review
Management of venous thromboembolism controversies and
the future
David Keeling1 and Raza Alikhan2
1
Oxford University Hospitals, Oxford, UK and 2University Hospital of Wales, Cardiff, UK
Summary
Despite the availability of comprehensive evidence-based
guidelines there are difficult and controversial areas in the
management of venous thromboembolism. Institutions and
even countries disagree on the importance of calf vein
thrombosis, with some rigorously detecting and treating it
and others deliberately not looking for it. The need to treat
proximal deep vein thrombosis and pulmonary embolism is
accepted but which patients with an unprovoked first event
should have long-term anticoagulation has become a difficult
clinical decision. We are uncertain how to reduce the inci-
dence of post-thrombotic syndrome seen in a substantial
number of patients. How hard to look for an undiagnosed
underlying cancer has become a contentious issue particu-
larly in the United Kingdom following the recent publication
of a guideline from the National Institute for Health and
Clinical Excellence. Whilst we are wrestling with these dilem-
mas we are entering an era of new anticoagulants and have
to solve the logistical problems of introducing them into
clinical practice despite cost pressures. These issues will be
explored in this review.
Keywords: deep vein thrombosis, pulmonary embolism,
venous thromboembolism, anticoagulation, cancer.
Venous thromboembolism (VTE) manifesting as deep vein
thrombosis (DVT) or pulmonary embolism (PE) is an
important disease affecting approximately 1 in 1000 of the
population annually. The American College of Chest Physi-
cians (ACCP) have produced evidence based guidance, now
in its 9th edition (Bates et al, 2012; Kearon et al, 2012), and
2012 also saw publication of the United Kingdoms National
Institute for Health and Clinical Excellence (NICE) guideline
(NICE, 2012a). However, there remain controversial issues
Correspondence: Dr David Keeling, Consultant Haematologist,
Oxford Haemophilia & Thrombosis Centre, Churchill Hospital,
Oxford OX3 7LE, UK.
E-mail: david.keeling@ndm.ox.ac.uk
2013 John Wiley & Sons Ltd
British Journal of Haematology, 2013, 161, 755763
and the introduction of new oral anticoagulants targeting
factor Xa (FXa) and thrombin render this a fast changing
area of medicine. We examine some of the controversial
areas and explore where the future may lead.
Isolated calf vein thrombosis and the
development of rival diagnostic strategies for
DVT diagnosis
There has been much discussion as to the importance of
DVT confined to the calf. DVT usually starts in the calf
(Kakkar et al, 1969; Philbrick & Becker, 1988; Cogo et al,
1993), but by the time symptoms develop most patients have
thrombus in the popliteal or more proximal veins (proximal
DVT) (Agnelli et al, 1993; Cogo et al, 1993). In the past it
was said that 20% of isolated calf DVT extend into the prox-
imal veins (Kakkar et al, 1969; Philbrick & Becker, 1988),
usually within 1 week. However, a more recent study found
an extension rate of only 3% (Kahn et al, 2002). Calf DVT
that do not extend rarely lead to clinically significant emboli
(Kakkar et al, 1969; Kahn et al, 2002), but in those that do
extend into the proximal veins the risk of pulmonary embo-
lism becomes significant (Kakkar et al, 1969; Lagerstedt et al,
1985). For some time we have known it to be safe to with-
hold anticoagulant treatment from patients with clinically
suspected DVT who have normal compression ultrasonogra-
phy of the proximal veins at the time of presentation and
1 week later (Cogo et al, 1998). The first ultrasound will
detect any proximal thrombosis, a calf vein thrombus will
remain undetected but a repeat scan 1 week later will pick
up the clinically important ones that have extended.
