Thromboembolism in Older Adults

Abstract

Arterial and venous thromboembolism are both more common in older adults. The use of anticoagulants, the mainstay to prevent thromboembolism, requires consideration of the balance between risk and benefit. Such consideration is even more important in the very elderly in whom the risk of anticoagulant-related bleeding and thrombosis are higher. This review will focus on the challenges of implementing and managing anticoagulant therapy in older patients in an era when the options for anticoagulants include not only vitamin K antagonists (VKAs), but also direct-acting oral anticoagulants (DOACs).

Full text

REVIEW
published: 27 January 2021
doi: 10.3389/fmed.2020.470016
Frontiers in Medicine | www.frontiersin.org 1January 2021 | Volume 7 | Article 470016
Edited by:
Maw Pin Tan,
University of Malaya, Malaysia
Reviewed by:
Danuza Esquenazi,
Oswaldo Cruz Foundation
(Fiocruz), Brazil
Paolo Prandoni,
Arianna Foundation on
Anticoagulation, Italy
*Correspondence:
Peter L. Gross
peter.gross@taari.ca
Specialty section:
This article was submitted to
Geriatric Medicine,
a section of the journal
Frontiers in Medicine
Received: 03 May 2019
Accepted: 21 December 2020
Published: 27 January 2021
Citation:
Gross PL and Chan NC (2021)
Thromboembolism in Older Adults.
Front. Med. 7:470016.
doi: 10.3389/fmed.2020.470016
Thromboembolism in Older Adults
Peter L. Gross*and Noel C. Chan
Department of Medicine, Thrombosis and Atherosclerosis Research Institute, McMaster University, Hamilton, ON, Canada
Arterial and venous thromboembolism are both more common in older adults. The use of
anticoagulants, the mainstay to prevent thromboembolism, requires consideration of the
balance between risk and benefit. Such consideration is even more important in the very
elderly in whom the risk of anticoagulant-related bleeding and thrombosis are higher. This
review will focus on the challenges of implementing and managing anticoagulant therapy
in older patients in an era when the options for anticoagulants include not only vitamin K
antagonists (VKAs), but also direct-acting oral anticoagulants (DOACs).
Keywords: atrial fbrillation, venous thomboembolism, direct-acting anticoagulant, vitamin K antagonist (VKA), falls
among older adults, COVID-19
GENERAL CONSIDERATIONS IN THE ANTITHROMBOTIC
MANAGEMENT OF OLDER ADULTS
Thromboembolism is a preventable cause of morbidity and mortality in older patients and
the most effective strategy to prevent these outcomes is anticoagulant therapy. Effectively
implementing this therapy in older adults is, however, challenging because contraindications
and factors that complicate anticoagulation are more prevalent with increasing age (Table 1
and Figure 1). Prevalent features that complicate anticoagulant management in older adults
are: non-adherence, falls, chronic kidney disease (CKD), polypharmacy, food-drug, and drug-
drug interactions. At a prescriber level, concerns about bleeding have led to the underuse and
underdosing of anticoagulants in this population. In this review, we highlight issues that complicate
anticoagulation therapy in older patients, discuss up-to-date evidence that will facilitate the
assessment of the risk and benefit of anticoagulation therapy, and promote its rational use in older
patients with AF or at risk of venous thromboembolism.
Adherence
Factors contributing to non-adherence are more common in older patients (1) and non-adherence
to a prescribed anticoagulant regimen predisposes to therapeutic failure. Because of differences
in the half-lives of VKAs and DOACs, the impact of omitting medications may differ. DOACs
have a more rapid offset of action than VKAs (2), and there is concern that missing DOAC doses
might result in an inadequate antithrombotic effect more readily than with a VKA. However,
the concentration threshold associated with a lack of benefit for each DOAC is unclear (3).
