forum

IdentIfyIng the Source

of SuperfIcIal reflux In venouS

leg ulcerS uSIng duplex ultraSound

page 6

factorS predIctIng development of

poSt-thrombotIc Syndrome

In patIentS wIth a fIrSt epISode of deep

veIn thromboSIS: prelImInary report

page 12

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From the Editor-in-Chief

dr. nick morrison 5

Outpatient versus inpatient treatment for patients with acute pulmonary embolism: an international, open-label, randomised, non-inferiority trial

contributing editor/reviewer: patrick h. carpentier, md

associate editor: Sukirtharan Sinnathamby, md, facc, fScaI, rvt 19

Identifying the Source of Superficial Reflux in venous leg ulcers using duplex ultrasound

contributing editor/reviewer: Joseph Zugmunt, rvt, rphS

associate editor: eric mowatt-larssen, md 6

Long-term outcome after additional catheter-directed thrombolysis versus standard treatment for acute iliofemoral deep vein thrombosis (the CaVenT study): a randomised controlled trial

contributing editor/reviewer: James laredo, md, phd

associate editor: mark forrestal, md, facph 22

Factors Predicting Development of Post-Thrombotic Syndrome in Patients with a First Episode of Deep Vein Thrombosis: Preliminary Report

contributing editor/reviewer: Stephen f. daugherty, md

associate editor: ted King, md, faafp, facph 12

Patients with Multiple Sclerosis with Structural Venous Abnormalities on MR Imaging Exhibit an Abnormal Flow Distribution of the Internal Jugular Veins

contributing editor/reviewer: fausto passariello, md

associate editor: neil Khilnani, md, facph 15

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4

disclosureof interests

Name Role Disclosure

Stephanie dentoni, md recruitment & retention cmte (c), leadership development

nothing to disclose

mark forrestal, md, facph acp cooltouch: Stockholder

mitchel p. goldman, md, facph merz: grant/research Support, consultant, Speakers’ bureau; bioniche: consultant; Std pharmaceudicals: consultant; btg: grant/research Support, consultant; new Star lasers: Stock and/or Shareholder; lumens: consultant, Stock and/or Shareholder

Jean-Jerome guex, md, facph acp bod, communications Standing committee (c), International affairs (c), leadership development Standing committee, uIp 2013 task force, ama hod task force

Innotech International- Investigator; pierre fabre: consultant; Sigvaris: Investigator; vascular Insights, llc: Scientific advisory board; Servier-eutherapie: Speaker

lowell Kabnick, md, facS, facph

acp bod, education Standing committee (c), uIp 2013 task force, exhibitor advisory (c), phlebology forum, program development, leadership development

angiodynamics: consultant, Scientific advisory, Stockholder; merz: Speaker; vascular Insights llc: consultant, Scientific advisory

neil Khilnani, md, facph acp Sapheon: consultant

ted King, md, faafp, facph acpf bod angiodynamics: Investigator; btg: Investigator; merz: Speaker, consultant

mark meissner, md acp nothing to disclose

eric mowatt-larssen, md cme committee btg: consultant

nick morrison, md, facS, facph acp btg: principal Site Investigator; venx: Scientific advisory board; medi: Speakers bureau

diana neuhardt, rvt, rphS acp bod, member Services Standing committee, education Standing committee, public education (c), recruitment & retention, uIp 2013 task force, cme committee, distance learning, leadership development

nothing to disclose

pauline raymond-martimbeau, md, facph

uIp 2013 task force nothing to disclose

5

From the

Editor-in-Chief

Dear Readers,

In this issue of Phlebology Forum you will see we have concentrated on

patients at the more severe end of the venous disorder spectrum with deep

venous thrombosis and cutaneous ulcerations. these articles are really critical

for understanding where treatment of such patients is heading, regardless of

whether one treats such patients directly and we are pleased to have such expert

reviewers within the acp.

If you have not been aware of the apparent multiple Sclerosis/chronic

cerebrospinal venous Insufficiency connection, this controversy continues to

rage and more good scientific data is emerging such as the article from one of

the strongest investigators in the u.S.

again the editors welcome suggestions for future Phlebology Forum topics.

Nick Morrison, MD

Editor-in-Chief

Phlebology Forum

6

Identifying the Source of Superficial Reflux in venous leg ulcers using duplex ultrasoundAuthors: Alfred Obermayer MD, and Katarina Garzon MSc

Published: J Vasc Surg 2010;52:1255-61

Contributing Editor/Reviewer: Joseph Zygmunt, RVT, RPhS

Associate Editor: Eric Mowatt-Larssen, MD

7

our austrian colleagues have produced an outstanding paper that not only provides technique description and

tips, but that also provides prevalence information on crossover reflux patterns in ulcer patients. as the authors

noted, “abolition of superficial refluxes has been shown to achieve beneficial effects on ulcer healing even in

the presence of concomitant deep venous refluxes and can be offered on a general basis.” the purpose of the

study was to “identify the exact reflux routes associated with medially or laterally located venous leg ulcers,”

through the use of detailed duplex ultrasound techniques. the authors premise is that “the triggering venous

pressure is transmitted along the reflux route (blood column) into the microcirculation”, and sought to “show the

source of local superficial hypertension, straining the skin, and the frequency of atypical reflux routes, linking this

knowledge to differential diagnosis and therapy planning.”

