Deep Vein Thrombosis Current Management Strategies
Heike Endig, Franziska Michalski and Jan Beyer-Westendorf
Division of Angiology, Center for Vascular Medicine and Department of Medicine III, University Hospital Carl Gustav Carus,
TechnischeUniversitt Dresden, Dresden, Germany.
Abstract: Deep vein thrombosis (DVT) is a frequent and potentially life-threatening condition, and acute and late complications are common. The
diagnostic approach to DVT needs to be reliable, widely available, and cost-effective. Furthermore, several therapeutic options are available for DVT treat-
ment and the choice of anticoagulant drug, dosage, and treatment duration has to reflect the specific situation of the individual DVT patient. This review
was aimed to provide bedside guidance for clinicians faced with common (and less common) clinical scenarios in DVT treatment.
Keywords: deep vein thrombosis, diagnosis, therapy, anticoagulantion
Citation: Endig etal. Deep Vein Thrombosis Current Management Strategies.
Clinical Medicine Insights: Therapeutics 2016:8 1120 doi: 10.4137/CMT.S18890.
TYPE: Review
Received: June 16, 2015. ReSubmitted: October 27, 2015. Accepted for
publication: October 29, 2015.
Academic editor: Garry Walsh, Editor in Chief
Peer Review: Seven peer reviewers contributed to the peer review report. Reviewers
reports totaled 1956 words, excluding any confidential comments to the academic editor.
Funding: Authors disclose no external funding sources.
Competing Interests: Jan Beyer Westendorf received honoraria for presentations
and Advisory Boards from Aspen, Bayer Healthcare, Boehringer Ingelheim, Daiichi Sankyo,
Leo Pharma, Pfizer. Jan Beyer Westendorf received institutional research support from
Bayer Healthcare, Boehringer Ingelheim, Daiichi Sankyo, Pfizer. Franziska Michalski
received honoraria from Bayer Healthcare. Heike Endig: nothing to disclose.
Introduction
Acute or subacute deep vein thrombosis (DVT) usually, but
not exclusively, occurs in the legs with an estimated incidence
of 1:1000/year.14 The most dangerous complication of DVT
is pulmonary embolism (PE), which can either be asymp-
tomatic (30% of DVT patients have silent PE at the time
of DVT diagnosis5) or symptomatic (tachycardia, dyspnea, or
hypoxemia, which are usually caused by increased right ven-
tricular pressure and/or reduced pulmonary perfusion). DVT
and PE are two manifestations of venous thromboembolism
(VTE), which may be caused by provoking factors such as
major surgery, trauma, immobilization, or hormonal contra-
ceptives, may be associated with cancer or cancer therapy,
may be caused by thrombophilia, or may occur spontaneously
without any of these factors present.6 Insufficient diagnostic or
therapeutic workup for DVT or PE treatment accounts for a
considerable number of fatal complications.7 In addition to the
acute mortality, patients surviving with PE are at a consider-
able risk of developing chronic thromboembolic pulmonary
hypertension, which impacts quality of life, treatment costs,
and long-term prognosis. Finally, patients with DVT may
develop postthrombotic syndrome (PTS), which constitutes
symptoms and organic changes of the leg veins and tissues
caused by increased venous pressure, residual vein occlusion, or
venous valve damage following the acute thrombotic event.
This review focused on the current standard of DVT
diagnosis and therapy, which, to our understanding, is the
best approach to prevent potentially fatal complications, such
as severe PE, and to prevent long-term health consequences.
Correspondence: jan.beyer@uniklinikum-dresden.de
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Current Standards for Diagnosing DVT from
Symptoms to Diagnostic Reliability
Pain, swelling, and discoloration due to venous stasis are the
most common symptoms of DVT patients. However, several
other conditions such as infections, hematoma, joint and/or
muscle injuries, and chronic joint conditions may present in
the same way. As a consequence, clinical examination alone
is insufficient to safely establish or rule out DVT. However,
if findings from clinical examination are combined with the
assessment of DVT triggers in recent history (such as trauma,
surgery, immobilization, long-distance travel, cancer, hor-
mone treatment, and pregnancy), preferably with a standard-
ized scoring system such as the Wells score (Table1),8,9 a much
more accurate assessment of DVT probability is possible. The
use of the Wells score still does not reliably diagnose or rule
out DVT, but it defines the correct diagnostic procedure for
patients with different probabilities of having DVT. Patients
with a simplified Wells score (2003 version) of #2 points have
a low probability of having DVT, and in ultrasound examina-
tion, only 5% of patients were found to have the disease.9 If
the Wells score is #2, ultrasound is needed only in patients
who also have elevated d-dimers, a fibrin degradation product
that forms during endogenous thrombolysis. Taken together,
DVT can be reliably ruled out in all patients who have a low
Wells score and negative d-dimers, and ultrasound would be
an unnecessary step in the diagnostic workup (Fig.1).9,10
In contrast, all other patients (namely, those with a Wells
score of .2 and those with low Wells score but abnormal
d-dimer) must be sent for objective testing, which comprises
Clinical Medicine Insights: Therapeutics 2016:8 11
Endig etal

