Conditions: Venous Thromboembolism Venous Thrombosis
Keywords: venous thromboembolism deep vein thrombosis pulmonary embolism prevention intermittent pneumatic compression sequential pneumatic compression surgery elastic compression low-molecular weight heparin prophylaxis
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 407
Healthy volunteers: no

Brief summary:
The aim of the study is to evaluate efficacy and safety of venous thromboembolism prophylaxis by the combination of graduated compression stockings (GCS), standard doses of low-molecular-weight heparins (LMWH) and sequential compression device (SCD) in the mixed group of surgical patients at high and extremely high risk for venous thromboembolism.

Detailed description:
Venous thromboembolism (VTE) is the most common complication after major surgery, especially in high-risk patients. But the high-risk group is inhomogeneous. Some patients included in this group have an extremely high prevalence of postoperative venous thrombosis and pulmonary embolism, in whom the standard complex prophylaxis with elastic compression and standard anticoagulation is less effective. This is particularly so, in patients having a Caprini score of 11 and more, so that at the background of standard prophylaxis postoperative DVT is 10 times higher. This group of patients needs a more effective protocol for VTE prevention.

Sequential compression devices (SCD) combined with graduated elastic compression stockings (GCS) or without them were found to be effective in the prevention of VTE in high-risk patients, especially after neurosurgical interventions, even without the administration of anticoagulants. However, their efficacy in patients at "extremely high risk", having 11+ Caprini scores has not been assessed yet. The aim of the current study is to evaluate efficacy and safety of VTE prophylaxis by the combination of graduated compression stockings (GCS), standard doses of low-molecular-weight heparins (LMWH) and sequential compression device (SCD) in the mixed group of surgical patients at high and extremely high risk for venous thromboembolism

The expected outcome of the study is a reduction of asymptomatic postoperative venous thrombosis rate in the hospital and reduction in all VTE during 6 months after discharge.

Arms:
arm 1: SCD: Intermittent pneumatic compression (IPC) with Kendall SCD™ Sequential Compression System 700 used continuously when the patient is in bed with 6-hours night interval free of compression: from 0 a.m. to 6 a.m. In the ICU SCD used continuously all day, and in surgery department - all time of bed resting. SCD used until discharge.

GCS: Thigh-length graduated compression stockings with pressure of 18-21 mm. Hg at the ankle used all the time until discharge plus one month after discharge

LMWH: LMWH enoxaparin (Clexane) 40 mg once a day subcutaneously started on 1st or 2-5th postoperative day according to the bleeding risk and used until discharge. arm 2: GCS: Thigh-length graduated compression stockings with pressure of 18-21 mm. Hg at the ankle used all the time until discharge plus one month after discharge

LMWH: LMWH enoxaparin (Clexane) 40 mg once a day subcutaneously started on 1st or 2-5th postoperative day according to the bleeding risk and used until discharge.

Interventions: intervention 1: SCD intervention 2: GCS intervention 3: LMWH
Intervention descriptions: intervention 1: Intermittent pneumatic compression (IPC) with Kendall SCD™ Sequential Compression System 700 used continuously when the patient is in bed with 6-hours night interval free of compression: from 0 a.m. to 6 a.m. In the ICU SCD used continuously all day, and in surgery department - all time of bed resting. SCD used until discharge. intervention 2: Thigh-length graduated compression stockings with pressure of 18-21 mm. Hg at the ankle used all the time until discharge plus one month after discharge intervention 3: LMWH enoxaparin (Clexane) 40 mg once a day subcutaneously started on 1st or 2-5th postoperative day according to the bleeding risk and used until discharge.

Protocol document:
Prot_SAP_001.pdf: 
Pirogov Russian National Research Medical University 
 
 
 
Investigator-initiated research according to the protocol: 
 
Trial to assess the effectiveness of intermittent pneumatic 
compression in the prevention of postoperative venous 
thromboembolism in surgical patients at extremely high risk. 
 
Version 1.1 dated on May 15, 2016 
 
 
 
 
Research title: Intermittent Pneumatic Compression in Surgical Patients at 
Extremely-high Risk of Venous Thromboembolism. 
 
Short title: IPC SUPER 
 
Primary Investigator and author of the Protocol:  
Kirill Lobastov, MD, PhD, Associated Professor 
 
 
 
 
 
 


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Table of contents 
Abbreviations ...................................................................................................................................... 3 
1. 
Background .................................................................................................................................. 4 
2. 
Rationale and objectives ............................................................................................................ 7 
3. 
Design ............................................................................................................................................ 8 
3.1. 
Randomization, Stratification, and Minimizing Bias ....................................................... 9 
3.2. 
Study population, inclusion, and exclusion criteria ....................................................... 10 
3.3. 
Patient’s withdrawal from the study ................................................................................. 11 
3.4. 
Protocol deviations ............................................................................................................... 12 
3.5. 
Endpoints and definitions ................................................................................................... 12 
4. 
Trial interventions .................................................................................................................... 13 
4.1. 
Anti-embolic stockings ......................................................................................................... 13 
4.2. 
Low-molecular-weight heparins ........................................................................................ 14 
4.3. 
Sequential pneumatic compression .................................................................................. 14 
5. 
Follow-up .................................................................................................................................... 15 
5.1. 
Baseline examination ........................................................................................................... 15 
5.2. 
VTE risk assessment ............................................................................................................. 15 
5.3. 
Duplex ultrasound scan ....................................................................................................... 16 
5.4. 
Examination during inpatient treatment ......................................................................... 17 
5.5. 
Examination during outpatient treatment ...................................................................... 18 
6. 
Patients safety ............................................................................................................................ 19 
7. 
Ethical issues .............................................................................................................................. 20 
8. 
Statistical analysis plan and sample size calculation ......................................................... 20 
9. 
Clinical Centers and collaborators......................................................................................... 21 
References .......................................................................................................................................... 23 
 