from a technical perspective, the method of duplex scanning and sourcing reflux is very well described, and the

level of specificity in this description is extremely valuable. highlights of their technique for standard venous

duplex investigations include the following:

1. Scanning the patient in the standing position

2. use of linear array 10-5mhz ultrasound probe, and use of 5-2mhz prove for deep veins in obese patients

3. doppler range was set for 9cm/sec and wall filters at their lowest settings

4. doppler gain increased for maximum sensitivity

5. manual distal compression and release to elicit reflux

6. reflux was defined as flow reversal for 0.5 (superficial veins) or 1.0 (deep veins) seconds

7. perforator reflux defined as bidirectional flow – based on pressure gradients and not vein size

the authors describe proximal evaluation of the common femoral vein (cfv) area through assessment of flow

velocity comparisons to the contra lateral signals. this emphasizes the importance of understanding proximal

obstruction because in most instances venous duplex examinations for cvd or cvI are primarily infra-inguinal. but

when flow changes are noted between the contra lateral cfv signals, there should be a high degree of suspicion

of proximal obstruction; however a negative finding for contra lateral comparison does not exclude proximal

obstruction or stenosis. a recent case report from the Journal of vascular ultrasound supports this, stating

“findings on duplex ultrasound associated with pelvic venous obstruction are subtle, making obstruction more

difficult to detect.1

1 Sandford et al, Importance of phasicity in detection of proximal Iliac vein thrombosis with venous duplex examination, Jour vasc ultrasound, 2011; 35(3):150-152

8

SourcIng technIque:

the ‘sourcing” technique is complementary to what is described above. this sourcing “is a simple method,

performed with duplex ultrasound, to follow the routes of venous insufficiency from the area of ulceration or skin

changes precisely up to their “source” and to determine the venous reflux routes penetrating in to the ulcer area.”

the specifics of this method which area additional to the typical duplex exam for cvd are noted below:

1. the exam is performed distal to proximal – following the reflux column from ulcer to source

2. as opposed to manual or cuff compressions, the ultrasound probe (scan head) has a sterile cover, and is

used to apply “compression and decompression of the ulcer with the scan head or of the lower leg at

locations proximal and distal to the ulcer.”

3. the area around the ulcer bed is investigated, and with compression and release bidirectional flow is

observed as a “swinging blood column” in all veins related to the ulcer.

4. tracing the “swinging blood column” allows identification of the source, that is, the responsible insufficient

vein. according to the authors, this can be done to the groin or knee or for incompetent perforators

as well. further this swinging blood column is not found in competent veins, or in other non-related

insufficient veins.

the authors provide valuable information on tips, tricks and difficulties which include:

1. avoidance of muscle pump activation during the process

2. Specifics of hand placement for manual compression techniques

3. Sourcing can be performed in the sitting position for those patients in which standing is prohibitive

reflux routeS

one of the key contributions of this work is the discussion of “axial vs. crossover” reflux patterns. axial reflux in a

classic pattern exists when gSv reflux leads to a medial ankle region ulcer, or SSv to the lateral ankle. crossover

patterns are those with “extraterritorial” ulcer locations. the authors state “the longer distance was chosen as the

main route, because the length of insufficient vein has essential influence on venous hypertension” further they

make reference to the general poor care that smaller ulcerations typically receive and that “often, the ulcer may

grow or new ulcers may develop as a result of wrong treatment.”

9

Key findings in their data of venous ulcer patients were the

following;

» the study included 169 patients with venous

ulceration (ceap class 6).

» using their algorithm (limited to spectral cfv

respiratory analysis), they found no signs of proximal

obstruction in this patient population. caution

should be noted regarding the sensitivity of this

approach, since suprainguinal duplex investigation

has limitations (see comment below related to iliac

obstruction in the patient population.)

» of 183 limbs – 79% showed axial reflux, while 21%

showed a crossover pattern

» If the ulcer was lateral, a crossover pattern was

present in 46% of patients (i.e. gSv source).