This has led to two different ultrasound strategies for
DVT diagnosis. Many deliberately only look at the proximal
veins and then perform a repeat test 1 week later in selected
patients with a negative first scan. Patients that do not
require a repeat scan are those with a low pre-test probability
(PTP) score (Wells et al, 1995, 1997) or a normal D-dimer
(Bernardi et al, 1998). An alternative strategy is to scan the
whole leg (proximal and calf veins). This means that no
patient requires repeat ultrasound though it does subject
more patients to anticoagulation. Both strategies are accept-
able and safe and have been shown to be clinically equivalent
in randomized trials (Bernardi et al, 2008; Gibson et al,
First published online 26 March 2013
doi:10.1111/bjh.12306
Review
2009). The authors of these studies concluded that a prefer-
ence mainly depends on the balance of available expertise
and facilities on the one hand, and willingness for repeated
testing and possible extra anticoagulant treatment on the
other.
Rapid compression ultrasound restricted to the proximal
veins is seen as simple, convenient, and widely available, but
requires repeat testing in 25% of patients. The whole leg
examination offers a 1-d answer in all, but is cumbersome,
more expensive, and risks unnecessary anticoagulation. NICE
recommended only scanning the proximal veins based on an
economic analysis (NICE, 2012a). The ACCP accept both
strategies (though favour only scanning proximal veins in
low PTP patients) (Bates et al, 2012). If the whole leg is
scanned and an isolated calf DVT found then, in the absence
of severe symptoms or risk factors for extension, the ACCP
suggest serial imaging of the deep veins over initial anticoag-
ulation (Kearon et al, 2012).
Treatment of VTE with FXa and thrombin
inhibitors versus standard treatment and how
to decide which agent to use
For the majority of patients with VTE the current standard
of care is initial treatment with a rapidly acting parenteral
anticoagulant, such as low molecular weight heparin
(LMWH) or unfractionated heparin (UFH) for a minimum
of 5 d. Concomitant treatment is commenced with an oral
vitamin K antagonist (VKA) and continued for at least
3 months (Kearon et al, 2012; NICE, 2012a). While effective,
these treatments are hampered by the inconvenience of daily
subcutaneous injections, anticoagulant monitoring, drug and
food interactions and potentially serious side effects, such as
heparin-induced thrombocytopenia (HIT).
During the past decade we have seen the development of
a plethora of novel anticoagulants for the prevention of
venous and arterial thromboembolism (Turpie et al, 2003;
Alberts et al, 2012; Gomez-Outes et al, 2012) and more
recently the treatment of venous thromboembolism. New
anticoagulants that have completed phase III studies in VTE
and are, or will soon be, available clinically can be subdivided
into (i) oral agents (novel oral anticoagulants; NOACs):
dabigatran, rivaroxaban and apixaban; and (ii) parenteral
agents: fondaparinux, idraparinux and idrabiotaparinux. It is
now possible for the first time, to consider fixed dose antico-
agulation, without monitoring, for the treatment of acute
VTE.
Novel oral anticoagulants
The direct thrombin inhibitor, dabigatran etexilate is a pro-
drug, converted rapidly after ingestion to its active metabolite
dabigatran. Rivaroxaban and apixaban are direct FXa inhibi-
tors, administered in their active form. All reach peak plasma
concentrations rapidly, within 24 h of oral administration,
756
and have similar short half-lives. Apixaban and dabigatran are
administered twice daily (bd) while rivaroxaban is given once
a day (od) and the latter should be taken with food to aid
absorption. Active drug is excreted by the kidneys in various
amounts, dabigatran (80%), rivaroxaban (33%) and apixaban
(25%) (Scaglione, 2013). There is therefore a risk of accumu-
lation of active drug in patients with renal impairment.
The RE-COVER studies of dabigatran 150 mg bd com-
pared to warfarin for the treatment of acute VTE (proximal
DVT and/or PE), both given with initial parenteral anticoag-
ulation, found dabigatran to be non-inferior to standard
treatment (Schulman et al, 2009, 2011a). The EINSTEIN
rivaroxaban studies also showed this NOAC to be non-inferior
to standard treatment for acute proximal DVT (Bauersachs
et al, 2010) and PE (Buller et al, 2012a) and in these studies
initial parenteral anticoagulation was not given to the
patients who received rivaroxaban. The apixaban acute VTE
study (AMPLIFY) is currently ongoing (clinical trials refer-
ence NCT00643201).
