Review Article

Evolving use of new oral anticoagulants for treatment of

venous thromboembolism
Calvin H. Yeh,1,2,3 Peter L. Gross,1,3 and Jeffrey I. Weitz1,2,3
1
Department of Medicine and 2Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, Canada; and 3Thrombosis and
Atherosclerosis Research Institute, Hamilton, ON, Canada

The new oral anticoagulants (NOACs),
which include dabigatran, rivaroxaban,
apixaban, and edoxaban, are poised to
replace warfarin for treatment of the major-
ity of patients with venous thromboembo-
anticoagulant therapy for prevention of
recurrence and are associated with less
bleeding. Rivaroxaban and dabigatran are
already licensed for VTE treatment in the
United States, and apixaban and edoxa-
unique design features of the phase 3
trials that evaluated the NOACs for VTE
treatment, (3) reviews the results of these
trials highlighting similarities and differ-
ences in the findings, (4) provides per-

Downloaded from http://ashpublications.org/blood/article-pdf/124/7/1020/1383171/1020.pdf by guest on 27 September 2021

lism (VTE). With a rapid onset of action
and the capacity to be administered in
fixed doses without routine coagulation
monitoring, NOACs streamline VTE treat-
ment. In phase 3 trials in patients with
acute symptomatic VTE, NOACs have been
shown to be noninferior to conventional
ban are under regulatory consideration for
this indication. As the number of approved
drugs increases, clinicians will need to
choose the right anticoagulant for the
right VTE patient. To help with this decision,
this review (1) compares the pharmaco-
logic profiles of the NOACs, (2) outlines the
spective about which VTE patients should
receive conventional treatment or are can-
didates for NOACs, and (5) offers sug-
gestions about how to choose among the
NOACs. (Blood. 2014;124(7):1020-1028)

Introduction
Venous thromboembolism (VTE), which includes deep vein throm-
bosis (DVT) and pulmonary embolism (PE), occurs for the first time
in about 1 in 1000 persons each year, and the incidence rises with
age to at least 5 in 1000 persons in those over the age of 80 years.1,2
About one-third of patients with symptomatic VTE present with PE,
whereas the remainder manifests with DVT.3 Within 1 month of
diagnosis, death occurs in approximately 6% of patients with DVT
and 12% of those with PE.4 Although VTE often occurs after
surgery, with immobilization, or in patients with cancer, as much
as 50% of VTE patients have no identifiable risk factors and are
identified as having unprovoked VTE.5 If anticoagulant therapy is
stopped in patients with unprovoked VTE, the risk of recurrence is at
least 10% at 1 year and 30% at 5 years.6 Recurrent DVT increases the
risk of postthrombotic syndrome, a chronic disorder that occurs in
20% to 50% of DVT patients and is characterized by leg swelling and
discomfort; venous ulcers can develop in severe cases.7 Chronic
thromboembolic pulmonary hypertension develops in 2% to 4% of
patients with PE and can be life threatening.8 Therefore, VTE is a
common disorder associated with significant morbidity and mortality.
Anticoagulants are the cornerstone of VTE treatment. The goal of
therapy is to prevent thrombus extension or embolization and to
prevent new thrombi from forming. Traditionally, treatment occurs
in 2 overlapping steps.9 It starts with a rapidly-acting parenteral
anticoagulant, usually low-molecular-weight heparin (LMWH),
which is overlapped with a vitamin K antagonist, such as warfarin.
As initial therapy, the parenteral anticoagulant is given for at least
5 days and is stopped when the anticoagulant response with warfarin
is therapeutic, as evidenced by an international normalized ratio
(INR) between 2 and 3. Warfarin is then continued as long-term therapy
for a minimum of 3 months. At this point, the decision to stop or continue
treatment depends on the balance between the risk of recurrence
if warfarin is stopped and the risk of bleeding if it is continued. Patients
with VTE in the setting of transient and reversible risk factors, such as
surgery, have a low risk of recurrence if anticoagulant therapy is stopped
at 3 months provided they are fully mobile.5 In contrast, those with
ongoing risk factors, such as active cancer, and patients with unprovoked
VTE are often prescribed extended anticoagulation therapy as long as
the bleeding risk is not excessive. Therefore, anticoagulant treatment
of VTE has been divided into 3 stages: initial therapy, long-term
treatment, and extended anticoagulation.
Although current therapy is effective and safe, it is a cumbersome
process for patients and physicians because LMWH needs to be
administered via daily subcutaneous injections, and warfarin requires
frequent coagulation monitoring and dose adjustments to ensure that
the INR remains therapeutic. The limitations of warfarin prompted
the development of new oral anticoagulants (NOACs), which can be
given in fixed doses and produce such a predictable anticoagulant
response that routine monitoring is unnecessary. Because of their
rapid onset of action, the NOACs have the potential to enable all-oral
regimens, which can replace parenteral anticoagulants and warfarin for
initial, long-term, and extended VTE treatment.
Four NOACs have been evaluated for VTE treatment: dabigatran
(an oral thrombin inhibitor) and rivaroxaban, apixaban, and edoxaban,
which are oral factor Xa inhibitors. All 4 agents have been compared
with conventional anticoagulant therapy for the treatment of acute
symptomatic VTE, and all but edoxaban have been compared with
placebo for extended treatment. Dabigatran has also been compared
with warfarin for extended therapy. Rivaroxaban is currently
licensed for initial, long-term, and extended VTE treatment, whereas
dabigatran is approved for the latter 2 indications. With apixaban and
edoxaban currently under consideration for licensing for the VTE
indication, it is likely that we will soon have 2 additional choices.

Submitted March 25, 2014; accepted June 4, 2014. Prepublished online as © 2014 by The American Society of Hematology
Blood First Edition paper, June 12, 2014; DOI 10.1182/blood-2014-03-
563056.