Table1. Pretest probability scores for suspected DVT, evaluated by Wells etal.8,9

DVT-Pretest probability score Score DVT-Pretest probability score Score

(Wells 1997) (Wells 2003)
Active cancer (treatment ongoing or within 1 Active cancer (patient receiving treatment for cancer 1
previous 6 months or palliative) within the previous 6 months or currently receiving
palliative treatment)
Paralysis, paresis or recent plaster 1 Paralysis, paresis or recent plaster immobilization of 1
immobilization of te lower extremities the lower extremities
Recently bedridden for more than 3 days 1 Recently bedridden for 3 days or more, or major surgery 1
or major surgery, within 4 weeks within the previous 12 weeks requiring general or regional
anesthesia
Localized tenderness along the distribution 1 Localized tendemess along the distribution of the deep 1
of the deep venous system venous system
Entire leg swollen 1 Entire leg swollen 1
Calf swelling by more than 3 cm when 1 Calf swelling at least 3 cm larger than on the asymptomatic 1
compared with the asymptomatic leg leg (measure 10 cm below tibial tuberosity)
(measured 10 cm below tibial tuberosity)
Pitting edema (greater in the symptomatic 1 Pitting edema confined to the symptomatic leg 1
leg)
Collateral superficial vein (non-varicose) 1 Collateral superficial vein (non-varicose) 1
Alternative diagnosis at least as likely as -2 Previously documented deep-vein thrombosis 1
deep-vein trrombosis
Alternative diagnosis at least as likely as deep-vein -2
thrombosis
Score 0 or less Low probability Score less than 2 DVT unlikely
Score 1 or 2 Intermediate Score 2 or more DVT likely
probability
Score 3 or more High probability

venous compression ultrasound. This stepwise diagnostic workup
is recognized by most current VTE guidelines(Fig.1).10,11
Important notes for Wells score and d-dimer testing are
the following:
- Wells score and other DVT probability scores are only
useful in outpatients with suspected DVT. Hospitalized
patients with DVT symptoms are by definition at high
probability to have DVT, and objective testing (usu-
ally with ultrasound) is always indicated. Consequently,
d-dimer testing is not useful to guide diagnostic deci-
sions in hospitalized patients.
- All currently available laboratory-based d-dimer tests
have high sensitivity. In contrast, so-called bedside or
point-of-care (POC) d-dimer tests vary considerably
with regard to sensitivity.1214 Users of POC are advised
to obtain sensitivity data from the manufacturer or from
the published literature to interpret the POC results cor-
rectly. For all quantitative or semiquantitative d-dimer
tests, a cutoff has been defined. It was recently estab-
lished that the cutoff of normal d-dimers is higher in
elderly patients, and age-adjustments are now recom-
mended to avoid too many false-positive d-dimer results
in elderly patients,15 which would result in a high number
of unnecessary ultrasound examinations.
- All d-dimer tests lack specificity. d-Dimer values are
often increased in acute infections, cancer, or pregnancy,
and from a positive d-dimer test alone, the presence of
DVT cannot be concluded.16 Consequently, the practical
value of d-dimer testing derives from the negative pre-
dictive value (or high sensitivity). Patients with low Wells
score and negative d-dimers do not have DVT.
- Negative d-dimer as a stand-alone test is insufficient
to rule out DVT, since, without the preselection of
patients with low Wells score, the sensitivity of dimers
decreases considerably.
Important notes for ultrasound are as follows:
- Venous compression ultrasound using B mode and pelvic
vein doppler can be safely regarded as the gold standard
of DVT imaging, and the additional use of color mode or
distal doppler mode is not routinely needed. The concept
is simple: if a venous segment is not compressible, some-
thing inside has to prevent compressibility and venous
thrombosis can be diagnosed.
- For compression ultrasound, a single examination of the
whole leg vein system (complete compression ultrasound
[CCUS] including all below-the-knee or distal veins) has
been shown to be accurate and safe both in patients with