On-the-other-hand, VKAs need to be dose adjusted according to the INR. Missing doses is
associated with under-anticoagulation and extra doses are associated with over-anticoagulation
(4), but missed doses, that a prescriber is unaware of, might lead to inappropriate dose increases,
and subsequent over-anticoagulation. For VKA, adherence to treatment not only requires taking
the drug but also to INR monitoring and taking the correct dose, a regimen which might not be
simple. In the very elderly in whom auditory, visual, cognitive, or mobility limitations are common,
the requirement for dose adjustment based on laboratory INR monitoring can be burdensome
(5). There is no evidence that the lack of routine laboratory monitoring contributes to decreased
adherence or persistence to therapy with DOACs. However, the particular dosing regimens (once
daily or twice daily) or food requirement (rivaroxaban needs to be taken with food to optimize
absorption) of a DOAC might influence adherence.

Gross and Chan Thromboembolism in Older Adults
Falls
Falls are more common in the very elderly and are often used as
a justification to avoid anticoagulation (6). However, the decision
to use or to avoid anticoagulant therapy in such patients needs
to take into perspective the risk of harm from falls (particularly
the risk of traumatic intracranial bleeding) and the benefit of
preventing thromboembolism. Despite the risk of traumatic
intracranial hemorrhage, compared with no anticoagulation,
observational data suggest a benefit of anticoagulant therapy
in older AF patients at risk of falls, who have an estimated
annual risk of stroke above 5% (7). Similarly, a modeling
study showed that older patients with AF with an additional
risk factor for stroke would have to fall 295 times a year for
the risk of a subdural hematoma to outweigh the reduction
in stroke risk with anticoagulant therapy (8). In a trauma
registry of ground-level falls, neither intracranial bleeding nor
TABLE 1 | Contraindications to anticoagulant therapy in older patients.
Absolute contraindication
Active bleeding
Relative contraindications
Amyloid angiopathy
Recent intracranial bleed or major bleeding
Recurrent GI bleeding not responsive to intervention
Severe hypertension
Recent major surgery (e.g., neurosurgical)
Bleeding diathesis or severe thrombocytopenia
FIGURE 1 | Challenges in managing thromboembolism in older patients.
mortality was higher in patients on VKA than on antiplatelets
(9). Also, our ability to predict who will fall and incur bleeding
is poor; in one study, those classified as high risk of falls
had only a 1.09-fold higher annual risk of bleeding than those
classified as low risk of falls (10). Thus, the evidence that
anticoagulation causes substantial harm in AF patients with falls
is lacking.
Chronic Kidney Disease
Chronic kidney disease (CKD) is more common in the elderly.
Like age, CKD is a risk factor for both thrombosis and
bleeding. Although there is a lack of high-quality evidence
for anticoagulation in AF patients with severe CKD (estimated
glomerular filtration rate (eGFR) <30 ml/min/1.73 m2) or end-
stage CKD (eGFR <15 ml/min/1.73 m2), VKAs have been used in
those patients. A meta-analysis of 11 cohort studies showed that
compared with no anticoagulation, warfarin was associated with
a lower risk of stroke/thromboembolism or mortality without
appreciable increase in major bleeding in AF patients with
severe CKD (11). In contrast, warfarin was associated with an
increase in the risk of major bleeding without reduction in
stroke/thromboembolism or mortality in patients with end-stage
CKD requiring dialysis. The DOACs have varying degree of
renal clearance and as such renal function is a criterion in the
selection of dose. In the trials evaluating the DOACs in stroke
prevention in AF (SPAF), patients with creatinine clearance
(CrCl) <30 ml/min were excluded. Although most regulatory
labels indicate a CrCl <15 ml/min as a contraindication for
use of a DOAC, most treatment guidelines recommend caution
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Gross and Chan Thromboembolism in Older Adults
when using DOACs in AF patients in patients with CrCl
15–30 ml/min.
