the clinical significance of calf vein deep vein thrombosis

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i The clinical significance of calf vein deep vein thrombosis NICE guidelines for VTE, are they best practice?

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i

The clinical significance of calf vein

deep vein thrombosis

NICE guidelines for VTE, are they best practice?

ii

Table of contents

Introduction and background ………pg. 1

Aim ………pg. 1

Literature search strategy ………pg. 2

NICE Guidelines and evidence based practise ………pg. 2

Defining distal DVT ………pg. 3

A general consensus, to treat or not to treat ………pg. 3

A case for stratification of scanning and treatment protocols ………pg. 5

Patient outcome, the heart of the matter ………pg. 6

Post Thrombotic Syndrome (PTS) ………pg. 7

Local perspective, utopia and compromise ………pg. 8

Conclusions and recommendations ………pg. 9

References ………pg. 10

Bibliography ………pg. 13

Appendix A ………pg. 14

Appendix B ………pg. 17

Appendix C ………pg. 25

1

Introduction and background

Controversy surrounding the value of performing ultrasound examination of the calf

veins for diagnosing deep vein thrombosis (DVT) still exists (Righini, 2007 &

Schellong, 2007). In June 2012 the National Institute of Clinical Excellence (NICE)

published guidelines for the management of venous thromboembolic diseases

(NICE, 2012). They summarised that “ultrasound techniques are effective for ruling

out proximal DVTs but not calf vein or distal DVTs” (NICE, 2012 p.52). Their

evidence suggests that compared to reference levels (venography) ultrasound of the

distal veins has a sensitivity of just 29% (NICE, 2012). Despite these guidelines a

recent study by Shahi and Murali (2013) identified that 68% of health-care

professionals trained in vascular ultrasound scanned the whole leg routinely. They

also found that all accredited vascular scientists in their study scanned the whole leg

routinely. This is in accordance with the performance guidelines for the assessment

of DVT published by the Professional Standards Committee of the Society for

Vascular Technology (SVT) (2012).

Current protocol at the hospital at which the author is employed is to scan the entire

leg reducing the need for a re-scan in the event of a negative ultrasound test result

and positive D-dimer test. The majority of DVT examinations are referred through the

Urgent Care Centre (UCC) outpatient pathway. Any form of identified calf vein DVT

(CDVT) is treated with anticoagulation. This study is relevant as the local standard

operating procedure for assessment of DVT is due for review in June 2014 and

current protocol is not in accordance with NICE guidelines.

Aim

This review will aim to evaluate findings regarding the clinical significance of

performing ultrasound examination of the calf veins and identifying and treating

CDVT.

2

Literature search strategy

An initial search was performed using Library Plus. Relevant articles were identified

and scanned for keywords. A full search of Library Plus was then performed. Four

searches produced 2,031,454 hits, these searches were combined to produce a

result of 68 articles. Articles published in a language other than English were

excluded, as were articles published prior to 2009. 2009 was chosen as the cut off

as this was the latest evidence (Gibson et al.) reviewed and referenced within the

NICE guidance and because the aim of this review is to provide an up to date

perspective on the topic. These exclusions left 16 articles. These were filtered for

inclusion and relevant articles were then extensively cross referenced. It would have

been preferable to only include and review randomised controlled trials (RCT),

however in this date range that would have left just Schwarz et al. (2010). It was

decided to include the RCT of Bernardi et al. (2008) to add strength to the review.

Therefore, prospective (5) and retrospective (4) studies and four pertinent meta-

analyses and systematic reviews were also included to make a total of 15 articles

that were reviewed. The search strategy is included in appendix A. Major findings of

each article reviewed are tabulated in appendix B.

NICE Guidelines and evidence based practise

In creating the guidelines the rationale for only scanning proximal veins of the leg

was based on the findings of three studies. Gibson et al., (2009) found little

difference in patient outcome between a group undergoing complete leg ultrasound

examination and those undergoing a proximal leg veins only technique with a repeat

examination for those with a negative first examination. They concluded that both

strategies were equally valid. This outcome was reflected in the work of Bernardi et

al. (2008) who’s study stated that complete examination offered a one day answer

but was harder to perform and may result in more patients receiving unnecessary

anticoagulation therapy, whereas the proximal vein only technique was simple to

perform but required follow up examination in approximately a quarter of their

sample. Finally, Goodacre et al., (2006) was a large meta-analysis including 100

cohorts but only research published to 2004. Results suggested that the evidence for

use of a repeat proximal veins scan technique was based on the findings of

3

observational studies identifying that 1.3% of repeat scans will be positive, but they

summarised with the caveat that ‘Use of ultrasound requires a strategy for managing

possible distal DVT or a conviction that these DVT are of little pathological

significance’ (2006 p.39).

Guidelines should be firmly anchored in rigorous evidence based practise. NICE

(2012) acknowledge that the quality of the evidence is of low to moderate quality, yet

these were deemed sufficient to base the guideline on.

Defining distal DVT

One issue of contention within the literature is what constitutes distal DVT. Pengas et

al, (2013) found little agreement as to whether muscular vein thrombosis (MVT)

(thrombosis of the muscular veins i.e. the gastrocnemius and soleal veins) should be

classified as superficial or deep and therefore whether it deserved treating as DVT or

not. Patients may face a lottery on treatment depending on the significance of MVT

to a centre, and whether the centre treats MVT as DVT. Sales et al., (2010) found

much of their literature failed to distinguish between distal DVT and MVT, an

example being Palareti et al., (2010) who use the term ‘Isolated Calf DVT’ but fail to

clarify what this includes. Parisi et al., (2009) and Bernardi et al., (2008) identified

that there was no significant differences in the progression rates between MVT and

tibio-peroneal DVT suggesting the same treatment for these thrombi is justified.

