Blood Coagulation, Fibrinolysis and Cellular Haemostasis 1137

Graduated compression stockings to treat acute leg pain associated

with proximal DVT
A randomised controlled trial
Susan R. Kahn1; Stan Shapiro1,2; Thierry Ducruet1; Philip S. Wells3; Marc A. Rodger3,4; Michael J. Kovacs5; David Anderson6,7;
Vicky Tagalakis1; David R. Morrison1; Susan Solymoss8; Marie-José Miron9; Erik Yeo10; Reginald Smith11; Sam Schulman12,13;
Jeannine Kassis14; Clive Kearon12; Isabelle Chagnon15; Turnly Wong16; Christine Demers17; Rajendar Hanmiah18; Scott Kaatz19;
Rita Selby20; Suman Rathbun21; Sylvie Desmarais22; Lucie Opatrny23; Thomas L. Ortel24; Jean-Philippe Galanaud25;
Jeffrey S. Ginsberg12
1Centre for Clinical Epidemiology, Jewish General Hospital, Montreal, Quebec, Canada; 2Department of Epidemiology, Biostatistics, and Occupational Health, McGill University,
Montreal, Quebec, Canada; 3Ottawa Hospital Research Institute, Ottawa, Ontario, Canada; 4Thrombosis Program, Division of Hematology, Department of Medicine, University of
Ottawa, Ottawa, Ontario, Canada; 5Division of Hematology, London Health Sciences Centre, London, Ontario, Canada; 6Department of Medicine, Dalhousie University, Halifax,
Nova Scotia, Canada; 7Capital Health, Halifax, Nova Scotia, Canada; 8Division of Hematology, Montreal General Hospital, Montreal, Quebec, Canada; 9Department of Medicine,
Hôpital Notre-Dame, Montreal, Quebec, Canada; 10Division of Hematology, University Health Network, Toronto, Ontario, Canada; 11Divisions of Cardiology and Thrombosis, Victoria
Heart Institute Foundation, Victoria, British Columbia, Canada; 12Department of Medicine, McMaster University and Thrombosis and Atherosclerosis Research Institute, Hamilton,
Ontario, Canada; 13Karolinska Institute, Stockholm, Sweden; 14Division of Hematology, HôpitalMaisonneuve-Rosemont, Montreal, Quebec, Canada; 15Department of Medicine,
Hôpital du Sacré-Coeur de Montréal/University of Montreal, Montreal, Quebec, Canada; 16Department of Medicine, St. Boniface General Hospital/University of Manitoba, Winnipeg,
Manitoba, Canada; 17Division of Hematology, CHU de Quebec, Quebec, Quebec, Canada; 18Division of General Internal Medicine, St. Joseph’s Hospital, Hamilton, Ontario, Canada;
19Academic Hospital Medicine, Hurley Medical Center, Flint, Michigan, USA; 20Departments of Medicine and Clinical Pathology, Sunnybrook Health Sciences Centre/University

Health Network/University of Toronto, Toronto, Ontario, Canada; 21Vascular Medicine, Oklahoma University Health Sciences Center, Oklahoma City, Oklahoma, USA; 22Department
of Medicine, Hôpital Pierre-Boucher, Longueil, Quebec, Canada; 23Vice-President Professional Services, St. Mary’s Hospital Center, Montreal, Quebec, Canada; 24Division of Hematol-
ogy, Duke University Medical Center, Durham, North Carolina, USA; 25Internal Medicine, Montpellier University Hospital, Montpellier, France

Summary
Acute deep venous thrombosis (DVT) causes leg pain. Elastic compres-
sion stockings (ECS) have potential to relieve DVT-related leg pain by
diminishing the diameter of distended veins and increasing venous
blood flow. It was our objective to determine whether ECS reduce leg
pain in patients with acute DVT. We performed a secondary analysis of
the SOX Trial, a multicentre randomised placebo controlled trial of active
ECS versus placebo ECS to prevent the post-thrombotic syndrome.The
study was performed in 24 hospital centres in Canada and the U.S. and
included 803 patients with a first episode of acute proximal DVT. Pa-
tients were randomised to receive active ECS (knee length, 30–40 mm
Hg graduated pressure) or placebo ECS (manufactured to look identical
to active ECS, but lacking therapeutic compression). Study outcome was
leg pain severity assessed on an 11-point numerical pain rating scale (0,
no pain; 10, worst possible pain) at baseline, 14, 30 and 60 days after
randomisation. Mean age was 55 years and 60% were male. In active
ECS patients (n=409), mean (SD) pain severity at baseline and at 60
days were 5.18 (3.29) and 1.39 (2.19), respectively, and in placebo ECS
patients (n=394) were 5.38 (3.29) and 1.13 (1.86), respectively. There
were no significant differences in pain scores between groups at any as-
sessment point, and no evidence for subgroup interaction by age, sex or
anatomical extent of DVT. Results were similar in an analysis restricted
to patients who reported wearing stockings every day. In conclusion,
ECS do not reduce leg pain in patients with acute proximal DVT.
Keywords
Randomised controlled trial, venous thrombosis, stockings, compres-
sion, pain, placebos, therapeutics