 
 


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Abbreviations 
ABI – ankle-brachial index 
ATV – anterior tibial vein 
BMI – body mass index 
CFV – common femoral vein 
CHF – congestive heart failure 
CI – confidential interval 
CRF – case report form  
CRNM – clinically relevant non-major bleeding 
CTPA – computed tomography pulmonary angiogram 
CVD – chronic venous disease 
DIC – disseminated intravascular coagulation syndrome 
DUS – duplex ultrasound scan 
DVT – deep vein thrombosis 
ECS – elastic compression stockings 
FV – femoral vein 
GSV – great saphenous vein 
ICU – intensive care unit 
IPC – intermittent pneumatic compression 
IQR – interquartile range 
IRB – Institutional Reviewal Board 
ISTH – International Society of Thrombosis and Hemostasis 
ITT – intention-to-treat 
IVC – inferior vena cava 
LMWH – low-molecular-weight heparin 
NNH – number needed to harm 
NNT – number needed to treat 
PE – pulmonary embolism 
PeV – peroneal vein 
PTV – posterior tibial vein 
PV – popliteal vein 
SCD – sequential compression device 
SD – standard deviation 
SPECT/CT – single-photon emission computed tomography with a conventional 
computed tomography 
SSV – small saphenous vein 
SVT – superficial vein thrombosis 
UHF – unfractionated heparin 
VTE – venous thromboembolism 
 
 
 


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1. Background 
Venous thromboembolism (VTE), including deep vein thrombosis (DVT), 
superficial vein thrombosis (SVT), and pulmonary embolism (PE), has been considered 
an important medical-social problem for decades. According to well-known 
epidemiological data, the VTE incidence in the general population is estimated as 1.0–1.9 
cases per 1000 population per year, which can be further classified as 0.5–0.7 cases of 
pulmonary embolism and 0.5–1.2 cases of deep vein thrombosis 1-9. The official data of 
the Statistical Service of the Russian Federation exceed the average world figures and 
demonstrate the incidence of venous thrombosis at the level of 1.5–1.6 cases per 1000 
population per year10,11. It is well known that one of the important risk factors for VTE 
development is the recent inpatient treatment, especially accompanied by major 
surgery12-23. Therefore, stratification of the hospitalized patients according to their 
individual VTE risk and providing adequate preventive measures are crucial during 
inpatient treatment24,25. Early ambulation, elastic compression stockings, prophylactic 
anticoagulation, active blood drainage, and a combination of these methods significantly 
reduce the risk of postoperative VTE, especially fatal pulmonary embolism, in most 
surgical patients24,26. 
Today, the Caprini score (version 2005)27 is considered the most validated 
individual risk assessment model for postoperative VTE. The Caprini score was verified 
in about 15,000 surgical patients and showed a strong correlation between the total score 
and the frequency of symptomatic VTE events (personal communication with JA Caprini). 
In patients with scores of 9 or more, the frequency of VTE was as high as 11%. However, 
a further increase in Caprini score might be accompanied by an increase in the VTE rate. 
A prospective analysis taking into account both symptomatic and asymptomatic VTE 
episodes that occurred at the top of standard prophylaxis (elastic compression and 
injections of unfractionated heparin [UFH]), demonstrated that in patients with a Caprini 
score of 11 or more, VTE incidence reached 59%, compared with 3% in those who had 
Caprini scores of 10 or less28. However, there is as yet no consensus on which threshold 
of Caprini score should be used to choose adequate mechanical and pharmacological 
prophylaxis. A meta-analysis of 13 studies found that only patients with a Caprini score 
of 7–8 and >8 had a significant VTE reduction after surgery with chemoprophylaxis 
(personal communication with JA Caprini). At the same time, in patients with a score of 
>10, prophylaxis with elastic compression plus standard doses of UFH appears to be 