Trust policy at the author’s place of work is to treat MVT as per DVT. For the

purpose of this review MVT and distal DVT will be given the same significance.

A general consensus, to treat or not to treat

Bernardi et al., (2008) and Gibson et al., (2009) were the only research comparing

the effectiveness of a whole leg ultrasound scan versus a proximal veins technique.

With the exception of two studies, all other research reviewed began with methods

that already identified CDVT and then watched its progress against a treatment

group to examine the differences. Most used end points such as proximal

propagation and pulmonary embolus to determine significance. The two exceptions

were Sevestre et al., (2009) and Johnson et al., (2010), they sought to determine

4

whether anticoagulation could be safely withheld in patients with a single negative

whole leg ultrasound scan. Appendix C provides a general overview of how the

authors view the clinical significance of CDVT based on their own outcomes.

Whether they feel it is necessary to scan the calf veins and identify CDVT has been

assumed by the results and conclusions of each study.

Three articles reviewed expressed definitive favour for treating CDVT with

anticoagulation therapy. In their retrospective study Lautz et al., (2009) found

statistical significance comparing incidence of subsequent venous thromboembolic

events (VTE) in groups of patients receiving therapeutic anticoagulation with those

receiving no treatment or prophylactic treatment. The therapeutic treatment group

had a VTE incidence of 12% compared with 30% and 27% in the groups with no

treatment and prophylactic treatment respectively (p=0.0003). Resolution of CDVT at

follow up was also found to be higher in the treatment group. These results may

have been skewed by the large number of ambulatory low risk patients represented

in the treatment group possibly being less predisposed to having a VTE event.

Kret et al., (2013) found similar results. In their treatment group 65% had complete

resolution at the follow up scan compared to just 21% who were given no treatment

or prophylactic anticoagulation. Their study had weaknesses. It was retrospective,

excluding patients without multiple follow up scans. It could be argued that those

included were more prone to VTE events and that is why they needed multiple follow

up scans. Likewise, excluded patients may have had spontaneous resolution and not

needed a follow up. Statistically their findings also need to be placed in perspective.

They stated that at follow up 25% of their patients had either propagation of

thrombus or a new thrombus at a remote site. However, over a period where 7283

lower extremity venous duplex exams were performed, that 25% of 57 patients with

CDVT represents less than 0.2% of all scans undertaken. However, of nine patients

in their study who developed a pulmonary embolism (PE) none were taking

therapeutic anticoagulation at the time of diagnosis and they therefore concluded

that CDVT warrants therapeutic anticoagulation.

De Martino et al., (2012) stated that the ‘quality of evidence to support

anticoagulation for reduction of thrombus propagation is adequate’ (p.235). They

found a link between therapeutic anticoagulation for CDVT and reduced proximal

5

propagation and PE. They stated that their reviewed literature was based on studies

with small sample sizes. Additionally the researchers used the reviewed literature to

attempt to answer questions these studies were not specifically designed to answer.

Contrary to these results Sales et al., (2010) found no difference in the rate of

thrombus propagation when comparing a group of patients undergoing

anticoagulation therapy for CDVT and a group with no treatment. This outcome was

reflected in the RCT of Schwarz et al., (2010). They found no significant difference in

propagation between a group receiving therapeutic anticoagulation and compression

stocking therapy and a group just using the compression stockings. However their

sample was 89% outpatients and mostly ambulatory and therefore not generalizable

to higher risk patient groups.

Gibson et al., (2009) and Bernardi et al., (2008) were not in favour of routine

anticoagulation therapy speculating that though a whole leg scan discovers CDVT it

may also lead to unnecessary treatment and therefore ‘detecting isolated calf vein

DVT may not be as relevant as previously believed’ (Bernardi et al., 2008 p.1657).

Sule et al., (2009) in a small study of 51 patients was also in favour of surveillance

scans to detect significant propagation.

Pengas et al., (2013) were not in favour of routine anticoagulation therapy pointing to

a well-documented risk of haemorrhage in their sample of orthopaedic patients with

CDVT. Though Masuda et al., (2012) found no compelling evidence for routine

anticoagulation therapy they did note that proximal DVT is universally treated with

anticoagulation with seemingly little obvious concern for bleeding issues and

therefore couldn’t understand the controversy over anticoagulation for CDVT.

Between the studies there is no real consensus as to whether anticoagulation

therapy should be routine. The one recurring agreement is that the rules are different

for patients in higher risk groups.