» however only 11% of the time was a medial ulcer the result of a SSv reflux route

» a positive sourcing sign (swinging blood column) is evidence of a venous origin in cases of mixed (arterial

and venous) ulceration

» twenty percent of limbs in these c 6 patients had no visible varicose veins

» extremely obese patient with signs, symptoms and ulceration, sometimes had no reflux on duplex

examination. comment: this second issue may be related to the need for a more sensitive method to

evaluate proximal obstruction in the iliac system, which as noted in the uIp consensus document iliac vein

obstruction in the general population is far more common than was previously suspected, and in at least

one group has found symptomatic patients (c3-6) patients such lesions are present in >90% of patients

when examined with IvuS2. this may also be due to “pseudo-obstruction” from the pannus, especially in

patients such as these who may be largely sedentary3.

the authors point out that “sometimes, the diameter of refluxing superficial veins may be quite small; however,

long refluxes may nourish massive ulcers”. one would assume that a long reflux would refer to distance. Similarly,

labropolous has found “when the refluxing vein is small and the capacitor is large, velocity is low and rf duration

is long.”4 one needs to also understand the significance of the network of veins that surround most venous stasis

2 lurie, et al, Invasive treatment of deep venous disease: a uIp consensus, Int angiol 2010;29:199-204.

3 willenberg, t et al, the Influence of abdominal pressure on lower extremity venous pressure and hemodynamics: a human In-vivo model Simulating the effect of abdominal obesity, eur J vasc endovasc Surg (2011) 41, 849-855.

4 labropolous et al, definition of reflux in lower extremity veins, J vasc Surg 2003;38:793-8

...superficial reflux is more frequent in ulceration than previously believed...

10

ulcers that significantly influence “local” venous hypertension, and represent a “large capacitor” at the bottom

of the hydrostatic column. more significantly, this also supports that vein diameter alone is not diagnostic of the

presence of reflux or the severity of disease.

the authors note that superficial reflux is more frequent in ulceration than previously believed, and further that

despite worsening severity with multiple (superficial deep and perforating) system involvement, surgical therapy of

superficial venous insufficiency, regardless of deep incompetence, leads to good long term results in healing and

recurrence.

In summary, this is an outstanding paper, with valuable contributions to the field. the authors point out that

“sourcing” has an essential influence on therapy planning for the ulcerated patient, because abolition of local

venous hypertension is the primary goal. further they indicate the need for these techniques to be used to

prevent venous ulceration at first signs of skin changes in patients at risk (c4). crossover routes of reflux are

vital to understand in that one of every five patients will have a crossover pattern which may lead to inaccurate

treatment and early recurrence.

the other key contribution of this paper is the importance of understanding reflux along the entire length of an

investigated vein. Incomplete ultrasound studies in which reflux is documented at only one level display either a

lack of commitment to the diagnostic process, or outright deliberate attempt to obfuscate the extent of reflux in

order to achieve insurance justification for unnecessary procedures. although the above is a tangential comment

to this paper, this work demonstrates the importance of understanding the full extent of reflux for differential

diagnosis and therapy planning.

The 2012 Program Committee of the American College of Phlebology invites you to submit an abstract for consideration at the 26th Annual Congress on any of the following topics:

DEADLINE FOR SUBMISSIONS IS FRIDAY, JUNE 29, 2012

Abstracts must be submitted online and are limited to 250 words. For additional details or to submit an oral or poster abstract for presentation at the 26th Annual Congress, please visit www.acpcongress.org/Speaker-Resources/Abstract-Submission

510.346.6800 • www.acpcongress.org • www.phlebology.org

• Basic Science• Venous Thrombosis• Superficial Venous Disease• Deep Venous Disease• Chronic Venous Insufficiency

• Compression• Epidemiology and Outcomes in Venous Disease• Ultrasound & Other Diagnostic Studies in Venous Disease• Miscellaneous Venous Topics

advancing vein care

We welcome a new wave of knowledge.

CALL FOR ABSTRACTS

12

Factors Predicting Development of Post-Thrombotic Syndrome in Patients with a First Episode of Deep Vein Thrombosis: Preliminary ReportT. Yamaki, A. Hamahata, K.Soejima, T. Kono, M. Nozaki, H. Sakurai

Eur J Vasc Endovasc Surg 2011; 41: 126-133

Contributing Editor/Reviewer: Stephen F. Daugherty, MD

Associate Editor: Ted King, MD, FAAFP, FACPh

13

ABSTRACT

this prospective study of 154 consecutive Japanese patients presenting with a first episode of acute symptomatic

unilateral lower extremity dvt was designed to evaluate factors predicting the development of post-thrombotic

syndrome (ptS). thirty patients were excluded for potentially-confounding variables such as recurrent dvt,

arterial insufficiency, muscle atrophy or weakness, and other causes of limb swelling such as lymphedema.

twenty-one percent of the 121 patients followed developed ptS with a mean follow-up period of 66 months. at

initial presentation, iliofemoral dvt was the single variable closely associated with the development of ptS with

an odds ratio of 3.4 and confidence interval of 95%. at 6 months after presentation, the factors most closely

associated with development of ptS were the presence of venous occlusion and popliteal vein reflux, an elevated

peak reflux velocity in the popliteal vein, and calf muscle pump dysfunction as measured by near-infrared

spectroscopy venous retention index (nIrS rI).

