagonists (VKAs) irrespective of age for patients with atrial fibrillation creasing prescription of these drugs [6], they are yet widely underused,
(AF) and a CHA2DS2-VASc score ≥ 2 in men and ≥3 in women, and particularly in the oldest patients [7-14]. In this review, implications of
without contraindications to DOACs (mechanical prosthetic valves or frailty and geriatric syndromes and persistent uncertainties on DOACs
moderate-to -severe mitral valve stenosis) [1, 2]. Phase III DOAC ran- use in real-world older persons will be discussed, and an approach for
domized clinical trials (RCTs) enrolled a significant proportion of el- practical use of DOACs in older patients will be proposed.
derly subjects, and consistently demonstrated a greater net clinical
benefit compared to VKAs also in persons aged 75 years and over, who 2. Material and methods
account for the largest proportion of AF patients. Barco et al reported a
significant reduction in stroke and thromboembolic events and in in- Several studies and meta-analysis based on results of DOAC phase III
tracranial hemorrhages, compared to warfarin, in patients receiving RCTs have provided extensive information about efficacy, safety and
full-dose dabigatran and apixaban, this latter being also associated with clinical benefit of DOACs compared with warfarin in elderly persons [3-
a reduced incidence of major bleedings [3]. In a review of DOACs phase 5], and recent European recommendations dealt with some wedge is-
III trials, including also the data from the ENGAGE AF TIMI 48 study, in sues concerning use of DOACs in older persons [2]. For a more in depth
patients aged ≥ 75 years [4], apixaban and higher-dose dabigatran evaluation of persistent uncertainties about DOACs practical use in real
were associated with a significant reduction of stroke/systemic embo- world elderly people, scientific literature focused on use of DOACs in
lism, whereas major bleeding were significantly reduced in patients older persons published in the last 8 years was retrieved by the authors
receiving apixaban and edoxaban compared with warfarin; all DOACs, (MB, NM) from the MEDLINE database using the terms “atrial fibrilla-
with the exception of rivaroxaban, were associated with a significant tion” AND “antithrombotic therapy”, OR “new oral anticoagulants” OR
reduction of intracranial bleedings [4]. A very recent meta-analysis “direct oral anticoagulants”, OR “aged” OR “elderly” OR “older” as
including 28135 AF elderly patients (≥ 75 years) demonstrated that keywords. Reviews, recommendations and expert opinions, as well as
DOACs were associated with a significant reduction in stroke/systemic clinical trials and large observational studies in English published until

⁎
Corresponding author: Mario Bo, MD, PhD, Section of Geriatric, Department of Medical Sciences, AOU Città della Salute e della Scienza, Molinette, Corso
Bramante 88, 10126, Turin, Italy
E-mail address: [email protected] (M. Bo).
1
This author takes responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation
2
on behalf of the Italian Society of Geriatric Cardiology (SICGe)

https://doi.org/10.1016/j.ejim.2019.10.026
Received 23 July 2019; Received in revised form 16 September 2019; Accepted 22 October 2019
Available online 15 November 2019
0953-6205/ © 2019 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.
M. Bo and N. Marchionni European Journal of Internal Medicine 71 (2020) 32–38