A case for stratification of scanning and treatment protocols

Rates of proximal propagation of CDVT have been found to be as high as 25%

(Lagerstedt et al., 1985). Many of the reviewed articles identified that patients in a

high risk group (those with malignancy, hospitalised, bed bound or with unprovoked

6

CDVT) may benefit from anticoagulation therapy. Parisi et al., (2009) commented

that 80-90% of patients probably do not need anticoagulation therapy, the challenge

is identifying the 10-20% that do. Their results found that proximal propagation was

always associated with unprovoked DVT. They recommended treating with

prolonged anticoagulation therapy. Masuda et al., (2012) and Sales et al., (2010)

demonstrated links between CDVT propagation and malignancy. These results

resonate closely with the findings of Singh et al., (2012). In their prospective study

they found that 7% of their sample had proximal propagation of CDVT. All were high

risk group patients. They also found that 43% of their sample had persistent

thrombus but without propagation. This may indicate that in lower risk patient groups

the risk of proximal propagation is less and anticoagulation may not be routinely

necessary. They also found that all propagations that occurred were found on the

follow up scans between 1 and 3 months. Therefore a single follow up scan 6-8 days

after a negative proximal scan as per NICE (2012) guidelines may not be sufficient

time to identify all the significant CDVT that propagate. They concluded that high risk

patients may need immediate anticoagulation therapy whereas low risk ambulatory

patients could be safely observed with ultrasound.

In their small sample RCT Schwarz et al., (2010) advocated an ‘individual approach’

(p.1248) to treatment where each case is treated according to the individual’s

situation. They stated the probable need for anticoagulation in high risk patients.

These results are complemented by the findings of Johnson et al., (2010) and

Sevestre et al., (2009). The three studies all felt anticoagulation therapy could be

withheld in low risk ambulatory patients.

The evidence points to the potential for stratified treatment according to identified

patient risk group on identification of CDVT. All patients with CDVT cannot be

generically treated since risk factors appear to have a bearing on outcome.

Patient outcome, the heart of the matter

In their summary of research recommendations NICE concluded that an ‘RCT with

cost-effectiveness analysis could answer the crucial question of whether full-leg

ultrasound improves patient outcomes and allows for more effective use of NHS

resources’. (NICE, 2012 p.267). If the sole purpose of the examination is to rule out

7

significant DVT then the proximal vein only technique recommended by NICE (2012)

may be sufficient. However, Gibson et al., (2009) and Bernardi et al., (2008) on

whose evidence the guidelines were based used 94% outpatients and outpatients

from the emergency department or primary care pathways respectively as their

sample. As has been shown previously, these samples and patient types may not

represent the full spectrum of patients at risk from developing proximal DVT from

CDVT. Additionally, as practitioners with our patients’ best interests at heart is it

sufficient to simply rule out DVT when there is the potential there to diagnose other

causes? Moody and Hafner (2009) identified a pooled DVT incidence of 19% in their

sample. Palareti et al., (2010) estimated the rate of DVT positive scans to be 25%.

Sevestre et al., (2009) made a valid point in that of 2848 patients in their study

scanned for DVT 23.6% were found to have an alternative cause.

Lohr and Fellner (2010) found that a proximal only technique with follow up scans is

less cost effective than a single whole leg scan. They found patients to be frequently

non-compliant in attending follow up scans. Mcilrath et al., (2006) found similarly low

rates of return for follow up scans. Despite the added time concerns with a whole leg

scan Schwarz et al., (2002) found this to be only an additional 4 minutes per calf.

Gibson et al., (2009) identified that a whole leg technique had a low rate of

inconclusive scans and offered the patient a one visit only experience.

Post Thrombotic Syndrome (PTS)

Proximal DVT is associated with development of PE but avoiding fatality in the short

term does not exclude long term issues associated with DVT. Kahn and Ginsberg

(2002) and Guanella (2013) showed that CDVT is not free of embolic risk and can

trigger PTS. Cowell et al., (2007) stated that CDVT may be significant ‘because of its

recognised association with post-phlebitic syndrome’ (p.861). Lautz et al., (2009)

found that 90% of patients receiving anticoagulation therapy for CDVT remained free

of VTE events 2 years after their initial diagnosis, suggesting anticoagulation was

linked to a reduced rate of further VTE events. Their sample was a mixture of high

and low risk patients. Furthermore Sales et al., (2010) found ‘no haemorrhagic

complications in the therapy group’ (p.1254) stating that this may refute the

argument that anticoagulation is associated with significant bleeding risk. One

8

concern with a proximal only technique is that regardless of origin there is only scope

for finding proximal DVT. The whole leg technique gives the clinician the option to

treat before CDVT becomes proximal DVT. The longer term outcomes for the patient

must be weighed against the practicalities of the scanning method used.

Local perspective, utopia and compromise

Sule et al., (2009) recommend rescan at one week one month and three months.

Bernardi et al., (2008) noted that 30.9% of their patients needed re-scheduling for a

follow up scan. From a local perspective it would be unrealistic to perform this

amount of follow up scans while trying to stay current with acute cases needing their

first investigation. This viewpoint may be reflected elsewhere in the country with one

consultant radiologist in a rapid response letter to the BMJ calling the NICE

guidelines timeframes utopian (Makowska-Webb, 2012). The authors’ department

relies on an accurate whole leg scan technique aimed at discovering all DVT and

thereby negating the need for a follow up scan where possible, however, not

everyone performing a DVT scan will have the skill and training of a vascular

sonographer. The authors’ viewpoint is that NICE (2012) have created a set of

guidelines that will provide in most cases an immediate answer from a technique that

can be learnt quickly by practitioners. This may not be thorough or suitable for all

patients but it is achievable, repeatable and auditable. The SVT (2012) guidelines

assume that all practitioners are capable of scanning the calf veins to a high

standard. NICE (2012) have disregarded completely the need to scan the calf veins.

