Expert Opinion on Pharmacotherapy

ISSN: 1465-6566 (Print) 1744-7666 (Online) Journal homepage: http://www.tandfonline.com/loi/ieop20

Pharmacological management of pulmonary

embolism

Bobby Gouin, Helia Robert-Ebadi, Marc Righini & Marc Blondon

To cite this article: Bobby Gouin, Helia Robert-Ebadi, Marc Righini & Marc Blondon (2016):
Pharmacological management of pulmonary embolism, Expert Opinion on Pharmacotherapy,
DOI: 10.1080/14656566.2016.1268122

To link to this article: http://dx.doi.org/10.1080/14656566.2016.1268122

Accepted author version posted online: 03

Dec 2016.

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Download by: [Athabasca University] Date: 04 December 2016, At: 03:05

Publisher: Taylor & Francis

Journal: Expert Opinion on Pharmacotherapy

DOI: 10.1080/14656566.2016.1268122

Review

Pharmacological management of pulmonary embolism

Bobby Gouin 1,2, Helia Robert-Ebadi 1, Marc Righini 1, Marc Blondon 1

1. Division of Angiology & Hemostasis, Geneva University Hospitals and Faculty of

Medicine, Geneva, Switzerland.
2. Division of General Internal Medicine, Universit de Sherbrooke, Sherbrooke, Canada

Correspondence:
Marc Blondon
Division of Angiology and Hemostasis
Geneva University Hospitals and Faculty of Medicine
4 rue Gabrielle-Perret-Gentil
1205 Geneva
Switzerland
Telephone +41.22.372.92.92 / Fax +41.22.372.92.99
Email marc.blondon@hcuge.ch

Funding
This paper was not funded.

Declaration of Interest
The authors have no relevant affiliations or financial involvement with any organization or entity
with a financial interest in or financial conflict with the subject matter or materials discussed in
the manuscript. This includes employment, consultancies, honoraria, stock ownership or options,
expert testimony, grants or patents received or pending, or royalties.

1
LIST OF ABBREVIATIONS

ACCP: American College of Chest Physicians

CrCl: Creatinine clearance

DOAC: Direct oral anticoagulant

DVT: Deep vein thrombosis

ESC: European Society of Cardiology

GFR: Glormerual filtration rate

HIT: Heparin-induced thrombocytopenia

INR: International normalized ratio

IV: Intravenous

LMWH: Low molecular weight heparin

PE: Pulmonary embolism

PTT: Partial thromboplastin time

RCT: Randomized-controlled trial

RV: Right ventricle

UFH: Unfractioned heparin

VKA: Vitamin K antagonist

VTE: Venous thromboembolism

2
ABSTRACT

Introduction:

Pulmonary embolism (PE) is a common and potentially severe manifestation of venous

thromboembolism. Its management has relied on anticoagulation by vitamin K antagonists

(VKA) for the past fifty years. Recently, new alternative drugs have been developed and

dramatically modified both the treatment of acute PE and its secondary prevention.

Areas covered:

This review discusses the contemporary pharmacological treatment for PE, with a focus

on anticoagulation options for non-high risk PE. In particular, the advent of direct oral

anticoagulants (rivaroxaban, apixaban, edoxaban and dabigatran) and modalities for long-term

prevention will be described. Options for anticoagulation for pregnancy-related PE are presented

separately.

Expert opinion:

Direct oral anticoagulants represent the first-line therapy of non-high risk PE, with better risk-

benefit ratios compared with VKA due to lower bleeding risks. In specific groups of patients,

however, older generations of anticoagulants such as VKA or heparins still play an important

role. Multiple alternatives are available for the secondary prevention of PE, with different

efficacies in reducing thrombotic risk and bleeding safety profiles.

Key Words: pharmacological treatment, pulmonary embolism, review, venous

thromboembolism

3
1. Introduction

Pulmonary embolism (PE) results from the blockage of pulmonary arteries by one or

multiple clots, that most often originate from the deep veins of the legs.2 With an estimated case-

fatality of 10-20%,3-5 it represents the most severe manifestation of venous thromboembolism

(VTE), which also comprises deep vein thrombosis (DVT). Venous thromboembolism is a

common disease, with an estimated 900000 to 1 million events in the United States and in

Europe annually.6, 7 Among its many genetic and acquired risk factors, advanced age, cancer and

post-operative status are some of the most important predictors of its incidence.8, 9

The cornerstone of treatment of most VTE remains anticoagulation, in order to prevent

the extension of thrombi, further embolization, recurrences of thrombosis and the occurrence of

chronic pulmonary hypertension (CTEPH). In recent years, the advent of new drugs for this

purpose has greatly modified the management of patients with VTE, both for the treatment of the

acute phase of PE and for long-term prevention of its recurrence. Within VTE, pharmacological

treatments of PE and proximal DVT are very similar, as they are considered as two different

presentations of a similar disease. This is well illustrated by the fact that 40-50%5 patients with

proximal DVT have a subclinical or asymptomatic PE and that 50-60% of patients with

symptomatic PE have a DVT.2, 10

The aim of this narrative review is to discuss the contemporary pharmacological

treatments of PE. We will not review long-term complications of PE such as CTEPH.11

2. Risk stratification of pulmonary embolism

Right ventricular (RV) failure is the primary cause of death due to PE, as it interferes with

cardiac output and gas exchange. The severity of PE and its associated short-term mortality relate

substantially to the localization and burden of pulmonary thrombi and the previous cardio-
4
pulmonary condition of patients. Clinical markers and biomarkers help to stratify patients with

documented PE into low-risk, intermediate-risk and high-risk of early mortality, in order to select

the most appropriate early-phase therapies (ESC approach): hemodynamic status, cardiac

enzymes (BNP/NT-proBNP, troponins), imaging of RV dilation from CT angiography or

echocardiography and a clinical prediction rule including patients age, cardio-pulmonary and

general frailty and hemodynamic consequences of PE (PESI score)4 (Figure 1).12 Accordingly, 5-

10% of patients can be classified into high-risk (previously called massive) PE. These patients,

who present with shock, hypotension or signs of circulatory failure, regardless of other elements,

have an estimated 15-50% early mortality.13 They benefit from primary pulmonary reperfusion

therapy. Normotensive patients can be classified into low-risk (~20-30% of all patients with PE)

and intermediate-risk PE (~60-70%) with associated 1-month overall mortality rates of ~1% and

~5-10%, respectively, depending if their PESI or simplified PESI (sPESI) scores are low (85 or

0 points) or high (>85 or 1 points). Intermediate-risk PE are further cathegorized as

intermediate-high risk if PE is associated with both signs of RV dysfunction and increased

cardiac biomarkers, or as intermediate-low risk if either one or none of these two criteria is

positive. Low and intermediate-risk patients are usually managed with simple anticoagulation,

and the role for active surveillance and reperfusion therapy in patients with intermediate-risk PE

is debated.12, 1314

3. Treatment of acute PE

In 1960, Barritt and Jordan showed a substantial benefit of heparin followed by vitamin K

antagonists (VKA) over no treatment in patients with clinically overt and likely severe PE in a

randomized trial.15 Since then, the need for anticoagulation after VTE has been further supported

5
by studies showing early recurrences in the absence of rapidly efficient anticoagulation.16 Today,

several anticoagulant modalities are available for this purpose.

The anticoagulant treatment of acute PE can be divided into three different periods

(Figure 1): the initiation period, the early maintenance and the secondary prevention. Treatment

is initiated with parenteral drugs (heparins, 5 days minimum) or high-dose rivaroxaban / apixaban

(21 / 10 days) (initiation period). Then, multiple drugs can be given in the early maintenance

phase (until 3-6 months after PE). An extension of anticoagulation after 3-6 months may be

beneficial in some patients and this will be discussed later in this review (secondary

prevention).12, 17

Acute PE was treated until recently in-hospital for all patients. With the availability of

stratification scores (PESI, sPESI) and new oral anticoagulant options, ambulatory treatment of

patients with low-risk acute PE is now possible. A randomized controlled management trial has

established the safety of outpatient treatment (hospital stay <24h) of low-risk PE, defined by a

PESI score 85, among 339 patients at low bleeding risk who were initially treated with LMWH

followed by VKA.14 Outpatient treatment was non-inferior to in-hospital treatment for VTE

recurrence, bleeding and death. In a meta-analysis of 13 studies assessing outpatient treatment of

1657 patients with low-risk PE, the 3-month VTE recurrence, major bleeding and death rates

were 1.7%, 1.0% and 1.9%, respectively, which are comparable to in-hospital treatment.18

Current guidelines suggest outpatient treatment of low-risk PE (ESC: IIa,B, ACCP : IIB).12,19 The

direct oral anticoagulants (DOAC) which do not require an initial parenteral anticoagulation with

heparin also facilitate outpatient treatment of low-risk PE.