1020 BLOOD, 14 AUGUST 2014 x VOLUME 124, NUMBER 7

BLOOD, 14 AUGUST 2014 x VOLUME 124, NUMBER 7
Table 1. Comparison of the pharmacologic properties of warfarin, rivaroxaban, apixaban, and edoxaban
Warfarin Dabigatran
Target VKORC1
Prodrug No
Bioavailability (%) 100
Dosing OD
Time-to-peak effect 4-5 d
Half-life (h) 40
Renal clearance as unchanged drug (%) None
Monitoring Yes
Interactions Multiple
OD, once daily; BID, twice daily; P-gp, P-glycoprotein; VKORC1, C1 subunit of the vitamin K epoxide reductase enzyme; 3A4, cytochrome P450 3A4 isoenzyme.
Focusing on VTE, this paper (1) compares and contrasts the
pharmacologic properties of the NOACs with those of warfarin;
(2) highlights how differences in the design of the phase 3 clinical
trials impact how each of the NOACs will be used; (3) describes
the results of these trials, pointing out the class effects with the
NOACs, and the findings that potentially differentiate one agent
from another; (4) provides perspectives on the emerging role of the
NOACs for treatment of VTE with a focus on identification, of
which patients are or are not candidates for the new agents; and (5)
offers suggestions on how to choose among the NOACs.
Comparison of the pharmacologic properties
of NOACs with those of warfarin
As is outlined in Table 1, warfarin acts as an anticoagulant by reducing
the function of the vitamin K–dependent clotting proteins—factors II,
VII, IX, and X—thereby attenuating the extrinsic, intrinsic, and
common pathways of blood coagulation. Because of its indirect
mechanism of action, the onset and offset of action with warfarin
take several days. In contrast, the NOACs inhibit only a single
target—either factor Xa or thrombin—and have a rapid onset of
action such that peak plasma levels are achieved 1 to 4 hours after
oral administration.10 With half-lives of about 12 hours, the
NOACs also have a rapid offset of action.
Although warfarin is predominantly cleared through nonrenal
mechanisms, the NOACs are excreted, at least in part via the kidneys.
The extent of renal clearance varies depending on the agent: about
80% of dabigatran is cleared unchanged by the kidneys, and 50%,
33%, and 27% of edoxaban, rivaroxaban, and apixaban, respec-
tively, are cleared unchanged via the renal route. Because of their
renal clearance, NOACs should be used with caution in patients with
a creatinine clearance ,30 mL/min and should not be used in
patients with a creatinine clearance ,15 mL/min.
The dose of warfarin varies among patients, reflecting differences
in dietary vitamin K intake, multiple drug-drug interactions, and
common polymorphisms that affect warfarin metabolism or
pharmacodynamics. Furthermore, warfarin has a narrow therapeutic
window and in patients with VTE, deficient anticoagulation can lead
to recurrent thrombosis, whereas excessive anticoagulation can
cause bleeding. Consequently, frequent coagulation monitoring and
dose adjustments are necessary to ensure that the INR remains within
the therapeutic range. In contrast, because the NOACs produce a
more predictable anticoagulant response, they can be given in fixed
doses without routine monitoring, thereby simplifying VTE treatment.
There are few clinically important drug-drug interactions with the
NOACs, although potent inhibitors or inducers of CYP 3A4 and/or
NEW ORAL ANTICOAGULANTS FOR VTE TREATMENT 1021
Rivaroxaban Apixaban Edoxaban
Thrombin Factor Xa Factor Xa Factor Xa
Yes No No No
7 80 60 62
BID OD (BID) BID OD
1-3 h 2-4 h 1-2 h 1-2 h
14-17 7-11 8-14 5-11
80 33 27 50
No No No No
P-gp 3A4/P-gp 3A4/P-gp P-gp
p-glycoprotein can be problematic, and there are no dietary restrictions,
except that rivaroxaban should be administered with a meal to maximize
Downloaded from http://ashpublications.org/blood/article-pdf/124/7/1020/1383171/1020.pdf by guest on 27 September 2021
its absorption.
Vitamin K is the antidote for warfarin. When given orally or by
slow intravenous infusion, vitamin K will restore the INR to baseline
levels, but this often takes more than 24 hours. Rapid warfarin reversal
can be achieved with 4-factor prothrombin complex concentrate
(PCC). Fresh frozen plasma is an alternative to PCC, but plasma
infusion takes longer and large volumes are often needed, which
can be problematic for patients with compromised cardiopulmonary
function. There are no specific antidotes for the NOACs, but these are
under development.11,12 Although PCC may be effective for reversal
of the NOACs, clinical data are limited.13
Comparison of the designs of the clinical
trials evaluating NOACs for VTE treatment
The studies comparing the NOACs with conventional therapy for
initial and long-term VTE treatment and those comparing NOACs
with placebo or warfarin for extended therapy vary in design. The
trial designs for the 2 indications will be discussed separately.
Initial and long-term VTE treatment
Dabigatran, rivaroxaban, apixaban, and edoxaban were compared
with conventional treatment in the RE-COVER I and II, EINSTEIN-
DVT and PE, AMPLIFY, and Hokusai-VTE trials, respectively.14-19
The designs of these trials are summarized in Table 2. Except for
EINSTEIN, which used a prospective, randomized, open-label, blinded
end point evaluation (PROBE) design, all of the trials were conducted
in a double-blind fashion. A list of expanded clinical trial abbreviations
can be found in the Appendix.
The primary efficacy outcome of these trials was recurrent VTE.
Although all of the studies were designed to show noninferiority of
the NOACs compared with conventional therapy, the noninferiority
margins differed and ranged from 1.5 to 2.75. The primary safety
outcome in these trials was major bleeding, or the composite of major
or clinically relevant nonmajor bleeding.
In patients with acute VTE, the risk of recurrence is highest in the
first month after diagnosis.20 Phase 2 VTE treatment studies with
rivaroxaban and apixaban not only helped to identify the dose to be
carried into phase 3 but also provided reassurance that an all-oral
approach was possible from the start.21,22 Consequently, the EINSTEIN
and AMPLIFY trials used oral regimens that started with more
intensive therapy; with rivaroxaban, this involved administering
15 mg twice daily for 3 weeks followed by 20 mg daily thereafter,
whereas the apixaban regimen consisted of 10 mg twice daily for
1022 YEH et al BLOOD, 14 AUGUST 2014 x VOLUME 124, NUMBER 7