The majority of patients diagnosed with a DVT, as well
as selected patients with PE, are managed as outpatients
(Kearon et al, 2012). However, as current initial treatment
requires a minimum of 5 d of daily heparin injections,
patients unwilling or incapable of self-injecting have to
attend hospital daily or wait at home for a district nurse to
administer their treatment. The decision to omit the initial
parenteral injection phase of anticoagulation for patients
receiving a FXa inhibitor in the EINSTEIN and AMPLIFY
studies is particularly appealing. To address concerns
that the absence of initial treatment with heparin might
result in increased rates of early VTE recurrence (Buller
et al, 2007), higher concentrations of study drug are admin-
istered initially, rivaroxaban 15 mg bd for 3 weeks (followed
by 20 mg od) and apixaban 10 mg bd for 7 d (followed by
5 mg bd).
In terms of bleeding there is little to choose between
dabigatran and rivaroxaban, with the overall risk of major
bleeding and clinically relevant non-major bleeding being
lower for both when compared to warfarin. There is however
a difference in the sites of bleeding; intracranial and retro-
peritoneal bleeding was significantly more common in
patients receiving warfarin, whereas rates of gastrointestinal
bleeding were higher with both dabigatran and rivaroxaban
(Schulman et al, 2009; Bauersachs et al, 2010; Buller et al,
2012a). There is an increased risk of dyspepsia seen in
patients receiving dabigatran (Schulman et al, 2009) a side-
effect previously observed in the stroke prevention trial for
atrial fibrillation (Connolly et al, 2009).
In addition to the appeal of fixed-dose VTE treatment,
there is also no need for regular anticoagulation monitoring.
However, the ability to measure anticoagulant effect may be
of paramount importance to the treating clinician when
faced with a patient who is bleeding, suffered a recurrent
VTE event, has deteriorating renal function or requires an
urgent invasive procedure. Dabigatran results in prolongation
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British Journal of Haematology, 2013, 161, 755763
 Review

of the activated partial thromboplastin time (APTT) and Table I. Choosing an anticoagulant.
thrombin time (TT) but has little or no effect on the pro-
Our preference
thrombin time (PT). Rivaroxaban and apixaban prolong the Consideration (see text) Rather than
PT and APTT but not the TT. Using appropriate calibrators
it is possible to measure the plasma concentration of drug, CrCL < 15 ml/min Warfarin
using either a modified TT for dabigatran or anti-Xa assay CrCL 1529 ml/min Warfarin Apixaban,
rivaroxaban
for rivaroxaban or apixaban. Guidelines have recently been
CrCL 3050 ml/min Warfarin, rivaroxaban, Dabigatran
published by the British Committee for Standards in Haema-
apixaban
tology (Baglin et al, 2012) and the topic has been reviewed
Liver dysfunction Warfarin Apixaban,
elsewhere in detail (Garcia et al, 2013). rivaroxaban,
Rivaroxaban is currently the only NOAC that is licensed dabigatran
for the treatment of acute DVT and PE as well as for long- Previous Apixaban, rivaroxaban, Warfarin
term treatment to prevent VTE recurrence. The results of intracranial bleed dabigatran
AMPLIFY, the apixaban VTE treatment study (clinical trials Previous GI bleed Apixaban, warfarin Dabigatran,
reference NCT00643201), are expected to be available in rivaroxaban
mid- to late 2013 and it is envisaged that a submission for ACS Rivaroxaban, apixaban, Dabigatran
dabigatran and VTE treatment will be made to the regulatory warfarin
Dyspepsia Rivaroxaban, apixaban, Dabigatran
authorities in the near future.
warfarin
The increased cost of introducing new treatments is always
Poor compliance Warfarin Apixaban,
a concern in these austere times. The omission of initial par-
rivaroxaban,
enteral anticoagulation for patients treated with rivaroxaban dabigatran
(and apixaban) and the absence of International Normalized
Ratio (INR) monitoring offsets the cost of the drugs. The CrCL, creatinine clearance; GI, gastrointestinal; ACS, acute coronary
recent review of rivaroxaban for DVT treatment by NICE syndrome.