3.1. Anticoagulant therapy

3.1.1. Unfractionated heparin

6
 Unfractionated heparin (UFH) was the first discovered anticoagulant drug and acts by

dramatically potentiating the activity of antithrombin, a physiological inhibitor of coagulation

factors IIa and Xa. It is mainly eliminated by endothelial cells and macrophages, therefore still

representing an interesting treatment option in patients with severe renal failure. Due to its short

half-life (0.5-2h) and the availability of an antagonist (protamin), it is also commonly used in

patients with necessary short-term interruptions for planned interventions or high acute bleeding

risk. Another specific indication is found in patients with intermediate-high risk PE who are

monitored for possible short-term need for thrombolysis and patients after thrombolysis for PE.

Apart from these specific clinical situations, some features render UFH disadvantageous in most

patients. First, its dose-response is somewhat unpredictable, with the need for regular monitoring

with coagulation measurements such as aPTT (target: 1.5-2.5 times basal aPTT prolongation) or

anti-Xa activity levels, and consequentially greater bleeding risk than other anticoagulant drugs.20

Second, UFH can cause immune-allergic (type II) heparin-induced thrombocytopenia (HIT) in up

to 5% of patients, which is paradoxically associated with thrombotic complications, especially in

surgical patients.21-23 Third, UFH is given parenterally, with a preferable continuous intravenous

infusion. The FIDO trial suggested that a subcutaneous treatment is possible, but the

generalizability of its findings to PE patients is limited as the majority of patients suffered a DVT

only (81%).24

3.1.2. Low-molecular-weight heparin

Low-molecular-weight heparin (LMWH) are anticoagulants that act indirectly by binding

to antithrombin and potentiating its inhibition of factor Xa (more than factor IIa, ratio 2-4:1).

They follow a renal elimination (half-life of 3-6h). Available molecules for the treatment of PE

include enoxaparin, dalteparin, tinzaparin, reviparin and nadroparin, with once or twice daily
7
subcutaneous injections. Because their dose-response is predictable, doses are simply adjusted to

patients weights and monitoring of the anticoagulant activity is unnecessary in most situations.

In patients with extreme weights (e.g. <50 kg and >100 kg) or moderate renal failure (creatinine

clearance (CrCl) 30-50ml/min), LMWH should be used with caution. Monitoring of plasma anti-

Xa activity is often performed in these patients and the treatment dose adjusted accordingly:

despite the lack of strong evidence on the association of monitoring (anti-Xa assays) and clinical

outcomes, this pragmatic approach seems acceptable in clinical practice. A glomerular fraction

rate (GFR) <30ml/min generally represents a contra-indication to the use of therapeutic LMWH.

The 1% risk of HIT associated with LMWH is lower than that of UFH.21 As opposed to UFH,

protamin is only partially effective in reversing LMWH anticoagulant effect and is used only in

case of severe active bleeding. A potential burden associated with LMWH is the need for

subcutaneous injections.

A large body of evidence supports the use of LMWH for the treatment of VTE. A meta-

analysis of 23 randomized controlled trials (RCT) comparing LMWH with intravenous (IV)

UFH, both with a switch to VKA, for the initiation of treatment demonstrated better outcomes

with LMWH. There was a reduction in VTE recurrence (3.6% vs. 5.5%, RR 0.7, 95% CI 0.6-

0.9), in major bleeding (1.1% vs. 1.9%, RR 0.6, 95% CI 0.4- 0.8) and in all-cause mortality

(4.3% vs. 5.8%, RR 0.8 95% CI 0.6-0.9) at 3 months.25 When restricting to patients with PE,

similar findings were observed, however with less precision.

LMWH are also well-fitted for some particular clinical situations. In cancer-related VTE,

prolonging the treatment with LMWH during the early maintenance phase and even afterwards

may be more efficient than VKA to prevent thrombotic recurrences, as suggested by two large

randomized trials that evaluated dalteparin or tinzaparin versus warfarin in cancer patients.26, 27

Of note, the more recent trial (tinzaparin) failed to attain a statistical significant reduction of
8
thrombotic risk, but point estimates from both trials seem consistent (hazard ratios 0.65 and

0.48). LMWH are also the anticoagulant of choice in pregnant women (discussed in specific

section). Finally, in complex cases of thrombosis in patients with liver disease and secondary

coagulopathy, as monitoring of VKA action with INR may be unreliable and DOAC are contra-

indicated, LMWH may be the safest and most predictable alternative.28

3.1.3. Fondaparinux

Fondaparinux is a synthetic pentasaccharide that imitates the active site of heparin that

binds to antithrombin. Its lack of a long saccharide chain prohibits the interaction of antithrombin

with factor IIa, and fondaparinux is therefore an indirect and specific factor Xa inhibitor.

Similarly to LMWH, it is administered subcutaneously, has a predictable pharmacokinetic profile

with weight-adjusted dosing and is contra-indicated in severe renal failure with CrCl <30 ml/min

because of its renal elimination. An interesting feature of fondaparinux lies in the rarity, or even

perhaps the lack of risk, of HIT. As such, many patients with suspected or confirmed HIT due to

UFH or LMWH are treated with fondaparinux, although more evidence would be welcome to

support this strategy.29 Further, this synthetic drug is not extracted from animal tissues, unlike

LMWH or UFH, which is a major advantage over the heparins.

The use of fondaparinux in patients with PE is supported by one clinical trial (MATISSE-

PE).30 Investigators randomized 2213 patients to a mean of 7 days of UFH or fondaparinux

followed by VKA. Thrombotic and major bleeding outcomes were similar at 3 months between

the two groups (3.8% and 2.0% respectively in the fondaparinux arm). A similar study for DVT

patients showed comparable efficacy and safety of fondaparinux and LMWH for anticoagulant

treatment initiation.31 Of importance, there are no data demonstrating the long-term safety of

9
fondaparinux in VTE patients, in contrary to VKA or LMWH. Hence, this treatment should only

be considered for the initiation of anticoagulation.

3.1.4. Vitamin K antagonists

Vitamin K antagonists (VKA) are involved in the hepatic synthesis of four coagulation

factors (II, VII, IX, X) and two coagulation inhibitors (proteins C and S). Specifically, vitamin K

acts as a cofactor of the gamma-glutamyl carboxylase for the carboxylation of glutamate residues

on vitamin-K dependant proteins. VKA inhibit the enzyme vitamin K epoxide reductase

(VKORC1), thereby decreasing the levels of the active form of vitamin K and leading to the

production of coagulation proteins with reduced procoagulant activities. The initiation of

anticoagulation takes 3-10 days, depending on the half-life of the drug: acenocoumarol (11h),

warfarin (36h), fluindion (69h), phenprocoumon (160h). Further, an early pro-thrombotic phase,

due to earlier inhibition of coagulation inhibitors than of coagulation factors, can lead to

thrombotic but rare complications such as skin necrosis, especially in patients with protein C or S

deficiency. In a trial comparing VKA alone to heparin plus VKA after proximal DVT, a 13%

increase in absolute risk of symptomatic extension of thrombosis or VTE recurrence at 6 months

was shown in patients on VKA alone.16 For these reasons, VKA can only be given after a

thrombotic event such as PE if another anticoagulant with immediate efficacy, such as heparins,

LMWH or fondaparinux is given simultaneously in the initiation treatment phase.

Because the effect of VKA is highly unpredictable, monitoring of anticoagulation levels is

necessary through measurement of prothrombin times, standardized between laboratories as

International Normalized Ratio (INR) with a target of 2.5 (2.0-3.0). Lower INR levels (<2.0)

are associated with increased risks of thrombotic recurrences and higher INR levels (>3.0) with

increased bleeding risks. Many factors influence the response to VKAs, in particular some
10
genetic polymorphisms, diet (vitamin K intake) and other medications such as antibiotics or

anticonvulsive agents. Achieving stable INR in patients remains challenging: a systematic review

demonstrated that study participants INR was in the therapeutic range only 54% of the time in

the first month after VTE (TTR, time in therapeutic range).32 This TTR is a measure of quality of

anticoagulation with VKA, with a goal of >70% in individual patients.