Table 2. Design and patient characteristics of the trials comparing NOACs with conventional therapy for acute VTE treatment
Dabigatran Rivaroxaban Apixaban Edoxaban
Trial RE-COVER I & II EINSTEIN AMPLIFY Hokusai-VTE
Indication VTE DVT PE VTE VTE
Design Double-blind PROBE Double-blind Double-blind
Number of patients 2539 2568 3449 4832 5365 8240
Mean age 6 SD (y) 54.9 6 16.0 56.1 6 16.4 57.7 6 7.3 57.0 6 16.0 55.8 6 16.3
CrCl ,30 mL/min, n (%) 22 (0.4) 15 (0.4) 6 (0.1) 29 (0.5) n/a
Age $75 y, n (%) 529 (10) 440 (13) 843 (17) 768 (14) 1104 (13)
Prior VTE (%) 22 19 20 16 18
Unprovoked VTE (%) 35 62.0 64.5 89.8 65.7
Index event PE 6 DVT (%) 31 0.7 100 34 40
Noninferiority margin 2.75 2.0 1.8 1.5
Bridge with heparin/LMWH Yes No No Yes
Treatment protocol 150 mg BID 15 mg BID for 3 wk; 10 mg BID for 7 d; 60 mg OD; 30 mg OD for those with a
then 20 mg OD then 5 mg BID creatinine clearance of 30-50 mL/min,

Downloaded from http://ashpublications.org/blood/article-pdf/124/7/1020/1383171/1020.pdf by guest on 27 September 2021

weight ,60 kg, or taking potent
P-gp inhibitors
Duration (mo) 6 3, 6, 12 6 3-12
TTR (%) 60 58 63 61 64

n/a, not available; OD, once daily; BID, twice daily; P-gp, P-glycoprotein; LMWH, low-molecular-weight heparin; PROBE, prospective, randomized, open-label, blinded
endpoint; TTR, time in therapeutic range with warfarin.

7 days followed by 5 mg twice daily thereafter. Phase 2 studies in
VTE treatment were not conducted with dabigatran or edoxaban;
doses for the RE-COVER and Hokusai-VTE trials were selected
based on the results of phase 2 studies in patients with atrial
fibrillation.23,24 In the absence of evidence supporting the immediate
use of dabigatran or edoxaban in patients with acute VTE, the treatment
regimens in the RE-COVER and Hokusai-VTE trials started with a
minimum of a 5-day course of a parenteral anticoagulant, and patients
were then transitioned to warfarin or given dabigatran or edoxaban,
respectively.
Treatment duration varied among the trials; it was fixed at
6 months in the RE-COVER and AMPLIFY trials, and it was flexible
at 3, 6, or 12 months in the EINSTEIN and Hokusai-VTE trials. In the
EINSTEIN trials, investigators selected the treatment duration when
patients were enrolled; in Hokusai-VTE, investigators determined
treatment duration in an ongoing fashion. Treatment duration can be
an important design variable; a flexible treatment period more closely
mirrors current practice where treatment duration depends on patient
characteristics. In contrast, fixing treatment duration at 6 months may
limit enrollment of patients with provoked VTE because guidelines
recommend a 3-month course of anticoagulant treatment of such
patients provided that their reversible risk factors have resolved.9 This
explains why the majority of patients enrolled in the AMPLIFY trial
had unprovoked VTE, but it does not explain the under-representation
of such patients in the RE-COVER I and II trials (Table 2).
The case fatality rate in patients with PE is twice that in those with
DVT.2 Consequently, it was important to recruit sufficient numbers
of PE patients into these trials to ensure that the efficacy and safety of
the NOACS in PE and DVT patients were similar. In RE-COVER,
AMPLIFY, and Hokusai-VTE, this was accomplished by ensuring
that at least 30% of the enrolled patients had PE with or without
concomitant DVT. In contrast, in the EINSTEIN program, patients
with PE, with or without associated DVT, and those with DVT alone
were enrolled into separate trials. All of the trials excluded PE
patients with hemodynamic compromise because such patients often
undergo advanced therapies, which may include administration of
fibrinolytic agents.
Although the clinical characteristics of patients enrolled in the
various trials differed, few patients with a creatinine clearance
,30 mL/min were included, and the proportion of patients over
the age of 75 years ranged from only 10% to 17% (Table 2). Heavier
patients were better represented than underweight patients in all of
the studies.
Extended VTE treatment
Rivaroxaban, apixaban, and dabigatran were compared with
placebo in the double-blind EINSTEIN-Extension, AMPLIFY-
Extension, and RE-SONATE trials, respectively (Table 3).16,25,26
Patients enrolled in the EINSTEIN and AMPLIFY-Extension studies
had received 6 to 12 months of anticoagulation therapy for their
index VTE event, whereas those entered in the RE-SONATE study
had received 6 to 18 months of treatment. Although single-dose
regimens of rivaroxaban and dabigatran were evaluated in the

Table 3. Comparison of the designs of the trials evaluating NOACs for extended VTE treatment
Dabigatran Rivaroxaban Apixaban
Trial RE-SONATE RE-MEDY EINSTEIN-Ext AMPLIFY-Ext
Comparator Placebo Warfarin Placebo Placebo
Design Double-blind Double-blind Double-blind Double-blind
Number of patients 1343 2856 1197 2486
Noninferiority margin — 2.85 — —
Duration of prior anticoagulation treatment (mo) 6-18 3-12 6-12 3-12
Treatment protocol 150 mg BID 150 mg BID 20 mg OD 2.5 or 5 mg BID
Duration (mo) 6 6-36 6-12 12

BID, twice daily; Ext, extension; OD, once daily.

BLOOD, 14 AUGUST 2014 x VOLUME 124, NUMBER 7 NEW ORAL ANTICOAGULANTS FOR VTE TREATMENT 1023

EINSTEIN-Extension and RE-SONATE trials (20 mg once daily

23.2 (24.6, 21.8)

25.4 (26.8, 24.1)

21.8 (23.1, 20.6)
ARR % (95% CI)

20.6 (21.9, 0.7)

and 150 mg twice daily, respectively), 2 dosage regimens of apixaban
were studied in the AMPLIFY-Extension trial (2.5 and 5 mg twice
daily). All of the trials were powered to demonstrate superiority of
the NOACs over placebo, and the primary efficacy outcome was
recurrent VTE.
Dabigatran is the only agent to be compared with warfarin for

Major and CRNB

Warfarin, n/N (%)
extended VTE treatment in the RE-MEDY trial.26 Patients enrolled

412/4116 (10.0)

423/4112 (10.3)
217/2554 (8.5)

261/2689 (9.7)
in this trial had received 3 to 12 months of anticoagulant treatment of
their index VTE event, and the study was designed to show non-
inferiority of dabigatran compared with warfarin with the non-
inferiority margin set at 2.85. Although edoxaban has yet to be
evaluated in an extension study, because of the flexible treatment
duration in the Hokusai-VTE trial, the drug has been administered for

NOAC n/N (%)

136/2553 (5.3)
388/4130 (9.4)
115/2676 (4.3)
349/4118 (8.5)
up to 12 months.