A compromise could be found in the guidelines of the American Institute of

Ultrasound in Medicine (AIUM). They recommend a standard examination of the

proximal leg including compression, colour and spectral techniques. If the cause is

not found from this examination and there are focal symptoms they recommend

examination of the symptomatic region. (AIUM, 2011). Similarly, the American

College of Chest Physicians (Kearon et al., 2012) altered their guidelines. In 2008

they recommended routine anticoagulation therapy for all CDVT (Kearon et al.,

2008), the 2012 guidelines suggest that only patients with ‘severe symptoms or risk

factors for extension’ (Kearon et al., 2008 p.420s) should receive anticoagulation

therapy.

9

Conclusions and recommendations

In general the quality of recent research is at best moderate with most studies having

serious flaws. Twelve of the fifteen studies pointed to the need for further in-depth

RCT to enlighten current practise. The quality of evidence was certainly a limitation

of this review. Additionally, current trust protocols to scan the whole leg routinely

may have had influence on the authors’ perspective and an element of bias in favour

of a whole leg technique cannot be ruled out.

Within this review only three of fifteen articles found in favour of routinely treating

CDVT. Two (the articles used as evidence in the NICE guidelines) concluded that a

proximal veins only scan with repeats had similar patient outcomes as a whole leg

ultrasound but led to less patients undergoing potentially unnecessary treatment.

The remaining articles varied in the degree of significance placed on CDVT. Most

stated that routine anticoagulation is not necessary except in certain patient types.

The key recurring theme was that high risk group patients were almost always

associated with CDVT propagation to the proximal veins. This finding strengthens

the case for a stratification process whereby high risk patients always get a full whole

leg scan. With high risk being associated with proximal propagation it should be a

duty of care to diagnose at the earliest point and begin treatment if appropriate at the

earliest point.

Another theme also showed that a flexible approach to treatment should be a

consideration and that although guidelines limited by cost effectiveness and

simplicity of implementation are auditable and may account for the majority, health

care is about doing the best you can by every patient, not shoehorning all patients to

fit a single process.

The authors’ personal view is that the guidelines are a compromise between skill and

practicality. The majority of patients will not need more than a single proximal leg

scan. For others finding and treating CDVT at the earliest possibility is probably

essential. The sonographer can only attempt to find the cause of the patients’

symptoms. However guidelines are not rules and ultimately, at a local level the

significance of CDVT and the risk of beginning anticoagulation therapy versus the

risk of developing a proximal DVT will depend on the viewpoint of the referring

clinician.

10

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Bernardi, E. Camporese, G. Buller, H. Siragusa, S. Imberti, D. Berchio, A. Ghirarduzzi, A. Verlato, F. Anastasio, R. Prati, C. Piccioli, A. Pesavento, R. Bova, C. Maltempi, P. Zanatta, N. Cogo, A. Cappelli, R. Bucherini, E. Cuppini, S. Noventa, F. and Prandoni, P. (2008) Serial 2-point ultrasonography plus D-Dimer vs whole-leg color-coded doppler ultrasonography for diagnosing suspected symptomatic deep vein thrombosis - A randomized controlled trial. Journal of the American Medical Association. 300 (14) pp. 1653-1659.

Cowell, G. Reid, J. Simpson, A. and Murchison, J. (2007) A profile of lower-limb deep-vein thrombosis: the hidden menace of below-knee DVT. Clinical Radiology. 62 (9) pp. 858-863.

De Martino, R. Wallaert, J. Rossi, A. Zbehlik, A. Suckow, B. and Walsh, D. (2012) A meta-analysis of anticoagulation for calf deep venous thrombosis. Journal of Vascular Surgery. 56 (1) pp. 228-237.

Gibson, N. Schellong, S. Kheir, D. Beyer-Westendorf, J. Gallus, A. McRae, S. Schutgens, R. Piovella, F. Gerdes, V. and Buller, H. (2009) Safety and sensitivity of two ultrasound strategies in patients with clinically suspected deep venous thrombosis: a prospective management study. Journal of Thrombosis and Haemostasis. 7 (12) pp. 2035-2041.

Goodacre, S. Sampson, F. Stevenson, M. Wailoo, A. Sutton, A. Thomas, S. Locker, T. and Ryan, A. (2006) Measurement of the clinical and cost-effectiveness of non-invasive diagnostic testing strategies for deep vein thrombosis. Health Technology Assessment. 10 (15) pp. 1-168.

Guanella, R. (2013) Post-thrombotic syndrome: the forgotten complication of venous thromboembolism. Revue Médicale Suisse. 9 (372) pp. 321-325.

Johnson, S. Stevens, S. Woller, S. Lake, E. Donadini, M. Cheng, J. Labarère, J. and Douketis, J. (2010). Risk of deep vein thrombosis following a single negative whole-leg compression ultrasound: a systematic review and meta-analysis. Journal of the American Medical Association. 303 (5) pp. 438-445.

Kahn, S. and Ginsberg, J. (2002) The post-thrombotic syndrome: current knowledge, controversies, and directions for future research. Blood Review. 16 (3) pp.155-165.

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Kearon, C. Kahn, S. Agnelli, G. Goldhaber, S. Raskob, G. and Comerota, A. (2008) Antithrombotic therapy for venous thromboembolic disease: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. 133 (6 Suppl) pp. 454-545.

Kret, M. Liem, T. Mitchell, E. Landry, G. and Moneta, G. (2013) Isolated calf muscular vein thrombosis is associated with pulmonary embolism and a high incidence of additional ipsilateral and contralateral deep venous thrombosis. Journal of Vascular Surgery: Venous and Lymphatic Disorders. 1 (1) pp. 33-38.