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insufficient28. So, according to these data, patients with a score of 5–7 might be classified 
as a high-risk group, a score of 8–10 as the highest-risk group, and a score of 11 and more 
as an extremely high-risk group. The extremely-high-risk group needs improvement in 
the VTE preventive protocol. 
Intermittent pneumatic compression (IPC) is as effective as pharmacoprophylaxis 
in reducing VTE risk but does not affect the bleeding rate. The previous meta-analysis of  
16,164 hospitalized patients from 70 trials reported a DVT risk reduction (by 57%) and 
PE risk reduction (by 52%) when IPC was compared with no prophylaxis, and DVT risk 
reduction (by 39%) when compared with elastic compression alone29. In comparison 
with pharmacoprophylaxys, there was no difference in the risk of DVT (relative risk, 0.93; 
95% CI, 0.69–1.26) or PE (relative risk, 1.19; 95% CI, 0.62–2.29), but there was a 
significant decrease in the risk of bleeding (by 39%) (relative risk, 0.41; 95% CI, 0.25–
0.65). These advantages usually suggest IPC as an alternative to anticoagulants in those 
patients who have an increased risk of hemorrhagic complications, especially after 
intracranial and spinal surgery26. However, the combination of IPC and prophylactic 
anticoagulation, also known as pharmaco-mechanical modality, is more effective than the 
mechanical or pharmacological approaches alone. A meta-analysis of 16 clinical trials 
reported a DVT risk reduction (by 48% accompanied by the 5-fold increase in the 
bleeding risk) when the pharmaco-mechanical modality was compared with IPC alone; 
and a PE risk reduction (by 61% without increased bleeding rate) (relative risk, 0.80; 
95% CI, 0.30–2.14) when IPC with anticoagulation was compared with prophylactic 
anticoagulation alone30. 
Thereby, the pharmaco-mechanical modality might be a solution to improve VTE 
prophylaxis in patients with a Caprini score of 11 or more, who are at extremely high risk 
for VTE. However, there are some crucial issues with IPC application.  
First, there are many types of IPC devices that apply different pressure to the leg 
surface, provide various insufflation and deflation times (slow or rapid), and employ 
different sleeves according to the length (foot pump, below knee sleeve, above knee 
sleeve) and pressure distribution (uniform compression or sequential graduated 
compression). All these parameters might affect the hemodynamic and clinical response 
to IPC application31,32. Moreover, there is no good clinical evidence that one IPC device is 
better than another. In one non-randomized open clinical trial that enrolled 1,350 
unidentified patients who received IPC during inpatient treatment, was compared five 


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IPC SUPER trial, May. 2016, v.1.1 
different IPC manufactures (with various pumps and sleeves) according to the clinical 
efficacy, compliance, patient’s and nurse’s satisfaction33. The authors found some 
significant differences in the incidence of DVT, which ranged from 2.0% to 9.8% among 
the devices (p = 0.003), and the best figures were observed for graduated sequential 
compression devices (SCD): 2.5% and 2.0% respectively. However, taking into account 
compliance and patient’s and nurse’s satisfaction, the best scores were demonstrated for 
the tight-length intermitted compression, which was associated with a DVT rate of 3.2%.  
So, the second critical concern is compliance with IPC. Usually, compliance is far 
from 100% and typically ranges between 48 and 53%34-37. It seems that compliance is 
higher in the intensive care unit (ICU) than in the profile surgical department34,37. The 
main disadvantages of the IPC devices are related to their cumbersome size and their 
requirement to be connected to a static power source, both of which tended to confine 
patients to bed and delayed hospital discharge and rehabilitation32. The studies that have 
aimed to assess compliance with IPC report that there might be a lack of device 
application as well as device functions. One study found that of all IPC devices that were 
applied, in 16% the pump did not function during the investigator’s control visits34.  
The third point is that the minimal time of IPC application is unclear. Various studies 
have reported different durations of IPC application per day (14–20 h) depending on the 
type of device (portable or stationary)38. Another trial found that IPC in addition to 
pharmacoprophylaxis after orthopedic procedures was effective when applied for 6 h or 
more39. However, the usual recommendation is to achieve 18 h of daily compliance40. 
These and other unresolved issues formed the basis of this study. The main 
hypothesis of the study was that the combination of IPC with standard preventive 
measures (above knee anti-embolic elastic compression stockings [ECS] and standard 
doses of low-molecular-weight heparin [LMWH]) would reduce the incidence of 
postoperative VTE in patients at extremely high risk (Caprini score of 11 or more). Also, 
to improve the compliance with IPC, we decided to find out if providing a 6-h free-of-
compression night interval (from midnight to 6 am) with the preservation of 18 h of 
target duration for device application will result in better compliance combined with 
good clinical outcomes. 
 
 
 


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IPC SUPER trial, May. 2016, v.1.1 
 
2. Rationale and objectives 
The rationale for the Study. There are no randomized controlled trials examining 
the effect of the adjunct use of IPC with pharmacologic prophylaxis compared to 
pharmacologic prophylaxis (LMWH) alone in patients at extremely-high-risk (Caprini 
score of 11 and more) for VTE prevention. 
Use of Trial Results. This trial expects to have significant patient safety 
implications. If the combined use of IPC with pharmacologic prophylaxis proves to be 
effective, this would change the standard of practice of thromboprophylaxis and will be a 
major advancement in patient safety. 
Study objectives: To assess the superiority of IPC at the top of standard 
prophylaxis with LMWH and ECS compared to standard prophylaxis on postoperative 
asymptomatic venous thrombosis of lower limbs during inpatient treatment. 
Secondary objectives: 
• To study the effect of IPC on the asymptomatic venous thrombosis 
occurrence during inpatient treatment in prespecified groups of patients: 
o Surgical profile, 
o Type of surgery, 
o The urgency of surgery, 
o The radicalism of surgery, 
o Type of anesthesia, 
o Malignant or benign disorder; 
o Preoperative, postoperative or delayed start of LMWH injections, 
o Pre-operative or post-operative IPC application, 
• To study the effect of IPC on the isolated calf muscle DVT occurrence during 
inpatient treatment; 
• To study the effect of IPC on the proximal DVT occurrence during inpatient 
treatment; 
• To study the effect of IPC on the symptomatic PE occurrence during inpatient 
treatment; 
• To study the effect of IPC on the fatal PE occurrence during inpatient 
treatment, 