12 Clinical Medicine Insights: Therapeutics 2016:8


DVT suspected
Pretest probability such Not high
as wells-score
High
Positive
Treat DVT
Positive
Treat DVT
(alternatively: venography)
Figure1. Diagnostic workup of DVT.
and without DVT,17,18 but this protocol requires ultra-
sound experience.
- A limited compression ultrasound (LCUS) with exami-
nation of the groin and popliteal fossa is rapid and easy
to learn. This simple protocol is able to detect ascend-
ing clots that involve these regions. As a consequence,
LCUS seems ideal for emergency situations (emergency
room and intensive care unit), where a rapid assessment is
needed and dedicated venous ultrasound experience may
be limited. If no DVT is found in the groin and popliteal
fossa, the examination should either be continued toward
a single complete compression ultrasound or the patient
should be reexamined within the next five days. The
concept behind this is the fact that an ascending DVT
becomes visible in the groin or popliteal fossa, if progres-
sion toward these segments is allowed. Physicians may
be concerned about leaving patients with suspected DVT
untreated for five days, which is why the authors prefer
CCUS, but this repeated LCUS strategy with examina-
tion of the groin and popliteal fossa only has been shown
to be feasible and safe.19
- The authors are well aware that ultrasound examination
may not be possible in all patients or may not result in a
definite diagnosis. In such cases, repeat ultrasound after
five days or venography (rarely used in todays clinical
practice) would be the options. We are also aware that
CT and MRI protocols exist to visualize leg veins and
leg DVT, but we regard such examinations as mainly of
scientific value and little clinical usefulness because of
the limitations of contrast media side effects, relevant
radiation exposure with CT, lack of 24/7 availability, and
costs. However, patients with iliac or cava vein thrombo-
sis are usually diagnosed by CT scan, since ultrasound is
of limited value in these situations.18,20
Deep vein thrombosis
Negative DVT ruled out,
D-dimer
do not treat
Elevated
Complete compression Negative DVT ruled out,
ultrasound (cCUS) do not treat
Inconclusive
Repeated cCUS Negative DVT ruled out,
after 5 days
do not treat
Patients with suspected or confirmed DVT and chest
symptoms, such as pain, dry cough episodes, pleuritic, pneu-
monia refractory to antibiotics, dyspnea, tachycardia, or syn-
copes, need to be evaluated for the presence of PE. This is
not within the focus of this review, but ECG, Echo, and lung
CT angiography are the appropriate routine examinations for
suchpatients.21
Anticoagulation in DVT treatment. Today, the neces-
sity of immediate and adequately dosed anticoagulation for
acute DVT is undisputed, since anticoagulation has been
shown to effectively reduce thrombus progression, mortality,
and the risk of severe PTS.2224
In contrast to anticoagulation, the role of thrombolysis25,26
and the relevance of compression therapy in acute and chronic
DVT are still matters of debate.2730
Before the different anticoagulation options are discussed,
it is essential to understand the four different treatment phases
that need to be discussed for every DVT (or PE) patient.
- Pretherapy: This treatment phase starts with the sus-
picion of DVT, in many cases hours or days before the
diagnosis is established, until the diagnosis is made or
ruled out.
- Initial therapy: This treatment phase starts with the estab-
lished diagnosis and lasts for 510days post diagnosis.
- Maintenance therapy (or early secondary prevention):
This treatment phase follows the initial therapy and lasts
for three months.
- Extended secondary prevention: This treatment phase
starts three months after DVT diagnosis and is highly
variable across the DVT population.
For a number of reasons, the differentiation of these four
phases is important.
Clinical Medicine Insights: Therapeutics 2016:8 13
Endig etal
- The risk of major and potentially fatal complications from
DVT changes over time and is the highest in the first one
to four weeks after diagnosis.
- Different treatment options exist for each treatment
phase, and the correct choice of drug and dosing regimen
depends on the knowledge of these treatment phases.
- The long-term risk of recurrent VTE is the main factor
for deciding for or against long-term or indefinite antico-
agulant treatment. The understanding of the concept of
treatment phases is essential for the correct timing of this
decision, for thrombophilia testing, and for the choice of
drug and dosage, if long-term treatment is warranted.
- The risk of bleeding needs to be included in all treatment
decisions. However, bleeding risk needs to be assessed at
regular intervals, which need to be defined.
For acute DVT treatment, a number of options exist for