Downloaded from http://ashpublications.org/blood/article-pdf/124/7/1020/1383171/1020.pdf by guest on 27 September 2021

Safety outcomes
Results of clinical trials

20.8 (21.3, 20.3)

21.3 (21.8, 20.6)
ARR % (95% CI)
20.5 (21.3, 0.2)

20.2 (20.8, 0.3)

Initial VTE treatment

In patients with acute symptomatic VTE, rates of recurrent VTE with

Table 4. Efficacy and safety outcomes of the trials comparing NOACs with conventional therapy for acute VTE treatment

ARR, absolute risk reduction; CRNB, clinically relevant nonmajor bleeding; n/N (%), number of events/number of patients in group (percentage).
the NOACs are similar to those with conventional therapy
(Table 415,18,19,27) in both PE and DVT patients (Figure 1). The
consistency of the findings across trials is reassuring and suggests
that as a class, NOACs are noninferior to conventional therapy for

Major bleeding
Warfarin, n/N (%)
treatment of PE and/or DVT. Rates of major bleeding are

51/2554 (2.0)
72/4116 (1.7)
49/2689 (1.8)
66/4122 (1.6)
significantly lower with rivaroxaban and apixaban than with
conventional therapy, and with the exception of rivaroxaban, the
rates of the composite of major or clinically relevant nonmajor
bleeding also are significantly lower with the NOACs than with
conventional therapy (Figure 2).27,28 The absolute risk reductions in
safety shown in Table 4 translate to the prevention of one major or
NOAC, n/N (%)
37/2553 (1.4)
40/4130 (1.0)
15/2676 (0.6)
56/4118 (1.4)
clinically relevant nonmajor bleed in every 19 to 167 patients treated
with a NOAC instead of warfarin. Overall, therefore, NOACs are
noninferior to conventional therapy for VTE treatment and are
associated with less bleeding. Furthermore, NOACs are more
convenient to administer. Rivaroxaban and apixaban can be given in
all-oral regimens that obviate the need for a parenteral anticoagulant
ARR, % (95% CI)
0.2 (20.6, 1.0)
20.2 (20.8, 0.4)
20.4 (21.3, 0.4)
20.4 (21.2, 0.4)

at the outset, and all of the NOACs are easier to administer than
warfarin because they can be given in fixed doses without the need
for routine coagulation monitoring.
Recurrent VTE and VTE-related death

In a predefined subset of PE patients with right ventricular

dysfunction, as evidenced by right ventricular dilatation on computed
tomography of the chest and/or an elevated level of N-terminal pro-
Efficacy outcome

Warfarin, n/N (%)

brain natriuretic peptide, edoxaban was superior to warfarin. Right

55/2554 (2.2)
95/4131 (2.3)
71/2635 (2.7)
146/4122 (3.5)

ventricular dysfunction occurs in patients with extensive PE, which

explains the higher mortality rates reported in such patients.5
Although the mortality rates in PE patients with and without right
ventricular dysfunction were similar in the Hokusai-VTE trial, the
superiority of edoxaban in patients with right ventricular dysfunction
supports the effectiveness of edoxaban for VTE treatment.19
NOAC, n/N(%)
60/2553 (2.4)
86/4130 (2.1)
59/2609 (2.3)
130/4118 (3.2)

Extended VTE treatment

Dabigatran, rivaroxaban, and apixaban are superior to placebo for the

prevention of recurrent VTE and are associated with low rates of
major bleeding.16,25,26 Compared with placebo, both the treatment
Rivaroxaban27

and the prophylactic dose of apixaban (5 mg and 2.5 mg twice daily,

Dabigatran15

Edoxaban19
Apixaban18

respectively) significantly reduced the risk of recurrent VTE.25

Although both dose regimens were associated with low rates of major
bleeding, there was a trend for less clinically relevant nonmajor
1024 YEH et al BLOOD, 14 AUGUST 2014 x VOLUME 124, NUMBER 7

Figure 1. Hazard ratios (HR) for recurrent VTE and

VTE-related death and their 95% confidence inter-
vals (CI) in phase 3 trials comparing NOACs with
conventional therapy for acute VTE treatment.

Downloaded from http://ashpublications.org/blood/article-pdf/124/7/1020/1383171/1020.pdf by guest on 27 September 2021

bleeding with the lower-dose apixaban regimen. This finding
raises the possibility that the intensity of treatment with NOACs
can be lowered for extended VTE treatment to reduce the risk
of bleeding without compromising efficacy. In contrast, attempts
to lower the intensity of warfarin therapy for extended VTE
treatment resulted in reduced efficacy without evidence of less
bleeding.29
Dabigatran was noninferior to warfarin for extended VTE treatment
in the RE-MEDY trial, and was associated with less bleeding.26
Although the number of events was small, myocardial infarction
was more common with dabigatran than with warfarin, a phenom-
enon observed in other studies that compared dabigatran with
warfarin.15,30,31 The clinical relevance of this finding is uncertain,
however, because the rates of all-cause mortality and cardiovascular
mortality tend to be lower with dabigatran than with warfarin.32
Choosing the right anticoagulant for the right
VTE patient
Acute VTE
When faced with a patient with acute VTE, the first question to ask is
whether the patient is suitable for treatment with a NOAC (Table 5).
Patients who require advanced treatment, such as those with