(2012b) found it to be clearly cost-effective if a patient
receives 36 months of anticoagulation, cost-effective for
12 months treatment and probably cost-effective treatment For patients with a history of or at increased risk of intra-
for people who need anticoagulation treatment for longer cranial bleeding, any of the NOACs would be preferred to
than 12 months. However, these calculations are very sensi- warfarin. A history of previous gastrointestinal bleeding
tive to the cost of monitoring treatment with warfarin and might prompt one to consider warfarin or apixaban in pref-
although controversial, a pragmatic approach for a clinician erence to dabigatran or rivaroxaban, whilst a history of dys-
considering the introduction of a NOAC to their repertoire pepsia would suggest dabigatran might be best avoided.
could see a phased introduction with treatment initially There is a suggestion from the dabigatran VTE studies
offered to patients who have a low risk of recurrence and that acute coronary syndrome (ACS) events are more com-
therefore only require 3 months anticoagulation. Similarly, mon with dabigatran than with warfarin (Schulman et al,
patients who require long-term treatment but are poorly 2009). A recent meta-analysis has also suggested that the risk
controlled or intolerant of VKAs currently either stop antico- of myocardial infarction (MI) and ACS was increased in
agulation or commence therapeutic LMWH. NOACs could other dabigatran studies (Mak, 2012). However, when assess-
be offered to these patients in their initial introduction phase ing the placebo-controlled dabigatran extension VTE study
to the formulary; casting the VTE treatment net wider once there was no excess of cardiac events (Schulman et al,
confidence and experience is gained (and prices become 2011b). This suggests that warfarin has a greater cardiopro-
more competitive). tective effect rather than dabigatran having a prothrombotic
When all three NOACs are available for the treatment of arterial effect. Nevertheless, the potential of a cardiac signal
VTE, in addition to cost, patient demographics will dictate with dabigatran will no doubt see caution in its use in
which anticoagulation is most appropriate (see Table I). patients with a history of ischaemic heart disease and prior
Apixaban, rivaroxaban and dabigatran are contraindicated MI. In particular, caution might also be exercised in those
if the creatinine clearance (CrCl) is <15 ml/min. For patients with a history of recent ACS and therefore rivaroxaban, apix-
with CrCl 1529 ml/min, apixaban and rivaroxaban can be aban or warfarin may be preferred in these patients.
used in reduced dosage though warfarin, for now, is our The presence of cancer in a patient with VTE poses us
preference; in patients with moderate renal impairment with a difficult conundrum. It is currently recommended that
(CrCl 3050 ml/min) there is likely to be an increased risk patients with cancer and VTE are treated with LMWH in
of dabigatran accumulation and therefore we prefer rivarox- preference to warfarin (Lyman et al, 2007; NICE, 2012a).
aban or apixaban if a new agent is to be used. Patients with The promising results from the phase III programmes for
liver dysfunction will probably be safer using monitored rivaroxaban and dabigatran may tempt one to consider them
warfarin. as viable options for patients with cancer. However, it must

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British Journal of Haematology, 2013, 161, 755763
Review
be remembered that LMWH has been shown to be superior
to warfarin in terms of efficacy and reduced risk of VTE
recurrence (Louzada et al, 2009). Only small numbers
(c. 5%) of patients in each NOAC study had cancer and
these studies only confirmed non-inferiority to warfarin, not
superiority (Schulman et al, 2009; Bauersachs et al, 2010).
Therefore, until trials of NOACs have been performed in
cancer patients that show either superiority to warfarin or
non-inferiority to LMWH, the latter should remain the treat-
ment of choice in this population.
Novel parenteral anticoagulants
Following the results of the MATISSE trials (Buller et al,
2003, 2004) the short-acting pentasaccharide, fondaparinux,
an indirect inhibitor of FXa, is the only novel parenteral
anticoagulant licensed for the acute treatment of DVT and
PE. Whilst the synthetic pentasaccharide sequence has
removed the risk of HIT (Warkentin et al, 2011) and con-
cerns that may be raised by those who object to the porcine
origin of heparin, these benefits have been superseded by the
arrival of the NOACs. Subgroup analyses of the MATISSE
trials have failed to show a benefit for fondaparinux in can-
cer patients (van Doormaal et al, 2009) and therefore, as
with the NOACs, LMWH remains the preferred option in
this patient group.