March 2019 were systematically analyzed and included according to dwelling older persons [29]. This “frailty phenotype”, which should not
their relevance to the objective. Additional references were obtained be confused with disability or comorbidity, may also be identified using
from the reference list of the selected full-text manuscripts. other tools, such as the Simplified Fried test, the Short Physical Per-
formance Battery (SPPB) [30], the 5 meter gait speed [31], the Study of
Osteoporotic Fractures (SOF) index [32, 33] and the simple Frail Scale
2.1. Real world patients, frailty and geriatric syndromes
[34]. On the other side, the Frailty Index [35] is a 70-item form based
on the accumulation of deficits (including functional limitations and
Some uncertainties in DOACs use in older patients might arise from
disabilities, cognitive and sensory impairment, psycho-social variables
the concern that the significant proportion of older persons enrolled in
and number of diseases), whose score is associated with increased short
DOACs RCTs might not be not fully representative of real world (RW)
term risk of institutionalization, mortality and hospitalization. The 7-
patients. Indeed, only 40-60% of RW AF patients enrolled in the
point Clinical Frailty Scale (a semi-quantitative eye-ball global judg-
Michigan Anticoagulation Quality Improvement Initiative (MAQI2)
ment of frailty or vulnerability) was shown to be highly correlated with
registry taking warfarin would have met the selection criteria adopted
the Frailty Index and significantly associated with increased risk of
for phase III DOACs trials [15]. Whereas patients with severe co-
death and entry into an institution [36]. The Multidimensional Prog-
morbidities, reduced life expectancy, potentially interacting drugs, and
nostic Index (MPI) [37] (including information on functional basic and
mild-to-moderate blood work abnormalities were systematically ex-
instrumental activities of daily living, cognitive and nutritional status,
cluded from phase III DOACs trials [4], RW AF patients are older, more
comorbidities, medications, and social support network) has also been
frequently of female gender, with high prevalence of comorbidities and
demonstrated to be predictive of mortality and adverse clinical out-
of functional and/or cognitive impairment [9,12,13,16,17].
comes [38]. In summary, the “frailty phenotype” based tools identify
Most of the RW studies on DOAC use are registry-based and retro-
patients at risk of disability, but not of short term mortality, whereas
spective, mainly include community-dwelling older persons, use 65
high scores in the Frailty Index, Clinical Frailty Scale and MPI identify
years as the cut-off for defining older patients, and may be flawed by
patients with poor health status and increased risk of mortality. Despite
undocumented selection bias, although they used statistical tools such
inherent limitations according to different frailty tools adopted, frail
as the propensity score to correct selection bias within heterogeneous
older patients with AF are less likely to receive an appropriate antic-
groups of RW patients. Despite these inherent limitations, these studies
oagulant prescription and, at the same time, are at greater risk of em-
confirm a greater net clinical benefit of DOACs compared with VKAs
bolic stroke and death [10, 13, 14, 17, 28, 39,40]. The lack of evidence
also in older patients, with an apparent better safety profile for apix-
to guide optimal care for patients with AF and frailty might in part
aban and low dose dabigatran [18–22]. Few studies focused on the
explain the gap between current guidelines and clinical practice in
oldest AF patients. A propensity-matched analysis of patients ≥ 90
management of these patients [40]. On the basis of current evidence
years of age from the National Health Insurance Research Database in
there is general agreement that the “frailty phenotype” should not be an
Taiwan showed similar efficacy and reduced incidence of intracranial
exclusion criterion to anticoagulate, since these patients are at an in-
hemorrhage with DOACs over warfarin [23]. In 3285 elderly patients
creased risk of stroke and have been shown to benefit from OAC [2].
from the PREFER in AF registries, the primary net composite end-point
The benefit of NOACs over VKA has best been demonstrated for edox-
(ischemic cardiovascular events and major bleeding) was lower with
aban and apixaban in this patient population [2].
DOACs than with VKAs (6.6% vs 9.1%, respectively, OR 0.71, 95% CI
Predisposition to falls is common in frail patients, and is often
0.51-0.99), with a net clinical benefit of DOACs primarily due to lower
perceived as an important issue in starting DOACs [41, 42]. Patients on
rates of major bleedings [24]. In a propensity score adjusted analysis of
OAT at high risk of falls did not consistently have a significantly in-
a retrospective US Medicare cohort of new-user AF patients who in-
creased risk of major bleedings [43–45]. Current guidelines do not re-
itiated warfarin or full doses of dabigatran, rivaroxaban and apixaban,
quire fall risk estimation in candidates to OAT, and the risk of fall per se
compared to warfarin each DOAC was associated with reduced risks of
should not be considered a contraindication to the use of DOAC [1, 2].
thromboembolic stroke (20-29%), intracranial hemorrhage (35-62%)
However, use of simple falls risk tools has been recommended (Table 2)
and mortality (19-34%) [25].
[46, 47]. and patients at high risk for fall on OAC should be referred to
However, geriatric syndromes such as frailty, cognitive impairment
a falls service for multi-disciplinary assessment and to address re-
and functional dependence, which have been demonstrated to influence
mediable pathology, correct polypharmacy and inappropriate pre-
physicians’ decision about DOACs use in older persons [9–11, 13, 26,
scriptions and/or prescribe interventions (e.g. exercise programs; home
27], were not considered in RW studies as well as in DOACs trials.
environmental assessment etc.) that reduce risk of further falls [2].
Although cardiologists usually recognize frailty based on the presence
There is evidence that these patients may derive greater benefit from
of a mix of problems of motility, cognition, nutrition and inappropriate
apixaban and edoxaban compared to warfarin [46, 48].
loss of body weight and muscle mass [28], there are two basic con-
Many older adults have both cognitive impairment or overt de-
ceptualizations of frailty (Table 1). The frailty “phenotype” is based on
mentia and AF. Moreover AF is a recognized risk factor for later oc-
the presence of at least three of five criteria – slow gait speed, low
currence of cognitive impairment and dementia [49], and there is
physical activity, unintentional weight loss, self-reported exhaustion,
suggestive evidence that OAT might have the potential for reducing this
and muscle weakness –, and is associated with worsening mobility and
risk [50, 51]. Dementia is a well-recognized risk factor for under-use of
disability, hospitalizations, and mortality over 7 years in community-