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Lohr, J. and Fellner, A. (2010) Isolated calf vein thrombosis should be treated with anticoagulation. Disease a Month. 56 (10) pp. 590-600.

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McIlrath, S. Blaivas, M. and Lyon, M. (2006) Patient follow-up after negative lower extremity bedside ultrasound for deep venous thrombosis in the ED. American Journal of Emergency Medicine. 24 (3) pp. 325-328.

Moody, J. and Hafner, J. (2009) Evidence-based emergency medicine/rational clinical examination abstract: The evidence-based diagnosis of deep venous thrombosis. Annals of Emergency Medicine. 54 (3) pp. 461-464.

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Palareti, G. Agnelli, G. Imberti, D. Moia, M. Ageno, W. Pistelli, R. Rossi, R. and Verso, M. (2010) A commentary: To screen for calf DVT or not to screen? The highly variable practice among Italian centers highlights this important and still unresolved clinical option. Results from the Italian Master registry. Thrombosis and Haemostasis. 99 (1) pp. 241-244.

Parisi, R. Visona, A. Camporese, G. Verlato, F. Lessiani, G. Antignani, P. and Palareti, G. (2009) Isolated distal deep vein thrombosis: efficacy and safety of a

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Pengas, I. Nash, W. Reed, N. and Kumar, S. (2013) Evidence for treatment of muscular vein thrombosis in orthopaedic patients. Journal of Orthopedic Traumatology. 14 (3) pp. 159-164.

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Schwarz, T. Buschmann, L. Beyer, J. Halbritter, K. Rastan, A. and Schellong, S. (2010) Therapy of isolated calf muscle vein thrombosis: A randomized, controlled study. Journal of Vascular Surgery. 52 (5) pp. 1246-1250.

Sevestre, M. Labarère, J. Casez, P. Bressollette, L. Haddouche, M. Pernod, G. Quéré, I. and Bosson, J. (2009) Outcomes for Inpatients with Normal Findings on Whole-leg Ultrasonography: A Prospective Study. The American Journal of Medicine. 123 (2) pp. 158-165.

Shahi, F and Murali, K (2013) Variations in ultrasound scanning protocols in the UK for suspected deep vein thrombosis in outpatients. Phlebology. 28 (8) pp. 397-403.

Singh, K. Yakoub, D. Giangola, P. DeCicca, M. Patel, C. Marzouk, F. and Giangola, G. (2012) Early follow-up and treatment recommendations for isolated calf deep venous thrombosis. Journal of Vascular Surgery. 55 (1) pp. 136-140.

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Sule, A. Chin, T. Handa, P. and Earnest, A. (2009) Should symptomatic, isolated distal deep vein thrombosis be treated with anticoagulation? International Journal of Angiology. 18 (2) pp. 83-87.

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Galanaud, J. Sevestre, M. Genty, C. Laroche, J. Zizka, V. Quere, I. and Bosson, J. (2010) Comparison of the clinical history of symptomatic isolated muscular calf vein thrombosis versus deep calf vein thrombosis. Journal of Vascular Surgery. 52 (4) pp. 932-938.

Gillet, J. Perrin, M. and Allaert, F. (2007) Short-term and mid-term outcome of isolated symptomatic muscular calf vein thrombosis. Journal of vascular surgery. 46 (3) pp. 513-519.

Guanella, R. Le Gal, G. Quere, I. and Righini, M. (2009) Distal venous thrombosis: another source of discord - The rationale of the CACTUS study. Sang Thrombose Vaisseaux. 21 (7) pp. 315-321.

Guanella, R. and Righini, M. (2012) Serial Limited versus Single Complete Compression Ultrasonography for the Diagnosis of Lower Extremity Deep Vein Thrombosis. Seminars in respiratory and critical care medicine. 33 (2) pp. 144-150.

Labropoulos, N. Waggoner, T. Sammis, W. Samali, S. and Pappas, P. (2008) The effect of venous thrombus location and extent on the development of post-thrombotic signs and symptoms. Journal of vascular surgery. 48 (2) pp. 407-412.

Masuda, E. and Kistner, R. (2010) The case for managing calf vein thrombi with duplex surveillance and selective anticoagulation. Disease a Month. 56 (10) pp. 601-613.

Palareti, G. and Schellong, S. (2012) Isolated distal deep vein thrombosis: what we know and what we are doing. Journal of Thrombosis and Haemostasis. 10 (1) pp. 11

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Appendix A. Literature search strategy results

Search

ID# Search Terms Search Options Last Run Via Results

S1

AB calf vein OR AB

distal OR AB

thrombus OR SU calf

vein

Search modes - Find all my

search terms

Interface -

EBSCO

Discovery

Service

Search Screen -

Advanced

Search

Database -

Library Plus -

for books,

articles and

more

638,306

S2 SU ultras* Search modes - Find all my

search terms

Interface -

EBSCO

Discovery

Service

Search Screen -

Advanced

Search

Database -

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1,306,872

S3

AB distal extremity

OR AB calf vein OR

SO calf vein

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16,941

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AB deep vein

thrombosis OR AB

dvt OR TI dvt OR

AB calf vein

thrombosis

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69,335

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494

S8 ( S4 AND S6 ) AND

TI calf

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S9 ( S4 AND S6 ) AND

TI calf

Limiters - Date Published:

20080101-20131231

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19

S10 ( S4 AND S6 ) AND

TI calf

Limiters - Date Published:

20080101-20131231

Limiters - Language

English

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16

17

Appendix B.