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IPC SUPER trial, May. 2016, v.1.1 
• To study the effect of IPC on the total VTE events that occur during inpatient 
treatment, 
• To study the effect of IPC on the leg skin injury occurrence during inpatient 
treatment; 
• To study the effect of IPC on the major and clinically relevant non-major 
bleeding occurrence during inpatient treatment; 
• To study the compliance with IPC applied in the suggested regimen-required 
night free-of-compression interval; 
• To study the effect of IPC on the symptomatic and asymptomatic venous 
thrombosis of lower limbs, symptomatic pulmonary embolism occurrence, 
and VTE related and VTE-non-related mortality during outpatient treatment 
and rehabilitation 30 and 180 days after surgery. 
3. Design 
A two-center, prospective, randomized (with independent allocation), open-label 
clinical trial with a blinded assessor for efficacy outcomes, enrolling patients at extremely 
high risk for postoperative VTE (Caprini score of 11 and more). The patients should be 
randomly allocated into two groups (experimental [IPC] group and control group) 
according to the VTE prophylaxis they received. Both groups will receive anti-embolic 
stockings and injections of LMWH, and patients in the IPC group additionally will receive 
IPC. The total duration of prophylaxis should amount of 1 month, and patients will be 
followed-up for 6 months with regular clinical examination and duplex ultrasound scans. 
Figure 1 represents the global design of the study.  
 
 
Figure 1. The global design of the study. 
 
 


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IPC SUPER trial, May. 2016, v.1.1 
 
 
3.1. Randomization, Stratification, and Minimizing Bias 
The randomization should be performed independently for both clinical centers 
and should be based on the number of hospital medical records. After screening, only 
eligible patients will be randomized. If the last digit in the number of the hospital medical 
record is even, the patient should be allocated to the IPC group, and if odd, to the control 
group. If the last digit in the number of the hospital medical record is zero, the previous 
digit should be used. Both clinical centers contain multiple medical departments of 
different specialties, and the numbering of the medical records is performed sequentially 
through all departments. It starts at the beginning of the year (for example, the first 
medical record in 2017 is 1/17) and finishes at the end of the year. Taking into account 
the large admission rate to all medical departments, there is an extremely low probability 
that two consistently included patients would have sequential medical records. To reduce 
the bias of the deliberate non-inclusion of the patients with higher VTE risk in the IPC 
group all non-eligible subjects should be repeatedly evaluated for exclusion criteria by 
the Data Monitoring Committee. 
After allocation to the group, the patient will be assigned an individual code, 
containing his index number, initials, and year of birth (for example, 1IV1961). This 
individual code will be used in all study documentation. The allocation list will be stored 
by the investigator. The blinded expert who will perform a duplex ultrasound scan (DUS) 
would not have access to the primary medical record or allocation list; he will use only 
individual patients code for identification. Also, to achieve blindness, most duplex scans 
will be performed in a separate room away from the patient’s bed. If it will be impossible 
to transfer a patient to the room, the DUS will be performed at the bed, but the IPC device 
will be removed before the blinded expert’s visit. A schematic diagram of the patient 
allocations is shown in Figure 2. 
 


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IPC SUPER trial, May. 2016, v.1.1 
 
Figure 1. Scheme of the randomization and blindness. 
 
 
3.2. Study population, inclusion, and exclusion criteria 
All patients admitted to the clinical centers for emergent or elective surgery will be 
screened for eligibility criteria. In the case of elective surgery, patients will be screened 1 
day before the intervention, and in case of emergency surgery, just before or within 12 h 
after the intervention. 
 
Inclusion criteria: 
• Age over 40 years; 
• Major surgery required; 
• High risk of postoperative VTE; 
• Caprini score of 11 or more (at extremely high risk of VTE); 
• Informed consent is given. 
 
Age over 40 years is suggested as an inclusion criterion by the Russian National 
Guidelines on VTE prevention41, which recognize these patients as a standard high-risk 
group if undergoing major surgery. 
Major surgery is recognized as any procedure under general or regional anesthesia 
with the leg motor block with a duration of 45 min and more that are equal to major 
surgery (>45 min) or laparoscopic surgery (>45 min) in the Caprini model. 
Primary risk assessment for postoperative VTE should be made according to the 
rules of the Russian National Guidelines41, and only patients at high-risk (major surgery 
in patients of 40–60 years old with additional individual risk factors, or major surgery in 


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IPC SUPER trial, May. 2016, v.1.1 
patients of 60 and more years old independent of additional risk factors) will be screened 
for eligibility according to the Caprini score. 
The Caprini score should be assessed twice: at the baseline screening before 
inclusion and before discharge or after death. It will be allowed to include patients with 
supposed scores of ≥11 (e.g., supposed cancer, supposed long bed rest, supposed CHF, 
CVD, etc.), but not less than 9. The final assessment of concomitant diseases as risk factors 
will be performed by an invited specialist. The maximal Caprini score will be taken into 
account. 
 
Exclusion criteria: acute DVT at baseline; performed IVC plication or implanted 
IVC filter; regular preoperative anticoagulation; postoperative anticoagulation needed at 
therapeutic doses; absence of anticoagulation >5 days after surgery; coagulopathy (not 
related to DIC syndrome); thrombocytopenia; hemorrhagic diathesis; lower limb soft-
tissue infection; lower limb skin lesion; ankle-brachial index <0.6. 
 