COMMENTARY

this well-designed study is an important contribution to the increasing body of evidence that iliofemoral venous

thrombosis and continuing venous obstruction are critical factors in the development of post-thrombotic

complications. recurrent dvt and obesity have been associated with development of ptS in the past. In this

study, 13 of 25 patients who developed ptS presented with iliofemoral dvt which was the only one of twenty-four

characteristics/risk factors studied which was predictive of the development of ptS. conversely, the presence of

dvt limited to the calf veins at initial presentation as a negative predictor for ptS.

this study may underestimate the incidence of iliac vein dvt since the iliac vein segment studied was limited

to the external iliac vein. yamaki comments that the common and internal iliac vein cannot be visualized by

ultrasound. In our experience with color duplex ultrasound, we find thrombus or post-thrombotic changes in

the common iliac vein associated with an arterial compression of the common iliac vein more often than we find

thrombus in the external iliac vein, especially in patients with a previous history of lower extremity dvt.

the morbidity of ptS is substantial, ranging from discomfort to more serious problems such as edema or skin

changes progressing to recurrent cellulitis or venous leg ulcers. comerota, et al.1, have shown that with treatment

of acute iliofemoral dvt using catheter-directed techniques of thrombus removal, there is a direct correlation of

post-phlebitic morbity with the degree of residual thrombus. thus, thrombolysis of acute iliofemoral thrombus

would appear to be the most important therapy in appropriately-selected patients to prevent ptS and its

sequelae.

the finding at 6 months that residual venous obstruction with popliteal vein reflux is a predictor of future

development of ptS would suggest that treatment of major residual venous outflow obstruction might be

1 comerota, a., et al., postthrombotic morbidity correlates with residual thrombus following catheter-directed thrombolysis for iliofemoral deep vein thrombosis. J vasc Surg 2012;55:768-73.

14

of value. neglen, et al.2, have demonstrated

considerable relief of symptoms of ptS and a

reduction in the recurrence rates for venous leg

ulcers with balloon angioplasty and stenting of

occluded or stenotic iliofemoral veins.

many patients who present with acute iliofemoral

dvt are not treated with catheter-directed

thrombolysis for a variety of reasons. when such

patients do present to vein specialists, the window

of opportunity for catheter-directed thrombolysis

may have lapsed. yamaki, et al, have provided

additional evidence to support the concept of

close patient follow up for early evidence of ptS in

patients with residual venous outflow obstruction

and consideration of balloon angioplasty and

stenting of obstructed iliac vein lesions before ptS

progresses to cause further morbidity.

yamaki, et al, found that a peak reflux velocity in the popliteal vein of >30 cm/sec at 6 months is predictive of

future development of ptS. this might be useful information to the clinician to help convince the patient to

continue long-term use of support hose and to lose weight, if obese, in order to improve lower extremity venous

outflow. yamaki, et al, report a technique using near-infrared spectroscopy (nIrS) to measure calf venous

retention index, thought to reflect increased calf muscle deoxygenation during exercise. at 6 months after

presentation, a nIrS-derived retention index (nIrS rI) >3.5 is highly predictive of deterioration of ptS. nIrS rI

may not be widely available, but it may be useful in assessing changes in calf muscle pump function with treatment

such as balloon angioplasty and stenting for post-thrombotic residual obstructive iliofemoral vein lesions.

the study sample size may not have been large enough to discriminate other variables which might predict

development of ptS and other variables may be factors in a less homogenous population such as in north

america. nonetheless, the identification of iliofemoral thrombosis at initial presentation and residual obstruction

and popliteal vein reflux at 6 months as important predictors of ptS is important information.

2 neglen p, hollis J, olivier J, raju , Stenting of the venous outflow in chronic venous disease: long-term stent-related outcome, clinical and hemodynamic result. J vasc Surg 2007; 46:979-90

The morbidity of PTS is substantial, ranging from discomfort to more serious problems...

15

Patients with Multiple Sclerosis with Structural Venous Abnormalities on MR Imaging Exhibit an Abnormal Flow Distribution of the Internal Jugular VeinsE. Mark Haacke, PhD, Wei Feng, PhD, David Utriainen, BS, Gabriela Trifan, MD, Zhen Wu, MD,

Zahid Latif, RT, Yashwanth Katkuri, MS, Joseph Hewett, MD, and David Hubbard, MD

J Vasc Interv Radiol 2012; 23:60-68

Contributing Editor/Reviewer: Fausto Passariello, MD

Associate Editor: Neil Khilnani, MD, FACPh

16

ABSTRACT

aim to show that extracranial venous anomalies exhibit abnormal flow patterns in patients with multiple Sclerosis (mS).

METHODS

200 patients from 2 sites (100 each) were examines with magnetic resonance (mr), using a specially designed

protocol for the detection of chronic cerebro-Spinal venous Insufficiency (ccSvI), to evaluate both anatomy and

function of venous cerebral outflow. according to the detected venous anomalies, patients were divided into

stenotic/nonstenotic groups, stenoses being localised at the upper (c2/c3) or lower level (c5/c6-t1/t2) with a

threshold cross sectional area of 25 and 12.5 mm2 respectively.

flow rates were normalised to the total arterial flow. the ratio fsd/fd of the subdominant venous flow rate (fsd) to

the dominant flow rate (fd) was computed, being fd and fsd the two veins of the highest flow.

the arterial/venous flow mismatch (avm) was computed, as the amount of outflow through small or collateral veins.

examinations were performed with 3 different processors. a 3-ways anova was set to test the inter/intraprocessor

variability.