There is very broad clinical experience of VKA (after initiation with heparin) for PE, as

these drugs were the only orally administered drugs available until the development of direct oral

anticoagulants (DOAC). They offer an excellent protection against recurrent VTE, with an

estimated 1-5% absolute risk of recurrent VTE after 3-6 months of treatment. [Gouin B, Chest

2016, in press].30, 33 We can estimate that VKA prevents 90-95% of recurrent VTE events, from

studies comparing long-term VKA to short-term VKA after VTE.34

Bleeding risk remains the major challenge in users of VKA. About 2% of VTE patients

suffer a major haemorrhage during the 3 months after VTE treated with heparin (initiation) and

VKA (early maintenance phase).33, 35

These bleeding events have important clinical

consequences: 25% are fatal and 7% are intracranial.36 These events appear more frequent in

older patients, who have already suffered a previous hemorrhage, with cancer, anemia or

thrombocytopenia. An elevated INR is a major risk factor for VKA-associated bleeding, and

especially for intracranial events.37

Recently, the pharmacogenomics of warfarin have been explored to minimize the risks of

these negative outcomes. Two polymorphisms explain more than 30% of the variance associated

with therapeutic doses of warfarin in individuals: VKORC1 and CYP2C9 (the enzyme that

metabolises VKA). Measuring these polymorphisms in patients to achieve correct

anticoagulation levels faster has been tested recently in several clinical trials (COAG38, EU-

PACT39). These trials differed in the warfarin dose prediction model (including or not clinical
11
factors other than age) and in their population of interest, but yielded similarly disapointing

results: the adequation of anticoagulation (measured by the time in therapeutic range) at 4-12

weeks was not or only modestly improved by genetic measurements, and no improvement of

clinical outcomes was observed.40 Such an approach is therefore not recommended in clinical

practice.

3.1.5. Direct oral anticoagulants

Since 2010, DOAC have appeared as therapeutic options for PE (Table 1).41 DOAC are

orally administered medication acting through direct inhibition of a specific coagulation factor.

To date, marketed DOAC act through direct inhibition of factor IIa (dabigatran) or factor Xa

(rivaroxaban, apixaban, edoxaban). By inhibiting factor IIa (thrombin), dabigatran directly

inhibits the conversion of fibrinogen to fibrin, the clot substrate. Factor Xa acts at the so-called

final common pathway of coagulation that, in association with factor Va and co-factors, forms

the prothombinase complexe that cleaves prothrombin into thrombin.

Dabigatran, rivaroxaban, apixaban and edoxaban are considered as alternatives to VKA

for treatment of PE by the ESC guidelines (1B), and are favoured over VKA in the 2016 ACCP

recommendations (2B).12,17 All four have been studied in non-inferiority phase III trials compared

to a standard treatment with LMWH and VKA, which confirmed their efficacy and safety for the

acute treatment of VTE (Table 2).33, 42-44 DOAC were all as efficient as (non-inferior to) VKA,

in terms of reduction of risk of recurrent VTE, and as a group, DOAC are safer than VKA, with a

39% risk reduction of major bleeding and a dramatic 60-65% risk reduction of intracranial and

fatal bleeding.45 Overall, there were 11539 patients with PE in the DOAC phase III studies,

representing 43% of the samples. No difference in efficacy was observed between PE and DVT
12
participants. Because there are no direct comparison studies between DOAC yet, evaluation of

different efficacy or safety outcomes between these drugs rely on indirect comparisons using

network meta-analyses. Such analyses suggest that dabigatran, rivaroxaban, apixaban and

edoxaban have similar efficacy to prevent recurrent VTE, and that apixaban may cause less major

bleeding than the other drugs.46 Real-world data for DOAC in VTE patients are scarce. The

Dresden NOAC Registry observed 575 VTE patients treated with rivaroxaban who were older

than those in the EINSTEIN trials (mean age 68y vs. 58y) and who had greater risks of major

bleeding (4.1/100 person-years vs. ~1.5/100 person-years, respectively). A recently published

large prospective cohort of DVT patients treated with rivaroxaban or VKA in multiple hospitals

and community care centres showed findings very similar to those of the EINSTEIN-DVT study,

with regards to efficiency and safety of rivaroxaban, but patients treated with rivaroxaban were

similar to those in the EINSTEIN-DVT trial.47

The phase III clinical trials including PE participants excluded those with high-risk PE.

Hence, only low and intermediate-risk PE were included in those phase III trials, often without

determination of this stratification. The HOKUSAI-VTE trial for edoxaban provided information

on RV dysfunction, defined either by an increased RV to LV diameter on the CT-scan or NTpro-

BNP 500 pg/mL, representing respectively 35.0% and 28.3% of this study.44 For patients with

intermediate-risk PE, edoxaban, which was preceded by at least five days of LMWH, was shown

to be non inferior to VKA to prevent VTE, and perhaps even more efficient in cases with

increased-NTproBNP (VTE recurrence: 3.3% VS 6.2% HR 0.52, 95%CI 0.28-0.98). Based on

the overall high prevalence of intermediate risk PE, there appears to be good evidence to support

the use of DOAC for both low and intermediate risk PE.

DOAC do not need specific monitoring of their action and thus are associated with greater

ease of use and patients comfort than VKA. Nevertheless, measurements of anticoagulation level
13
is available, often through specific assays. Dabigatran levels can be qualitatively tested in a

thrombin time assay and quantitatively in a calibrated anti-II activity assay. Levels of

rivaroxaban, apixaban and edoxaban can be measured through specific anti-Xa activity assay

with specific calibrations. Such measurements should not be performed routinely, but may be

useful in case of an urgent intervention, major bleeding or recurrent thrombosis in current users

of these drugs, although there are neither validated normograms nor clear anticoagulation

thresholds to assess bleeding risks before an intervention. Of note, usual clotting times such as

activated partial thromboplastin time or prothrombin time, are modified in patients on DOAC,

especially at therapeutic dose, but a correlation between clotting time prolongation and

anticoagulation level cannot be made due to the high variability depending on the laboratory

reagent used. Also, the results of any other assay based on clotting times (including many of the

thrombophilia screening tests) are considered unreliable in patients on DOAC.

Aside from their mechanisms (anti-IIa vs. anti-Xa activity), these four DOAC also differ

with regards to their prescription scheme, their metabolism and their interactions.

First, edoxaban and dabigatran should be preceded by a minimum of five days of

parenteral anticoagulation, typically with a LMWH.42, 44 On the contrary, anticoagulation can be

directly initiated orally with higher-dose rivaroxaban (15 mg bid) or apixaban (10 mg bid) for 21

and 10 days, respectively, before decreasing to their respective maintenance dose (rivaroxaban 20

mg od or apixaban 5 mg bid).33, 43 The simplicity of these introduction regimens may influence

the choice of the DOAC, especially if outpatient treatment is considered. The rationale behind the

intensive initiation of treatment or the need for LMWH as the initiating anticoagulant comes from

the demonstrated importance of the initial anticoagulation to prevent early recurrent VTE.16, 48

Second, the importance of renal elimination varies between DOAC. In the phase III RCT,

all patients with a glomerular filtration rate (GFR) <30ml/min (25ml/min for apixaban) were
14
excluded, based on the estimation by the Cockcroft and Gault formula. Rivaroxaban and

apixaban have a low renal elimination (25-33%).33, 43 Edoxaban is 50% cleared by the kidney.

Dabigatran has a 80% renal metabolism.42 Edoxaban is the only DOAC tested at reduced dose in

VTE treatment in phase III trials (30mg instead of 60mg od in patients with GFR between 30-

50ml/min), as opposed to AF phase III trials in which reduced doses were tested for all DOAC.44

Regardless of these differences, as a group, DOAC appear in phase III trials as efficient and safe

in patients with GFR of 30-50ml/min as in those with GFR >50ml/min.45 However, the

subgroups of patients with GFR <50ml/min were small in all studies (6.6% of all participants,

n=1789), and consisted of selected patients who might be different from real-life moderate renal

failure patients. Apixaban might be associated with decreased major bleeding risk compared to

other DOAC for patients with CrCl <50ml/min, but such indirect comparisons between DOAC

should be interpreted with great prudence.49 When prescribing DOAC in patients with moderate

renal impairment with a CrCl close to 30 ml/min, it seems cautious to monitor creatinine level

once or twice yearly and in case of an acute illness, especially in older patients with low body

weight.