each respective treatment phase. Together with unfractionated
heparin (UFH), low-molecular weight heparin (LMWH),
fondaparinux and vitamin K antagonists (VKA) we discuss
all approved non-vitamin K oral anticoagulants (NOACs),
which will be addressed in alphabetical order, which does not
indicate a grading. Of note, although NOACs are commonly
discussed as a specific class of direct anticoagulant drugs, they
demonstrate relevant differences in their pharmacological
profile. Dabigatran is a direct thrombin inhibitor with a high
degree of renal elimination, whereas apixaban, edoxaban, and
rivaroxaban are direct factor Xa inhibitors with considerably
lower renal clearance. For a more detailed information, the
reader should refer to a dedicated NOAC review.31 Table 2
provides an overview of phase III NOAC VTE treatment
programs. These trials mainly differed with regard to the
management of NOAC patients in the pretherapy and initial
therapy phases; as a result, there are now different recommen-
dations for each NOAC in these treatment phases.
Pretherapy. The risk of developing potentially fatal DVT
complications such as severe PE is highest at the very begin-
ning of the disease and treatment. While ultrasound should be
performed as soon as possible, it may not be available within
the first few hours. As a consequence, guidelines recommend
to start anticoagulant therapy even before the diagnosis of
DVT is established.32 However, not all the available antico-
agulants can be used in this situation.
- UFH, LMWH, 32 fondaparinux, and two of the NOACs,
namely, apixaban33 and rivaroxaban, 34 can be used, since
they are specifically approved for the initial treatment
phase. All these drugs demonstrate an immediate onset
of action and offer sufficient protection within two to
four hours after initiation. Fondaparinux is a parenteral
indirect factor Xa inhibitor, which is handled similar to
LMWH. However, it is a pentasaccharide, not a protein
like heparin, and, therefore, demonstrates a lower risk
of heparin-induced thrombocytopenia or skin allergies,
14 Clinical Medicine Insights: Therapeutics 2016:8
which makes it an option for patients with heparin aller-
gies. In contrast, UFH should only be used as a first-line
option for patients with severe renal impairment or those
in need of thrombolytic therapy.
- VKA are not suitable for initial treatment, since they
exhibit a slow onset of action (days) and increase the risk of
thromboembolic complication in the first few days because
of their inhibition of endogenous proteins C and S.
- The other two NOACs, dabigatran35 and edoxaban, 36 also
have a rapid onset of action but they are only approved
for being started after an initial LMWH therapy of at
least five days. Consequently, they should not be used
forpretreatment.
Since ultrasound is usually performed within 24 to
48hours of DVT suspicion, most patients in daily care receive
one or two injections of a parenteral drug or rivaroxaban or
apixaban at a therapeutic dosage in the pretreatment phase.
Initial therapy. As soon as the diagnosis of DVT
is established, therapeutic anticoagulation is even more
important. The risk of DVT complication is high for the
first four weeks and highest in the first week after diag-
nosis. 37 Consequently, the initial therapy phase is charac-
terized by intensified anticoagulation. The choice of drugs
follows the same considerations as for pretreatment but also
includes the consideration of the planned therapy for the
maintenance phase, since the choice of drug and regimen in
the initial phase is routinely driven by the treatment plan for
the next three months:
- If the maintenance phase is planned with apixaban of
5mg BID, treatment in the initial phase should consist
of apixaban of 10mg BID for the first seven days.
- If the maintenance phase is planned with rivaroxaban of
20mg BID, treatment in the initial phase should consist
of rivaroxaban of 15mg BID for the first 21days.
In these two scenarios, a pretreatment with LMWH
or fondaparinux is not necessary but, if given, would not be
problematic. Parenteral therapy can simply be stopped, and
the oral drug can be started at the time the next injection
would be due. The difference between apixaban (intensified
treatment of seven days) and rivaroxaban (21days) reflects the
regimen used in the respective phase III trials, which were
successful for both treatments.3840 However, it is impor-
tant to know that initial regimens are quite different for
differentanticoagulants.
- If the maintenance phase is planned with dabigatran of
150mg BID or edoxaban of 60 or 30mg OD, treatment
in the initial therapy should also be done with LMWH
for at least five days, and the oral drug should only be
started afterward at a time when the next LMWH injec-
tion would be due.
 Deep vein thrombosis