Correspondence to: Financial support:

Susan R. Kahn, MD MSc This study was funded by Canadian Institutes of Health Research (MCT 63142, MOP
Centre for Clinical Epidemiology 102610), with active and placebo stockings provided as in-kind support by Sigvaris.
Jewish General Hospital
3755 Cote Ste. Catherine, Room H420.1 Received: May 14, 2014
Montreal, QCH3T1E2, Canada Accepted after minor revision: July 5, 2014
E-mail: susan.kahn@mcgill.ca Epub ahead of print: August 28, 2014
http://dx.doi.org/10.1160/TH14-05-0430
Trial registration: clinicaltrials.gov (NCT00143598) and Current Controlled Thromb Haemost 2014; 112: 1137–1141
Trials (ISRCTN71334751).

Introduction
Deep venous thrombosis (DVT) is frequently associated with
acute leg pain. Elastic compression stockings (ECS) have the po-
tential to reduce DVT-related leg pain by reducing the diameter of
distended veins, increasing venous blood flow and reducing oede-
ma (1, 2). To date, however, the effect of ECS on leg pain in pa-
tients with acute DVT has only been studied in one small trial that
compared active compression plus walking exercises to no com-
pression plus complete bed rest for nine days (3).
The SOX Trial was a large, multicentre double-blind, randomis-
ed trial that compared active with placebo ECS worn for two years