The long-acting pentasaccharide, idraparinux, has a half-
life of 80 h and can be administered once weekly. Idrapari-
nux is non-inferior to warfarin for the treatment of proximal
DVT but is inferior for the treatment of PE (Buller et al,
2007). When studied in patients with atrial fibrillation, idra-
parinux was also associated with significantly more bleeding
than warfarin (Bousser et al, 2008). As a result, idrabiotapar-
inux, a biotinylated derivative of idraparinux, has been devel-
oped so that administration of intravenous avidin (a protein
extracted from egg white) will bind tightly to the biotin
moiety and rapidly reverses the anticoagulant effect (Paty
et al, 2010). Idrabiotaparinux has been shown to be equivalent
to idraparinux for the treatment of DVT (EQUINOX, 2011)
and this modified molecule is as effective as warfarin for the
treatment of PE with less bleeding (Buller et al, 2012b).
Unfortunately, despite the great deal of time and effort in
developing and testing these long-acting pentasaccharides, it
is likely that the emergence of NOACs in the treatment of
VTE will limit the impact of idrabiotaparinux. However, at
present it is important to acknowledge the concern regarding
the absence of an antidote for any of the NOACs (Siegal &
Crowther, 2013). Idrabiotaparinux is currently the only one
of the novel anticoagulants in which it is possible to reverse
its anticoagulant activity.
A dabigatran neutralizing monoclonal antibody (van Ryn
et al, 2011) and an anti-FXa inhibitor (Lu et al, 2010) with
activity against fondaparinux, rivaroxaban and apixaban are
under development, but they have yet to be tested in
humans. These haemostatic antidotes are not likely to be
758
available clinically for a number of years and therefore
management of bleeding complications is likely in the main
to be supportive with off-label use of haemostatic agents
used as a last resort (Keeling & Cotter, 2013; Makris et al,
2013).
Duration of anticoagulation
In theory, therapy should be continued if the risk from
recurrence on stopping treatment is greater than the risk
from anticoagulant-related bleeding. If recurrence has a case-
fatality of approximately 5% (Douketis et al, 2007; Carrier
et al, 2010) then a recurrence rate of 5% per annum (p.a.)
would match mortality from recurrence with the 0
25%
annual risk of fatal bleeding on warfarin (Palareti et al, 1996;
Linkins et al, 2003; Carrier et al, 2010). If the new oral anti-
coagulants cause less fatal bleeding than warfarin then long-
term anticoagulation will be favoured at lower recurrence
rates. The risk of recurrence is low (0
7% p.a.) after proximal
DVT or PE following surgery, moderate (4
2% p.a.) follow-
ing non-surgical transient risk factors (such as plaster cast,
combined oral contraception) and high (7
4% p.a.) after
unprovoked events (Iorio et al, 2010).
The difficult clinical question is which patients should
receive long-term anticoagulation after a single unprovoked
proximal DVT or PE? In 2008 the ACCP gave a strong
recommendation for long-term anticoagulation in such
patients in whom risk factors for bleeding are absent and for
whom good anticoagulant monitoring is achievable (Kearon
et al, 2008), though by 2012 this had become a weak recom-
mendation (in those with a low or moderate bleeding risk)
(Kearon et al, 2012). For unprovoked proximal DVT NICE
say consider (NICE-speak for a weak recommendation)
long-term anticoagulation and for PE offer (NICE-speak for
a strong recommendation) long-term anticoagulation, taking
into account the risk of recurrence and risk of bleeding
(NICE, 2012a). A recent review in this journal took a more
sceptical view of the advantages of long-term treatment,
suggesting a limited duration for most patients after a first
VTE (de Jong et al, 2012).