Polypharmacy
Polypharmacy, defined by the use of multiple medications,
is very common in older adults and is associated with
increased comorbidity, drug-drug interactions, and worse
clinical outcomes. In the pivotal SPAF trials of apixaban
and rivaroxaban, polypharmacy was associated with increased
thromboembolism, bleeding, and mortality. Therefore, caution is
required when managing anticoagulant therapy in older patients.
Polypharmacy (defined as ≥5 drugs in the ARISTOTLE trial)
was observed in 76.5% of enrolled patients and was more
prevalent in older patients. In this trial, patients taking ≥9
concomitant drugs had a 1.5, 1.7, and 2-fold increase in the risk
of stroke/SEE, major bleeding, and mortality, respectively, than
those taking <5 drugs (12). Likewise, in the ROCKET-AF trial,
patients taking ≥10 drugs had a 1.4 and 1.5-fold increase in
the risk of major cardiovascular events and clinically relevant
bleeding, respectively, when compared with those taking <5
drugs (13). In both trials, the treatment effect of the DOACs
vs. VKAs on stroke or systemic embolism was not mitigated
by polypharmacy but it diminished the safety advantage of
the DOACs.
Drug-Drug Interactions
Drug-drug interactions are especially relevant in older patients
because polypharmacy is common. Cardiovascular drugs,
analgesic medications, antimicrobial agents, and drugs acting on
the central nervous system are common drug classes that interact
with anticoagulants in older patients.
Antiplatelets and non-steroidal anti-inflammatory drugs
(NSAIDS) are the most common drugs implicated in adverse
drug-drug interactions with anticoagulants. Aspirin increases
the risk of bleeding in patients receiving a VKA by 2-
fold. For the DOACs, the increased risk of bleeding with
concomitant aspirin is 1.3–1.6-fold (14–17). Most guidelines
recommend that concomitant aspirin or NSAID use be avoided
with anticoagulant therapy, except in circumstances in which
there is a strong clinical indication such as after an acute
coronary syndrome or after a intravascular stent implantation
in the setting of coronary artery or carotid or peripheral
artery disease. Concomitant use of NSAIDS is associated with
a similar increased risk of bleeding as aspirin and thus should
be avoided.
Drug-drug interactions with VKAs include medications that
inhibit or induce cytochrome P450 enzymes, contain vitamin
K, or alter gastrointestinal flora that metabolize vitamin K
(18). Edoxaban and dabigatran are P-glycoprotein substrates,
thus drugs that inhibit P-glycoprotein result in higher levels
of these anticoagulants. Rivaroxaban and apixaban have a
dual mode of clearance, including clearance by efflux pumps
such as P-glycoprotein in the kidneys and gastrointestinal
system and metabolism by hepatic cytochrome P450-3A4
subtype. Drugs that induce the activity of both P-glycoprotein
and cytochrome P450-3A4 result in very low levels of
rivaroxaban and apixaban, examples of such medications include:
phenytoin, carbamazepine, St. John’s Wort and rifampin. The
use of rivaroxaban and apixaban with these medications
is contraindicated.
Food-Drug Interactions
Food-drug interactions complicate VKA management, whereby
vitamin K-rich foods can quickly reduce the anticoagulant effect.
Of the DOACs, rivaroxaban needs to be taken with food for
optimal absorption.
Frailty, Dependency, and Cognitive
Function
Randomized prospective studies evaluating the effects of
anticoagulants in the elderly likely include subjects with less
frailty, dependency, and less cognitive dysfunction than in the
real world. Cohort studies that include patients with these factors
(19–21) have lower use of anticoagulation. Age and frailty alone
should not deter the use of anticoagulation when there is a
clinical indication. Both DOACs and warfarin are effective in
preventing thrombosis but each has specific advantages and
disadvantages which need to be taken into account when
selecting an anticoagulant in this population. Advantages of the
DOACs include less drug interactions, more simplified dosing
and lower risk of intracranial bleeding than warfarin, but some
DOACs may have a higher risk of gastrointestinal bleeding. How
dependency and cognitive impairment alter the perception of
the benefit of anticoagulants in stroke and venous thrombosis
prevention in patients, caregivers and prescribers, is not well-
studied (22).