Third, because monitoring is not performed, interactions with medications that can

increase or decrease levels of DOAC need to be recognized and avoided. The absorption of Xa-

inhibitors is mediated by P-glycoprotein (P-gp) and their metabolism by cytochrome CYP3A4

with the exception of edoxaban which is barely metabolised by CYP3A4. The absorption of

dabigatran is also dependent on P-gp, but no interactions with CYP3A4 modulators exist.

Because of the wide therapeutic range of DOAC, concomitant use of drugs with minor

interactions with P-gp and CYP3A4 do not seem to be clinically relevant. Antifungal agents

(azols), HIV protein inhibitors (ritonavir, indonavir, etc) and other strong inhibitors of CYP3A4

and P-gp should be avoided with all DOAC (risk of increased levels of DOAC). Conversely,
15
rifampicin, carbamazepine, dexamethasone and other strong inducers of CYP3A4 and P-gp

should be avoided (risk of decreased levels of DOAC). Strong inductors of CYP3A4 but not of P-

gp, such as phenytoin, should also be avoided with xabans but are permitted with dabigatran and

edoxaban. Finally, some common medications are moderate P-gp and/or CYP3A4 inhibitors and

should be used with caution with DOAC, in particular in presence of renal impairment or in case

of association of multiple moderate inhibitors: amiodarone, clarithromycine, diltiazem. An

exhaustive listing of possible interactions can be found in other reviews.50

With increasing prevalences of obesity, whether DOAC may be used in obese patients is

an important issue. In their product labelling, none of the approved DOAC recommends a dose

adjustment for obese patients, but data on these patients are limited. Patients with extreme obesity

represented only a small proportion of participants in DOAC phase III trials (14-19%> 100kg).33,
42-44
Pharmacocinetics and pharmacodynamics evidence suggest shorter half-life and reduced-

peak concentration of DOAC in case of extreme obesity.51, 52

Therefore, the 2016 ISTH

recommendations suggested not to use DOAC in patients with a BMI>40 kg/m2 or weight > 120

kg, in whom VKA would be more appropriate.53 Conversely, few participants of DOAC phase III

trials had weights <50kg, in whom the efficacy and safety of these anticoagulant are therefore

mostly unknown.

One major criticism to the DOAC has been the lack of antidotes. RCT data have been

overall reassuring, by showing that DOAC-associated major bleeding (and in particular

intracranial bleeding) occurs less often than with VKA and that their severity and mortality, in

the absence of specific antidotes, are lower.54 The necessity of specific antidote is thus

questionable. However, on an individual basis, such antidotes could hypothetically improve

clinical outcomes. Reversion of DOAC and the advent of specific antidotes are described later in

this review.
16
 3.2. Thrombolytic therapy

Thrombolytic agents activate plasminogen to plasmin, which then cleaves fibrin and leads

to clot degradation. Hence, in cases of acute PE, systemic thrombolytic agents are associated with

an early hemodynamic improvement compared to anticoagulation therapy alone.55 Thrombolytic

drugs include urokinase, streptokinase and recombinant rt-PA such as alteplase, reteplase and

tenecteplase. Differences in fibrin specificity and side effects exist. Streptokinase is antigenic,

may produce hypotension and both streptokinase and urokinase activate plasminogen

independently of the presence of fibrin. Theoretically, drugs with specificity for plasminogen in

the presence of fibrin (rt-PA recombinants such as alteplase) have bleeding advantage. Further,

rt-PA recombinants have the advantage of short infusion times or even boluses (tenecteplase),

compared to 12-24h treatments with streptokinase or urokinase.

In high-risk PE with hemodynamic instability, the use of systemic thrombolysis reduces

mortality by half according to a recent meta-analysis (n=4 studies, 224 patients).13 However,

given their aggressive mechanism, thrombolytic drugs triple the risk of major haemorrhage and

intracranial haemorrhage (ICH), with a global incidence of major bleeding of 9.9% and of ICH of

~ 2%. Nevertheless, given the poor prognosis of PE with hemodynamic instability, thrombolysis

is both recommended by the ACCP (IIB) and the ESC (IB) guidelines.12, 17 Less than 5% of high-

risk PE present persistent shock despite vasopressors and thrombolysis or shock and

contraindications to thrombolysis.13 In those particular situations, reperfusion methods by

surgical thrombectomy (ESC 1C, ACCP 2C) or thrombolysis directed by catheter (ESC IIaC,

ACCP 2C) can be considered, depending on local expertise.12, 17 Also, extracorporeal membrane

oxygenation (ECMO) may be an interesting bridge therapy in patients with contra-indications to

thrombolysis, but the evidence is currently limited to small cases series.56

17
 In intermediate-risk PE, also called submassive PE, with evidence of RV dysfunction,

the use of thrombolysis is much debated. The recent PEITHO trial was aimed to specifically

answer this question.57 This randomized, controlled, double-blind trial included 1006 patients

with confirmed PE, with a right heart dysfunction and troponin elevation. Participants were

treated by IV heparin, plus either a weight adjusted bolus of tenecteplase or a placebo. The

primary outcome, mortality or hemodynamic collapse at day 7, was significantly reduced by

thrombolysis (2.6% vs. 5.6%, OR 0.44 95% CI 0.23-0.87, p = 0.02), mostly due to reduction of

hemodynamic collapse, as the impact on mortality itself was not significant. However, this

benefit was amended by high risks of major bleeding (11.5%) and hemorrhagic stroke (2.0%) in

the tenecteplase group. Therefore, thrombolysis does not seem to be a reasonable first-line

therapy in intermediate risk PE, but is a useful rescue treatment in case of poor early clinical

course. In the 2016 guidelines, the ACCP modified the grade of his recommendation not to use

thrombolysis for intermediate risk PE from 1C to 1B, because of the PEITHO trial.17

Thrombolysis should not be considered for low risk PEs.

Before initiating any thrombolytic agent perfusion, it is essential to rule out any contra-

indications, including structural intracranial disease, a previous intracranial haemorrhage, a recent

ischemic stroke or neurosurgery, active bleeding (Table 3).

4. Secondary prevention of PE recurrence

In the past 20 years, VTE has been recognized as a potential chronic disease with a high

recurrence rate in subgroups of patients. First, studies demonstrated a benefit of an extension of

anticoagulation after 6 months in patients who had suffered >1 episodes of VTE.58 Then, a shift

18
toward extending anticoagulation was observed after only one episode of VTE, particularly after

unprovoked episodes in men.

Extending anticoagulation after 3-6 months after a first PE (secondary prevention) should

only be considered if the benefit in terms of decreased recurrent risk is greater than the risk of

bleeding associated with anticoagulation. Several factors help to identify patients at high risk of a

recurrent VTE, in particular whether the incident PE was provoked59 or not and male sex.60, 61

Minor thrombophilic abnormalities, such as factor V Leiden mutation62, age59, obesity63, or the

centrality of PE are modest predictors of recurrence risk [Gouin B, Chest 2016, in press]. After a

VTE provoked by a transient risk factor, such as surgery, trauma, immobilization or, in women,

due to oral estrogens, the risk of recurrence is too low to consider secondary prevention.

However, after an unprovoked PE or a PE with a permanent risk factor, a long-term secondary

prevention should be discussed with patients, taking into consideration estimated risks of

thrombotic recurrences, anticoagulation-associated bleeding and patients preferences. Cancer-

related VTE is known to be associated with high recurrence risk, with a clear benefit to prolong

anticoagulation until the cancer is considered cured.

Several drugs are available to decrease the long-term risk of recurrent VTE:

anticoagulants (VKA, DOAC), antiplatelet agent (aspirin) and perhaps other drugs, such as

statins or sulodexide. These drugs differ in their efficacy to reduce recurrent VTE, and likely

conversely, in their bleeding safety. Apart from the PADIS-PE study64, most trials of secondary

prevention included participants with either incident DVT or incident PE (Table 4). We will

review pharmacological agents for the secondary prevention of VTE here, given that the risk of

major bleeding associated with anticoagulation and the risk of overall recurrent VTE (PE and

DVT)65 are similar in patients after incident proximal DVT or PE. Importantly, since an incident
19
PE usually recurs as a PE (in 80% of cases), and an incident DVT as a DVT [Gouin B, Chest

2016, in press], the higher case-fatality rate associated with PE than with DVT should be

considered.