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1138 Kahn et al. Compression stockings for acute leg pain in DVT
after an acute episode of proximal DVT to prevent the chronic
complication the post-thrombotic syndrome (PTS) (4). The SOX
Trial’s results did not affirm the results of two previously published
open label studies which suggested that ECS were effective for the
prevention of PTS in patients with DVT.
However, because ECS may have the potential to relieve symp-
toms associated with acute DVT, we performed a secondary analy-
sis to determine the effectiveness of active ECS, compared with
placebo ECS, in reducing leg pain associated with acute proximal
DVT.
Methods
The SOX Trial enrolled patients in 24 Canadian and United States
centres between 2004 and 2010 (4). The study was approved by the
research ethics boards at all participating centres, and written in-
formed consent was obtained from all patients.
Patients presenting with a first episode of symptomatic, proxi-
mal DVT were potentially eligible to participate. Proximal DVT
was defined as DVT in the popliteal or more proximal deep leg
veins that was confirmed by ultrasound. Patients were excluded if
they had a contraindication to the use of compression stockings
(e.g. allergy or severe arterial claudication), an expected lifespan of
less than six months, geographic inaccessibility precluding return
for follow-up visits, inability to apply stockings, or received throm-
bolytic therapy for the initial treatment of acute DVT.
Patients were randomly assigned to receive (1:1 allocation) ac-
tive graduated knee-high ECS (30–40 mm Hg at the ankle) or an
identical appearing placebo stocking that delivered less than 5 mm
Hg compression. Patients, physicians and study personnel were
blinded to treatment allocation. Randomisation was performed
using a web-based randomisation system to ensure concealed allo-
cation, was stratified by centre and used varying block sizes of four
and eight. At randomization, an alert was sent to the stocking
manufacturer’s central distribution centre (Sigvaris Corp; St. Laur-
ent, QC, Canada) with the patient’s treatment code, leg measure-
ments and mailing address, and a pair of active or placebo stock-
ings was shipped to the patient by overnight delivery. Patients were
asked to wear the stocking on the affected leg from waking to retir-
ing for two years, and were encouraged to maintain their usual ac-
tivity level. Stockings were replaced every six months or earlier, if
stockings had torn or leg size had changed.
Patients attended in-person follow-up visits at 1, 6, 12, 18 and
24 months, and were contacted by telephone at 14 and 60 days.
Frequency of stocking use since the last visit was recorded at each
in-person follow-up visit.
The primary outcome of the SOX Trial was the cumulative inci-
dence of PTS, diagnosed at the six month visit or later, using crite-
ria described by Ginsberg (5). The total sample size for the SOX
Trial was 800, which provided 80% power to detect a 33% risk re-
duction for the primary outcome, with a two-tailed α of 0.05 and a
projected 25% rate of loss-to-follow up or death. The main analysis
showed that active ECS did not reduce the incidence of PTS com-
pared to placebo ECS (cumulative incidence 14.2% vs 12.7%; haz-
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ard ratio [HR] 1.13; 95% confidence interval [CI] 0.73, 1.76;
p=0.58) (4).
As a secondary outcome, we assessed leg pain severity in the
DVT-affected leg at baseline, 14, 30 and 60 days after randomis-
ation, which reflected clinically relevant acute and subacute assess-
ment points after DVT. Using an 11-point numerical pain rating
scale (6), patients were asked to indicate a rating for the worst leg
pain they had experienced in the past 24 hours, where 0 was no
pain and 10 was the worst possible pain.
We sought to see whether there was an effect at any of the pre-
specified assessment points and compared mean pain scores at
each point in the active ECS vs placebo ECS groups using t-tests.
We repeated this analysis, restricted to patients who reported daily
use of study stockings at the one-month visit (the first visit at
which patients were asked about frequency of stocking use). Re-
sults are presented as difference in mean (95% CI) pain intensity
score between groups at each assessment point. We conducted pre-
specified subgroup analyses by age, sex, and anatomical extent of
DVT. All statistical tests were two-sided and significance was set at
P<0.05. Analyses were performed using SAS version 9.3 (SAS In-
stitute Inc., Cary, NC, USA).
Role of the funding source
The study was funded by Canadian Institutes of Health Research,
with active and placebo stockings provided as in-kind support by
Sigvaris. The funding sources had no role in the design and con-
duct of the study, in the collection, analysis and interpretation of
the data, in the writing of the report, or the decision to submit the
paper for publication.
Results and discussion
Between June 2004 and February 2010, 410 patients were ran-
domly assigned to active ECS and 396 to placebo ECS. Three pa-
tients found to be ineligible soon after randomisation were ex-
cluded from further analysis. The trial’s CONSORT diagram is
shown in the primary publication (4). Baseline characteristics were
similar in the two groups (▶ Table 1). Overall, 60.1% of patients
were male, mean age was 55.1 years (SD 15.5) and 87.1% were out-
patients when DVT was diagnosed. Mean time from DVT diag-
nosis to randomisation was 4.7 (SD 3.9) days. The most proximal
extent of DVT was iliac vein in 11.6%, common femoral vein in
26.9%, femoral vein in 31.3%, and popliteal vein in 30.3%.
Most patients received standard anticoagulant therapy consist-
ing of subcutaneous low-molecular-weight heparin for 5–10 days
and oral warfarin for a median duration of ~6 months (▶ Table 1).
At baseline, similar proportions (~one-fifth) of patients in each
group reported taking non-steroidal anti-inflammatory drugs
(NSAID) during the previous month, for an average of ~4 days
total use (▶ Table 1). At the one-month visit, new use of an non-
steroidal anti-inflammatory drugs (NSAID) since the baseline visit
was reported by 1.7% (7/409) of patients in the active ECS group
and 0.5% (2/394) in the placebo ECS group (p=0.18).
© Schattauer 2014
 Kahn et al. Compression stockings for acute leg pain in DVT 1139

Mean pain scores diminished at each successive timepoint in
both groups, from 5.18 (3.29) at baseline to 1.39 (2.19) at 60 days
in active ECS patients and from 5.38 (3.29) to 1.13 (1.86) in place-
bo ECS patients. There were no differences in pain scores between
groups at any of the follow-up assessments (▶ Table 2). Results
were similar in an analysis restricted to patients who reported at
the one month visit that they used ECS daily (70.1% of active ECS
patients and 77.0% of placebo ECS patients; ▶ Table 3). There was
no evidence for subgroup interaction by age category, sex or ana-
tomical extent of DVT at any time point (all p-values for interac-
tion >0.05; ▶ Table 4).
Hence, in a large randomised placebo-controlled trial in pa-
tients with symptomatic proximal DVT, leg pain improved during
the first 60 days to a similar degree in patients randomised to ac-
tive ECS and placebo ECS. We did not find evidence that ECS re-
duced pain in patients with acute proximal DVT as a whole or in
subgroups defined by age, sex, and anatomical extent of DVT, or in
those who reported daily use of study stockings.
Our study has several strengths, including its large size, multi-
centre design, and that several strategies were used to protect
against bias, including randomisation with allocation conceal-
ment, use of a placebo stocking to achieve blinding and use of a