ARTERIAL THROMBOSIS—STROKE
PREVENTION IN ATRIAL FIBRILLATION
(SPAF)
Atrial fibrillation (AF) is an abnormal cardiac rhythm that
increases the risk of stroke by 5-fold (23–26). The incidence of
AF increases with age, doubling every decade; it is about 5% a
year in those in their 70’s and 10% in those in their 80’s (27). The
case-fatality rate of a stroke with AF is 50% at 1 year, which is
double that of a non-cardioembolic stroke (28–30). Similarly, the
morbidity of a stroke associated with AF is higher than a non-
cardioembolic stroke, 41% of patients with a stroke related to
AF are bedridden. Anticoagulant therapy is the most effective
strategy to prevent cardioembolic stroke. Thus, compared with
placebo or untreated control, VKAs adjusted to an INR range
of 2–3 reduce the risk of stroke or systemic embolism by
64%. Shockingly, in an era when VKAs were the only available
anticoagulants, anticoagulant use in the elderly declined with
increasing age (31,32); a 5-year increment in age was associated
with 0.6 [95% confidence interval (CI) 0.5–0.9] fold reduction
of VKA use in patients with AF. Even more astounding is that
in optimal environments (single government payer of medical
care and medications), anticoagulation in patients with AF is
underutilized and up to 50% of eligible AF patients did not
receive VKA therapy (33).
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The DOACs have been evaluated as alternatives to VKA.
Pooled data from 4 large randomized trials indicate that
compared to VKAs, DOACs significantly reduce stroke or
systemic embolism by 19%, major bleeding by 14% and mortality
by 10%. Importantly, irrespective of the degree of INR control,
the DOACs had better risk-benefit profile than warfarin (34).
Accordingly, several guidelines recommend anticoagulation to
prevent stroke in AF and prefer the use of the DOACs over
VKAs in most patients (35); a notable exception include AF
patients with mechanical heart valve, in whom DOACs are
contraindicated and warfarin is still preferred based on data from
the RE-ALIGN trial (36). In addition, guidelines currently prefer
warfarin over DOACs in AF patients with severe mitral stenosis
or with a bioprosthetic valve, conditions that are more prevalent
with age, because these patients were underrepresented in the
pivotal AF trials. Emerging evidence from a recently completed
and from ongoing randomized trials may lead to practice change
in the future. Thus, in the recent RIVER trial, that enrolled 1,005
patients with atrial fibrillation and a bioprosthetic mitral valve,
rivaroxaban was non-inferior to warfarin with respect to the
mean time until the primary composite outcome of death, major
cardiovascular events and major bleeding (37).
The Elderly in the DOAC Trials of SPAF
Four major SPAF trials (38–41) compared the DOACs with
VKAs adjusted to an INR range of 2–3. These trials included
22,283 patients aged ≥75, which represented 38% of the overall
population. The risk reduction (RR) in stroke and systemic
embolism was similar (P-interaction =0.38) in patients ≥75
years old (RR 0.78; 95% CI: 0.66–0.88) and in those <75 years
old (RR 0.85; 95% CI: 0.73–0.99) for the comparison of DOACs
vs. VKAs. Likewise, the risk reduction in major bleeding was
similar (P-interaction =0.28) in those ≥75 years old (RR 0.93;
95% CI: 0.74–1.17) and in those <75 years old (RR 0.79; 95%
CI: 0.67–0.94) (42). Therefore, older patients in the trials had
similar benefit in stroke reduction on a DOAC when compared
with warfarin.