Summary of reviewed articles and key findings.

Glossary of abbreviations

Abbreviation Full Abbreviation Full Abbreviation Full

VTE Venous thromboembolism

IGSVT Isolated gastrocnemius or soleal vein thrombosis

RCT Randomized controlled trial

CUS Cereal ultrasound MVT Muscular vein thrombosis

ICDVT Isolated calf deep vein thrombosis

Ca Cancer ICVT Isolated calf vein thrombosis

DVT Deep vein thrombosis

PE Pulmonary embolism ATV Anterior tibial vein US Ultrasound

ED Emergency Department

Author/Year Sample size (n)

Study type Population Type

Topic Study limitations

Conclusions Recommendations Statistics Comments

Kret et al., 2013

57 patients Non randomised retrospective review of a vascular lab database

Not specified but must have had a follow up US scan to be included

Rates of VTE progression and resolution, effects of anticoagulant therapy in patients with IGSVT.

Small sample size. Retrospective, uniform follow up not possible. Selection bias from only including patients who had a follow up scan.

IGSVT is associated with significant VTE progression, therapeutic anticoagulation is associated with resolution.

Untreated patients with IGSVT should be monitored with follow up scans.

P< .002 that resolution was attributable to therapy but this was based on findings from follow up scans, mean follow up was 113 days but the range was 2 – 1505 days, can we expect resolution after

Sample size is very small to be drawing statistical conclusions. Only take into account those with a follow up scan, there must be a reason that others with confirmed IGSVT did not have a follow up scan ? resolved on its own? This would significantly skew the overall figures. There was no standardised treatment protocol, so

18

2 days? And in some patients it might be expected that after 1505 days a clot may have resolved without the need for therapy.

difficult to comment on the effectiveness of treatment.

Pengas, 2013

N/A Literature review Orthopaedic patients

Does below knee IGSVT warrant investigation and treatment?

Only as strong as studies being reviewed.

Lack of consensus in answering the question and lack of solid evidence solely from orthopaedic groups. MVT should not be routinely treated but observed with CUS and treated if found to have propagated

RCT or further scientific study to indicate whether treatment and investigation of IGSVT is warranted in these patients

None attempted.

Difficult to draw any meaningful conclusions from this limited work.

Singh et al., 2012

156 patients 180 Limbs

Prospective experimental trial.

Mixed patients, any patient with suspected and ultrasound confirmed ICDVT 35% outpatients.

Lysis of clot, incidence of propagation to proximal veins and pulmonary emboli.

Non- randomised, convenience sample, single centre study, Figures suggest no subjects were lost to follow up over a course of potentially 8 months.

ICDVT can be safely observed in asymptomatic patients, High risk groups of patients (Ortho, Ca, etc.) recommended anticoagulation therapy until resolved or ambulant.

Large randomized control trial needed to identify the best treatment for sub-groups of patients e.g. Orthopaedic patients.

Used descriptive statistics only, probably appropriate given small sample size and mixture of sub-groups involved.

At 1-3 month follow up the patients with propagation of ICDVT were all from a high risk background i.e. CA patients, immobile or post orthopaedic surgery. There is confusion over which patients received therapeutic doses of anticoagulation, who received prophylactic and when this occurred. Difficult to draw any meaningful conclusion from this study beyond the actual sample.

19

De-Martino et al., 2012

N/A Meta-analysis Varied according to included studies.

Assess efficacy and safety of anticoagulation therapy for adult patients with isolated calf vein DVT

Only as strong as the data being analysed, failure of included studies to analyse the full spectrum of treatment benefits and harms makes objective assessment by meta-analysis difficult. Included studies were not designed to answer the meta-analysis question. Lack of relevant studies to perform a full meta-analysis

Found that included studies were mostly of low methodological standard. Issues with the RCT’s of blinding and sequence generation leading to less confidence in the outcomes. Anticoagulation therapy for CDVT significantly reduces proximal propagation. No comment made on anti- coagulation therapy effect on PE, death etc.

Rigorous RCT is necessary to further enhance current practise

P=0.001 for rates of thrombus propagation to the proximal vein, this compares anti-coagulated patient outcome to control patients that received no treatment, however there were significantly more patients in the control group than the treatment group (93 treated 326 not treated) difficult to draw meaningful conclusion.

Acknowledged that the methods of the analysed studies were mostly poor. Pooled studies were not like for like, some dealt with ambulatory patients and one with mixed, difficult to make assumptions based on different sub-groups of patients. Some studies made the diagnosis of CDVT by venography and others by US, is there a potential difference in the sensitivity of these methods that may lead to over/underreporting of the true number of positives? This review used data from research to answer questions that the initial research was not purposefully designed for.

Masuda et al., 2012

N/A Systematic review

Varied according to included studies

Ultrasound observation vs anti-coagulation for CDVT

Lack of evidence to perform a full meta-analysis. Only as strong as the studies being reviewed.

In the absence of solid scientific evidence either option i.e. surveillance or anticoagulation should be sought. Doing nothing should not be an option.

Need for further well designed and adequately powered studies to enlighten further

Descriptive statistics only used.

Studies that are reviewed are not all designed to answer this question.