RESULTS

patients from the stenotic group showed lower total internal jugular vein normalized flow and a lower fsd/fd ratio,

while the avm was significantly greater. neither the inter-processor nor the intra-processor variability was significant.

CONCLUSIONS

combining anatomical and functional measures, mr shows that most mS patients with anomalies in the internal

jugular veins also exhibit low total internal jugular flow rates.

COMMENTARY

the article from m. haak et al. is interesting because it provides new objective data in the diagnosis of chronic

cerebro-Spinal venous Insufficiency (ccSvI) in multiple Sclerosis (mS).

the use of a protocol for magnetic resonance (mr) allows better identification of structural and functional

abnormalities of the extra-cranial venous vessels.

the mr protocol can visualize in great detail the extra-jugular compensating pathways and the anastomoses with the

vertebral venous plexus in correspondence with the position of the anatomical jugular anomalies.

the mr flow is normalized to the total arterial and venous flow and the use of this quantitative method certainly will

17

be a further stimulus to research work on a more rigorous basis.

the arterial-venous flow mismatch, computed as the flow difference between the arteries and the main veins of the

extra-cranial district in the neck, is an index of the percentage of the cerebral venous outflow which is transported

through small veins and generally through compensating pathways.

Interesting is the analysis of flow in the two main veins in the neck, the dominant (fd) and the subdominant (fsd), and

of the relationships

» fsd <= 3ml;

» fsd + fd <= 8 ml

» fsd <= 1/3 fd.

which in all the mS patients identified some regions in the chart fsd/fd comprising 67% of patients in the stenotic

group. outside of these regions instead 70% of subjects were found in the nonstenotic group.

this article uses an anatomical terminology for the internal jugular vein (IJv), explored at the higher vertebral levels

(c2/c3) and lower (c5/c6 and t1/t2), while other papers use the terms J3 for higher IJv, J2 for the middle IJv, J1 for

the lower IJv. a future use of unique and unambiguous anatomical terms is desirable to allow a better understanding

of the topic.

currently, the article sets a new method for mr reclassification of the mS population, suggesting the use of an mr

protocol in place of the ultrasound (uS) protocol.

however, the article is not able to give answers to very frequent questions about the relationship between mS and

ccSvI. In fact the use of anatomical and functional evaluation by mr simply shifts the problem to the relationship

between mS and mr functional findings.

at least for mS, the usefulness of measuring the flow value is not clear. the authors report the flow as a risk factor

in craniotomy, premature infants, transient global amnesia and optic neuritis. currently, however, we have no

information about mS patients.

the analyzed sample is composed only of mS patients, while as acknowledged by the authors normal subjects are

completely missing. they instead would have allowed the objective quantification of the prevalence of anatomical

and functional alterations. moreover, although the type of mS was available in 2/3 of the cases (primary progressive

mS, secondary progressive mS, relapsing/remitting mS), no correlation study with the anatomical and flow anomalies

was performed.

as to the use of the mr protocol as a substitute for the uS protocol in the diagnosis of ccSvI, the uS protocol is

center/operator-dependent, i.e. it requires a learning period of the operator and provides in general conflicting data,

18

also depending on the center where the examinations are performed.

In comparison, the mr protocol is precise and not operator dependent. measurements performed in two centers, and

on multiple processors show how it is independent of these factors and the presence of the reliability requirements

of the procedure. however, the uS protocol, though much criticized for its variability, has elements of doubtless

value. despite being rich in functional findings, the mr protocol is totally missing the analysis of postural changes,

which instead are typically functional data.

the possibility of performing repeated measurements on patients in several postures (supine, sitting, standing), during

the valsalva, during respiratory phases or breathing mixtures of o2/co2 fully supports uS examination, which is able

to collect detailed information on the behavior of the system under different solicitations.

response to valsalva and measurements during respiratory phases are essential to search for reflux in the intracranial

vessels (venous tcd is one of the 5 criteria of the uS). the postural responses instead allow one to suspect

obstructions at the level of the azygos system, although the system cannot be explored with uS.

moreover, the uS protocol has other points in its favor, such as its easy repeatability and it is definitely less expensive

in terms of organization and economy. an uS examination can be executed at anytime, the equipment required is low

cost and easily available even in centers which are not super-equipped. with uS, there is no use of electromagnetic

radiation and therefore no special organization requirement of the center.

finally, regarding the usefulness of the research, the questions arise whether the mr protocol is easily applicable

and in large-scale in all centers with all the necessary equipment and what are the costs. are they sustainable only in

research work or also in a super-specialized clinical activity? the authors don’t say anything about these questions,

perhaps because the procedure is still at an early stage of study.