In patients with AF who have failed or are unsuitable for
warfarin, the AVERROES trial showed that apixaban significantly
decreased the risk of stroke or systemic embolism (Hazard Ratio
[HR] 0.45; 95% CI: 0.32–0.62) without increasing the risk of
major bleeding (HR 1.13; 95% CI: 0.74–1.75) when compared
with warfarin (43). In this trial, the absolute rates of stroke or
systemic embolism in patients ≥85 were 1.0%/year on apixaban
and 7.5%/year on aspirin (HR 0.14; 95% CI 0.02–0.48) and the
rates of major bleeding were similar on apixaban and aspirin
(4.7% and 4.9%/year) (44). In the recent ELDERCARE-AF
trial, that included older Japanese patients with AF (age ≥80
years), compared with placebo, low dose edoxaban (15 mg daily)
significantly reduced the rate of stroke or systemic embolism (2.3
vs. 6.7%/year, HR 0.34; 95% CI: 0.19–0.61) without significant
increase in the rate of major bleeding (3.3% vs. 1.8%/year, HR
1.87; 95% CI: 0.90–3.89) (45). These findings highlight that older
patients with AF remain at high risk of stroke if untreated
or given aspirin. Because older patients have higher baseline
ischemic risk (46), they stand to benefit the most from the use
of an anticoagulant (47–52).
Practical Considerations in Dosing DOACs
for SPAF in the Elderly
Age is an independent criterion for dose adjusting dabigatran
and apixaban (53). For apixaban, age ≥80 is one criterion (the
others being weight ≤60 kg and serum creatinine ≥133 mM) for
selection of the 2.5 mg BID over the 5 mg BID. In the RE-LY trial,
compared to younger patients, those aged ≥80, or ≥75 who had
an additional bleeding risk factor, had a higher risk of bleeding
on the 150 mg BID dose, so such patients are usually given the
110 mg BID dose, where it is available, or 75 mg BID in the US
for Cockroft-Gault creatinine clearance (CrCl) between 15 and
30 ml/min. Both edoxaban and rivaroxaban have recommended
dose reductions if the CrCl is under 50 mL/min. Age is an
important factor in the CrCl calculation. Thus, the usual dose of
edoxaban is 60 mg daily, but is reduced to 30 mg daily for CrCl
between 15 and 50 ml/min and the usual dose of rivaroxaban is
20 mg daily but is reduced to 15 mg for CrCl between 15 and 50
ml/min. It is important that the labeled dosing of the DOACs,
although complicated, be followed to minimize the risk of DOAC
under- or overexposure. Post-marketing studies have reported a
high prevalence of underdosing, particularly with apixaban (54–
56). Off-label dosing has been associated with inferior efficacy
(57,58). Like the results of the phase 3 trials, observational studies
showed that the DOACs are at least as effective as VKA and are
associated with less intracranial hemorrhage in older patients but
some DOAC regimens have been associated with a higher risk
of gastrointestinal bleeding. Therefore, caution is required when
selecting a DOAC in those at risk of GI bleeding (59,60).
The Case to Continue VKA in a Stable
Patient
An open question is whether to switch an older person who is
optimally anticoagulated with a VKA (with an excellent time
in therapeutic range [TTR]) to a DOAC. Most of the patients
in the major DOAC SPAF trials enrolled subjects who were
new to anticoagulation. Excellent TTR is associated with better
outcomes (61). Thus, it might be reasonable for a patient with
an excellent TTR to remain on VKAs (48). It is impossible to
match subjects with excellent TTR on VKA to another subject
receiving a DOAC. In the major DOAC trials, center TTR, which
is the average TTR of patients in that center, correlated inversely
with bleeding and ischemic events (62–64). Although one of the
reports matched patients with good TTR on VKA with DOAC
patients and found that the DOAC benefits remain (64).
VENOUS THROMBOEMBOLISM IN THE
ELDERLY
Venous thromboembolism (VTE), which includes deep vein
thrombosis (DVT) and pulmonary embolism (PE), occurs in
about 1 in 1,000 persons each year. Incidence rises with age to
at least 5 in 1,000 persons in those aged ≥80 (65). Less people
present with PE, than DVT alone. Within 1 month of diagnosis,
death occurs in ∼6% of patients with DVT and 12% of those with
PE (66).