Table 1: Baseline characteristics. No. (%)*

Active stockings Placebo stockings
(N=409) (N=394)
Age, mean (SD), years 55.4 (15.3) 54.8 (15.8)
Men 255 (62.4) 228 (57.9)
Outpatients 355 (86.8) 344 (87.3)
Caucasian 371 (90.7) 354 (89.9)
Body mass index, mean (SD), kg/m2 29.0 (6.1) 28.9 (6.1)
Days from DVT diagnosis to randomization, mean 4.8 (4.1) 4.6 (3.8)
(SD)
Most proximal extent of deep venous thrombosis
Iliac vein 44 (10.8) 49 (12.4)
Common femoral vein 109 (26.7) 107 (27.2)
Femoral vein 128 (31.3) 123 (31.2)
Popliteal vein 128 (31.3) 115 (29.2)
Venous thrombosis risk factors
Surgery, last 3 months 77 (18.8) 64 (16.2)
Trauma, last 3 months 42 (10.3) 51 (12.9)
Immobilised in last month 67 (16.4) 61 (15.5)
Active cancer + 52 (12.7) 46 (11.7)
Pregnant, postpartum, oral contraceptives or 37 (24.0) 55 (33.1)
hormonal replacement therapy#
Deep venous thrombosis treatment
Low-molecular-weight heparin 388 (94.9) 384 (97.5)
Unfractionated heparin 31 (7.6) 21 (5.3)
Warfarin 330 (80.7) 317 (80.5)
Investigational anticoagulant& 15 (3.7) 11 (2.8)
Any use of NSAIDs during the last month 71 (17.4%) 79 (20.1%)
Number of days used, mean (SD) 4.8 (2.6) 4.4 (2.4)
Use of antiplatelet drugs during the last month 73 (17.9%) 68 (17.3%)
Abbreviations: SD, standard deviation; DVT, deep venous thrombosis; NSAID, non-steroidal anti-inflamma-
tory drug. * Unless otherwise indicated. + Diagnosed within last 6 months or treatment ongoing or
metastatic or palliative. # In women only (active ECS, 154 women; placebo ECS, 166 women). & A few
patients were participants in concurrent studies comparing investigational anticoagulants (oral dabi-
gatran, oral rivaroxaban, or subcutaneous idraparinux) to standard anticoagulation.

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1140 Kahn et al. Compression stockings for acute leg pain in DVT

Visit Mean (SD)* Difference in means P-value Table 2: Pain scores in the active ECS and
(95% CI) placebo ECS groups, by study visit.
Active ECS Placebo ECS
N=409 N=394
Baseline 5.18 (3.29) 5.38 (3.29) 0.20 (-0.26, 0.66) 0.39
409 393
14-day 2.39 (2.59) 2.47 (2.61) 0.08 (-0.29, 0.45) 0.67
392 385
1-month 1.88 (2.67) 1.70 (2.33) -0.18 (-0.53, 0.18) 0.33
386 377
60-day 1.39 (2.19) 1.13 (1.86) -0.27 (-0.56, 0.03) 0.08
377 365
* mean (standard deviation) numerical pain rating score, based on a scale of 10 (0, no pain; 10, worst
possible pain).

Mean (SD)* Difference in means P-value Table 3: Pain scores in the active ECS and
(95% CI) placebo ECS groups among patients who
Active ECS Placebo ECS reported wearing study stockings every
N=272 N=291 day, at 1 month visit#, by study visit.
Visit
Baseline 5.08 (3.33) 5.27 (3.33) 0.19 (-0.36, 0.74) 0.50
14-day 2.20 (2.54) 2.40 (2.63) 0.21 (-0.22, 0.64) 0.35
1-month 1.73 (2.50) 1.71 (2.36) -0.02 (-0.42, 0.38) 0.93
60-day 1.35 (2.24) 1.10 (1.88) -0.25 (-0.59, 0.10) 0.16
# numbers who attended the one-month follow-up visit were 388, active ECS, and 378, placebo ECS.
* mean (standard deviation) numerical pain rating score, based on a scale of 10 (0, no pain; 10, worst
possible pain).