Figure 2. Hazard ratios (HR) for major bleeding or

major plus clinically relevant nonmajor bleeding
(CRNB) and their 95% confidence intervals (CI) in
phase 3 trials comparing NOACs with conventional
therapy for acute VTE treatment.
BLOOD, 14 AUGUST 2014 x VOLUME 124, NUMBER 7
Table 5. Suggestions for choice of anticoagulant for acute VTE treatment
Characteristic Drug choice
Extensive DVT or massive PE Heparin
High initial risk of bleeding Heparin
Active cancer LMWH
Pregnancy LMWH
Liver dysfunction with increased prothrombin time/ Warfarin
INR at baseline
Unable to afford NOACs LMWH followed by warfarin
Limited access to anticoagulation clinic because of NOAC
impaired mobility or geographical inaccessibility
All-oral therapy Rivaroxaban or apixaban
Creatinine clearance ,30 mL/min Warfarin
Creatinine clearance 30-50 mL/min Rivaroxaban, apixaban, or edoxaban
Dyspepsia or upper gastrointestinal symptoms Rivaroxaban, apixaban, or edoxaban
Recent gastrointestinal bleed Apixaban
Recent acute coronary syndrome Rivaroxaban, apixaban or edoxaban
Poor compliance with long-term twice-daily dosing Rivaroxaban or edoxaban
OD, once daily; LMWH, low-molecular-weight heparin.
massive PE who are candidates for systemic or catheter-directed
thrombolytic therapy or patients with extensive proximal DVT
who may benefit from pharmaco-mechanical therapy, should not
receive NOACs to start because such patients were excluded from
the clinical trials and because the NOACs have not been evaluated
in conjunction with thrombolytic therapy. Intravenous unfractio-
nated heparin is probably the best choice for these patients
because of its short half-life, the option to tailor the dose as
needed, and the availability of protamine sulfate as an antidote
should serious bleeding occur. For the same reasons, heparin may
also be the best choice for patients at high initial risk for bleeding,
such as those whose VTE occurs soon after major surgery or
trauma.
Other groups of patients who should not receive NOACs include
those with a creatinine clearance ,15 mL/min and those with hepatic
dysfunction. NOACs are contraindicated in patients with a creatinine
clearance ,15 mL/min because efficacy and safety data in such
patients are lacking, and the drugs should be used with caution in
patients with a creatinine clearance between 15 and 30 mL/min
because few such patients were included in the trials. All of the
NOACs require some degree of hepatic metabolism; consequently,
they should be avoided in patients with liver dysfunction as evidenced
by an increased prothrombin time/INR and reduced serum albumin at
baseline, important indicators of an increased Child-Pugh score.33
Patients with VTE in the setting of active cancer for which they
are receiving chemotherapy, biological agents, and/or radiation may
do better with LMWH, which has been shown to be superior to
warfarin for the prevention of recurrent VTE in this population.34
Although some patients with active cancer were included in the
studies with the NOACs, the numbers are small and studies comparing
NOACs with extended LMWH in patients with VTE in the setting of
active cancer are lacking. Likewise, NOACs have not been evaluated
in patients with VTE in the setting of antiphospholipid antibody
syndrome (APS) or other high-risk thrombophilic conditions, or in
patients who develop VTE as a complication of heparin-induced
thrombocytopenia (HIT). Until more data are available, VTE patients
with APS should receive conventional anticoagulant therapy and
those with HIT should be given fondaparinux or a parenteral direct
thrombin inhibitor. Patients who cannot afford the NOACs should
NEW ORAL ANTICOAGULANTS FOR VTE TREATMENT 1025
Rationale
Such patients often require advanced therapy and were excluded
from trials with the NOACs
Enables dose titration; rapid offset and availability of protamine as
an antidote simplify management should bleeding occur
No trials comparing NOACs with LMWH
Warfarin and NOACs cross the placenta
Such patients were excluded from the trials because NOACs undergo
hepatic metabolism
NOACs cost less than LMWH but are more expensive than warfarin
Given in fixed doses without monitoring
Only NOACs to be evaluated in all-oral regimens
Such patients were excluded from trials with NOACs
Less affected by renal impairment than dabigatran; if edoxaban is
Downloaded from http://ashpublications.org/blood/article-pdf/124/7/1020/1383171/1020.pdf by guest on 27 September 2021
chosen, the 30-mg OD dose should be used
Dyspepsia in as much as 10% given dabigatran
More gastrointestinal bleeding with dabigatran, rivaroxaban, and
edoxaban than with warfarin
Small myocardial infarction signal with dabigatran
OD regimens for long-term use
receive conventional anticoagulant treatment because NOACs are
more expensive than warfarin. Finally, if compliance is a concern,
warfarin may be a better choice because of its need for monitoring.
In VTE patients eligible for NOACs, there is no evidence to
recommend one agent over another because the NOACs have never
been compared in head-to-head trials. Nonetheless, suggestions can
be provided based on the distinct pharmacologic profiles of the
NOACs and the designs of the trials in which they were investigated.
Thus for patients with a creatinine clearance between 30 and 50 mL/min,
an oral factor Xa inhibitor may be a better choice than dabigatran
because the factor Xa inhibitors are less dependent on renal excretion.
If edoxaban is chosen for such patients, the dose must be reduced from
60 mg to 30 mg once daily to maintain similar drug exposure. The
NOACs should be avoided in patients with a creatinine clearance
,30 mL/min.
An all-oral regimen streamlines transition of care from the clinic
or the emergency department to home; rivaroxaban and apixaban, the
only agents to be evaluated in all-oral regimens, are the agents of
choice for this purpose. Selection between the two may depend on the
ease of switching from the higher initial dose to the maintenance dose
at 3 weeks and 1 week, respectively, and patient preference for a once
daily or twice daily regimen thereafter. In contrast, dabigatran and
edoxaban should only be prescribed after patients have received a
minimum of a 5-day course of heparin or LMWH treatment.
Rivaroxaban or apixaban may be good choices for patients over the
age of 75 with reduced renal function (creatinine clearance of
30-50 mL/min), particularly females with low body weight, because
the benefit-to-risk profile of these agents in frail patients is superior
to that of conventional therapy.18,27 Dabigatran may not be the best
choice in patients with a history of coronary artery disease because of
its higher risk of myocardial infarction compared with warfarin.32
Dabigatran should be avoided in patients with upper gastrointestinal
complaints because dyspepsia can occur in as much as 10% of