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Physiological changes in the hemostatic system, such as
increasing levels of procoagulant factors (factor VIII, factor VII,
and fibrinogen) together with impairment in the fibrinolytic
pathway, that occur with aging contribute to the higher risk of
VTE in older patients (67). In addition, acquired risk factors, such
as cancer and chronic inflammatory disease, are more common
and accentuate the risk of VTE in older patients. Not surprisingly,
about two-thirds of all VTE events occur in patients over 70 years
of age (68).
Acquired risk factors may be found about 50% of patients
with VTE and can be categorized into those that are persistent
or transient as well as those that are major or minor.
Examples of major transient risk factors are surgery, trauma
and hospitalization for acute medical illness. With the expanding
coronavirus disease (COVID) 2019 pandemic, which has already
affected millions of people globally, hospitalization with severe
acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is
becoming a topical and common acquired risk factor for
VTE, particularly in older patients who have higher risks of
severe illness, respiratory failure requiring ICU admission, and
death (69).
Emerging data indicate that in hospitalized patients with
COVID-19, the rates of VTE are high, with estimates ranging
from 4.8 to 33.7% despite prophylactic anticoagulation (70–72).
The highest VTE rates occur in older patients, in whom the
reported rates may be about 1.5–2-fold higher (73). Because of
the high VTE risk, many physicians are calling for intensified
prophylactic anticoagulation or the empiric use of therapeutic
anticoagulation in hospitalized patients with severe COVID-
19, but intensifying anticoagulant therapy could result in an
even higher risk of bleeding, particularly in critically ill older
patients. In a multicenter retrospective study of 400 hospitalized
patients with COVID-19 who were receiving prophylactic doses
of anticoagulant, the rate of major bleeding was already high,
at about 5.6%, and in those with bleeding risk factors such
as thrombocytopenia, the corresponding rate was 3-fold higher
(70,72).
Guidance statements from the International Society on
Thrombosis and Haemostasis (ISTH) discourage the use of
treatment-dose heparin for primary VTE prevention, and are
emphasizing the need for universal prophylaxis with standard-
dose UFH or LMWH in hospitalized COVID-19 patients, and
suggest a 50% increase in the dose of anticoagulant prophylaxis
in critically ill patients at the highest risk of VTE or in
obese patients in the absence of bleeding contraindications
but there is no specific recommendation based on age (74).
Ultimately, identifying the optimal approach to prevent VTE
in older patients with COVID-19 requires evaluation in
randomized trials.
Up to 50% of patients with VTE have no identifiable
risk factors and are classified as having unprovoked VTE.
Such distinction is important because in general, patients with
unprovoked VTE have higher lifetime risk of VTE recurrence
after discontinuing anticoagulant treatment, with the risk of
FIGURE 2 | The dynamic between thromboembolic and bleeding risks according to age in various settings. The figure shows the dynamic between thromboembolic
and bleeding risks according to age and to clinical indications. In the acute VTE setting, without anticoagulant therapy, the risk of recurrent VTE is very high
irrespective of age. Although bleeding risk on anticoagulation increases with age, anticoagulant therapy is associated with a net clinical benefit in acute VTE treatment
in younger and older patients. In the secondary VTE prevention setting, the risk of VTE recurrence after a treated index event is lower compared to the acute VTE
setting and similar in both younger and older patients. Because of higher bleeding risk, the benefit of anticoagulation for secondary VTE prevention is likely reduced in
older patients compared with younger patients. Consequently, VTE guidelines are less strong in recommending extended anticoagulation in older patients. By
contrast, the risk of cardioembolic stroke in AF rises with age and thus most older patients continue to benefit from anticoagulant therapy despite a higher bleeding
risk. Despite the similar definition of major bleeding, the consequence of a venous thromboembolic event and an arterial thromboembolic event are not equal. Green,
thromboembolic risk in absence of anticoagulant therapy; Red, major bleeding risk with anticoagulation.