3.3. Patient’s withdrawal from the study  
Patient’s withdrawal from the study will be possible in case of the patient’s refusal 
from further participation, the occurrence of serious adverse events necessitating early 
termination of study procedures, as well as meeting the criteria for patient’s withdrawal 
from the study.  The criteria for withdrawal are as follows: the occurrence of any VTE 
event, considered as a primary or secondary endpoint; the occurrence of major or non-
major clinically relevant bleeding, considered as secondary endpoints, required the 
discontinuation of LMWH administration; the occurrence of leg skin injury, considered as 
a secondary endpoint; required discontinuation of IPC application; the occurrence of any 
clinical condition required discontinuation of IPC or ECS application (e.g., leg ischemia, 
compartment syndrome); the occurrence of any clinical condition that required 
discontinuation of LMWH administration (e.g., thrombocytopenia, allergic reaction); the 
occurrence of any clinical condition that required changes in the VTE prophylaxis 
modality (e.g., change in dose and type of anticoagulation); and the occurrence of any 
exclusion criteria after randomization. 
 
 
 


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IPC SUPER trial, May. 2016, v.1.1 
3.4. Protocol deviations 
The serious protocol deviations that required patient exclusion from the final 
analysis are: missed two or more scheduled DUS; missed the final scheduled DUS before 
discharge; autopsy rejected; inability to assess compliance with IPC (no information in 
the Compliance sheet); gross inconsistencies between source documentation and an CRF; 
violations of the procedure for obtaining informed consent; failure to follow the 
procedures of the trial protocol; the inability to collect all the data used in evaluating the 
final goals of the study (for example, the lack of records in the source documentation 
necessary to verify the inclusion/exclusion criteria, safety, and efficiency criteria); any 
other protocol deviations considered as significant. 
 
3.5. Endpoints and definitions 
Primary endpoint: asymptomatic venous thrombosis of the lower limbs detected 
by DUS during inpatient treatment. 
 
Secondary endpoints: 
During inpatient treatment: isolated calf muscle DVT; proximal DVT; symptomatic 
PE; fatal PE; total VTE events; postoperative mortality; leg skin injury; combination of 
major and clinically, relevant non-major bleeding; and compliance with IPC. 
 
At 30 days after surgery: 
• Combination of symptomatic, asymptomatic venous thrombosis of the 
lower, limbs and symptomatic PE; 
• VTE-related mortality; 
• Non-VTE-related mortality. 
 
At 180 days after surgery: 
• Combination of symptomatic, asymptomatic venous thrombosis of the lower 
limbs, and symptomatic PE; 
• VTE-related mortality; 
• Non-VTE-related mortality. 
 


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IPC SUPER trial, May. 2016, v.1.1 
Following DUS, distal DVT is defined as incompressibility of the affected calf vein, 
re-occlusion of the previously affected calf vein in case of personal DVT history. Proximal 
DVT is defined as incompressibility of the affected popliteal and thigh veins, re-occlusion 
of previously affected popliteal and thigh veins in case of personal DVT history, no blood 
flow with color flow imaging. Superficial vein thrombosis is defined as incompressibility 
of the affected superficial vein (GSV and its branches and SSV and its branches). Isolated 
calf muscle DVT is defined as occlusion of any calf veins except PTV, ATV, and PeV (sural 
veins, soleal veins). Proximal DVT is defined as occlusion of popliteal and all further 
cranial venous segments up to the iliac veins (PV, FV, CFV, external iliac vein, common 
iliac vein). Pulmonary embolism will be suspected according to the classical clinical 
symptoms and verified with SPECT/CT or CTPA by specific defects of contrast. 
Major bleeding is defined by the ISTH criteria42 as: fatal bleeding; bleeding that is 
symptomatic and occurs in a critical area or organ; extra-surgical site bleeding causing a 
fall in hemoglobin level of ≥20 g/L, or leading to transfusion of ≥2 units of whole blood or 
RDC, with temporal association within 24–48 h to the bleeding; surgical site bleeding that 
requires a second intervention; or surgical site bleeding that is unexpected and prolonged 
or sufficiently large to cause hemodynamic instability, as assessed by the surgeon. 
Clinically relevant non-major (CRNM) is defined as any other bleeding, that does not 
match the criteria of major but needs some specific measures for hemostasis and/or 
interruption or preliminary abortion of anticoagulation. 
Leg skin injury is defined as the appearance of skin hyperemia, blisters (and further 
erosions), and necrosis (and further ulceration) in the zone of contact with GCS, especially 
at the anterior surface of the ankle joint. 
 
4. Trial interventions 
All randomized patients will receive a standard VTE prophylaxis according to the 
Russian National Guidelines, that are complementary to ACCP 9th Edition26, contained 
using of above-knee anti-embolic ECS and LMWH injections. In the experimental group, 
an IPC device will be applied in adjunction to standard prophylaxis. 
 