Recurrences after unprovoked VTE are more likely in
males (Douketis et al, 2010; Eichinger et al, 2010; Tosetto
et al, 2012), those whose first event occurs at <50 years of
age (Tosetto et al, 2012), those with post-thrombotic syn-
drome (Stain et al, 2005; Rodger et al, 2008), and those with
raised D-dimers after completing anticoagulation (Verhovsek
et al, 2008; Douketis et al, 2010; Tosetto et al, 2012). Predic-
tion scores, such as HER DOO2 (Rodger et al, 2008) and
DASH (Tosetto et al, 2012) have been proposed. The
D-dimer carried most weight in the DASH score.
A further consideration is that patients with an initial
unprovoked PE are 34 times more likely to suffer recur-
rence as PE compared with patients with an initial DVT
(Murin et al, 2002; Schulman et al, 2006; Baglin et al, 2010)
and the risk of fatal PE is 24 times more likely in patients
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British Journal of Haematology, 2013, 161, 755763

with symptomatic PE as compared to patients with
symptomatic DVT alone (Douketis et al, 1998, 2007; Laporte
et al, 2008).
On the other hand bleeding risk on anticoagulation
increases with age. The case for continuing anticoagulation is
strongest in males whose first event occurred at <50 years of
age, particularly in the case of PE. These patients and some
others (e.g. those with severe post-thrombotic syndrome)
may prefer to continue anticoagulation (without stopping for
a D-dimer test). Other patients may have a clear preference
for stopping or continuing. For those in whom the best
course of action is not clear, determination of D-dimer levels
1 month after stopping treatment may further refine risk.
For the future we need to improve our assessment of risk of
recurrence, collect more data on bleeding with new anticoag-
ulants and develop better tools to predict bleeding.
Post-thrombotic syndrome
The post-thrombotic syndrome (PTS) is the most commonly
occurring long-term complication of DVT with a third to
half of all patients being affected within the first 2 years after
their thrombotic event. It is characterized by symptoms in
the affected leg that includes a feeling of heaviness, aching,
swelling, cramp, and often itching or a tingling sensation.
Signs include oedema, skin pigmentation, varicose eczema
and, in its most severe form, skin ulcers (Kahn, 2011). PTS
has a significant impact on quality of life and results in a
substantial cost burden to patient and society alike. Treat-
ment options for PTS are limited. Strategies to prevent PTS
occurrence are of crucial importance and include the preven-
tion of recurrent DVT, compression stockings and possibly
endovascular catheter-directed thrombolysis. The ability to
predict which patient is likely to develop PTS is desirable but
currently limited (Latella et al, 2010; Roberts et al, 2013).
Thrombolysis
In a meta-analysis of 12 studies assessing systemic thrombol-
ysis for the treatment of acute DVT, the occurrence of PTS
was reduced by a third. However, this was associated with a
an almost two-fold increase in the risk of bleeding (Watson
& Armon, 2004). There have been no head-to-head studies
of thrombolytic agents but streptokinase appears to be asso-
ciated with a higher risk of bleeding.
Catheter-directed thrombolysis (CDT) is a novel method
that involves the insertion of a peripheral catheter, usually via
the popliteal vein, and advancing it directly into the vessel
where the thrombus is present. The catheter has side-vents,
which allow low doses of thrombolytic agent to be adminis-
tered directly on to the clot. The CaVenT study is the first
prospective randomized study to assess the long-term out-
come of this technique (Enden et al, 2012). Patients with
proximal DVT received standard therapy (LMWH + warfarin)
and were randomized to receive CDT or not. Patients were
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British Journal of Haematology, 2013, 161, 755763
Review
followed for 24 months and advised to wear class II
(30 mmHg) below-knee graduated compression stockings
(Enden et al, 2012). The absolute risk reduction of PTS in
those patients randomized to CDT was 14% (P = 0
05). There
were 3 (3%) major bleeds in the CDT group and none in the
control arm. There are currently two further prospective CDT
trials actively recruiting patients (clinical trials reference num-
bers NCT0079035 and NCT00970619). For patients with
extensive proximal DVT (i.e. ilio-femoral) in whom the risk
of bleeding is low and functional status is good with normal
life expectancy who wish to reduce the risk of PTS and accept
the risk of bleeding, thrombolysis should be considered
(Kearon et al, 2012). The risk of bleeding is lower with CDT
when compared to systemic thrombolysis and this would be
the preferred option. It would appear that seven patients need
to be treated with CDT to prevent one episode of PTS, with
an acceptable small increase in the risk of bleeding (Enden
et al, 2012).
