Journal of Thrombosis and Thrombolysis

https://doi.org/10.1007/s11239-021-02415-5

Current use of rivaroxaban in elderly patients with venous

thromboembolism (VTE)
Xin Zhang1 · Qiyan Cai1 · Xiaohui Wang1 · Ke Liao2 · Changchun Hu1 · Hong Chen1 

Accepted: 16 February 2021

© The Author(s), under exclusive licence to Springer Science+Business Media, LLC part of Springer Nature 2021

Abstract
Venous thromboembolism (VTE), which is characterized by pulmonary embolism and deep vein thrombosis, has become a
serious public concern. Notably, over half of the patients with VTE are over 70 years of age, but elderly patients are at high
risk of anti-coagulation and bleeding, which increase with age. Moreover, risk factors and frailty also show a difference
between elderly patients and ordinary patients diagnosed with VTE. Rivaroxaban is a direct inhibitor of activated factor Xa
and has the advantage of predictable pharmacodynamics and pharmacokinetics, no coagulation monitoring, and few drug
interactions. As a first-line therapy for VTE, this drug is more advantageous than traditional therapy and exhibits good effi-
cacy and safety for ordinary patients. However, the effectiveness and safety of rivaroxaban in elderly patients have not been
fully elucidated. This article reviewed the use of rivaroxaban in elderly patients, including drug interactions, monitoring,
reversal agents of rivaroxaban, and the use of small dosages of rivaroxaban in elderly patients.

Keywords  Rivaroxaban · Elderly patients · Venous thromboembolism · Pulmonary embolism · Deep vein thrombosis

Highlights • The article also conducted the risk factor, monitor and
the reversal agents in elderly patients used rivaroxaban.

• Elderly patients diagnosed VTE are special individuals

during the use of rivaroxaban. Introduction
• The article reviewed the clinical treatments related to
rivaroxaban and elderly patients. Venous thromboembolism (VTE), which is characterized
by pulmonary embolism (PE) and deep vein thrombosis
(DVT), has become a serious public concern in recent
* Hong Chen years. The overall annual prevalence is 0.1% per year
hopehong2019@126.com in adult patients, but has increased sharply to 1% in the
Xin Zhang elderly, and the risk doubles every decade beyond the age
1215453439@qq.com of 40 [1–3]. In the community setting, more than 60% of
Qiyan Cai VTE events occur in patients of age 65 and above [4]. The
805157188@qq.com increased prevalence in older patients (≥ 65 years of age)
Xiaohui Wang may result from increased risk factors for elderly patients,
404375131@qq.com increased number of comorbidities, pathophysiology
Ke Liao changes in coagulation system, and frailty.
402201983@qq.com The gold standard treatment for VTE patients is low-
Changchun Hu molecular-weight heparin (LMWH) or fondaparinux plus
1131081701@qq.com vitamin K antagonist (VKA) warfarin [5]. However, con-
sidering the initial bridging therapy with LMWH or fonda-
1
Department of Pulmonary and Critical Care Medicine, The parinux, variable pharmacokinetics, multiple drug interac-
First Affiliated Hospital of Chongqing Medical University,
Chongqing, China tions, genetic polymorphisms that do not respond to warfarin,
2
and increased bleeding risk, suitable anticoagulation with
Chongqing Medical University, Chongqing, China