4.1. Vitamin K antagonists in secondary prevention of PE

Several clinical trials have tested the risk-benefit ratio of warfarin after an initial 3-6

months of anticoagulation, mostly in patients with unprovoked VTE (Table 4).34, 58, 64, 66-68 The

proportion of participants with PE ranged from 15 to 100%. Compared with placebo or no

treatment, warfarin at an INR of 2.0-3.0 dramatically reduces the risk of thrombotic recurrence,

by about 85-95%. This translated, in these studies, into absolute risk differences of ~5-20% per

year, with corresponding number needed to treat (NNT) to prevent 1 recurrent VTE of 5-20.

Conversely, warfarin increased bleeding episodes by about 3-7-fold, with an absolute risk

increase of 10% for major or clinically relevant non-major bleeding.

To reduce the risk of bleeding, two trials have tested an intermediate-dose anticoagulation

with warfarin, to obtain an INR between 1.5-1.9/2.0 [ELATE68, PREVENT67]. Logically, a lower

INR offered less protection than an INR 2.0-3.0, with a relative risk reduction of ~65%.

However, the benefit of lowering INR on hemorrhages was not observed in the ELATE study,

with similar bleeding risks between participants with INR 1.5-1.9 and 2.0-3.0. Although the 2012

ACCP guidelines recommend INR of 2.0-3.0 over INR <2.0,19 it must be recognized that only 1

study tested these two regimens for secondary prevention of VTE and that perhaps lower INRs

may be appropriate for some patients if VKA is the only alternative.

20
 The risk of major bleeding in RCT of warfarin with a target INR of 2.0-3.0 for the

secondary prevention after VTE is low (~1.5/100 person-years), and this may be due to a

selection of healthy participants and strict anticoagulation monitoring. Real-life data are scarce

after the initial treatment period of 3-6 months for VTE, but suggest that the risks are greater. A

systematic review combining RCT and observational studies reported a major bleeding risk of

2.7/100 person-years69. In patients with anticoagulation for atrial fibrillation, who may be older,

suffer from more comorbidities and have greater co-medications than patients with VTE enrolled

in clinical trials, risks of 4.0/100 person-years arise from a registry of patients treated in the

community.70 These elements must be taken into account when evaluating the risk-benefit of

VKA for the secondary prevention of VTE.

4.2. DOAC in secondary prevention of PE

Rivaroxaban, apixaban and dabigatran have been formally tested against placebo after

several months of anticoagulation for incident VTE (Table 4).

In the Einstein-Extension study, rivaroxaban 20mg reduced the risk of recurrent VTE by 82%,

but increased bleeding risks by 5-fold.71 In a re-analysis of the net clinical benefit, comprising

both recurrent VTE and major bleeding, investigators estimated that one additional symptomatic

recurrent VTE or major bleeding event would be avoided for every 17 patients treated with

rivaroxaban.72 The ongoing EINSTEIN-Choice trial is comparing the risk-benefits of rivaroxaban

at a 20mg therapeutic dose, of rivaroxaban at a 10mg prophylactic dose and of aspirin 100mg for

the secondary prevention of VTE, with the hypothesis of a good thrombotic protection at less

bleeding cost for the lower rivaroxaban dose.73

The 3 arms of the AMPLIFY-Extension study (apixaban 5mg b.i.d, apixaban 2.5mg b.i.d.

and placebo) demonstrated that the low dose (2.5mg bid) had the best risk-benefit ratio: it was as
21
efficient as the 5mg b.i.d. therapeutic dose, with a 80% risk reduction of recurrent VTE compared

with placebo, with no apparent incremental bleeding risk compared to placebo.74

The high therapeutic dose of dabigatran (150mg b.i.d.) was tested in two parallel studies,

with an active control group of warfarin (INR 2.0-3.0) and a non-active control group with

placebo.75 For recurrent VTE, a relative risk reduction of 92% was found compared with placebo,

and no difference compared with warfarin. Dabigatran appeared safer than warfarin, with about

50% less bleeding episodes, but still tripled the risk of bleeding compared with placebo.

Overall, these studies may bring paradigm shifts for future patients care. DOAC appear

very efficient in reducing the long-term risk of recurrent VTE, similarly to warfarin, but with

likely better safety profiles. In particular, the use of lower doses of anticoagulant for secondary

prevention may yield the best risk-benefit profile, as suggested by the data from the AMPLIFY-

Extension study.74A major limitation of the current data is that these studies, while enrolling large

samples, were of short follow-up (5-12 months), which contrasts with the long durations of

secondary prevention of VTE. Real-world data will be of critical importance to appreciate both

the translation of RCT findings into more generalizable samples and for longer durations.

The efficacy and safety of edoxaban as an extended treatment after VTE has been

evaluated as a post-hoc analysis of the Hokusai-VTE trial.76 When comparing participants who

remained on anticoagulation with warfarin and with edoxaban after the initial 3 months, risks of

recurrent VTE were similar and risks of major bleeding were lower with edoxaban. Such findings

are concordant with other DOAC, but the evidence remains less strong given the post-hoc

analysis and the fact that the duration of anticoagulation was determined by treating physicians.

4.3. Aspirin in secondary prevention PE

22
 Aspirin is a well-known anti-platelet agent used in prevention and treatment of arterial

thromboses (coronary artery disease, cerebrovascular disease, peripheral artery disease). It

inhibits the platelet COX-1 activity, which suppresses the amplification response to diverse

agonists that are dependent on thromboxane A2. Through different mechanisms, this results in a

down-regulation of thrombin generation and a possible improvement of fibrinolysis.77

For many years, a mild reduction of incident VTE had been observed with aspirin in

clinical studies, specifically after orthopaedic surgery. Recently, two large clinical trials of very

similar design (WARFASA78 and ASPIRE79) randomized 1200 participants after several months

of oral anticoagulant treatment for incident unprovoked VTE to aspirin 100mg daily or placebo.

When pooling these data, aspirin reduced the risk of recurrent VTE by 32%, with no statistically

or clinically relevant increased bleeding risks.80 Results were concordant in the 2 studies and the

follow-ups were long (2-3 years). Further, risks of arterial cardiovascular disease were also

reduced. Care providers and patients may therefore select aspirin as a modest protection against

recurrent VTE, which, although not as powerful as anticoagulant, may have an appropriate risk-

benefit balance in case of intermediate risk of recurrent VTE. Confirmation of this statement may

come from the EINSTEIN-CHOICE study, in which a direct comparison of a DOAC with aspirin

is ongoing.73

4.4. Others

Two other oral drugs may play a role in the future for the secondary prevention of VTE.

First, sulodexide is a purified glycosaminoglycan that contains heparin sulphate and dermatan

sulphate with affinities for antithrombin and heparin cofactor, respectively. In the SURVET

study, compared to placebo, a twice daily treatment with sulodexide decreased the risk of

recurrent VTE by 50%, with no effect on bleeding risk.81 Confirmation of these findings would
23
be welcome, because of some methodological limitations of this study and of the low number of

events (and thus limited precision of the main results). Second, several pharmacoepidemiological

studies have observed an association between current statin use and a 30% relative risk reduction

of recurrent VTE.82 The causality of this association remains to be determined in a formal

randomized controlled trial before any definite conclusions can be drawn for the role of statin in

clinical practice.