Schwarz et al., 2010

107 patients Randomized Controlled study

89% outpatients 11% inpatients

Compare efficacy and safety of anticoagulation for CDVT vs compression therapy alone

Small numbers, not representative of cross section of patients, only 11% were from higher risk groups for DVT

Neither method anticoagulation nor compression alone showed as superior, in an acknowledged low risk patient group. High risk patient

Individual treatment depending on findings, for low risk patients US scan 1 week post diagnosis, anticoagulation therapy for patients with proximal

There appears to be reasonable statistical conclusions drawn with no extreme conclusions drawn from

Agreed through pilot and consensus the protocol for examination. Appears to be a quite well thought out study but with some weaknesses that could potentially skew the figures.

20

i.e. hospitalised, active Ca etc. Once randomized patients who had been prescribed prophylactic heparin for other reasons were permitted to continue this treatment. There is no mention of how many of these patients were included in the study

groups cannot be commented on by this study.

progression. In high risk groups immediate anticoagulation therapy for at least 4 weeks.

what is quite a small sample.

May have been better to just examine outpatients or those at low risk of VTE events as it is there is no mention of the prior risk factors in those patients that had a propagation. Could it be more expected in certain types of patient?

Johnson et al., 2010

4731 patients from pooled studies with negative whole leg CUS

Systematic review and meta-analysis

Various according to studies mostly ambulatory with a small amount of inpatients

Assessment of safety of withholding anticoagulation in patients with a single negative CUS by estimating the incidence of VTE in the 3 months following a negative test result

In a mix of studies there is likely to be a difference in compression ultrasound technique. Of limited value for generalizing to populations not well represented within this study e.g. active Ca, pregnant etc. The individual studies had their own exclusion factors for example one chose to exclude patients with high pre-test probability possibly leading

Withholding anticoagulation after a negative whole leg CUS has a low failure rate in patients from a primarily ambulatory background and is associated with low risk for VTE in the following 3 months post negative test result

Further studies into the use of single whole leg CUS for patients with a high pre-test probability are needed.

No obvious statistical issues.

General impression a good piece of work, few flaws. Analysed research not specifically designed to answer the meta analysis question. Strategies implemented in articles to reduce risk of selection bias. Difficult to generalize to a population as most patients came from an ambulatory back-ground. Studies were only traced for follow up for 3 month period

21

to under-reporting of incidence in a true representative cross section of patients.

Sales, 2010 141 patients Retrospective review of medical records

Hospitalised patients

Compared effectiveness of treatment vs non treatment through anti-coagulation of patients with IGSVT through measurement of thrombus progression

Retrospective design, single centre, limited generalizability. Sample were all inpatients and therefore more likely to develop DVT may lead to over reporting of cases There was no standard treatment protocol for the therapy group of patients.

In the absence of thrombus propagation anticoagulation cannot be recommended from the results of this study.

RCT is needed to investigate fully the necessity of anticoagulation treatment for IGSVT patients.

Descriptive statistics performed plus some statistical testing with strong confidence levels in the results.

Lack of standard treatment protocol in the therapy group. Some interesting findings but some study weaknesses. Limitations were stated and conclusions are not overly exaggerated.

Palareti et al., 2010

431 out-patients

Prospective, blinded, 2 centre study

Symptomatic outpatients fulfilling criteria of not having proximal thrombosis on a proximal U/S scan

Investigation of the complications rate of untreated CDVT. Anti-coagulation was withheld from a group of patients with a possible CDVT.

Small numbers and only 2 centres, therefore limited generalizability. All patients were issued with compression stockings which in itself is a form of treatment. This may lead to under-reporting of the true outcome rate. ATV’s were not scanned. Patients were not all

Untreated CDVT has an uneventful clinical course at 3 month follow up, The rate of complications at three was significantly higher in those with CDVT.

Need for clinical studies to identify those symptomatic patients in need of investigation and treatment. Clinical relevance of CDVT should be decided by specifically designed, multicentre, prospective studies with larger samples.

Good example of how small numbers in studies can significantly skew statistical figures, 2 DVT’s discovered due to proximal extension made a difference from P number of 0.003 to P.0.049 when just 2 patients are excluded with dubious findings.

Selection bias possible, Does not state whether all the examining sonographers were following the same protocol for scanning the calf veins, just that they were experienced. Looking at the statistics, feel you can only draw limited conclusions from this work. Larger numbers needed to make it worthwhile and generalizable beyond this group of patients.

22

consecutive patients elements of selection bias cannot be ruled out.

Proves need for a larger sample.

Lautz et al., 2009

406 patients Retrospective review of medical records

Mixed inpatients and outpatients.

Determine incidence of IGSVT and determine the effect of anti-coagulation on VTE events in patients with IGSVT.

Retrospective design. Results may have been skewed by the number of low risk patients examined in one group. May have led to under-reporting of true number of events from this group. Large numbers (296) were lost to follow up and were subsequently excluded from the study.

Therapeutic anti-coagulation significantly decreased the rate of VTE events and increased the rate of IGSVT resolution in this study.

A randomized control trial is needed to evaluate the risk vs benefit of therapeutic anti-coagulation for IGSVT.

Statistical analysis showed a link between therapeutic anticoagulation and IGSVT resolution but numbers in the study were small and different types of anticoagulant were used to treat not a standardised drug or dose.

Retrospective design only dealt with muscular vein thrombosis not all deep calf veins.