13
Vol.:(0123456789)
 X. Zhang et al.

warfarin is hardly achieved [5–9]. Rivaroxaban is a direct
inhibitor of activated factor Xa. Considering the predictable
pharmacodynamics and pharmacokinetics of rivaroxaban,
coagulation monitoring is no longer needed in the gen-
eral population. Fewer drug interactions also make it more
advantageous than traditional therapy [10–14]. It peaks in
the plasma at 2–4 h after oral administration with a half-life
of 5–9 h in adults and extends to 11–12 h in patients above
the age of 65; two-thirds of the drug is metabolized by the
liver, while the one-third remaining is renally excreted [15].
The EINSTEIN-PE and EINSTEIN-DVT studies demon-
strated that rivaroxaban could offer equal safety and efficacy
as VKA [16, 17]. Guidelines now recommend the intake of
15 mg rivaroxaban twice daily (bid) for 21 days followed by
20 mg daily (qd) for the management of PE and DVT [14].
However, increased bleeding risk and mortality in elderly
patients were observed after using rivaroxaban [4]. In recent
years, rivaroxaban plays an important role in the pharmaco-
therapy treatment of VTE patients; in the present review,
we specifically discussed notes during the use of rivaroxa-
ban in elderly patients diagnosed with VTE, focusing on
risk factors in older VTE patients, patients with fragility,
different anticoagulant doses of rivaroxaban, drug interac-
tions, monitoring in elderly patients, and reversal agents for
rivaroxaban.
Definition of elderly patients
The elderly, for whom the cut-off point of 65 years was
adopted by the International Conference on Harmonisation
of Technical Requirements of Pharmaceuticals for Human
Use (ICH) E7 guideline on geriatric patients, represent the
fastest growing demographic segment of the patient popula-
tion [18]. In most of these clinical trials, a substantial pro-
portion of participants was over 65 years (Table 1). Elderly
patients are characterized by increased blood levels of
FVIII, increase in other coagulation factors such as plasma
fibrinogen and von Willebrand factor, vascular endothelium
injury in pathogenesis, and pathophysiology [19]. Old age
is regarded as a risk factor in increased bleeding risk when
evaluating the bleeding risk among patients receiving anti-
coagulation treatment [14].
Risk factors for increasing VTE in elderly
patients
Conventional risk factors
Conventional risk factors are attributable risks in the
younger and elderly individuals, and the risk factors below
represent the most common conventional risk factors among
elderly patients with VTE.
Immobility
Trauma, surgery, fractures in the lower limbs, replacements
of joints, and injuries in the spinal cord are risk factors that
are strongly connected with VTE, while oral contraception
in fertile women and infection are also frequent predispos-
ing factors in general individuals [14]. In elderly patients,
immobility, which can increase blood stasis and viscosity,
is strongly connected with the increased risk of VTE. Short-
term bed immobility, which spans for less than 14 days, is
related to a sixfold increase in thrombotic risk in inpatients
over the age of 65 years, and the highest risk time window
is the first four weeks of bed stay [20, 21].

Table 1  Baseline characteristics of the trials and participants of EIN- Comorbidity

STEIN
Study Rivaroxaban Enoxaparin/VKA P value In elderly patients, numerous diseases attributed to VTE risk
can be specifically identified, including cancer, heart failure,
EINSTEIN-DVT [16]
stroke, chronic obstructive pulmonary disease, and diabetes
 Total bleeding 139 (8.1%) 138 (8.1%) 0.77
mellitus. Although the relative risk differs between differ-
 Major bleeding 14 (0.8%) 20 (1.2%) 0.21
ent locations and numerous types of primary tumor, cancer
EINSTEIN-PE [17]
increases the risk of VTE by sevenfold [22, 23]. The overall
 Total bleeding 249 (10.3%) 274 (11.4%) 0.23
risk of VTE in congestive heart failure patients is 2.5- to 3.5-
 Major bleeding 26 (1.1%) 52 (2.2%) 0.003
fold greater than that of patients without congestive heart
EINSTEIN-Extension [16]
failure [24, 25]. Stroke, which is a common disease in old
 Total bleeding 36 (6.0%) 7 (1.2%, placebo)  < 0.001
patients, is related to a 1.3- to 3.5-fold increase in patients
 Major bleeding 4 (0.7%) 0 (Placebo) 0.11
over the age of 65 years [26–28]. Chronic obstructive pulmo-
Buller et al. (2012) [52]
nary disease is also a risk factor for VTE in the elderly, and
 Major bleeding 40 (1.0%) 72 (1.7%) 0.002
it can increase the risk of PE by 1.2- to 1.4-fold in patients
Prins et al. (2013) [9]
aged 60 years or over [29, 30]. A meta-analysis showed that
 Major bleeding 10 (1.3%) 35 (4.5%)
diabetes can increase the risk by almost 50% [31]. Other