In conclusion, the article of m. haak et al. is of doubtless interest for the research work into ccSvI in mS. further

studies or perhaps simple refinements could also provide a procedure for easy clinical use. 1

1 Zamboni p, morovic S, menegatti e, viselner g, nicolaides an: Screening for chronic cerebrospinal venous insufficiency (ccSvI) using ultrasound – recommendations for a protocol. Int angiol. 2011 dec;30(6):571-97.

2. Zamboni p, menegatti e, bartolomei I, galeotti r, malagoni am, tacconi g, Salvi f.: Intracranial venous haemodynamics in multiple sclerosis. curr neurovasc res. 2007 nov;4(4):252-8.

3. Zamboni p, menegatti e, galeotti r, malagoni am, tacconi g, dall’ara S, bartolomei I, Salvi f.: the value of cerebral doppler venous haemodynamics in the assessment of multiple sclerosis. J neurol Sci. 2009 Jul 15;282(1-2):21-7. epub 2009 Jan 13.

4. gorucu y, albayram S, balci b, hasiloglu ZI, yenigul K, yargic f, Keser Z, Kantarci f, Kiris a.: cerebrospinal fluid flow dynamics in patients with multiple sclerosis: a phase contrast magnetic resonance study. funct neurol. 2011 oct-dec;26(4):215-22.

5. Zamboni p, menegatti e, weinstock-guttman b, Schirda c, cox Jl, malagoni am, hojnacki d, Kennedy c, carl e, dwyer mg,bergsland n, galeotti r, hussein S, bartolomei I, Salvi f, ramanathan m, Zivadinov r.: cSf dynamics and brain volume in multiple sclerosis are associated with extracranial venous flow anomalies: a pilot study. Int angiol. 2010 apr;29(2):140-8.

19

Outpatient versus inpatient treatment for patients with acute pulmonary embolism: an international, open-label, randomised, non-inferiority trial.Drahomir Aujesky, Pierre-Marie Roy, Franck Verschuren, Marc Righini, Joseph Osterwalder,

Michael Egloff , Bertrand Renaud, Peter Verhamme, Roslyn A Stone, Catherine Legall, Olivier

Sanchez, Nathan A Pugh, Alfred N’gako, Jacques Cornuz, Olivier Hugli, Hans-Jürg Beer,

Arnaud Perrier, Michael J Fine, Donald M Yealy

Lancet 2011; 378: 41–48

Contributing Editor/Reviewer: Patrick H. Carpentier, MD

Associate Editor: Sukirtharan Sinnathamby, MD, FACC, FSCAI, RVT

20

abStract

treatment of pulmonary embolism is presently inpatient based in most cases. this international multicenter

randomized trial assesses the non-inferiority of outpatient care compared with inpatient care regarding efficiency

and safety.

patients with acute, symptomatic pulmonary embolism and a low risk of death (pulmonary embolism severity

index risk classes I or II) were randomly assigned to initial outpatient (i.e. discharged from hospital ≤24 h after

randomization) or inpatient treatment with subcutaneous enoxaparin (≥5 days) followed by oral anticoagulation

(≥90 days). the primary outcome was symptomatic, recurrent venous thrombo-embolism within 90 days; safety

outcomes included major bleeding within 14 or 90 days and mortality within 90 days. a non-inferiority margin of

4% was chosen for a difference between inpatient and outpatient groups.

between february, 2007, and June, 2010, 344 eligible patients were enrolled. one (0.6%) of 171 outpatients

developed recurrent venous thromboembolism within 90 days compared with none of 168 inpatients (95% upper

confidence limit [ucl] 2.7%; p=0.011). only one (0.6%) patient in each treatment group died within 90 days (95%

ucl 2.1%; p=0.005), and two (1.2%) of 171 outpatients and no inpatients had major bleeding within 14 days (95% ucl

3.6%; p=0.031). by 90 days, three (1.8%) outpatients but no inpatients had developed major bleeding (95% ucl 4.5%;

p=0.086). mean length of stay was 0.5 days (Sd 1.0) for outpatients and 3.9 days (Sd 3.1) for inpatients.

the authors’ conclusion is that in selected low-risk patients with pulmonary embolism, outpatient care can safely

and effectively be used in place of inpatient care.

commentary

the appearance of low molecular weight heparin in the 1990s, made it technically possible to treat patients with

venous thromboembolic disease (vted) as outpatients. this is currently the case for most patients with deep vein

thrombosis1, but not yet for those with mild pulmonary embolism, even if the treatment of both conditions is

similar, and if a subset of pulmonary embolism with good prognosis can be defined from the use of the recently

validated pulmonary embolism severity index2. the question addressed by this study appears therefore clinically

highly relevant.