Sule et al., 2009

51 patients Retrospective analysis of medical records

Origin not apparently stated

Determine whether treatment for CDVT with anticoagulation vs no treatment affects patient outcome

Very small numbers, retrospective design, single centre therefore only generalizable to this set of patients. No mention of risk group for patients

CDVT may not need treatment with anti-coagulation. However if symptoms worsen or the CDVT extends proximally then anti-coagulation is recommended.

No recommendations

Descriptive only, too small a sample to draw meaningful conclusions

Recommendation suggests follow up surveillance scans at 2 weeks 1 month and 3 months. How feasible is this at most NHS hospitals with finite resources?

Parisi et al., 2009

171 outpatients after exclusions

Appears to be prospective, but the sampling method is

Outpatients only

Assessment of a particular treatment regimen for

Small numbers Only covers a sub-group of the

2.9% of patients had a progression of thrombus to the proximal veins.

No recommendations

Descriptive statistics only.

Uncertainty due to absence of information on methodology is a shame because the

23

unclear. those with CDVT

people who may develop a DVT. Outpatients are probably at a lower risk than immobile inpatients. This could lead to potential under-reporting of the condition. No control group.

Most progressions occurred in patients with unprovoked CDVT. Prolonged treatment may be pertinent in patients with unprovoked CDVT

research appears to have produced a potentially useful set of data. Unclear on the sampling method? Therefore cannot rule out possible sample bias. Some exclusions due to loss at follow up.

Sevestre et al., 2009

3871 reduced to 1254 randomly selected for the follow up study.

Prospective multi centred cohort study

Ambulatory patients with suspected DVT

Determine the safety of withholding anticoagulant therapy from patients with a negative whole leg U/S scan.

Not all patients were followed up. Only looked at ambulatory patients with a negative first scan, Other patient sub-groups e.g. pregnant women or Ca patients may need further investigation. Episodes of fatal PE may be under-reported, no autopsies were carried out.

In ambulatory patients (not including certain sub-groups) anticoagulation therapy can be safely withheld following a single negative whole leg U/S examination.

Further study necessary to assess risk of withholding anticoagulant therapy from higher risk patient sub-groups.

Statistics are easy to understand and flow charts make the data straightforward to take in. They don’t try and draw too much from their figures and remain focussed on the research question.

Ambulatory outpatients probably one of the lower risk groups for DVT complication. Used a standardised examination protocol and the sample is a good size. Shame not all patients were followed up. Issue with follow up in that some were by phone call and not necessarily with the patient, sometimes the DR or a relative of the patient. Use of 255 certified sonographers from across the country could be seen to add generalizability to the research.

Gibson et al., 2009

1002 patients reduced after exclusions to 264 who underwent whole leg

Multi centre Prospective management study with elements of randomisation in patient selection

94% outpatients

Compared the safety and feasibility of two ultrasound examination methods, whole leg US and CUS

Certain patient types were excluded including. pregnant patients, expected low compliance,

Both methods are comparable in safety and efficiency, CUS has the drawback of needing a second scan where whole leg

RCT is needed to assess usefulness of anticoagulant therapy for symptomatic CDVT

Used appropriate testing. Statistical conclusions enforce findings with confidence.

Research acknowledges some small flaws in design but multi centred, multi country involvement, randomised patient samples, the methodological approach appears sound and is

24

US and 257 who underwent rapid proximal vein only US

ongoing anticoagulants therefore only generalizable to certain patient groups and mainly refers to outpatients Open design modest sample sizes

may lead to potential over-treatment

probably reasonably generalizable to a wider group of outpatients.

Bernardi et al., 2008

2098 Randomized controlled trial,

Outpatients from an ED or Primary care referral pathway

Comparison of whole leg US vs Proximal leg veins only plus D-dimer testing, decide if methods are comparable for management of symptomatic outpatients with suspected DVT

No significant obvious weaknesses, Excluded certain groups from the study, pregnant, previous VTE, suspected PE.

No difference in outcome reported, similar findings in both trial groups. Both methods are safe

Applied method of investigation is dependent on resources available, RCT is needed to decide whether the quest for finding distal DVT is leading to unnecessary and potentially harmful treatment for some patients

Mainly descriptive in style.

The largest trial of the reviewed research. Found the initial difference between the numbers of DVT found in each group could be accounted for by CDVT. It is likely that without calf vein scan these DVT would not have been found and not treated, what can’t be determined is how many actual DVT there were in the proximal only scan group that may have had a distal CDVT and therefore the significance of that CDVT.

25

Appendix C.

A general overview of significance by author.

Author Should

CDVT be

identified?

Is CDVT significant enough to

treat?

Kret et al. Yes Yes

Pengas et al. Yes Observe and treat if propagation

occurs.

Singh et al. Yes Yes, in high risk groups. Observe

in asymptomatic patients.

De-Martino et al. Yes Yes

Masuda et al. Yes Observation and treatment are

equally effective. High risk

patients may need

anticoagulation.

Schwarz et al. Yes Depends on the patient risk

group.

Johnson et al. Yes No comment made.

Sales et al. Yes Not routinely, risk dependent.

Palareti et al. Uncertain Not routinely.

Lautz et al. Yes Yes

Sule et al. Yes Observe, treat if propagation

occurs.

Parisi et al. Yes Observation and selective

treatment in higher risk groups.

Sevestre et al. Yes Identified CDVT was treated in

this study.

Gibson et al. Uncertain Uncertain

Bernardi et al. Uncertain Uncertain