13
Current use of rivaroxaban in elderly patients with venous thromboembolism (VTE)
risk factors such as the metabolic syndrome and obesity are
associated with VTE [32].
Pathogenesis and pathophysiology
Although the mechanism has not been fully understood,
increased blood levels of FVIII has been a well-known risk
factor [19]. Aging can lead to a change in the coagulation
cascade through increasing factors, such as plasma fibrino-
gen, von Willebrand factor, coagulation factors V, VII, VIII,
IX, and XI, fibrinolytic proteins, and plasminogen activator
inhibitor 1. Increased concentrations of blood coagulation
factors cause injury to the vascular endothelium, followed
by exposition of tissue factor, collagen and active platelets,
and other blood cells [1, 19, 33]. By contrast, a considerably
lower activity of factor XII is associated with the increasing
risk of VTE in elderly patients [34].
Genetic risk factors
The risk factors of venous thrombosis are usually divided
into genetic and environmental factors. Seven genetic risk
factors are well-established in previous research, includ-
ing factor V Leiden (FVL mutation), prothrombin 20210-
A, fibrinogen gamma, and blood group non-O. The three
other factors are all heterozygous deficiencies of the natural
coagulation inhibitors protein C, protein S, and antithrombin
[35]. In elderly patients, genetic risk factors also play an
important role. FVL mutation can increase the risk of VTE
by fivefold in patients over the age of 60 years [36]. Indi-
viduals with PT20210A mutation also experience a 1.5- to
4.5-fold increased risk of VTE [36, 37].
Through our review, conventional risk factors such as
immobility, comorbidities such as cancer, heart failure,
stroke, chronic obstructive pulmonary disease and diabetes,
increased factor XII, and genetic mutations such as FVL
mutation or prothrombin 20210-A should focused on clinical
practice in elderly VTE patients.
Unconventional risk factors
Although the mechanism has not been fully determined,
unconventional risk factors are almost exclusively present in
elderly patients. These risk factors can be explained partly,
and the most common risk factors are listed below.
Frailty in older VTE individuals
The international group defined frailty as a medical syn-
drome with numerous causes that is distinguished by
decreases in strength and endurance and diminished
physiologic function; it also means increased individual
vulnerability of the development of dependency or death
[38]. The most commonly used phenotype of frailty is the
existence of ≥ 3 of the following five criteria: weight loss,
exhaustion, weak grip strength, low physical activity, and
slow walking speed [39].
A prevalence ranging from 4.0 to 17.0% (mean 9.9%) in
the elderly with physical frailty was described in a system-
atic review that included 31 studies; when including psycho-
social frailty, the prevalence is higher [40]. Frail adults are
special individuals with an association of multiple comor-
bidities, polypharmacy, and physical, functional, and some-
times cognitive impairments [41].
In four US communities, a prospective cohort study that
involved 4859 individuals over the age of 65 showed that
immobility is an important component of frailty and VTE.
Through the activation of coagulation and inflammatory
pathways, frailty can increase the levels of coagulation fac-
tors, especially factor VIII, which has been discussed fre-
quently as a risk factor for VTE [42–44].
However, current research provides certain information
regarding coagulation in frail elderly VTE individuals. A
pooled analysis of the EINSTEIN-DVT and EINSTEIN-PE
studies defined fragility as at least one of the following crite-
ria: age over 75 years old, creatinine clearance < 50 ml/min,
and body weight ≤ 50 kg. This pooled analysis categorized
1573 patients (19.0%) as fragile and revealed that in fragile
individuals, compared with a prevalence of 4.5% in major
bleeding caused by warfarin, rivaroxaban showed a statisti-
cally significant difference of 1.3%; however, these differ-
ences were not observed in non = fragile individuals [9]. A
retrospective study evaluating the effectiveness and safety
between rivaroxaban and warfarin in frail individuals with
VTE suggested that individuals who received rivaroxaban
had a lower recurrent VTE and better bleeding results than
patients administered with warfarin [45]. However, a pre-
vious review recommended warfarin as the first choice of
high bleeding and fall risk [41], possibly because a lack of
antagonist for rivaroxaban during that time. Rivaroxaban can
result in a lower bleeding and recurrent risk than warfarin in
the general population [46]. Therefore, when clinicians face
the difficulty of the choice of anticoagulation, whether with
VKA or direct oral anticoagulants, they should carefully and
properly discuss and document the situation with the patient
and caregiver.
Other unconventional risk factors include muscle
strength, endothelial dysfunction, and venous insufficiency.
Muscle strength can decrease from the age of 50 years [47],
and diminished muscle strength can tightly affect the calf
muscle pump. Thrombosis that causes in elderly patients is
associated with reflux and stasis, and this condition can be
caused by the decreased function of the calf muscle pump
[1]. Endothelial dysfunction is regarded as an age-related
cardiovascular phenomenon [48], and it can be caused by
13