Table2. Overview of phase III NOAC trials in acute VTE treatment (first four trials with warfarin as active control arm) and secondary VTE
prevention (last three trials with placebo as control arm).

NOAC trial NOAC arm Comparator Recurrent Major Further relevant findings from
arm VTE bleeding subgroup analyses
RECOVER I+II LMWH/dabigatran LMWH/warfarin 2.7 vs. 2.4% 1.4 vs. 2.0%
(n=5107) (n.s.) (n.s.)
EINSTEIN DVT Rivaroxaban LMWH/warfarin 2.1 vs. 2.3% 1.0 vs. 1.7% Safety benefit much more pronounced in fragile
andPE (n.s.) (P=0.002) patients (.75 years, impaired renal function,
(n=8282) body weight,50kg); major bleeding 1.3% vs.
4.5% (P,0.05)
Rivaroxaban resulted in significantly lower rates
of major bleeding in patients with impaired
renal function compared to warfarin.
Rivaroxaban resulted in an improved treatment
satisfaction compared with enoxaparin/VKA,
particularly by reducing patient-reported
anticoagulation burden.
AMPLIFY Apixaban LMWH/warfarin 2.1 vs. 2.7% 0.6 vs. 1.8% Apixaban resulted in a significant reduction in
(n=5395) (n.s.) (P,0.001) hospitalizations over time.
HOKUSAI LMWH/edoxaban LMWH/warfarin 3.2 vs. 3.5% 1.4 vs. 1.6% Edoxaban significantly reduced recurrent VTE
(n=8292) (n.s.) (n.s.) in PE patients with NT-proBNP $ 500 pg/mL.
RESONATE Dabigatran Placebo 0.4 vs. 5.6% 0.3 vs. 0.0%
(n=1343) (P=0.08) (n.s.)
EINSTEIN EXT Rivaroxaban Placebo 1.3 vs. 7.1% 0.7 vs. 0.0%
(n=1196) (P,0.001) (n.s.)
AMPLIFY EXT Apixaban Placebo 1.7 vs. 8.8% 0.2 vs. 0.5% Apixaban resulted in a significant reduction in
(n=2486) (P,0.001) (n.s.) hospitalizations over time

Abbreviations: LMWH, low molecular weight heparin; ns, not significant.

- If the maintenance phase is planned with LMWH (in
cases of cancer-associated DVT), then initial therapy
will also be done with LMWH approved for cancer-
associated DVT.
- If the maintenance phase is planned with VKA, treatment
in the initial therapy needs to be done with a parenteral
anticoagulant, usually LMWH or fondaparinux, and VKA
started in parallel because of the slow onset of action. As
soon as VKA is sufficiently protective (international normal-
ized ratio [INR].2), the parenteral drug can be stopped.
Maintenance treatment. As stated earlier, the initial phase
lasts for approximately one week, although rivaroxaban should
be given in an intensified dosage until day 21. Initial treatment
is followed by a phase of secondary VTE prevention. All the
aforementioned treatment options are approved for this phase,
which ends approximately three months after DVT diagnosis.
Treatment options for this phase are asfollows:
- Apixaban of 5 mg BID, dabigatran of 150 mg BID,
edoxaban of 60mg OD, and rivaroxaban of 20mg OD;
- LMWH or fondaparinux; and
- VKA (target INR 23), requiring INR measurement and
dose adjustment at regular intervals (at least monthly).
Furthermore, frequent interactions with many drugs and
food limit the use of VKA, given the availability of more
convenient NOACs.
Figure 2 is a flowchart of treatment considerations in
patients with suspected or confirmed DVT.
Of note, especially high-risk patients may benefit from
NOAC treatment in the initial and maintenance phases of
DVT treatment. In daily care, many patients with VTE are
elderly and demonstrate significant comorbidities, which
contribute to high rates of VTE and bleeding complications,
especially in the early treatment phases. Such patients are
often referred to as being frail or fragile, which can be defined
as older than 65 years, renal impairment (creatinine clear-
ance,50mL/minute), or low body weight (,50kg).41 Due to
the partial renal elimination of the NOACs, there is potential
for accumulation of the anticoagulant in patients with renal
impairment. Of note, all NOACs demonstrate different pro-
portions of renal excretion, which results in different label rec-
ommendations for patients with renal impairment. 34 Detailed
data for more than 1500 fragile patients are available from a
subgroup analysis of the pooled EINSTEIN DVT and PE
results.41 Rates of recurrent VTE were numerically higher in
fragile patients than in nonfragile patients (rivaroxaban 2.7%
vs 1.9%; standard therapy 3.8% vs 1.9%). Within the group
of fragile patients, treatment with rivaroxaban was associ-
ated with a similar risk of VTE recurrence compared to VKA
with a trend toward risk reduction (2.7% vs 3.8%; hazard
ratio [HR] 0.68; 95% confidence interval [CI] 0.391.18), but
major bleeding was drastically reduced by rivaroxaban therapy
(1.3% vs 4.5%; HR 0.27; 95% CI 0.130.54).41 R ivaroxaban

Clinical Medicine Insights: Therapeutics 2016:8 15

Endig etal

No Start AC (LMWH,
Ultrasound (CT)
Suspected DVT fondaparinux, apixaban,
immediately available?
rivaroxaban)
Yes

LAE symptoms Confirm diagnosis

severe DVT symtoms

Relevant comorbidity
All others: consider
suspected;
outpatient therapy
outpatient care not feasible