patients treated with this agent, a problem that tends to subside over
time and can often be resolved by taking the drug with food. Except
for apixaban, the rate of gastrointestinal bleeding with the NOACs
is higher than that with warfarin, particularly in the elderly.18,35
Consequently, apixaban may be the best choice for patients with
a recent history of gastrointestinal bleeding. Finally, potential
1026 YEH et al
drug-drug interactions may inform the selection of NOACs. For
example, as potent inducers of CYP3A4, phenytoin and carbama-
zepine may reduce plasma levels of apixaban or rivaroxaban but will
not affect the levels of dabigatran or edoxaban.
The risk of bleeding with NOACs or warfarin is increased with
concomitant use of antiplatelet agents, such as aspirin and nonsteroidal
antiinflammatory drugs, and these agents should be avoided if
possible. For patients who must use aspirin, the daily dose of aspirin
should not exceed 100 mg.
NOACs for treatment of prevalent cases of VTE
Patients already on warfarin for VTE treatment should be switched
to a NOAC if their INR is erratic. A switch can also be considered
for patients who find INR testing and warfarin dose adjustment
burdensome, such as those with limited mobility or patients with
active lifestyles. For extended treatment, the risk of bleeding is likely
to be lower with the NOACs than with warfarin, particularly if the
dose intensity can be reduced, as was investigated with apixaban.
Therefore, for patients who have already completed at least 6 months
of anticoagulant treatment of their index VTE event, apixaban 2.5 mg
twice daily is a good choice. It remains to be established whether
reduced dose regimens are effective for extended therapy with the
other NOACs and whether such regimens can be used in patients
with a history of recurrent VTE.
Compared with placebo, aspirin produces approximately a 32%
reduction in the risk of recurrence when used for secondary pre-
vention in patients with unprovoked VTE who have received at least
6 months of anticoagulant therapy for their index event.36,37 By
contrast, anticoagulants produce an 80% to 90% reduction in the risk
of recurrence compared with placebo. Therefore, anticoagulants
should be used instead of aspirin for secondary VTE prevention in
most patients, particularly when one considers the convenience of
the NOACs, their low risk of bleeding, and the fact that with the
lower-dose apixaban regimen, the rates of bleeding approached those
with placebo.
Potential limitations of NOACs for
VTE treatment
The lack of specific antidotes for the NOACs can complicate their
reversal in patients who require urgent surgery or in those with life-
threatening bleeding, a concern that makes some clinicians hesitant
to prescribe the NOACs.38 It is important to point out that despite the
lack of antidotes, the outcome in patients with intracranial bleeds or
major bleeds in other sites was no worse in patients taking dabigatran
than in those taking warfarin, and intracranial bleeding was less
frequent with dabigatran than with warfarin.39,40 Likewise, in patients
requiring urgent surgery or interventions, the shorter half-lives of
the NOACs relative to warfarin may be an advantage.41 Emerging
postmarketing data suggest that the safety of the NOACs in the
real world is similar to that observed in the trials.42 Nonetheless,
antidotes are under development to simplify the reversal of NOACs
in emergency situations.
In the absence of laboratory monitoring, adherence may be more
difficult to assess with NOACs than with warfarin. Ongoing education
and vigilance by physicians, nurses, and pharmacists can help to
ensure adherence, and there is evidence that persistence with
therapy may be better with NOACs than with warfarin.43
BLOOD, 14 AUGUST 2014 x VOLUME 124, NUMBER 7
Finally, although cheaper than LMWH, the NOACs are more
expensive than warfarin. However, the cost is likely to decrease
when all 4 agents are licensed for this indication, and with a reduced
risk of bleeding compared with conventional therapy, the NOACs
are likely to provide a cost-effective option.44
Conclusions and future directions
The NOACs represent an important advance in VTE treatment. By
streamlining transition of care, they facilitate out-of-hospital treatment
and are easier to use and safer than warfarin. Despite the availability
of all-oral regimens of rivaroxaban and apixaban, clinicians may be
more reluctant to initiate use of them in PE patients than in those with
Downloaded from http://ashpublications.org/blood/article-pdf/124/7/1020/1383171/1020.pdf by guest on 27 September 2021
DVT. Although more data are needed to evaluate the efficacy and
safety of the NOACs in patients with PE, even if treatment in these
patients starts with LMWH, it remains easier to transition and maintain
them on a NOAC than on warfarin.
To enable all-oral therapy with dabigatran and edoxaban, starting
doses need to be identified and their efficacy and safety determined.
Although the NOACs are a potentially attractive option in patients
with VTE in the setting of active cancer, they need to be compared
with extended LMWH in such patients. Gastrointestinal disturbances
associated with chemotherapy may limit intake of the NOACs in
cancer patients, and potential drug-drug interactions may increase or
decrease drug exposure. Furthermore, dose titration in cancer patients
with thrombocytopenia is likely to be more complicated with NOACs
than with LMWH. For these reasons, head-to-head trials comparing
the NOACs with extended LMWH in cancer patients with VTE are
needed.
Finally, the utility of the NOACs for VTE treatment in vulnerable
patients, such as those who are morbidly obese, those of very low
body weight, pregnant women, nursing mothers, those with serious
thrombophilic defects, or those requiring concomitant antiplatelet
therapy, remain to be established. Therefore, additional studies are
needed to optimize the role of NOACs for VTE treatment.
Acknowledgments
The authors thank Professor Robin Roberts for statistical support.
J.I.W. holds the Canada Research Chair (Tier I) in Thrombosis
and the Heart and Stroke Foundation J. Fraser Mustard Chair in
Cardiovascular Research at McMaster University.
This study was supported by a Doctoral Scholarship from the
Canadian Institutes of Health Research (C.H.Y.).
Authorship
Contribution: C.H.Y., P.L.G., and J.I.W. analyzed and interpreted
data, and wrote the manuscript.
Conflict-of-interest disclosure: P.L.G. has received honoraria
from Pfizer, Bayer, and Leo. J.I.W. has served as a consultant and
received honoraria from Bristol-Myers Squibb, Pfizer, Daiichi Sankyo,
Bayer, Janssen, Boehringer Ingelheim, and Portola. The remaining
author declares no competing financial interests.
BLOOD, 14 AUGUST 2014 x VOLUME 124, NUMBER 7 NEW ORAL ANTICOAGULANTS FOR VTE TREATMENT 1027