Compression therapy
Two prospective studies have randomized patients with
symptomatic proximal DVT to wear either below-knee com-
pression elastic stockings (CES) that apply an ankle pressure
of 3040 mmHg (equivalent to RAL standard compression
class III) or not to wear stockings (Brandjes et al, 1997;
Prandoni et al, 2004). The presence of PTS was measured
using a validated scale first described by Villalta (Villalta
et al, 1994; Kahn et al, 2009). Both studies reported a statis-
tically significant 50% reduction in PTS for patients wearing
CES (Brandjes et al, 1997; Prandoni et al, 2004). A recent
study comparing thigh-length with below-knee CES failed to
show any difference in PTS and the long-leg stockings were
less well tolerated (Prandoni et al, 2012). The results of these
studies and a meta-analysis (Kolbach et al, 2004) have led to
current VTE guidelines recommending below-knee CES for
patients with proximal DVT (Kearon et al, 2012; NICE,
2012a).
However, this perceived wisdom has been challenged
(Ginsberg et al, 2001). This is further added to by the recent
presentation of the results of the S.O.X trial at the American
Society of Hematology Annual Meeting (Kahn et al, 2012).
The S.O.X trial is the largest study of CES in patients with
proximal DVT; 397 patients were randomized to class II
(3040 mmHg) stockings and 406 to non-therapeutic com-
pression stockings. There was no observed reduction in
occurrence or severity of PTS between the two arms. It is of
interest that the two CES studies that have failed to show a
reduction in PTS both used placebo stockings (Ginsberg
et al, 2001; Kahn et al, 2012) while the two studies identifying
a significant benefit used no stockings in their control group
(Brandjes et al, 1997; Prandoni et al, 2004). We would suggest
a three-arm study comparing therapeutic (3446 mmHg) and
non-therapeutic CES with a no-CES control group to address
the discordant results. Until that time there remains doubt as
759
Review
to whether below-knee CES can prevent PTS in patients with
proximal DVT.
Screening for cancer
The association of cancer and VTE is well known. A systematic
review (Carrier et al, 2008) identified 36 studies that reported
the prevalence of undiagnosed cancer at baseline, 6 months
and 12 months after a VTE; 14 studies (plus an additional
abstract) met the inclusion criteria. The prevalence of previ-
ously undiagnosed cancer in patients with unprovoked VTE
was 6
1% [95% confidence interval (CI), 5
07
1%] at baseline
and 10
0% (CI, 8
611
3%) at 12 months. An extensive
screening strategy using computed tomography (CT) of the
abdomen and pelvis statistically significantly increased the
proportion of previously undiagnosed cancer detected from
49
4% (CI, 40
258
5%) to 69
7% (CI, 61
177
8%).
NICE (2012a) examined the one prospective randomized
clinical trial in the above systematic review (the SOMIT
study) (Piccioli et al, 2004). This looked at extensive screen-
ing for occult malignant disease in unprovoked VTE. Ninety-
nine patients were randomized to extensive screening for
occult cancer and 102 to no further testing. Extensive screen-
ing identified occult cancer in 13 (13
1%) patients with a
single (1
0%) further malignancy becoming apparent during
the 2-year follow-up. In the control group, a total of 10
(9
8%) malignancies became apparent during the 2-year
follow-up. Mean delay to diagnosis was reduced from 11
6 to
1
0 months (P < 0
001). Cancer-related mortality during the
2-year follow-up period occurred in two (2
0%) of the 99
patients of the extensive screening group versus four (3
9%)
of the 102 control patients [non-significant absolute differ-
ence 1
9% (95% CI, 5
5 to 10
9)].