LMWH
hospitalization Oral maintenance therapy intended?
No

OAC not Dabigatran/

VKA therapy Rivaroxaban Apixaban
feasible or edoxaban
intended intended intended
active cancer intended

Start VKA and Rivaroxaban Apixaban 10 mg

LMWH for 7d, then BID for 7d,
Long-term continue 15 mg BID for
Dabi. 150 mg BID* or then apixaban
LMWH LMWH, untill 21 days, then
Edoxaban 60 mg OD* 5 mg BID*
INR > 2.0 20 mg OD*

Figure2. Flowchart of treatment decisions in the management of patients with DVT.

also resulted in a significant net clinical benefit over warfarin
in fragile patients, with an HR of 0.51 (0.340.77) for the
combined endpoint of symptomatic recurrent VTE and
majorbleeding.
The investigators of the HOKUSAI trial also published
the results of treated subgroups in the supplementary material
of their publication.42 In fragile patients, edoxaban showed
a significantly lower rate of VTE recurrence than warfarin
(2.5% vs 4.8%; P = 0.0408), whereas the rate for major and
clinically relevant nonmajor bleeding was comparable (11.0%
vs 13.7%; P=0.8759).
Finally, a meta-analysis of elderly patients treated in
phase III NOAC trials demonstrated that the beneficial effects
of NOAC (compared to VKA) are especially pronounced in
elderly patients.43
Extended secondary prevention. While all DVT patients
undergo at least initial and maintenance therapies, treat-
ment during the extended phase is based on individualized
risk assessment, and only patients at increased risk of VTE
recurrence are in need of extended anticoagulation. However,
the balancing of prolongation or discontinuation of therapy
against the VTE recurrence risk is complicated in daily care
and predictive VTE recurrence scores are of limited value.
First, the decision of whether to apply extended antico-
agulation is simplest for the group of patients who have devel-
oped DVT after a relevant but transient trigger situation, such
as trauma, major surgery, immobilization for acute illness,
or pregnancy. These so-called provoked DVT patients are
at low risk to develop recurrent DVT (1.8% per year).44,45
Consequently, they do not need to receive extended second-
ary prevention and should stop anticoagulant treatment at
three months. This also applies to patients with recurrent
provokedDVT.
A second patient group is less well defined, but still easy
to counsel: patients with recurrent unprovoked DVT and those
with high-risk thrombophilia (such as antiphospholipid syn-
drome, established antithrombin or protein C deficiency, and
homozygous factor V mutation) are known to be at high risk
of recurrent DVT, PE, or even arterial thromboembolism. For
these patients, life-long anticoagulation is indicated and, in
most cases, therapeutic dosages should be used (at least until
clear evidence suggests otherwise).46
The remaining patients comprise the largest group, which,
unfortunately, is the most difficult to counsel.47,48 They include
- patients after a first episode of unprovoked DVT;
- patients who developed DVT after mild provocation,
such as long-distance travel, oral contraceptive, or mild
leg trauma. In these situations, the trigger may also be
regarded as transient, but certainly not comparable to
a major surgical procedure. Such mild triggers are much
more likely to reoccur;