the remodeling of the anatomy of the venous vessel wall,
decreased anticoagulant properties of the endothelium, and
unusual release of anti-inflammatory and anticoagulant fac-
tors [49–51]. Thus, the remodification of the venous ves-
sel wall in the elderly may contribute to increased risk of
thrombosis. The incidence of venous insufficiency increases
with age, but venous insufficiency and the increased risk of
thrombosis in the elderly have not been fully elucidated.
As the most important unconventional risk factor, frailty
is tightly connected to elderly patients who have been diag-
nosed with VTE, and frailty is important in elderly patients.
The use of rivaroxaban in frail elderly individuals will be
further studied.
Clinical treatments related to elderly
patients
EINSTEIN‑PE, ‑DVT, and ‑extension
Guidelines recommend the intake of 15 mg rivaroxaban bid
for 21 days followed by 20 mg qd for the medical treat-
ment of VTE [14]. Three large clinical trials (EINSTEIN-
PE, -DVT, and -extension) have evaluated the safety and
efficacy of rivaroxaban in the treatment of VTE [16, 17],
and the trials related to EINSTEIN are shown on Table 1.
The EINSTEIN-DVT is a large clinical study that compared
oral rivaroxaban (15 mg bid for 3 weeks + 20 mg qd) with
enoxaparin + VKA for 3, 6, or 12 months in 3449 patients
with DVT. Total bleeding episodes were observed in 139
patients (8.1%) administered with rivaroxaban and in 138
patients (8.1%) who received enoxaparin/VKA (P = 0.77).
Fourteen patients (0.8%) experienced major bleeding
when they received rivaroxaban, while 20 patients (1.2%)
experienced major bleeding in the enoxaparin/VKA group
(P = 0.21). The findings illustrated that rivaroxaban provided
an equally safe outcome compared with standard therapy for
acute DVT [16].
The EINSTEIN-PE is also a large randomized clinical
trial that included 4832 patients who were diagnosed with
PE with or without DVT through the comparison of rivar-
oxaban (15 mg bid for 3 weeks + 20 mg qd) with standard
therapy (enoxaparin/VKA) for 3, 6, or 12 months. Total
major bleeding was observed in 249 patients (10.3%) who
received rivaroxaban compared with 274 patients (11.4%)
administered with enoxaparin/VKA (p = 0.23). However,
major bleeding occurred in 26 patients (1.1%) administered
with rivaroxaban and in 52 patients (2.2%) in the enoxapa-
rin/VKA group (p = 0.003). Considering the safety outcome,
the rivaroxaban group showed fewer major bleeding events
and an improved benefit–risk effect [17].
The EINSTEIN-extension study is a large, double-blind
trial that included 1197 VTE patients who, after 6–12
13
X. Zhang et al.
months of anticoagulation with rivaroxaban or enoxaparin/
VKA, were randomly assigned to undergo an extended treat-
ment with rivaroxaban 20 mg qd or placebo for another 6
or 12 months. This trial showed that rivaroxaban can used
as a useful anticoagulation drug in the therapy of VTE, and
through this clinical trial, the principal safety outcome of the
major bleeding rates did not show a difference in rivaroxa-
ban and the placebo [16].
Buller et al. conducted a pooled analysis of the EIN-
STEIN DVT and PE, which enrolled all patients from
EINSTEIN DVT and PE. The results revealed that major
bleeding occurred in 40 (1.0%, three fatal) in the rivaroxaban
group and 72 (1.7%, eight fatal) in the enoxaparin followed
by VKA group (p = 0.002, Table 1). This study not only
revealed that rivaroxaban was non-inferior to enoxaparin/
VKA though different age groups in terms of efficacy but
also revealed that increasing age is possibly associated with
a large decline in major bleeding with rivaroxaban [52].
Prins et al. has conducted another pooled analysis of
EINSTEIN-PE and DVT, and the results revealed rivaroxa-
ban could be beneficial to fragile individuals beyond the
age of 75 years and result in a moderate impairment of renal
function (CrCl 30–49 mL/min) or body weight lower than
50 kg (Table 1). In this pooled analysis, no difference was
observed in recurrence events between oral rivaroxaban and
VKA groups. However, a statistically remarkable difference
in major bleeding was observed in rivaroxaban (1.3%) com-
pared with VKA (4.5%) in fragile individuals (absolute risk
reduction, 3.2%;) [9].
Therefore, EINSTEIN-PE, EINSTEIN-DVT, and EIN-
STEIN-extension have shown that rivaroxaban results in
equal efficacy and safety compared with warfarin, and rivar-
oxaban results in a better safety outcome. However, rivaroxa-
ban can cause bleeding in elderly patients more easily than
ordinary patients. Thus, we have also reviewed the use of
small doses of rivaroxaban in elderly patients.
Another clinical trial included 187 VTE patients,
which were divided into two groups: 57 elderly patients
(age ≥ 75 years) and 130 non-elderly patients, and all the
patients were treated with Xa inhibitors. In the present study,
no remarkable differences were observed between these two
groups in terms of the recurrence rates of VTE (p = 0.194),
bleeding episodes (p = 0.130), and death (p = 0.241). How-
ever, the respective proportions of administration of Xa
inhibitors were 85%:11%:4% for edoxaban, rivaroxaban, and
apixaban. Thus, this study revealed the efficacy and safety
of Xa inhibitors in elderly patients but cannot represent the
outcome of rivaroxaban in elderly patients [53].
A case report presented an 88-year-old woman with DVT
and PE who was administered with 10 mg rivaroxaban bid