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Gross and Chan Thromboembolism in Older Adults
recurrence being at least 10% at 1 year and 30% at 5 years (75).
The case fatality rate of a recurrence is 11% (76). The rate of
recurrent VTE declines over time after the index event (77). This
is a key distinguishing feature between VTE and SPAF in the
elderly (Figure 2). Age remains a risk factor for anticoagulation-
related bleeding in VTE patients. Thus, although the risk of VTE
increases with age, guidelines have less strongly recommended
extended anticoagulation in the elderly than in younger patients.
VTE Treatment: The elderly in DOAC Trials
of VTE
The four major DOAC VTE treatment trials (78–81) randomized
patients to low molecular weight heparin (LMWH) bridging to
VKA, or to DOAC with or without initial treatment with LMWH.
The median age of subjects in these studies was between 55 and
60 years of age; the edoxaban study (82) reported that about 15%
of patients were aged ≥75. Thus, the number of elderly patients
represented in these randomized trials in acute VTE treatment
was 3,294, which was less than in the SPAF trials. In those ≥75
years old, compared with VKAs, DOACs reduced recurrent VTE
by 45% and major bleeding by 61% (83). A real-world study (84)
reported outcomes of recurrent VTE and bleeding in over 12,000
patients on rivaroxaban and apixaban; 35% of the subjects were
aged ≥65. Crude rate of major bleeding was about 2-fold higher
in those ≥65 years old, but recurrent VTE was not more common
in older patients. Although the results are reassuring, it is unclear
how many very elderly patients were included.
Practical Considerations in Dosing DOACs
for VTE Treatment in the Elderly
VTE treatment is divided into initial (first week after the
event), long-term (next 3 months after the event), and extended
(3 months to indefinite) periods (77,85). In the four major VTE
treatment trials evaluating the DOACs for initial and long-term
treatment, DOAC doses were not adjusted for age. The edoxaban
study lowered the dose for subjects under 60 kg and with a CrCl
between 30 and 50 mL/min (17% of the subjects), thus age was
an indirect factor in dose reduction in this study, and subjects
receiving low dose edoxaban had a similar benefit. Thus, in the
absence of data, elderly patients with acute VTE treated with
DOACs usually receive the standard doses initially. But, given
that lower doses of apixaban and rivaroxaban have been validated
as being effective and with a trend to less clinically relevant
bleeding in extended treatment of unprovoked VTE and VTE
provoked by minor risk factors (81,86), it seems reasonable to
consider these lower doses in elderly patients who need or prefer
extended anticoagulation to prevent recurrent VTE.
CONCLUSION
Both arterial and venous thromboembolism are more common in
older adults, but so is the risk of anticoagulant-related bleeding.
Because the risk of recurrent venous thrombosis decreases after
the index event, unlike the persistent bleeding risk associated
with extended anticoagulation, stopping anticoagulant therapy
for secondary VTE prevention in some older adults can be
considered. However, the risk of stroke in AF continues to
increase with age and most older patients with AF benefit from
continuing anticoagulant therapy. Although preventing stroke
in AF has huge social and health economic benefits, older
adults with AF remain undertreated despite the introduction
of the DOACs. Bleeding remains an important complication
of anticoagulation that contributes to under treatment in older
patients at risk of thrombosis. Consequently, there is an unmet
need for safer anticoagulation therapy. Trials are now underway
to examine whether newer DOACs inhibiting FXI or FXII will be
effective and safer.
AUTHOR CONTRIBUTIONS
PG and NC wrote and edited the manuscript. Both authors
contributed to the article and approved the submitted version.
ACKNOWLEDGMENTS
NC was supported by a McMaster University Department of
Medicine Internal Career Research Award.
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Conflict of Interest: PG has received consulting fees from Bayer, Bristol-Myers-
Squibb, Pfizer, Leo Pharma, Servier Canada and Valeo Pharma. NC reports a
speaker fee from Bayer outside the submitted work.
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