taking a closer look to the events observed during the 90 days follow-up in the compared groups may seem to

show meaningful differences, since five major events occurred in the group of outpatients (one thromboembolic

recurrence, three major bleedings and one death) versus only one (one death) in the inpatients group (both

deaths being unrelated to the vted). however, the difference is below the non-inferiority margin of 4% for every

1 dolovich lr, ginsberg JS, douketis Jd, holbrook am, cheah g. a meta-analysis comparing low-molecular-weight heparins with unfractionated heparin in the treatment of venous thromboembolism: examining some unanswered questions regarding location of treatment, product type, and dosing frequency. arch Intern med 2000; 160: 181–8

2 aujesky d, obrosky dS, Stone ra, auble te, perrier a, cornuz J, roy pm, fine mJ. derivation and validation of a prognostic model for pulmonary embolism. am J respir crit care med 2005; 172: 1041–6

21

criterion, but for the major bleeds for which it was very

close. by contrast, the benefit regarding the saving of

medical resources was substantial in the outpatient group,

since both groups demonstrated similar rates of hospital

readmissions (11-14%) in spite of the important difference in

the initial length of stay.

the conclusions of the authors are supported by an

adequate methodology: (1) the randomization results

in quite comparable treatment groups; (2) few patients

(6.5%) switched from each groups; (3) although it was

by construction an open-label study, the outcomes

were confirmed by an expert committee unaware of the

treatment allocation assessed blindly. the interpretation

is also straightforward, but for the possibility of a small

increase in bleeding risk, which appears to be of the same

magnitude as what was found in outpatients treated with

low molecular weight heparin for deep vein thrombosis1.

It is of importance to note that these results only apply to

the mild cases of pulmonary embolism, i.e. those classified

as classes I-II according to the pulmonary embolism severity

index (peSI), which represent approximately one half of the

patients assessed for eligibility in this study. In addition,

they where obtained in patients volunteering for a clinical

trial, in the setting of highly specialized centers providing a top quality standard of care including therapeutic

education of the patients. the generalizability of these results remains to be confirmed in real life, through surveys

of similar patients diagnosed with mild pulmonary embolism as categorized with the peSI or its simplified version3

and treated as outpatients in the setting of community hospitals.

3 Jimenez d, aujesky d, moores l, gomez v, lobo Jl, uresandi f, otero r, monreal m, muriel a, yusen rd. Simplification of the pulmonary embolism severity index for prognostication in patients with acute symptomatic pulmonary embolism. arch Intern med 2010; 170: 1383–9

...since both groups demonstrated similar rates of hospital readmissions (11-14%) in spite of the important difference in the initial length of stay.

Long-term outcome after additional catheter-directed thrombolysis versus standard treatment for acute iliofemoral deep vein thrombosisEnden T, Haig Y, Kløw NE, Slagsvold CE, Sandvik L, Ghanima W, Hafsahl G, Holme PA, Holmen

LO, Njaastad AM, Sandbæk G, Sandset PM; CaVenT Study Group.

Lancet. 2012 Jan 7;379(9810):31-8.

Contributing Editor/Reviewer: James Laredo, MD, PhD

Associate Editor: Mark Forrestal, MD, FACPh

22

23

this paper by enden and colleagues, reports the results of the cavent study where the benefit of catheter

directed thrombolysis (cdt) was demonstrated in patients with acute lower extremity deep vein thrombosis (dvt).

this multicenter study from norway recruited patients with acute iliofemoral dvt and prospectively randomized

them to receive either cdt combined with anticoagulation, or anticoagulation alone for treatment. the primary

endpoints evaluated were frequency of post thrombotic syndrome (ptS) at two years and iliofemoral vein patency

after six months.

Inclusion criteria included age 18-75 years, onset of symptoms within the past 21 days, and dvt involving the

upper half of the thigh, common iliac vein, or the iliofemoral segment. patients with phlegmasia cerulea dolens

were excluded from the study as well as patients with a history of previous dvt of the ipsilateral limb, malignancy

requiring chemotherapy, and contraindication to thrombolysis.

cdt was performed using a multiple side hole infusion catheter via a popliteal vein approach. alteplase was

infused at a rate of 0.01 mg/kg per hour for a maximum of 96 hours. thrombolytic therapy was assessed daily by

venography and angioplasty of the involved vein and placement of a stent was performed at the discretion of the

operator to establish flow and to obtain < 50% residual stenosis. frequency of ptS was assessed by villalta score at

six and 24 months and iliofemoral vein patency was determined by ultrasonography.

the investigators randomized 209 patients (101 cdt, 108 control) and follow up data was obtained in 189 patients

(90%; 90 cdt, 99 control). at six months follow up, the frequency of ptS was similar in both groups (27 of 90 cdt

patients, 30.3% vs. 32 of 99 control patients, 32.2%, p=0.77) and iliofemoral vein patency was higher in the cdt

group compared to control (58 of 90 cdt patients,

65.9% vs. 45 of 99 control patients, 47.4%, p=0.012).

at 24 months, the frequency of ptS was lower in

the cdt group (37 of 90 cdt patients, 41.1% vs. 55 of

99 control patients, 55.6%, p=0.047). the absolute

risk reduction of ptS at 24 months in the cdt group

compared to the control group was 14.4%.

bleeding complications were confined to the cdt

group (20 patients, 22%) where three were classified

as major and five as clinically relevant. there were

no deaths, pulmonary emboli, or intracranial bleeds

in either the cdt or control group.

endovascular thrombolysis techniques have been

used in the treatment of lower extremity dvt over

the last two decades. these techniques such as cdt

and pharmacomechanical thrombectomy, have only

The absolute risk reduction of PTS at 24 months in the CDT group compared to the control group was 14.4%.