and experienced gum bleeding and hemoptysis after five
days. When the dose of rivaroxaban was reduced to 10 mg
qd, the bleeding disappeared gradually after three days. The
Current use of rivaroxaban in elderly patients with venous thromboembolism (VTE)
patient continued a treatment dosage of 10 mg once daily,
and a good outcome was observed after a 90-day follow-
up [54]. Another case report described an 80-year-old male
with a low-to-intermediate mortality risk of PE, and this
patient was successfully treated with 15 mg rivaroxaban bid.
The patient underwent a computed tomographic pulmonary
angiography after seven days of therapy, and improvement
of filling defects was observed in his lower lobes. This case
illustrates that a normal dose can be successfully used in
elderly patients, but the follow-up time was only seven days,
and the final outcome of this patient was not determined
[55].
The EINSTEIN-PE, EINSTEIN-DVT, and EINSTEIN-
extension trials have shown that rivaroxaban has an equal
efficacy as VKA, and the pooled analysis showed that rivar-
oxaban can reduce the risk of major bleeding compared with
warfarin. A reduced dosage of rivaroxaban has also been
reported in some clinical trials and some case reports, and a
reduced dosage has some effect. However, we must acknowl-
edge the limitations of subgroup analyses and the absence
of dedicated clinical trials in the elderly. Thus, more clinical
trials are still needed to confirm this conclusion.
Drug interaction of rivaroxaban
Numerous diseases can be diagnosed in elderly patients,
and multidrug can be easily found in elderly individu-
als. As a substrate for P-gp, rivaroxaban is degraded by
CYP3A4 (major), CYP2J2 (minor), and ABCG2 (minor).
Thus, this drug can interact with drugs that induce or inhibit
these pathways. Concomitant use with strong dual inhibi-
tors of CYP3A4 and P-gp, such as itraconazole, ketocona-
zole, dronedarone, and ritonavir, is not recommend, except
clarithromycin, which can be used together with rivaroxa-
ban, because pharmacokinetic data suggests the absence of
change in the bleeding risk [56]. Combined P-gp and strong
CYP3A4 inducers, such as phenytoin, carbamazepine,
rifampin, and St. John’s wort, should not be used concomi-
tantly with rivaroxaban in clinical practice [57, 58]. Elderly
patients are likely to develop kidney damage in individu-
als with Clcr 15 to 80 mL/min who are administered with
concomitant P-gp and moderate CYP3A4 inhibitors, and
rivaroxaban should be avoided [56]. Drugs that can inhibit
or oppose either CYP3A4 or P-gp do not interact with rivar-
oxaban [59, 60].
Monitoring
Rivaroxaban is an anticoagulation drug that does not need
routine blood monitoring; however, elderly patients, under-
weight individuals, people with renal disfunction, patients
with high bleeding risk, people with comorbidities, indi-
viduals with suspected overdose, and surgical patients may
benefit from monitoring [61–63]. Available coagulation
assays include prothrombin time (PT), activated partial
thromboplastin time (APTT), and anti-Xa assays. Rivar-
oxaban can prolong PT in plasma and show a modest effect
on PT; however, assay sensitivity can vary distinctly with
different thromboplastin reagents[64], and the prolongation
of APTT does not show a linear relationship [65–67]. Anti-
Xa activity and rivaroxaban concentration showed a linear,
concentration-dependent relationship over a wide range of
rivaroxaban concentrations (20–660 ng/ml) [68–72]. A low
(20 ng/ml) or high concentration (800 ng/ml) of rivaroxaban
cannot be detected satisfactorily [67, 73]. Anti-Xa assays can
also measure the concentration of rivaroxaban while using
rivaroxaban calibrators. In addition, negative anti-Xa means
that rivaroxaban is not present in clinically relevant concen-
trations. In comparison with PT and APTT, anti-Xa assay
is the best method for rivaroxaban monitoring, and elderly
patients can largely benefit from monitoring.
Reversal agents
Heparin can be reserved with protamine, and warfarin can
be reversed with vitamin K or plasma administration, but
the reversal of rivaroxaban can be more difficult, although
elderly patients need reversal agents more urgently because
of slower excretion.
Andexanet alfa
As a recombinant, modified human FXa decoy protein,
andexanet alfa can tightly bind with FXa inhibitors. First,
it can block the activity of FXa inhibitors by binding and
isolating FXa inhibitors. Second, it can bind and seques-
ter tissue factor pathway inhibitor tightly as a result of its
similarity to FXa [74, 75]. Phase II trial and Phase III have
demonstrated the safety and effectiveness of this compound
[76–82]. Andexanet alfa has been recommend as a first-line
treatment for the therapy of uncontrolled or life-threaten-
ing bleeding events for factor Xa inhibitors in several cur-
rent guidelines [83–85]. However, when andexanet alfa is
cleared, thrombotic events could occur [81, 86]. Meanwhile,
the high price for andexanet alfa can cause some difficulty
in clinical use [87].
Ciraparantag
Ciraparantag is a small, water-soluble cation that can bind
to Xa inhibitors, including rivaroxaban, through hydrogen
bond and charge–charge interactions and achieves complete
coagulopathy reversal. It can also bind dabigatran, unfrac-
tionated heparin (UF), and LMWH [88]. A phase I trial that
included 80 healthy individuals revealed that ciraparantag
can reverse edoxaban after drug administration [89]. Phase II
13