5. Anticoagulation of PE in pregnancy

Pregnancy increases the risk of VTE through different mechanisms (hormonal,

mechanical). About 1 out of 200-500 pregnant or postpartum women will suffer a VTE, of which

30% will be PE.83

Most anticoagulant agents are not to be used in pregnant women. Vitamin K antagonists

are teratogenic, with a 6% risk of warfarin embryopathy characterized by bone, cartilage and

neurological abnormalities.84 Only in pregnancies of very high thrombotic risk, such as in women

with mechanical heart valves, may VKA be considered because of their high efficacy. Very few

data exist on DOAC during pregnancy, although many fertile women use DOAC for the

treatment of VTE, during which they may become pregnant. Non-clinical studies suggest

potential fetal effects of DOAC. Placental models demonstrate that dabigatran, rivaroxaban and

apixaban cross the placental barrier, albeit in different maternal to fetal ratios.85 Teratogenic

effects are observed in animal studies with very high levels of rivaroxaban, edoxaban and

dabigatran. A recent review collected 137 cases of use of DOAC at some time during pregnancy,

from physicians, literature and pharmacovigilance systems.86 The rate of live birth was 59%, with

5% of fetal abnormalities and 2% of possible embryopathy. The authors conclude that these

limited data do not indicate a high risk of embryopathy. Considering the lack of clinical
24
experience and the sparcity of data, DOAC are currently contra-indicated during pregnancy

(ACCP: 1C)19. .Fondaparinux also crosses the placenta, with about a maternal to fetal ratio of

10:1. The significance of this observation is unknown, as only 30 to 40 pregnancies with

fondaparinux have been described with no warning signals for a high bleeding or teratogenic

effect.87 According to the latest ACCP recommendations, fondaparinux should be reserved to

pregnant women with severe allergies or previous adverse reactions to heparin/LMWH such as a

HIT.88

Therefore, heparins are the main anticoagulant during pregnancy for VTE, including PE,

as they do not cross the placenta and are not teratogenic. When used at therapeutic doses, the

efficacy and safety of LMWH appear satisfactory. In a meta-analysis of 981 pregnant women, the

incidence of antenatal and postnatal major bleeding was 1.4% and 1.9%, and 2% of women

suffered a VTE recurrence during pregnancy.89 The risk of HIT is low, if not null, during

pregnancy. Osteoporosis, once feared with heparins during pregnancy, does not appear to be a

problem with LMWH.90 Two challenges remain with LMWH during pregnancy: the need for

daily injections over several months, with potential local skin reactions and decrease in

compliance and the uncertainty of dosage, especially over the third trimester. In pregnancy, the

supra-normal renal clearance associated with an increased volume of distribution modify the

pharmacokinetics of LMWH, with decreased peak anti-Xa levels but increased through anti-Xa

levels.91 Whether and how to adjust the LMWH dose in this environment remains uncertain.

Treatment of high-risk (massive) PE in pregnant women is challenging, as pregnancy is

categorized as a relative contra-indication to thrombolysis. Current recommendations are based

on the experience published in case-reports with inherent publication bias, and suggest to reserve

thrombolytic therapy for life-threatening PE.88 Newer generations of thrombolytic drugs, such as

25
rt-PA, may be preferred in these patients given that they are believed not to cross the placental

barrier, in contrary to streptokinase.92, 93

88
In the postpartum, women who are breastfeeding may use heparins and VKA (with

vitamin K supplementation for newborns at higher dose than the usual dose administered to all

newborns). Apixaban is found in breast milk and DOAC should thus be avoided in case of

breastfeeding.85

6. Reversal of anticoagulation

6.1. VKA

Reversal of VKA with vitamin K (oral or intravenous) is effective but slow (hours). If an

immediate reversal of anticoagulation is required (need for urgent invasive intervention, major

bleeding), four-factor prothrombin complex concentrate (4F-PCC) should be used, as it is

efficient and quick. Fresh frozen plasma (FFP) is an alternative, albeit less efficient and rapid,

and leads to more volume overload.94 In a systematic review of studies comparing PCC to FFP

for reversal of VKA, a mortality benefit of PCC was demonstrated but arose mainly from

observational studies,95 Of note, PCC might contain heparin, and is thus contra-indicated in

patients with past history of HIT. FFP are biological products, being associated with a rare risk of

transfusion-related acute lung injury (TRALI). The use of either product is associated with a ~5%

risk of thromboembolic event, but whether this is due to the reversal itself is unclear.

6.2 DOAC

Some theoretical strategies exist to promote drug removal in case of bleeding emergencies

on DOAC: activated charcoal to limit gastrointestinal absorption, hemodialysis (for dabigatran).

In case of life-threatening bleeding or needed invasive procedure at risk of bleeding, activated or

unactivated prothrombin complex concentrates (PCC) with 3 or 4 clotting factors (II-IX-X +/-
26
VII) can be considered. Supporting literature is largely based on animal studies and non-bleeding

volunteers, showing reversal of anticoagulation for rivaroxaban, apixaban and edoxaban at a very

large dose of 50U/kg IV.96-100 Such high doses of PCCs are associated with an increased risk of

thrombosis, and thus shouldnt be administered routinely. Importantly, it must be recalled that

mechanical hemostasis, for instance through local cauterisation of gastro-intestinal bleeding, is

the most important step in the management of bleeding from a determined source and not the

reversal of anticoagulation itself.

Specific DOAC antidotes are being developed and studied in clinical trials. Idarucizumab,

a humanized dabigatran-specific antibody fragment, was developed to rapidly reverse the

anticoagulation effect of dabigatran, with no effect on anti-Xa anticoagulants. In the prospective

uncontrolled cohort RE-VERSE AD, 90 patients treated with dabigatran mostly for atrial

fibrillation received two IV doses of 2.5g each, given 15 minutes apart, for serious bleeding or in

urgent need of an invasive procedure.101 Hemostatic measures of anticoagulation were quickly

corrected. Clinically judged hemostasis appeared satisfactory to surgeons in 33/36 patients with

emergency surgery. However, 6% suffered a thrombotic complication, but only 1 was within 72h

of reversal. Further, 20% died. Since the study was not controlled, causal risks and clinical

benefits of idarucizumab cannot be completely understood, but based on these data the FDA has

approved the use of idarucizumab in these critical situations.

Andexanet alfa is a specific reversal agent that neutralizes both direct and indirect factor

Xa inhibitors. It is a recombinant modified human and inactive factor Xa decoy protein with the

ability to bind factor Xa inhibitors. It has been shown to reverse the effect of both xabans and

LMWH in a phase II trial. ANNEXA-A and ANNEXA-R trials, two randomized, double-blind,

placebo-controlled studies, were designed to evaluate the efficacy of andexanet to reverse the

anticoagulant effect of apixaban and rivaroxaban, respectively, as measured by the mean percent
27
change in anti-factor Xa activity.102 A total of 145 healthy 50-75 years old participants received

therapeutic dose of apixaban or rivaroxaban and were then randomized to receive either

andexanet (as a bolus alone or a bolus followed by a 2h fixed dose infusion) or a placebo. Anti-

factor Xa activity was reduced by 94% and 92% in the apixaban and rivaroxaban group who

received the andexanet bolus, compared to 21% and 18% in the placebo groups. Thrombin

generation was fully restored in 100% and 96% of the participants who received the andexanet,

respectively. No thrombotic events nor serious adverse event occurred. The use of andexanet alfa

in cases of acute major bleeding occurring among patients receiving a anti-Xa inhibitor

(apixaban, rivaroxaban, edoxaban, enoxaparin) is currently being studied in the ANNEXA-4 trial,

a multicentre, prospective, open-label, single-group study103. A descriptive, preliminary analysis

was recently published, including 67 patients (29% receiveing anticoagulation for VTE).

Andexanet alfa very effectively reduced anti-Xa levels and 79% of patients were adjudicated as

having had excellent or good hemostasis. Thrombotic events and mortality occurred in 18% and

15% of participants at 30 days.

The low number of participants and the lack of control groups in these two studies limit

our ability to adequately understand the utility and risks of these reversal agents. Mortality and

thrombotic risks are high, but perhaps not unexpected in such acute settings. Further data will be

welcome. Until then, a conservative use of these antidotes is warranted, if/when available locally.

Having effective reversal options in cases of urgent surgery and DOAC can be reassuring.

However, clinical benefit of such therapies in cases of major bleeding is to be proven,

considering the short half-life of DOAC, other mechanical options to alleviate bleeding (in case

of gastrointestinal haemorrhage) and the lack of proven survival benefit of quick reversal

strategies in patients with VKA and major bleeding. The FDA has approved the use of

idarucizumab, but not that of andexanet yet.

28
7. Conclusions

The pharmacological treatment of PE encompasses many different antithrombotic drug

options at different times of treatment (thrombolytic, anticoagulant, antiplalet agents). Overall,

DOAC are replacing other anticoagulants as the preferred treatment for a large proportion of

patients with non high-risk PE, based on their ease of use and lower bleeding risk. Data from

real-world setting will inform us for the generalizability of RCT findings and long-term tolerance

of DOAC. Still, older anticoagulants such as heparin, LMWH and VKA remain efficient drugs

and play important roles in specific groups of patients (chronic kidney failure, cancer, pregnancy,

need for invasive procedures).