Table 1
Main frailty tools for practical use.
CHS Frailty Scale – Frailty phenotype «physical» frailty tools, not including disability and disease burden
SOF Frailty Scale
SPPB & Gait speed
Green score
Frail Scale «hybrid» frailty tools, including measures of disease burden
Vulnerable Elders Survey-13
Groningen Frailty Indicator (GFI)
Clinical Frailty Scale «Deficit accumulation» tools, identifying frail and vulnerable patients, including measures of disabilities, disease burden, sensorial
Frailty Index deficits and psycho-social variables

Abbreviations: CHS: Cardiovascular Health Study; SOF: Study of Osteoporotic Fractures; SPPB: Short Physical Performance Battery

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M. Bo and N. Marchionni European Journal of Internal Medicine 71 (2020) 32–38

Table 2 are recommended every 3, 6 or 12 months, with increasing frequency

Fall risk tools. along with decreasing renal function or with dehydrating illness [55].
High risk of fall with presence of Probability falls assessment47 1 point for each At every follow-up contact or visit, the checklist should address
one or more of: thromboembolic and bleeding events, adherence, side-effects, careful
review of co-medications, reassessment of correct dosing and blood
Prior history of falls Previous falls
sampling (mainly hemoglobin and renal function) [45, 54].
Lower extremity weakness Medications > 4
Poor balance Psychotropics
Cognitive impairment Low visual acuity 2.3. Selection and dosing of DOAC
Orthostatic hypotension Diminished sensation
Use of psychotropic drugs Near tandem stand 10 Medical history and comorbidities may drive the choice of a particular
s
Severe arthritis Alternate step test 10 s
DOAC. Patients with AF and hepatic insufficiency Child-Pugh category A
Dizziness Sit to stand 12 s may receive full dose DOAC; dabigatran, apixaban and edoxaban may be
from ENGAGE-AF TIMI 4847 Score Probability of fall used with caution in patients with hepatic insufficiency Child-Pugh cate-
per year gory B, whereas all DOACs are contraindicated in category C [2]. It has
0-1 7%
been reported that patients with chronic liver disease treated with DOACs
2-3 13%
4-5 27% have a lower incidence of major bleeding compared with VKAs [56, 57].
6+ 49% Several DOACs rankings [58-60] and expert opinions have been published
to assist physicians to fit the best DOAC according to individual patient's
characteristics [61-64]. Apixaban has been suggested as a reasonable first
OAT [7, 8, 10]. A retrospective cohort study of 2572 older patients with choice either in older patients and in subjects with chronic renal failure
AF (73% aged ≥ 75 years) showed that after diagnosis of dementia, [63]. The recently updated 2019 American Geriatrics Society Beers criteria
those who persisted on OAT had lower rates of stroke and all-cause recommend a cautious use of dabigatran and rivaroxaban in AF patients
mortality, with no significant differences in risk of major bleedings aged ≥ 75 years because of greater risk of gastrointestinal bleeding [65]. In
[52]. Although cognitive impairment and frailty were associated with a recent report from the Fit-fOR-The-Aged (FORTA) classification (evalu-
increased risk of death and reduced probability of receiving OAT among ating benefit, risk and appropriateness of drugs for older patients in ev-
older AF patients enrolled in the ORBIT-AF registry [53], there was no eryday clinical settings) [66, 67], apixaban was labelled A among OATs,
interaction between OAT use and cognitive impairment or frailty in meaning it was seen as the drug with the most favorable risk/benefit ratio
their association with mortality, major bleeding and a composite end- in older patients [68].
point of stroke, systemic thromboembolism, myocardial infarction and AF patients who are going to receive a DOAC prescription should be
cardiovascular death [53]. Although cognitive impairment at mild-to assessed for DOAC specific dose-reduction criteria and for other factors with
moderate stage should not be viewed as a general contraindication to potential effect on DOACs plasma level [2], such as age > 80 years, low
DOAC therapy, especially if well-managed from a logistically point of body weight (< 60 kg), reduced renal function, concomitant use of non-
view, in states of poor physical functioning, limited life-expectancy and steroidal anti-inflammatory drugs (to be avoided), previous bleeding, frailty
high risk for competing causes of death there may be limited benefit and fall risk [2]. Table 3 reports approved doses for DOAC use in clinical
from OAT [2]. practice, and dose reduction of all DOACs is primarily recommended along
the published dose reduction criteria [2].. However, there is some rationale
2.2. Prescription, follow-up and surveillance for reducing the dose of NOACs in patients with a high bleeding risk and/or
when a higher plasma level of the drug can be anticipated based on a
In our view, in older patients candidate to OAT, at least a short combination of factors, including potential drug-drug interactions, espe-
Comprehensive Geriatric Assessment (CGA) should be routinely in- cially when combined with other clinical factors affecting DOACs plasma
cluded as a part of the initial clinical evaluation, aimed to assess cog- levels, such as advanced age, low body mass and reduced renal function [2].
nitive status, functional limitations, comorbidities, estimated residual DOACs have less food and drug-drug interactions than warfarin. Main drug-
life-expectancy and daily medications burden. In patients with cogni- drug interactions of DOACs involve P-glycoprotein (P-gp) and CYP3A4
tive impairment, a proxy or a caregiver should be identified as the CYP2Y2 competition and inhibition. Major contraindications for increased
person responsible for a correct assumption of therapy and as the re- anticoagulant effect include concomitant use of anti-fungal drugs (Itraco-
ferent for clinical surveillance. A formally designated coordinator nazole, Ketoconazole, Voriconazole, Posaconazole) and quinidine virtually
should be responsible for therapy and follow-up planning [2, 54]. A for all DOACs. Clarythromicin and Erythromicin increase the anticoagulant
leaflet anticoagulation card containing education and practical in- effect in DOAC-treated patients, as well as Amiodarone and Dronedarone do
formation about the medication, its potential side effects, relevant drug in patients receiving dabigatran, rivaroxaban and edoxaban: dose-adjust-
interactions and contraindications, “what to do when” and a phone ment or use of a different DOAC should be considered in these circum-
number or an e-mail to seek advice for emergencies might be very stances. Verapamil increases the anticoagulant effect in patients treated
appreciated, and motivate patients to drug adherence [54]. Modifiable with dabigatran and edoxaban. There is evidence that concurrent use of
bleeding risk factors should be corrected, and baseline blood works amiodarone, rifampin, fluconazole and phenytoin in patients taking DOACs
(including hemoglobin, liver and renal function and full coagulation is associated with increased risk of major bleeding compared with use of
panel) routinely performed. Measures of creatinine levels and the es- DOACs alone [69]. Either St John wort or rifampicin (P-gp inducers) reduce
timated glomerular filtration (using the Cockroft-Gault equation) rate the anticoagulant effect of DOACs and are therefore contraindicated. There