24

recently begun stringent clinical evaluation in prospective, multicenter, randomized controlled trials to determine

whether these techniques improve patient outcomes1-4.

the cavent trial is a landmark study being the first prospective randomized trial to evaluate the clinical efficacy

of cdt in patients with lower extremity dvt. the investigators should be commended for demonstrating the

efficacy of cdt in the treatment of acute lower extremity dvt and prevention of ptS in this well designed and

executed multicenter trial.

the incidence of ptS in the cdt group was higher than previously reported in other studies 1,4. the investigators

attributed this finding to the high proximal dvt in the patients enrolled where proximal thrombus extension is

associated with worse villalta scores and higher risk of developing ptS. procedural technique likely contributed to

the higher incidence of ptS in the cdt group. the cdt treatment did not include the use of pharmacomechanical

thrombectomy (pmt) devices or significant use of venous stents, which is different from contemporary practice

in the united States1-4. venoplasty was only performed in 23 cdt patients and stenting in only a small fraction of

patients (15 patients, 16.6%). pmt with the possis angiojet combined with vena cava filter placement was used in

only one patient with thrombus extension up to the renal veins.

regardless of these minor limitations, the results of the cavent trial provide direct clinical data in support of the

recommendation of cdt as first line treatment of patients with acute iliofemoral dvt to prevent ptS in selected

patients at low risk of bleeding complications1-5. other recommended indications for endovascular thrombolysis

in the treatment of dvt include phlegmasia cerulea dolens and iliofemoral dvt with rapid thrombus extension

despite anticoagulation1,4,5.

1 Strijkers rh, cate-hoek aJ, bukkems Sf, wittens ch. management of deep vein thrombosis and prevention of post-thrombotic syndrome. bmJ. 2011 oct 31;343:d5916. doi: 10.1136/bmj.d5916.

2 malgor rd, gasparis ap. pharmaco-mechanical thrombectomy for early thrombus removal. phlebology. 2012 mar;27 Suppl 1:155-62.

3 bækgaard n, Klitfod l, broholm r. Safety and efficacy of catheter-directed thrombolysis. phlebology. 2012 mar;27 Suppl 1:149-54.

4 meissner mh. rationale and indications for aggressive early thrombus removal. phlebology. 2012 mar;27 Suppl 1:78-84.

5 Jaff mr, mcmurtry mS, archer Sl, cushman m, goldenberg n, goldhaber SZ, Jenkins JS, Kline Ja, michaels ad, thistlethwaite p, vedantham S, white rJ, Zierler bK. management of massive and submassive pulmonary embolism, iliofemoral deep vein thrombosis, and chronic thromboembolic pulmonary hypertension: a scientific statement from the american heart association. circulation. 2011 apr 26;123(16):1788-830.

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advancing vein care

Phlebology Takes its Place in the SunJoin us in Hollywood, Florida this November for the ACP Annual Congress

Join your colleagues from all over the nation for the latest in venous education. The ACP Annual Congress provides opportunities for CME credit—with basic, intermediate and advanced seminar tracks available. Featuring two keynote addresses: Deep Vein Thrombosis and The Role of Ultrasound in Vein Care, this year’s curriculum will be more in-depth than ever before. Event exhibitors also will be showcasing the world’s most advanced products and services specific to phlebology.

• Approximately 1,000 primary care providers, allied health and industry professionals attend the ACP Annual Congress to network and incorporate the latest research, technology and techniques in the treatment of venous disease• More than 120 clinically relevant sessions, built around basic, intermediate and advanced tracks are available for attendees to customize their experience• Choose from a diverse collection of topics, including Sclerotherapy, Venous Malformations, Compression, Duplex Ultrasound, Aesthetics, Ulcer/Wound Care and Practice Management• Collaborate with colleagues and respected faculty in hands-on, interactive workshops• Discover the latest products, technology and treatment options from the industry’s leading exhibitors• Network with your peers in a variety of social activities, including the annual Golf Outing, Opening Reception, Dinner & Social, and Silent Auction• Hosted at The Westin Diplomat Resort & Spa, located steps away from the Atlantic and Blue Wave Certified beaches, and just moments from the mature Banyan and Royal Palm trees of their championship golf course, 30,000 square foot signature spa or numerous local shopping and dining options.

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