validated patient-reported instrument to assess pain (6, 7). While To our knowledge, only one previous study has examined the
this was a secondary analysis of a trial whose primary objective effect of compression on DVT-related leg pain. In an Austrian
was to assess the effectiveness of ECS to prevent the chronic PTS, trial, 53 patients with acute proximal DVT were randomised to
our sample of 803 patients provided 90% power to detect a differ- walking plus non-elastic compression (Unna boot bandages cover-
ence in pain scores between groups of as little as 0.5 at each visit. ed with short stretch bandages, changed every 3 days), walking
There are limitations to our study. As the first follow-up assess- plus compression with ECS (thigh-length, with 30 mm Hg press-
ment occurred at 14 days after randomisation, we were unable to ure at the ankle, worn day and night), or bed rest with no compres-
evaluate if ECS had a beneficial or detrimental effect on pain be- sion (3). Overall leg pain, measured with a visual analogue scale,
fore this time point. However, the fact that there were no differ- and calf pain, measured with the Lowenberg cuff inflation test, de-
ences between groups in pain scores at any of the three follow-up creased over nine days in all groups, but pain scores were signifi-
assessments makes an isolated early effect unlikely. cantly lower at nine days in the walking plus non-elastic bandages
group. However, it cannot be differentiated if this effect was at-
tributable to compression, exercise or both.
Table 4: P-value for interaction between pre-specified variables and The findings of this analysis are clinically important. ECS can
treatment assignment. be difficult to put on, uncomfortable, cause skin irritation, and are
costly (8); if they do not reduce leg pain, they should not be worn
Variable P-value for interaction for this purpose. Other approaches, such as analgesics or anti-in-
Baseline 14-Day 1-Month 60-Day flammatory medication, might be used to reduce DVT-related leg
Age 0.57 0.50 0.91 0.80 pain in preference to ECS. Finally, we show that on average, acute
DVT-related leg pain is in the moderate to severe range initially (6,
Sex 0.80 0.69 0.86 0.43
9), improves substantially in the first 14 days, and improves further
Most proximal 0.10 0.57 0.97 0.67 to the mild range by 60 days.
extent of DVT

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What is known about this topic?
• Pain is a common symptom of acute DVT.
• Elastic compression stockings are sometimes prescribed with the
goal of relieving DVT symptoms.
• No large scale randomised controlled studies have assessed the
effectiveness of elastic compression stockings to relieve acute
DVT-related leg pain.
What does this paper add?
• We performed a large, placebo controlled multicentre randomised
trial of active versus placebo compression stockings in patients
with proximal DVT.
• We found that active stockings did not reduce leg pain, compared
with placebo stockings, at any of the time points measured (14
days, 30 days and 60 days after DVT).
• Results were similar for frequent stockings users and by
categories of age, sex and extent of DVT.
• Thus, elastic compression stockings do not appear to reduce leg
pain in patients with acute proximal DVT.
In conclusion, we found that ECS did not reduce pain in pa-
tients with acute proximal DVT.
Acknowledgements
Funding for this study was provided by Canadian Institutes for
Health Research (grant number MCT 63142, MOP 102610), with
active and placebo stockings provided as in-kind support by Sigva-
ris Corp. Dr. Kahn was supported by a National Research Scientist
award from the Fonds de recherche du Québec – Santé (FRQS).
Dr. Rodger is supported by a Career Investigator award from the
Heart and Stroke Foundation of Ontario and a Tier 1 Research
Chair Award, Faculty of Medicine, University of Ottawa. Dr. Kear-
on is supported by a Career Investigator award from the Heart and
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Kahn et al. Compression stockings for acute leg pain in DVT 1141
Stroke Foundation of Ontario. Dr. Ginsberg is supported by a Ca-
reer Investigator award from the Heart and Stroke Foundation of
Ontario and is a recipient of the David Braley and Nancy Gordon
Chair for Investigation of Thromboembolic Diseases.
Author contributions
Susan Kahn had full access to all of the data in the study and takes
responsibility for the integrity of the data and the accuracy of the
data analysis. Thierry Ducruet MSc conducted the statistical
analysis. The funders of the study had no role in the design and
conduct of the study; collection, management, analysis, and inter-
pretation of the data; and preparation, review, or approval of the
manuscript.
Conflicts of interest
None declared.
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