Correspondence: Jeffrey I. Weitz, Thrombosis and Atherosclerosis
Research Institute, 237 Barton St E, Hamilton, ON, Canada L8L 2X2;
e-mail: weitzj@taari.ca.
Appendix
Abbreviations for clinical trials
AMPLIFY, Apixaban for the Initial Management of Pulmonary
Embolism and Deep-Vein Thrombosis as First-Line Therapy;
AMPLIFY-Extension, Apixaban after the Initial Management of
Pulmonary Embolism and Deep Vein Thrombosis with First-Line
Therapy–Extended Treatment, EINSTEIN-DVT, Oral, direct Factor
Xa inhibitor rivaroxaban in patients with acute symptomatic deep
EINSTEIN-Extension, Once-daily oral rivaroxaban versus pla-
cebo in the long-term prevention of recurrent symptomatic venous
thromboembolism; Hokusai-VTE, Comparative Investigation of Low
Molecular Weight Heparin/Edoxaban Tosylate Versus Low Molec-
ular Weight Heparin/Warfarin in the Treatment of Symptomatic
Deep-Vein Blood Clots and/or Lung Blood Clots; RE-COVER I,
Efficacy and Safety of Dabigatran Compared with Warfarin for 6 Month
Treatment of Acute Symptomatic Venous Thromboembolism;
RE-COVER II, Phase III Study Testing Efficacy & Safety of Oral
Dabigatran Etexilatevs Warfarin for 6 m Treatment of Acute
Symptomatic Venous Thromboembolism; RE-MEDY, A Phase
III, Randomized, Multicenter, Double-blind, Parallel-group, Active
Controlled Study to Evaluate the Efficacy and Safety of Oral
Dabigatran Etexilate Compared with Warfarin for the Secondary
Prevention of Venous Thromboembolism; RE-SONATE, Twice-