4.1. Anti-embolic stockings 
Above-knee anti-embolic compression stockings fitted by the leg size should be 
applied before the surgery. In the case of elective surgery, the size should be fitted before, 


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IPC SUPER trial, May. 2016, v.1.1 
and patients should be admitted to the hospital with their own stockings. In the case of 
emergent surgery, leg sizes should be obtained after admission, and the stockings should 
be received from the stocking bank. ECS should be applied round-the-clock during the 
inpatient period of treatment. After discharge, patients will be recommended to use 
stocking at night and during the long bed rest for 1 month. The manufacturer for the ECSs 
is not prespecified, so it is possible to use any available product. Stocking application 
should be controlled within standard medical care. 
 
4.2. Low-molecular-weight heparins 
Standard doses of 40 mg Enoxaparin (Clexane, Sanofi-Aventis, France) 
subcutaneously once daily is prespecified. Following Russian National Guidelines, the 
first injection should be done 12 h before the surgery (elective surgery without high 
bleeding risk) or within 12 h after surgery (emergent surgery, procedure with high 
bleeding risk). In the case of the highest bleeding risk, it is allowed to delay the first 
LMWH injection for 5 days. The patients who did not receive Enoxaparin after 5 days will 
be withdrawn from the analysis. The pharmacoprophylaxis should be continued until the 
patient’s discharge from the hospital (not less than 7 days) or death. The prolonged 
prophylaxis with LMWH is not pre-specified and will depend on the surgeon's preference. 
The enoxaparin administration and the control for injection should be made within the 
standard clinical practice. 
 
4.3. Sequential pneumatic compression 
Intermitted pneumatic compression should be applied with Cardinal Health™ 
Kendall SCD™ 700 Series Controller and Kendall SCD™ thigh-length Comfort Sleeves. The 
pumps will be provided by the Sponsor (10 pumps by Cardinal Health™), and the sleeves 
will be purchased by the Clinical centers. Sleeves should be fitted according to the 
manufacturer’s instructions and used in a disposable manner. Sleeves should be changed 
when they become soiled or lost their fixation. 
IPC should be started just before the surgery in the operating room during general 
anesthesia induction or after regional anesthesia application before covering the 
operating field with the sterile material. Also, it is allowed to apply IPC within 12 h after 
surgery. The main conditions of IPC application are as follows: no venous thrombosis 


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IPC SUPER trial, May. 2016, v.1.1 
confirmed by DUS, no skin lesions on the leg, no signs of skin and soft tissue infections of 
the legs, ABI >0.6.  
IPC should be applied around-the-clock in the ICU, and at the time of bed-rest with 
a 6 h free-of-compression interval from 0 am to 6 am in the profile surgical department. 
The IPC required to be used during the whole inpatient treatment period. 
 
5. Follow-up 
The follow-up is designed separately for the inpatient and outpatient settings. The 
total follow-up duration accounts for 6 months. 
 
5.1. Baseline examination 
The screening examination is designed to assess patient’s eligibility with the 
inclusion/exclusion criteria. The baseline examination will be performed a day before the 
surgery in case of elective surgery or just before or within 12 h after the urgent surgery. 
The basal examination contains the standard diagnostic procedures with special 
attention to the individual risk factors for postoperative VTE. Patients (or their 
representatives in case of unconsciousness or deep dementia) should be interviewed for 
the personal and family VTE history, any obstetrics complications, use of contraceptive 
pills or other estrogen-containing drugs, and current or previous malignant disorders. 
Lower limbs should be evaluated for the varicose veins and edema, skin and soft tissue 
infection, any skin lesions, and pedal pulsation.  The relevant co-morbidities, such as 
congestive heart failure (CHF), chronic obstructive pulmonary disease (COPD), serious 
lung disease or pneumonia, inflammatory bowel disease, sepsis, lower limb paralysis, and 
stroke should be evaluated and confirmed according to the medical records and involving 
other specialists. BMI will be calculated with the data from medical records. 
 
5.2. VTE risk assessment 
The primary VTE risk assessment should be performed by Russian National 
Guidelines41, and if the patient will be classified as having a high risk (major surgery in 
subjects over 60 years old or major surgery in subjects from 40 to 60 years old having 
additional individual risk factors for VTE), he should be assessed by Caprini score. A 
Russian adaptation43 of the 2005 version of the Caprini score27 will be used (Fig. 3). 


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IPC SUPER trial, May. 2016, v.1.1 
The primary risk assessment will be performed before randomization. Any patients 
that will receive or will be supposed to receive (e.g., supposed prolonged bed rest in ICU, 
supposed malignancy, CHF, COPD, bowel inflammatory disease, thrombophilia, etc.) a 
score of 11 or more, should be invited into the study. The calculation of the final Caprini 
score should be done before discharge or after patients’ death. So, all new condition and 
complications occurred during the inpatient treatment period will be considered. 
However, some enrolled patients may decrease their score because of unexpected early 
ambulation, misdiagnosis of malignant disease or other co-morbidities. 
 
 
Figure 3. The 2005 version of the Caprini score, reproduced from Bahl V et al., Ann 
Surg. 2010;251(2):344-50. 
 