Table 3
DOACs and approved doses2
STANDARD DOSE COMMENTS/DOSE REDUCTION

APIXABAN 2 × 5 mg 2 × 2.5 mg if two out of three: weight < =60, kg > =80 years, serum creatinine > = 1.5 mg/dl (or Creatinine Clearance 15-29
ml/min)
DABIGATRAN 2 × 150 mg/ 2 × 110 mg No pre-defined dose- reduction criteria
EDOXABAN 1 x 60 mg 1 × 30 mg if weight < =60 kg, Creatinine Clearance < =50 ml/min, concomitant therapy with strong P-Gp inhibitor
RIVAROXABAN 1 × 20 mg 1 × 15 mg if Creatinine Clearance < =50 ml/min

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M. Bo and N. Marchionni European Journal of Internal Medicine 71 (2020) 32–38

DOAC at standard dose

DOAC specific dose-reduction yes

Reduced-dose DOAC
criteria?

no

Other interactions with effects on DOAC

plasma levels?
(age>75, renal failure, low body weight,
comedications, high risk of bleeding)

0-1 2+
yes
Other DOAC with less interactions?

no

no
Concerned about disproportionate Concerned about disproportionate no
non modifiable bleeding risk? non modifiable bleeding risk?

yes yes

-Consider Dabigatran 110 bid Re-assess alternative strategy for

-Re-assess alternative strategy for stroke prevention
stroke prevention

Figure 1. DOAC selection based on drug-drug interactions and/or risk of bleeding.