8. Expert opinion

The advent of DOAC has dramatically modified the management of PE. Similarly to

recommendations, we have shifted our anticoagulant prescription from LMWH and VKA to

DOAC, and this has much simplified the early management of patients with PE. Our personal

and subjective preference in low-risk PE, most of whom are treated ambulatory, goes to anti-Xa

direct anticoagulant which can be used from the diagnosis, such as rivaroxaban and apixaban, to

avoid the need for injections in the initiation of treatment. When patients with PE are hospitalized

(intermediate risk, multiple comorbidities, need for investigations), we use DOAC, LMWH or

fondaparinux (often with DOAC as a switch), and especially the two latter when invasive

procedures or thrombophilia testing is planned, given the broad experience of hospitalists with

these drugs and their ease of monitoring. High-risk PE is usually managed with heparin after

thrombolysis, while in-hospital. Although there are no specific data for DOAC in this subgroup

29
of patients, we tend to prefer DOAC after discharge in these patients, for the same reasons as for

low-risk and intermediate-risk PE.

The use of DOAC, while much improving patients comforts and bleeding outcomes, in

particular for intracranial bleeding, has brought new challenges. First, compliance was easily

assessed with VKA, through regular INR monitoring, but it is not with DOAC. Care practioners

must therefore assess the compliance of patients to DOAC through a thorough history. Second,

while the bleeding risk associated with DOAC is lower than that with VKA, some types of

bleeding may be increased. Patients with AF treated with rivaroxaban suffered more gastro-

intestinal bleeding than with VKA in the ROCKET AF trial, but this was not observed for VTE

patients.33, 71, 104 However, rivaroxaban, and perhaps all xaban, doubles the risk of abnormal

uterine bleeding when compared with VKA.105 Among women <60 years of age with VTE, the

incidence of abnormal uterine bleeding with rivaroxaban was 22 per 100-patient years,

corresponding to 1 out of 5 women per year. Such risks should be discussed at the start of

treatment and throughout the anticoagulation with DOAC in women, as we expect that only an

active history taking will uncover most of these bleeding complications. Further, fertile women

should be informed of the lack of sufficient data to evaluate the teratogenicity of DOAC and the

need for an effective contraception while on DOAC.85 Third, as explained above, attention needs

to be brought to co-medications, in order to avoid interactions with P-gp or CYP3A4 modulators.

Fourth, strong data are lacking to evaluate the risk-benefit of DOAC in specific conditions such

as antiphospholipid syndrome (APS),106 paraneoplastic VTEs (NCT02073682), heparin-induced

thrombocytopenia107 and superficial venous thrombosis (SVT) (NCT01499953). Hence, we tend

not to use DOAC in such patients, noting that several studies are in progress.

Some authors advocate for measurements of levels of DOAC in broader patients than

those suffering from recurrent thrombosis, major bleeding or with necessary emergency surgery.
30
While there may be a relationship between levels of DOAC and risks of thrombosis and

bleeding,51, 108 subgroup analyses from phase III trials do not detect differences of the efficacy or

safety of DOAC in patients with low or high bodyweight, probably due to the wide therapeutic

range.109 In the absence of specific evidence, DOAC level measurement for dose adjustment

should therefore not be used in these patients. Our pragmatic approach is to use DOAC in

patients with similar characteristics to those included in these trials and not use monitoring.

Given the lack of clear normogram, we would tend not to use DOAC in patients with extreme

(low or high) bodyweights who were underrepresented in phase III trials, as well as in patients

with gastro-intestinal disease associated with possible malabsorption.

One key difficulty in the management of PE is the optional secondary prevention after the

first 3-6 months of anticoagulation. The selection of patients for secondary prevention is difficult

and out of the scope of this review. However, when such a long-term prevention is decided,

emerging evidence suggest that low-dose DOAC may be preferable. The AMPLIFY-EXT study

showed surprisingly good protection from a prophylactic dose of apixaban (2.5mg b.i.d.).74 We

are also impatiently waiting for the results of the EINSTEIN-CHOICE study (NCT02064439),

whose findings will help compare prophylactic dose of rivaroxaban (10mg) with a therapeutic

dose (20mg) and aspirin (100 mg). Results from phase IV clinical studies (such as the already

published XALIA study for rivaroxaban-treated DVT) are also of high interest.47 Such studies

from real-world setting will indeed help us evaluate the generalizability of the RCT findings, and

specifically the longer-term use of DOAC. In the future, it is also possible that refinements of risk

assessment methods will allow to choose from different strengths of secondary prevention.1

In our clinical experience, the reversal of DOAC has not been a major issue. In the vast

majority of situations, time has been the best reversal agent, given the short half-life of DOAC.

Antidotes for DOAC, such as idarucizumab, will certainly be an important addition for the safety
31
of patients, but we intend to use them with caution and in life-threatening situations only, before

a broader experience is known.

All current antithrombotic drugs appear to be tied to an increased bleeding risk. In the

future, we hope that new drugs or new dosages of current drugs will yield better risk-benefit

ratios. In particular, a new anti-factor XI antisense oligonucleotide may show promising features.

It has been studied in a small, open-label, randomized-controlled trial of thromboprophylaxis for

patients undergoing elective primary unilateral total knee arthroplasty. This new agent seemed

more effective than enoxaparin for VTE prophylaxis with possibly less bleeding.110

ARTICLE HIGHLIGHTS

The management of acute PE is tailored to its predicted associated short-term mortality

risk, and in the vast majority of cases relies simply on fast and efficient anticoagulation.

DOAC have become the preferred anticoagulant agent in most situations, because of their

effectiveness, favourable bleeding profile and lack of need for monitoring.

During pregnancy, LMWHs are the preferred anticoagulant agent to treat PE.

When secondary long-term prevention of recurrent VTE after PE is decided, the

anticoagulant agent must be chosen according its efficacy and safety profile, the patient's

comorbidities and preferences.

A specific dabigatran antidote was recently approved by the FDA. A specific anti-Xa

inhibitors (-xabans, LMWH) antidote is under clinical validation.

32
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40
Figure 1: Overview of the management of acute pulmonary embolism.

* Reduced dose of 30 mg od if CrCl 30-50 ml/min, body weight < 60 kg or use of p-GP inhibitor, and not tested in a dedicated phase III trial for
secondary prevention

41
Table 1. Characteristics of direct oral anticoagulants

Dabigatran Apixaban Edoxaban Rivaroxaban

Target IIa Xa Xa Xa
Dose dependent
Bioavailability 3-7% 50% 62% 80-100%
Increased with food
Tmax 0.5-2 h 3-4h 1-2h 2-4h
12-17h (young) 5-9h (young)
Half-life 12h 10-14h
14-17h (elderly) 11-13h (elderly)
Protein binding 35% 87% 55% 92-95%
Renal excretion 80% renal 25% renal 50% renal 33% renal
<10%
CYP substrate No CYP3A4 CYP3A4
CYP3A4
P-gp substrate Yes Yes Yes Yes

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Table 2. Phase III trials comparing direct oral anticoagulants to warfarin for the treatment of acute venous thromboembolism

AMPLIFY RE-COVER I + II HOKUSAI EINSTEIN-PE

Randomized Randomized Randomized
Double-blind Double-blind Double-blind Randomizedpen-label,
Double-dummy Double-dummy Double-dummy Non-inferiority
Non-inferiority Non-inferiority Non-inferiority
n (% PE) 5395 (34.0%) 5107 (31.2%) 8240 (40.3%) 4832 (100.0%)
Therapeutic regimen Apixaban Dabigatran Edoxaban Rivaroxaban
10 mg bid LMWH for a minimum LMWH for a minimum 15 mg bid
- Introduction
for 7 days of 5 days of 5 days for 21 days
- Maintenance dose 5mg bid 150 mg bid 60 mg od 20 mg od
30 mg o.d. if 1 :
- CrCl 30-50 mL/min
- Reduction dose No No No
- Body weight 60 kg
- P-gp inhibitors
Control arm Enoxaparin/VKA Enoxaparin/VKA LMWH/VKA Enoxaparin/VKA
INR TTR 61% 60% 63.5% 62.7%
3, 6, 12 months
Duration 6 months 6 months 3-12 months
(5%, 57%, 37%)
Thrombotic context
Idiopathic 89.8% N/A 62.9% 64.5%
Active cancer 2.7% 4.8% (RI), 3.9% (RII) 10.8% 4.6%
Previous VTE 16.1% 25.6% (RI), 17.5% (RII) 20.1% 19.5%
Efficacy outcome
2.3% VS 2.7% 3.2% VS 3.5% 2.1% VS 1.8%
2.4% VS 2.2%
Recurrent VTE or fatal RR 0.84 HR 0.89, HR 1.12
HR 1.09
PE 95%CI [0.60-1.18], 95%CI [0.70-1.13] 95%CI [0.75-1.68]
95%CI [0.76-1.57]
p<0.001 p<0.001 p=0.003
Safety outcome
4.3% VS 9.7% 8.5% VS 10.3% 10.3% VS 11.4%
Major or clinicaly 5.3% VS 8.5%
RR 0.44 HR 0.81 HR 0.90
relevant nonmajor HR 0.62
95%CI [0.36-0.55] 95%CI [0.71-0.94] 95%CI [0.76-1.07]
bleeding 95%CI [0.50-0.76]
p<0.001 p=0.004 p=0.23