and III trials will be started in the future. Although adverse
events were not reported formally, transient facial flushing,
allotriogeusia, headache, muscle cramp, and elevations of
creatinine phosphokinase levels can be observed during
administration.
Prothrombin complex concentrate (PCC)
PCC is a mixture of inactive factors II, IX, X, and VII. The
results for PCCs indicate that they are highly unstable in
terms of hemostatic efficacy through different trials. PCCs
may promote hemostasis, but their effects are not completely
effective [90].
Activated PCCs (aPCCs)
While PCC is unsuccessful in blocking the bleeds, aPCCs,
which include factor eight inhibitor bypassing activity
(Shire) and recombinant coagulation factor VIIa (rFVIIa),
are clinically recommended. Both aPCCs have been used in
the off-label management of life-threatening bleeding events
caused by new oral anticoagulants [91–94].
Considering the slow excretion in elderly patients, they
need reversal agents urgently, and andexanet alfa is the only
reversal agent that has been approved and has good effect
for the therapy of uncontrolled or life-threatening bleeding
events because of factor Xa inhibitors. However, its high
price limits its widespread clinical use. Ciraparantag can
not only bind to Xa inhibitors, but is also effective against
dabigatran, UF, and LMWH. However, its efficacy needs to
be clarified further in phase II and III trials. PCC and aPCC
are traditional reversal agents but showed unstable efficacy
in the trials.
Conclusions
Elderly patients are a special group in VTE patients. We can
identify special risk factors in elderly patients with VTE.
Although rivaroxaban has been regarded as a first-line treat-
ment for VTE based on the guidelines, rivaroxaban should
be used with caution in elderly patients, especially in frail
patients. Considering the lack of widespread use of rever-
sal agents and the associated drug interactions, rivaroxaban
requires special monitoring in elderly patients.
Future directions
More clinical trials on the VTE treatment of elderly patients
by using rivaroxaban should be conducted to determine
the safety and efficacy of rivaroxaban in elderly patients.
13
X. Zhang et al.
Moreover, an increased bleeding risk limits the effect of
anticoagulation in elderly patients, and the effectivity of a
lower dosage of rivaroxaban in elderly patients needs to be
further confirmed. Moreover, fragile individuals comprise
age-specific risk groups of VTE patients, and this special
group requires further study. Furthermore, the prevention of
VTE recurrence in the elderly, managing VTE with novel
oral anticoagulants in the elderly, and the effect of cancer on
elderly patients with VTE are needed to be further studied.
Author contributions  Dr. XZ and Dr. QC contributed equally to this
work as the first author.
Declarations 
Conflict of interest  At the end of this manuscript, we declare that none
of the authors has any conflict of interest to indicate.
Informed consent  Informed consent for publication was obtained from
all participants, and this work has been approved by the First Affiliated
Hospital of Chongqing Medical University.
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