5.3. Duplex ultrasound scan 
Duplex ultrasound scans will be performed by two blinded experts based at 
different clinical centers. At Center 1, all investigations will be done with MyLab30 
(Esaote, Italy) using a linear transducer with a frequency of 5–13 MHz. At Center 2, 
Voluson I (General Electric, USA) with a linear transducer frequency of 5–13 MHz will be 
used. All veins of the calf and thigh should be observed during every DUS.  
Examinations should be performed in a horizontal position: the common femoral 
(CFV), the femoral vein (FV), the great saphenous vein (GSV) and its tributaries should be 
evaluated in the supine position with light bending in the knee joint. The popliteal vein 
(PV), small saphenous vein (SSV), and its branches should be examined in the prone 
position. If it is not possible to move the patient or the patient is unconsciousness, the PV 


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IPC SUPER trial, May. 2016, v.1.1 
and SSV may be observed during leg supination and bending in the knee joint by ~45 
degrees. The posterior tibial veins (PTV) and the medial group of the calf muscle veins 
should be examined in the supine position with the supinated and slightly bent in the 
knee joint leg. The peroneal veins (PeV) and lateral calf muscle veins should be examined 
in the supine position with pronated and knee bent at 45–90 degrees leg. The anterior 
tibial veins (ATV) should be investigated in the supine position with an unbent knee. In 
case of any problems with calf vein visualization, the examination should be repeated in 
the sitting position with the leg bent in the knee joint at 45 degrees. 
The main criterion for vein patency is compressibility in the B-mode. If it is 
necessary, the color flow mode may be used to reveal blood flow in the target vein with 
the stimulation by manual compression or active movements in the ankle joint. Iliac veins 
and IVC should be observed in case of clinical suspicion of their thrombosis using convex 
transducer with the frequency of 2.5–5 MHz. 
During the primary DUS, it is obligatory to document all post-thrombotic vein 
changes, such as residual venous obstruction and valve insufficiency, and their 
localization in patients with a personal history of DVT. The re-occlusion of the previously 
affected vein revealed during DUS follow-up must be considered as a new DVT. However, 
any changes in the degree of residual venous obstruction should not be considered. 
Besides venous investigation, the ABI at the posterior tibial artery should be 
measured using the pulsed wave Doppler method44 in all screened patients. 
 
5.4. Examination during inpatient treatment 
The following data on surgical procedure should be obtained from the medical 
records after intervention: the surgical profile (e.g., abdominal, thoracic, neck, pelvis, 
cranial), type of surgery (open, endoscopic, endoscopy assisted), urgency of surgery 
(emergent = performed in 0–2 h after admission, urgent = performed in 0–6 days after 
admission, elective = performed independently at the time of admission), radicalism of 
surgery (radical, palliative), type of anesthesia (general, regional, combined), surgery 
duration, blood loss, and intraoperative infusion. 
The routine clinical examination of the patient will be performed in a daily manner 
with special attention to the possible complications, such as DVT, SVT, PE, bleeding, and 
leg skin injury. IPC sleeves should be removed for 15–20 mins every day for skin 
inspection and investigation of pedal pulsation. Consultation of any relevant specialist 


18 
IPC SUPER trial, May. 2016, v.1.1 
(cardiologist, neurologist, pulmonologist, infections) should be performed if any 
complication or development of new co-morbidity will be observed during the follow-up. 
DUS should be performed every 3–5 days after surgery and in emergency manner 
if any clinical suspicion for DVT or SVT appeared. In an emergency manner, DUS may be 
performed by a blinded expert or specialist on duty on weekend and holidays. However, 
all conclusions of non-investigational medical staff must be verified by a blinded expert. 
SPECT/CT or CTPA should be used to verify PE in an emergency manner if clinical 
suspicion appeared. An autopsy must be performed in all died patients to verify the 
absence of DVT and PE. 
In case of any clinical suspicion for a VTE event, IPC should be interrupted until final 
verification of the diagnosis. In the case of positive DUS, CTPA, and SPECT/CT, the 
therapeutic anticoagulation should be prescribed, and IPC should be removed. In the case 
of clinical suspicion for VTE with negative results of instrumental tests, IPC should not be 
returned until the proper diagnosis that mimics VTE will be found. 
Any revealed leg skin lesion should be judged individually for the possibility to 
continue ECS and IPC application. If the decision will be made to stop IPC, the patient 
should be withdrawn from the study according to the protocol. 
 
5.5. Examination during outpatient treatment 
After discharge, patients should be evaluated at 30 and 180 days after surgery. The 
target content of examination should include DUS and clinical examination. However, it 
is allowed to make a phone call to interview the patient about his status and any new 
symptomatic VTE events. 
During the clinical examination, the investigator should revise the patient's medical 
records for any symptomatic or asymptomatic VTE episodes, confirmed by appropriate 
radiological tests. 
DUS in the outpatient settings should be performed by a blinded expert using the 
same methodology. Any new postthrombotic change (residual venous obstruction, 
valvular insufficiency) revealed on the 30th or 180th day of observation and had not been 
documented previously should be considered as a new venous thrombosis corresponding 
with the secondary endpoint. 
If the patient would not be available for head-to-head examination, the phone call 
should be made, and the subject should be interviewed with special attention to possible 


19 
IPC SUPER trial, May. 2016, v.1.1 
clinical signs of symptomatic VTE episode. If the patient will report a VTE episode 
confirmed by an appropriate test, he should be asked to send the medical records on this 
issue by e-mail. If the investigator would find that a patient had died, he should to gather 
appropriate documentation, confirming the cause of the lethal outcome. 
 