Modified, from Eur Heart J 2018; 39: 1330-1393

is increasing evidence of several other drug interactions with potential rather than a simple addition of variables within cardio-embolic and
clinical significance, including antineoplastic and antiepileptic drugs, of bleeding risk scales [4]. It is likely that sometimes physicians perceive
common use in older patients [2]. Therefore, use of DOACs in older patients OAT as “futile” or potentially harmful in patients with multi-morbidity
mandate a careful evaluation of co-medications in order to select the most and short life-expectancy, and, moreover, cost-effectiveness considera-
appropriate drug and dose. Although antiplatelet drugs in combination with tions might affect decision about DOACs prescription in these patients.
DOAC therapy increase the risk of bleeding, there is some evidence that use Indeed, when considering OAT with DOACs in older persons, the high
of apixaban and low-dose edoxaban with concomitant aspirin therapy was risk of competing cardiovascular and non-cardiovascular causes of
associated with better safety profile compared with VKAs and aspirin [70, death in this population should be considered. In fact, while the ad-
71]. The EHRA algorithm shown in Figure 1 may assist physicians in a justed overall mortality in landmark phase III DOAC trials was 4.72%/
rational selection of a specific DOAC according to drug–drug interactions year, with cardiac death contributing for 46% of deaths [83], all-cause
and other clinical risk factors [2]. mortality in real-world older patients are definitely higher, with dif-
In RW clinical practice reduced-dose DOACs, particularly of apixaban, ference in cause-specific mortality. In the ORBIT-AF registry, patients
are largely used, mainly in the oldest patients and with poor health status not on OAT (mean age 73 years) experienced higher mortality rates
[72-75]. Inappropriate DOAC under-dosing is associated with increased risk (7.42 vs 5.78%, p=0.006) over a 2.5 years follow-up without sig-
of stroke/thromboembolism and hospitalization [73, 75, 76]. Indeed, in- nificant differences in thromboembolic event rates, compared with
appropriate low dose regimen is associated with lower DOAC levels [77] patients receiving OAT [84]. In a prospective study in nonagenarians
and with increased thromboembolic risk [78]. AF patients eligible for DOAC with AF receiving OAT, the rate of ischemic stroke/TIA/systemic em-
reduced-doses represent a common and troublesome scenario in clinical bolism was low (2.4%) with a not negligible rate of major bleeding
practice, as it has been recently demonstrated that these patients are at (5.5%), within the context of high one-year all-cause mortality rate
increased risk both of thromboembolic and hemorrhagic complications [72, (17.2%) [85]. Data from the Galician Healthcare Service showed that
79, 80]. However, in phase III DOAC trials patients who were appropriately among patients aged 80 years and older (45.6% of those with AF) two-
dose-adjusted, had a better benefit/harm ratio compared to warfarin [79]. year all-cause mortality was higher than in younger counterparts
A post-hoc analysis of the ARISTOTLE trial demonstrated that patients (27.8% vs 8.05%, p < 0.001), as well as thromboembolic and hemor-
fulfilling just one of the pre-specified criteria for apixaban dose-reduction, rhagic events (2.03% vs 0.9%, p < 0.01 and 2.5% vs 1.7%, p=0.01,
and appropriately treated with the standard dose, had similar rates of major respectively) [86]. In two studies including hospital discharged older
bleedings compared to those receiving full-dose apixaban in the absence of AF patients (mean age over 80 years) we documented high mortality
any dose-reduction criteria [81]. Therefore, adherence to DOAC approved rates, mainly for non-cardiovascular causes, which were about two-fold
dose should be recommended also in older patients, along with the EHRA higher in untreated patients, reflecting the higher proportion of poor
recommendations for a rational selection of DOAC (Figure 1). health status in these latter patients [16, 87]. Indeed, it has been de-
monstrated that the large reduction in thromboembolism with OAT use
3. Clinical uncertainties and open questions (HR=0.57, 95% CI=0.50-0.65) may be substantially attenuated after
accounting for competing death events (HR=0.87, 95% CI=0.77-0.99)
Despite recent studies reinforced the evidence of net clinical benefit [88]. Furthermore, mortality in individuals not prescribed OAT is
of OAT, including DOACs, in extremely elderly community-dwelling markedly higher than in those receiving OAT, and not accounted for by
persons (aged > =85 years) [82], prescription of OAT to older AF an excess of thromboembolic fatal events, but rather reflecting the
patients is often a troublesome decision, involving a global evaluation higher proportion of oldest old with complex comorbidities and poor
of health, residual life-expectancy, functional and cognitive status, health status in untreated population [88]. Data from the Swedish

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M. Bo and N. Marchionni European Journal of Internal Medicine 71 (2020) 32–38

National Patient Registry [89] demonstrated that, although AF is an Patients With Atrial Fibrillation Within a Primary Care Network Associated With the
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