43
 0.6% VS 1.8% 1.4% VS 1.6% 1.1% VS 2.2%
1.4% VS 2.0%
RR 0.31 HR 0.84 HR 0.49
Major bleeding HR 0.73
95%CI [0.17-0.55] 95%CI [0.59-1.21] 95%CI [0.31-0.79],
95%CI [0.49-1.11]
p<0.001 p=0.35 p=0.003
Fatal bleeding <0.1% VS 0.1% NA <0.1% VS 0.2% <0.1% VS 0.1%
Intracranial bleeding 0.1% VS 0.2% <0.1% VS 0.2% 0.1% VS 0.4% 0.1% VS 0.5%

NA: not available

INR: international normalized ratio
TTR: time in therapeutic range.
OD: once daily
Bid: twice daily

44
Table 3: Systemic thrombolysis contra-indications

Prior intracranial haemorrhage

Known structural cerebral vascular lesion
Known malignant intracranial neoplasm
Absolute
Ischemic stroke 3 mois
contra-indication
Suspected aortic dissection
Active bleeding or bleeding diathesis (excluding menses)
Significant closed-head trauma of facial trauma 3 months
Severe uncontrolled hypertension on presentation (SBP>180 mmHg or DBP >110 mmHg)
Ancient ischemic stroke
Traumatic or prolonged (>10 min) CPR
Major surgery 3 weeks
Recent internal bleeding (2-4 weeks)
Relative Non compressible vascular punctures
contra-indication Recent invasive procedure
Pregnancy
Age > 75 years
Current use of anticoagulant (ex: warfarin) that has produced an elevated INR > 1.7

45
 Table 4: Regimens tested for long-term secondary prevention of venous thromboembolism (VTE) recurrence in randomized controlled
trials after an initial course of anticoagulant treatment

Placebo/no treatment - controlled trials

VTE RECURRENCE (during treatment) MAJOR OR CLINICALLY RELEVANT
BLEEDING (during treatment)
Drugs (study) Proportion Duration Intervention arm Placebo arm Relative risk Intervention Placebo arm Relative risk
of of Annualized rate Annualized (95%CI) arm Annualized (95%CI)
pulmonary extended (n events /N) rate (n events Annualized rate (n events
embolism treatment /N) rate /N)
(N) (n events /N)
VITAMIN K ANTAGONISTS
Warfarin 15% (34) 43 months 0.8/100p-y ** 6.2/100p-y ** 0.13 N/A N/A N/A ****
INR 2.0-2.85 (3/116) (22/111) (0.04-0.4)
(DURAC II)***
Warfarin 100% (371) 18 months 2.2/100p-y ** 8.9/100p-y 0.15 1.5/100p-y * 0.4/100p-y * 3.96
INR 2.0-3.0 (3/184) (25/187) (0.15-0.43) (4/184) (1/187) (0.4-35.9)
(PADIS-PE)
Warfarin 28% (18) 18 months 2.1/100p-y 14.5/100p-y ** ~ 0.14 0/100p-y 0/100p-y N/A
INR 2.0-3.0 (1/32) (7/32) (0/32) (0/32)
Farraj RS, Saudi Med J 2004

Warfarin 25% (41) 10 months 1.3/100p-y 27.4/100p-y 0.05 1.4/100p-y 11.5/100p-y 7.1
INR 2.0-3.0 (1/79) (17/83) (0.01-0.37 (1/83) (9/79) (0.9-58)
Kearon C, NEJM 1999
Warfarin N/A 25 months 2.6/100p-y 7.25/100p-y 0.36 0.9/100p-y * 0.4/100p-y * 2.53
INR 1.5-2.0 (14/255) (37/253) (0.19-0.67) (5/255) (2/253) (0.49-13.0)
(PREVENT)
DOAC
Rivaroxaban 20mg 38% (454) 8 months ~2.2/100p-y ** ~12.2/100p-y ** 0.18 ~10.1/100p-y ** ~2.0/100p-y ** 5.19
od (8/602) (42/594) (0.09-0.39) (36/602) (7/594) (2.3-11.7)
(EINSTEIN
Extension)

46
Apixaban 2.5mg ~1.8/100p-y ** 0.19 ~3.8/100p-y ** 1.20
bid (14/840) (0.11-0.48) (27/840) (0.69-2.10)
35% (860) 12 months ~ 9.9/100p-y ** ~3.3/100p-y **
Apixaban 5mg bid (73/829) (22/829)
~1.8/100p-y ** 0.20 1.62
(AMPLIFY ~5.1/100p-y **
(14/813) (0.11-0.34) (0.96-2.73)
Extension) (35/813)

Dabigatran 150mg 33% (443) 5 months ~0.9/100p-y ** ~11.9/100p-y ** 0.08 ~12.5/100p-y ** ~4.2/100p-y ** 2.92
bid (3/681) (37/662) (0.02-0.25) (36/681) (12/662) (1.52-5.60)
(RE-SONATE)
ANTIPLATELET DRUGS
Aspirin 100mg 37% (150) 24 months 6.6/100p-y 11.2/100p-y 0.58 ~1.0/100p-y ** ~1.0/100p-y ** 0.98
(WARFASA) (28/205) (43/197) (0.36-0.93) (4/205) (4/197) (0.24-3.96)
Aspirin 100mg 42% (346) 37 months 4.8/100p-y 6.5/100p-y 0.74 1.1/100p-y 0.6/100p-y 1.73
(ASPIRE) (57/411) (73/411) (0.52-1.05) (8/411) (14/411) (0.72-4.11)

MIXED DRUGS
Sulodexide 500 ~2.7/100p-y ** ~5.6/100p-y ** 0.49 ~0.4/100p-y ** ~0.4/100p-y ** 0.97
LSU bid (SURVET) (15/307) (30/308) (0.27-0.92) (2/307) (2/308) (0.14-6.88)

47
 Warfarin (INR 2.0-3.0) - controlled trials
VTE RECURRENCE MAJOR OR CLINICALLY RELEVANT
BLEEDING
Drugs (study) Proportion Mean Intervention arm Warfarin arm Relative risk Intervention Warfarin arm Relative risk
of duration of Annualized rate (INR 2.0-3.0) (95%CI) arm (INR 2.0-3.0) (95%CI)
pulmonary extended (n events /N) Annualized Annualized Annualized
embolism treatment rate (n events rate rate (n events
(N) /N) (n events /N) /N)
VITAMIN K ANTAGONISTS
Warfarin INR 1.5- 35% (259) 26 months 1.9/100p-y 0.7/100p-y 2.8 1.2/100p-y * 0.9/100p-y * 1.2
1.9 (16/369) (6/369) (1.1-7.0) (9/369) (8/369) (0.4-3.0)
(ELATE)
DOAC
Dabigatran 150mg 35% (994) 16 months ~1.3/100p-y ** ~0.9/100p-y ** 1.44 ~4.8/100p-y ** ~9.2/100p-y ** 0.54
bid (25/1430) (18/1426) (0.78-2.64) (80/1430) (145/1426) (0.41-0.71)
(RE-MEDY)

* only major bleeding

** estimated from the available data
*** secondary prevention after a second episode of VTE
**** data for period after the initial 6 months of anticoagulation is not available
95%CI = 95% confidence interval; INR = International Normalized Ratio ; p-y = patient-year

Modified with permission from Blondon M, Bounameaux H. Secondary Prevention of Venous Thromboembolism: One Regimen
May Not Fit All. Circulation 2015 Nov 17;132(20):1856-9

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