The data of the SOMIT trial were used to perform a deci-
sion analysis (Di Nisio et al, 2005). The screening tests were
divided into several possible strategies. The number of
detected cancer patients and the number of patients investi-
gated further for an eventually benign condition were calcu-
lated for each strategy, e.g. CT of the abdomen combined
with sputum cytology and mammography detected 12 of the
14 patients with cancer and had one false-positive result. The
authors concluded that screening for cancer with a strategy
including abdominal/pelvic CT with or without mammogra-
phy and/or sputum cytology appears potentially useful
though the cost-effectiveness needs confirmation in a large
trial.
NICE further examined these data and concluded a strat-
egy based on abdominal/pelvic CT plus mammography
seemed to provide the best value-for-money leading to a
(weak) recommendation to consider further investigations
for cancer with an abdomino-pelvic CT scan (and a mam-
mogram for women) in all patients aged over 40 years with
a first unprovoked DVT or PE who do not have signs or
symptoms of cancer based on initial investigation (NICE,
2012a).
760
This is not widespread clinical practice. A more recent
prospective cohort study compared limited and extensive
cancer screening strategies (Van Doormaal et al, 2011); all
underwent baseline screening consisting of history, physical
examination, basic laboratory tests and chest X-ray. Of the
630 patients studied, 342 were seen in hospitals that per-
formed additional extensive screening with CT chest/abdo-
men and mammography and 288 in hospitals that did not.
The initial limited screening detected malignancy in 12/342
(3
5%) and 7/288 (2
4%) respectively. In hospitals perform-
ing extensive screening 302 of the 330 remaining patients
underwent screening and suspicion of cancer was raised in
91 (30% of 302) and confirmed in six (2
0% of the 302), of
which three were potentially curable. During a median
2
5 years of follow-up, cancer was diagnosed in an additional
12 patients in the extensive screening group and an addi-
tional 14 patients in the limited screening group. In the
extensive screening group, 26 patients (7
6%) died compared
with 24 (8
3%) in the limited screening group; adjusted haz-
ard ratio 1
22 (95% CI, 0
692
22). Of these deaths 17
(5
0%) in the extensive screening group and 8 (2
8%) in the
limited screening group were cancer-related; adjusted hazard
ratio 1
79 (95% CI, 0
744
35). The authors concluded that
the low yield of extensive screening and lack of survival ben-
efit do not support routine screening for cancer with abdom-
inal and chest CT scan and mammography in patients with a
first episode of unprovoked VTE.
Screening does identify malignancies at an earlier stage
(Monreal et al, 2004; Piccioli et al, 2004), but we know that
cancer diagnosed at the same time as or within 1 year after
an episode of VTE is associated with an advanced stage of
cancer and a poor prognosis (Sorensen et al, 2000) and it
would require a large study to ascertain whether early diag-
nosis results in a survival benefit. We also need to be aware
that extensive screening may cause anxiety, results in radia-
tion exposure [a CT abdomen is the equivalent of 400 chest
X-rays and 3
3 years of background radiation (Davies et al,
2011)] and unnecessary further testing in those with false
positive results.
Based on this data, some may favour screening for occult
cancer with abdomino-pelvic CT whilst others will not. Coun-
selling patients is important but also very difficult. In the
SOMIT study, randomization was performed according to the
Zelen design whereby patients randomized to extensive screen-
ing were informed about the study, the screening procedures
and their potential risks, and were asked for written informed
consent but patients randomized to the control group were
not informed about the study and consequently not asked to
give informed consent. This was because most patients, when
they hear the word cancer, hear little else and want to be
screened. The development of good quality patient informa-
tion is important so a truly informed decision can be made.
Cancer is more prevalent in those with bilateral DVTs
(Rance et al, 1997), early VTE recurrence (Prandoni et al,
1992), or very high D-dimers (Schutgens et al, 2005; Beckers
2013 John Wiley & Sons Ltd
British Journal of Haematology, 2013, 161, 755763

et al, 2006; Paneesha et al, 2006) and, if universal screening
is not implemented, these may be may useful in selecting
those for further investigation.
Concluding remarks
Management of deep vein thrombosis is largely evidence-
based but there are some difficult areas where more studies
are needed. We need to be able to better predict risk of
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