16 Clinical Medicine Insights: Therapeutics 2016:8


- patients with recurrent distal DVT and mild thrombo-
philia; and
- cancer patients who have developed DVT and have
recently completed cancer therapy and are currently
in remission.
Do these patients need to continue DVT therapy for lon-
ger than three months? For six months, for a year, or forever?
Which drug should be used, and at which dosage? Given the
heterogeneity of this group, a simple and clear answer to these
questions is lacking. However, for several scenarios, recom-
mendations can be made as follows:
- Patients with a first episode of proximal (ie, involving
iliac, thigh, or popliteal vein segments) unprovoked DVT
should continue with treatment provided the bleeding
risk is low.
- Patients with mild triggers that may have contributed to
the DVT occurrence, such as hormone treatment, long-
distance travel, or nonfracture trauma, may discontinue
anticoagulation, provided that they stop taking hormonal
contraceptives, consider thromboprophylaxis in recurrent
trigger situations, and are reliable to return for objective
testing in the case of symptoms of recurrent VTE.
- Patients with recurrent unprovoked distal DVT, with or
without mild thrombophilia, may stop anticoagulation,
but this decision requires a detailed patient information
and consent. While current guidelines recommend to
treat every distal DVT only for three months,46 the risk
of a recurrence, which may well be a proximal DVT or
PE, is still relevant. If the patient is not willing to take
that risk, long-term treatment should be discussed with
the patient.
- The same holds true for patients with cancer-associated
DVT who are in the early phase after curative cancer
treatment. Guidelines recommend the continuation
of anticoagulation for as long as the patient has active
cancer,46 but there is an ongoing debate as to how long
a nonmetastatic cancer is active and what impact long-
term antihormone or antiangiogenetic cancer therapies
have on VTE recurrence and, consequently, duration or
intensity of anticoagulation therapy.
In daily practice, most scenarios do not result in a clear-
cut determination of VTE recurrence risk and continuation or
discontinuation of anticoagulation. Consequently, the general
risk of DVT recurrence needs to be explained to the patient
and a decision involving patient preferences should be made.
Commonly, physicians and patients are afraid of the bleed-
ing risks related to long-term anticoagulation, which, together
with the impact of taking drugs or injections on quality of life,
often drives the wish to discontinue anticoagulation. How-
ever, for the NOACs, such as apixaban, dabigatran, and rivar-
oxaban, placebo-controlled studies have been performed on
Deep vein thrombosis
the efficacy and safety of extended secondary prevention in the
large group of patients with uncertain benefits of treatment
prolongation (Table2).4951 These studies consistently demon-
strated the following:
- a high rate of recurrent VTE (8% in the year following
maintenance therapy) in the placebo arms;
- an impressive relative risk reduction of 80% with an
extended NOAC treatment; and
- a very low risk of major bleeding (,1%).
A pooled analysis of the respective trials with apixa-
ban (AMPLIFY-EXT), dabigatran (RE-SONATE), and
rivaroxaban (EINSTEIN-EXT) demonstrated a reduction
of VTE recurrence (NOAC vs placebo, 1.9% vs 10.9%/year;
P,0.0001) and lower all-cause mortality (NOAC vs placebo,
0.6% vs 1.1%/year; P=0.1).52
Although prolonged oral anticoagulation is usually con-
sidered expensive, a study from the US demonstrated that
prolonged VTE treatment with NOACs results in a signifi-
cant avoidance in medical costs ($146, $482, $918, and
$344 for VTE patients treated with dabigatran, rivaroxaban,
apixaban, and edoxaban, respectively) compared to patients
treated with standard therapy.53 This cost reduction was
mainly driven by cost savings in major and clinically relevant
nonmajor bleedings (for all NOACs), and also by a reduction
of recurrent VTE costs (for apixaban, edoxaban, and rivar-
oxaban therapies) when compared to long-term VKA therapy.
Similarly, a model has demonstrated the cost-effectiveness
of extended rivaroxaban therapy in VTE against placebo (or
notreatment).54
Furthermore, in the apixaban study (AMPLIFY-
EXT),55 a prophylactic dose of apixaban of 2.5mg BID was
also tested and resulted in risk reduction as impressive as that
of the therapeutic dosage and, at the same time, in bleed-
ing complication rates at the level of placebo. Another study
evaluating prophylactic dosages of rivaroxaban in this popu-
lation is ongoing.
The potential of using prophylactic NOAC dosages of
anticoagulants to prevent recurrent VTE may be especially
important to patients at high risk of recurrent VTE with con-
current high risk of bleeding complications, such as fragile
patients or patients with frequent falls. However, the risk of
fatal VTE in elderly patients may be much higher than the
risk of fatal bleeding.56 Consequently, these patients usually
need to continue anticoagulation,52 but the search for the
lowest possible dosage may improve the riskbenefit ratio of
long-term anticoagulation.
Based on these considerations, the introduction of
NOACs in daily care will probably shift decisions regarding
long-term treatment toward continuation with prophylactic
NOAC dosages in many patients.
In contrast, although recent trials indicated that aspi-
rin may be superior over placebo to prevent recurrent VTE
Clinical Medicine Insights: Therapeutics 2016:8 17
Endig etal
in the extended secondary prevention phase (relative risk
reduction 30%), aspirin is less effective than NOACs (rela-
tive risk reduction 80%) and associated with a bleeding
risk. Consequently, while aspirin may have been considered
an alternative in the VKA era, it seems to have an inferior
riskbenefit ratio compared to that of NOAC. The ongoing
EINSTEIN CHOICE trial includes aspirin and two doses
of rivaroxaban to directly compare aspirin against NOACs in
extended secondary prevention.