Downloaded from http://ashpublications.org/blood/article-pdf/124/7/1020/1383171/1020.pdf by guest on 27 September 2021

vein thrombosis; EINSTEIN-PE, Oral, direct Factor Xa inhibitor daily Oral Direct Thrombin Inhibitor Dabigatran Etexilate in the
rivaroxaban in patients with acute symptomatic pulmonaryembolism; Long Term Prevention of Recurrent Symptomatic VTE.

References
1. Spencer FA, Emery C, Joffe SW, et al. Incidence
rates, clinical profile, and outcomes of patients
with venous thromboembolism. The Worcester
VTE study. J Thromb Thrombolysis. 2009;28(4):
401-409.
2. White RH. The epidemiology of venous
thromboembolism. Circulation. 2003;107(23 Suppl 1):
I4-I8.
3. Silverstein MD, Heit JA, Mohr DN, Petterson TM,
O’Fallon WM, Melton LJ III. Trends in the
incidence of deep vein thrombosis and pulmonary
embolism: a 25-year population-based study.
Arch Intern Med. 1998;158(6):585-593.
4. Heit JA, Silverstein MD, Mohr DN, Petterson TM,
O’Fallon WM, Melton LJ III. Predictors of survival
after deep vein thrombosis and pulmonary
embolism: a population-based, cohort study. Arch
Intern Med. 1999;159(5):445-453.
5. Kearon C. Natural history of venous
thromboembolism. Circulation. 2003;107(23 Suppl 1):
I22-I30.
6. Prandoni P, Noventa F, Ghirarduzzi A, et al.
The risk of recurrent venous thromboembolism
after discontinuing anticoagulation in patients
with acute proximal deep vein thrombosis or
pulmonary embolism. A prospective cohort study
in 1,626 patients. Haematologica. 2007;92(2):
199-205.
7. Prandoni P, Lensing AW, Cogo A, et al. The
long-term clinical course of acute deep venous
thrombosis. Ann Intern Med. 1996;125(1):1-7.
8. Pengo V, Lensing AW, Prins MH, et al;
Thromboembolic Pulmonary Hypertension Study
Group. Incidence of chronic thromboembolic
pulmonary hypertension after pulmonary
embolism. N Engl J Med. 2004;350(22):
2257-2264.
9. Kearon C, Akl EA, Comerota AJ, et al.
Antithrombotic therapy for VTE disease:
Antithrombotic Therapy and Prevention of
Thrombosis, 9th ed: American College of Chest
Physicians Evidence-Based Clinical Practice
Guidelines. Chest. 2012;141(2 Suppl):
e419S-e494S.
10. Scaglione F. New oral anticoagulants:
comparative pharmacology with vitamin K
antagonists. Clin Pharmacokinet. 2013;52(2):
69-82.
11. Schiele F, van Ryn J, Canada K, et al. A specific
antidote for dabigatran: functional and structural
characterization. Blood. 2013;121(18):3554-3562.
12. Lu G, DeGuzman FR, Hollenbach SJ, et al. A
specific antidote for reversal of anticoagulation by
direct and indirect inhibitors of coagulation factor
Xa. Nat Med. 2013;19(4):446-451.
13. Majeed A, Meijer K, Larrazabal R, et al. Mortality
in vitamin K antagonist-related intracerebral
bleeding treated with plasma or 4-factor
prothrombin complex concentrate. Thromb
Haemost. 2014;111(2):233-239.
14. Schulman S, Kearon C, Kakkar AK, et al;
RE-COVER Study Group. Dabigatran versus
warfarin in the treatment of acute venous
thromboembolism. N Engl J Med. 2009;361(24):
2342-2352.
15. Schulman S, Kakkar AK, Goldhaber SZ, et al;
RE-COVER II Trial Investigators. Treatment of
acute venous thromboembolism with dabigatran
or warfarin and pooled analysis. Circulation.
2014;129(7):764-772.
16. Bauersachs R, Berkowitz SD, Brenner B, et al;
EINSTEIN Investigators. Oral rivaroxaban for
symptomatic venous thromboembolism. N Engl J
Med. 2010;363(26):2499-2510.
17. Büller HR, Prins MH, Lensin AW, et al;
EINSTEIN–PE Investigators. Oral rivaroxaban
for the treatment of symptomatic pulmonary
embolism. N Engl J Med. 2012;366(14):
1287-1297.
18. Agnelli G, Buller HR, Cohen A, et al; AMPLIFY
Investigators. Oral apixaban for the treatment of
acute venous thromboembolism. N Engl J Med.
2013;369(9):799-808.
19. Büller HR, Décousus H, Grosso MA, et al;
Hokusai-VTE Investigators. Edoxaban versus
warfarin for the treatment of symptomatic venous
thromboembolism. N Engl J Med. 2013;369(15):
1406-1415.
20. Douketis JD, Foster GA, Crowther MA, Prins MH,
Ginsberg JS. Clinical risk factors and timing of
recurrent venous thromboembolism during the
initial 3 months of anticoagulant therapy. Arch
Intern Med. 2000;160(22):3431-3436.
21. Agnelli G, Gallus A, Goldhaber SZ, et al; ODIXa-
DVT Study Investigators. Treatment of proximal
deep-vein thrombosis with the oral direct factor Xa
inhibitor rivaroxaban (BAY 59-7939): the ODIXa-
DVT (Oral Direct Factor Xa Inhibitor BAY 59-7939
in Patients With Acute Symptomatic Deep-Vein
Thrombosis) study. Circulation. 2007;116(2):
180-187.
22. Buller H, Deitchman D, Prins M, Segers A;
Botticelli Investigators, Writing Committe. Efficacy
and safety of the oral direct factor Xa inhibitor
apixaban for symptomatic deep vein thrombosis.
The Botticelli DVT dose-ranging study. J Thromb
Haemost. 2008;6(8):1313-1318.
23. Ezekowitz MD, Reilly PA, Nehmiz G, et al.
Dabigatran with or without concomitant aspirin
compared with warfarin alone in patients with
nonvalvular atrial fibrillation (PETRO Study). Am J
Cardiol. 2007;100(9):1419-1426.
24. Weitz JI, Connolly SJ, Patel I, et al. Randomised,
parallel-group, multicentre, multinational phase 2
study comparing edoxaban, an oral factor Xa
inhibitor, with warfarin for stroke prevention in
patients with atrial fibrillation. Thromb Haemost.
2010;104(3):633-641.
25. Agnelli G, Buller HR, Cohen A, et al; PLIFY-EXT
Investigators. Apixaban for extended treatment of
venous thromboembolism. N Engl J Med. 2013;
368(8):699-708.
26. Schulman S, Kearon C, Kakkar AK, et al;
RE-MEDY Trial Investigators; RE-SONATE Trial
Investigators. Extended use of dabigatran,
warfarin, or placebo in venous thromboembolism.
N Engl J Med. 2013;368(8):709-718.
27. Prins MH, Lensing AW, Bauersachs R, et al;
EINSTEIN Investigators. Oral rivaroxaban versus
standard therapy for the treatment of symptomatic
venous thromboembolism: a pooled analysis of
the EINSTEIN-DVT and PE randomized studies.
Thromb J. 2013;11(1):21.
28. van der Hulle T, Kooiman J, den Exter PL,
Dekkers OM, Klok FA, Huisman MV.
Effectiveness and safety of novel oral
anticoagulants as compared with vitamin K
antagonists in the treatment of acute symptomatic
venous thromboembolism: a systematic review
and meta-analysis. J Thromb Haemost. 2014;
12(3):320-328.
29. Kearon C, Ginsberg JS, Kovacs MJ, et al;
Extended Low-Intensity Anticoagulation for
Thrombo-Embolism Investigators. Comparison of
low-intensity warfarin therapy with conventional-
intensity warfarin therapy for long-term prevention
of recurrent venous thromboembolism. N Engl J
Med. 2003;349(7):631-639.
30. Connolly SJ, Ezekowitz MD, Yusuf S, et al;
RE-LY Steering Committee and Investigators.
Dabigatran versus warfarin in patients with atrial
fibrillation. N Engl J Med. 2009;361(12):
1139-1151.
31. Connolly SJ, Ezekowitz MD, Yusuf S, Reilly PA,
Wallentin L; Randomized Evaluation of Long-
Term Anticoagulation Therapy Investigators.
Newly identified events in the RE-LY trial. N Engl
J Med. 2010;363(19):1875-1876.
32. Eikelboom JW, Weitz JI. Anticoagulation therapy.
Dabigatran and risk of myocardial infarction. Nat
Rev Cardiol. 2012;9(5):260-262.
1028 YEH et al
33. Pugh RN, Murray-Lyon IM, Dawson JL, Pietroni
MC, Williams R. Transection of the oesophagus
for bleeding oesophageal varices. Br J Surg.
1973;60(8):646-649.
34. Lee AY, Levine MN, Baker RI, et al; Randomized
Comparison of Low-Molecular-Weight Heparin
versus Oral Anticoagulant Therapy for
the Prevention of Recurrent Venous
Thromboembolism in Patients with Cancer
(CLOT) Investigators. Low-molecular-weight
heparin versus a coumarin for the prevention of
recurrent venous thromboembolism in patients
with cancer. N Engl J Med. 2003;349(2):146-153.
35. Desai J, Kolb JM, Weitz JI, Aisenberg J.
Gastrointestinal bleeding with the new oral
anticoagulants—defining the issues and the
management strategies. Thromb Haemost. 2013;
110(2):205-212.
36. Becattini C, Agnelli G, Schenone A, et al;
WARFASA Investigators. Aspirin for preventing
BLOOD, 14 AUGUST 2014 x VOLUME 124, NUMBER 7
the recurrence of venous thromboembolism.
N Engl J Med. 2012;366(21):1959-1967.
37. Brighton TA, Eikelboom JW, Mann K, et al;
ASPIRE Investigators. Low-dose aspirin for
preventing recurrent venous thromboembolism.
N Engl J Med. 2012;367(21):1979-1987.
38. Cotton BA, McCarthy JJ, Holcomb JB. Acutely
injured patients on dabigatran. N Engl J Med.
2011;365(21):2039-2040.
39. Hart RG, Diener HC, Yang S, et al. Intracranial
hemorrhage in atrial fibrillation patients during
anticoagulation with warfarin or dabigatran: the
RE-LY trial. Stroke. 2012;43(6):1511-1517.
40. Majeed A, Hwang H-G, Connolly SJ, et al.
Management and outcomes of major bleeding
during treatment with dabigatran or warfarin.
Circulation. 2013;128(21):2325-2332.
41. Healey JS, Eikelboom J, Douketis J, et al; RE-LY
Investigators. Periprocedural bleeding and
thromboembolic events with dabigatran compared
with warfarin: results from the Randomized
Evaluation of Long-Term Anticoagulation Therapy
(RE-LY) randomized trial. Circulation. 2012;
126(3):343-348.
42. Southworth MR, Reichman ME, Unger EF.
Dabigatran and postmarketing reports of
bleeding. N Engl J Med. 2013;368(14):
1272-1274.
43. Zalesak M, Siu K, Francis K, et al. Higher
persistence in newly diagnosed nonvalvular atrial
fibrillation patients treated with dabigatran versus
warfarin. Circ Cardiovasc Qual Outcomes. 2013;
6(5):567-574.
44. Lefebvre P, Coleman CI, Bookhart BK, et al.
Cost-effectiveness of rivaroxaban compared
with enoxaparin plus a vitamin K antagonist for
the treatment of venous thromboembolism.
J Med Econ. 2014;17(1):52-64.
Downloaded from http://ashpublications.org/blood/article-pdf/124/7/1020/1383171/1020.pdf by guest on 27 September 2021