Cancer-associated DVT. As indicated earlier, initial and
maintenance therapies should be performed with LMWH
in DVT patients with active cancer.46 However, we lack evi-
dence that LMWH offers further benefit for cancer patients
after three to six months; therefore, a switch to a more con-
venient oral drug such as an NOAC should be discussed with
the patient. The same holds true for patients who are not
able or not willing to tolerate LMWH injections through-
out the maintenance phase. While no specific NOAC trial for
cancer-associated DVT has been performed so far, subgroup
analyses of the phase III NOAC trials included several hun-
dred cancer patients and did not indicate a lack of effective-
ness.42,57,58 Recently, a randomized controlled trial comparing
six months of LMWH against edoxaban in cancer-associated
VTE wasinitiated.
DVT in pregnancy. Since VKA are associated with an
unacceptable risk of embryopathy and NOACS are contrain-
dicated in pregnancy because of their placental passage, the
standard of care in pregnant DVT patients is LMWH or, if
LMWH is not tolerated, fondaparinux.59
Massive DVT in need for thrombolysis. Patients with
acute iliac or caval thrombosis, such as cases of phlegmasia,
may in some cases require immediate revascularization,
which today is predominantly performed with catheter-
directed thrombolysis. Patients considered to be candidates
for thrombolysis should be treated with LMWH or intrave-
nous UFH.46 A switch from parenteral to oral anticoagula-
tion postlysis is possible but, without supporting evidence,
the authors recommend continuing LMWH until the end
of initial therapy (seven days postthrombolysis) before oral
drugs are started.
Role of immobilization or hospitalization in DVT
treatment. The concept of immobilizing DVT patients is out-
dated, since early mobilization has been demonstrated not to
increase the risk of embolization,60 and large cohort studies
have clearly proven that outpatient DVT treatment is feasible
and safe for the majority of patients being diagnosed with
DVT outside of hospitals.61 Furthermore, it is also reasonable
to state that patients developing DVT while in hospital may
be safely mobilized, provided that adequate anticoagulation is
immediately initiated.
Similarly, patients with acute DVT and extensive leg
swelling, suspected malignancy, or other acute conditions that
may have caused the DVT or may complicate VTE treatment
should be admitted, since surveillance, intensified treatment,
18 Clinical Medicine Insights: Therapeutics 2016:8
pain management, and discovery of underlying acute condi-
tions may be more feasible in hospital.
Role of compression therapy in DVT. A detailed discus-
sion of the pros and cons of compression therapy in acute and
chronic DVT within the limits of this review is impossible, and
the readers are advised to refer to the current literature.2730
However, the following statements may help for orientation:
- The more a DVT patient is affected by pain and leg swell-
ing, the more likely he/she will benefit from a compres-
sion therapy (stocking or bandages), provided that the
compression device is fitted correctly.
- In contrast, the usefulness of compression in asymptom-
atic DVT-affected legs is at least debatable.
- Patients receiving compression therapy need to be edu-
cated on proper use and the risk of developing pressure
ulcers, which is a significant risk especially in paralytic
or hemiplegic patients or patients with severe neu-
ropathy. Daily skin inspections are necessary during
compressiontherapy.
- The concept of long-term compression to prevent PTS
has been accepted for decades but a recent trial indi-
cated that the effect of compression stockings on PTS
isquestionable.62
In light of the current uncertainties, the authors recom-
mend the routine use of compression stockings in the ini-
tial and maintenance phases (for approximately three to six
months post-DVT diagnosis). At this timepoint, ultrasound
assessment of residual venous obstruction and reflux in com-
mon femoral and popliteal veins should be performed, as well
as a clinical assessment for symptoms of PTS. We would
then recommend discontinuation of compression therapy in
patients without clinical signs of PTS, recanalized veins, and
absence of relevant deep vein reflux. All other patients should
be instructed to either continue compression (if accepted) or
to temporarily interrupt compression and restart, if signs or
symptoms of PTS develop.
Conclusion
Although some readers may have had the impression that
DVT therapy has become more complicated in the past few
years, in fact, it has become better. Many well-performed
studies have clarified a number of issues over the past 15 years,
and with this improved understanding of DVT and the char-
acteristics and problems of DVT patients, better treatment
strategies have been developed. These new strategies allow
for a much more tailored therapy of a frequent and potentially
life-threatening condition. The last development at pres-
ent, namely, the introduction of NOACs, has the potential
to increase compliance, quality of life, and safety of DVT
treatment for millions of patients worldwide.63 The authors
strongly believe that this will also improve the effectiveness
of DVT therapy. However, to gain the best effectiveness

and safety benefit from NOACs, we all need to make sure
that physicians and patients develop an understanding of the
different treatment phases of DVT, the available treatment
options and their respective dosing regimens, and the need to
adapt DVT treatment standards on an individualized basis.
Author Contributions
Wrote the first draft of the manuscript: HE. Contributed to
the writing of the manuscript: HE, FM, JB-W. Agree with
manuscript results and conclusions: HE, FM, JB-W. Jointly
developed the structure and arguments for the paper: HE,
JB-W. Made critical revisions and approved final version:
HE, FM, JB-W. All authors reviewed and approved of the
final manuscript.
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