5.6. Compliance measure 
No specific compliance measures are designed for the use of ECS and LMWH 
injections. The compliance with the IPC device will be measured as follows. Every day, 
the investigator (weekdays) or surgeon on duty (weekends and holidays) should visit a 
patient five times and check that, if the subject is confined to bed, the sleeves are applied 
to his legs and that the pump is functioning. The results of such visits should be registered 
in a specifically designed compliance sheet (Fig. 4). The compliance will be calculated as 
a proportion of all marks testified that IPC was applied to the total number of visits that 
found patient in the bed.  
 
 
Figure 4. An example compliance sheet, which assessed compliance with IPC. The 
right column represents the result of the calculations.  
 
6. Patients safety 
Administration of the IPC device is a part of standard clinical practice, so patients 
will be not exposed to additional risk. The most common complication for ECS and IPC is 
a skin lesion on the legs. However, patients will be monitored for the possibility of 
developing any of the following: leg skin injury related to mechanical prophylaxis, 
ischemic changes in the lower limbs, and patient discomfort. There is no reason to expect 
the incidence would exceed what is encountered in daily practice.  
 
 
 


20 
IPC SUPER trial, May. 2016, v.1.1 
7. Ethical issues 
The study Protocol and all Amendments should be approved by Ethical Committee 
of the Pirogov Russian National Research Medical University. All subjects must be 
enrolled in the study after reading the patient’s information sheet and providing 
informed consent. All participants will be able to withdraw their consent and stop 
participation at any time. 
 
8. Statistical analysis plan and sample size calculation 
Statistical analysis plan. The primary statistical analysis is designed as intention-
to-treat with the use of two-tailed Fisher's exact test to compare the primary endpoint 
between two groups. The primary endpoint will be reported as an absolute number, 
percentage, and relative risk with 95% CI. Secondary statistical analysis of the primary 
endpoint will be made using an unadjusted Cox proportional-hazards model. The data 
will be censored on the time of VTE registration, or death, or discharge from the hospital 
and reported as a hazard ration with 95% CI. Kaplan-Meier curves will be used to 
compare time-to-event distribution. Cox proportional-hazards models adjusted for the 
clinical center, surgery profile, type of surgery, emergency of surgery, type of anesthesia, 
surgical radicalism, malignant disorder, Caprini score, and time to start LMWH injections 
will be used. 
A similar analysis for the per-protocol population, but that excluded patients with 
gross violations of the protocol and premature discontinuation of at least one component 
of combined prophylaxis (ECS, IPC or LMWH), will be performed for the primary 
endpoint. 
Secondary endpoints will be analyzed with two-tailed Fisher’s exact test and will be 
represented as an absolute number, percentage, and relative risk with 95% CI. 
Cox proportional-hazards models will be used for the prespecified subgroup 
analysis for the following subgroups: surgical profile; type of surgery; the urgency of 
surgery; the radicalism of surgery; type of anesthesia; malignant or benign disorder; 
preoperative, postoperative, or delayed start of LMWH injections; and pre-operative or 
post-operative IPC application. 
Sensitivity analysis will address to the per-protocol analysis, compliance with IPC 
(restricted for 90% and more), duration of follow-up (restricted to 7 days and more), and 
the number of postoperative DUS (restricted with two and more). 


21 
IPC SUPER trial, May. 2016, v.1.1 
Missing data on the primary endpoint are not anticipated in the inpatient settings, 
so no analysis for missing data being planned.  
Adjusting for multiple comparisons and imputation for missing values will not be 
performed. The 95% confidence intervals will be not adjusted for multiplicity, and 
therefore, inferences drawn from these intervals might be not reproducible. The interim 
analysis is not planned. 
Sample size calculation. The prevalence of asymptomatic postoperative vein 
thrombosis at the top of standard prophylaxis with ECS and LMWH was assumed as 30% 
based on our previous observations involving patients at high and extremely high 
risk28,45. Taking into account the fact that pharmaco-mechanical prophylaxis should 
provide a further 60% VTE risk reduction,30 the absolute difference of 18% is assumed. 
Using Fisher’s exact test for primary statistic analysis, with a power of 80% and type I 
error of 0.05, the sample size is estimated as 180 subjects (90+90 in each group). 
Assuming 10% withdrawal due to the protocol deviations, patient’s decision, or 
incomplete data, the sample size is calculated as 200 subjects. Considering prespecified 
subgroup analysis for the patients with an early and delayed start of LMWH, we decided 
to double the sample size to achieve sufficient power for separate analyses of the 
suggested subgroups. IBM SPSS will be used for data processing.  
 
9. Clinical Centers and collaborators 
The author of the study design, study protocol, and principal investigator of the 
study:  
• Kirill Lobastov, MD, Ph.D., Associated professor of the Pirogov Russian 
National Researching Medical University. 
 
Co-authors of the study design: 
• Victor Barinov, MD, Ph.D., Professor of the Central State Medical Academy; 
• Leonid Laberko, MD, Ph.D., Professor of the Pirogov Russian National 
Researching Medical University; 
• Valeriy Boyarintsev, MD, Ph.D., Professor of the Central State Medical 
Academy; 
• Grigoriy Rodoman, MD, Ph.D., Professor of the Pirogov Russian National 
Researching Medical University; 


22 
IPC SUPER trial, May. 2016, v.1.1 
 
Clinical centers:  
• Center 1 - Clinical Hospital no. 1 of the President’s Administration of the 
Russian Federation (10 Starovolynskaya street, Moscow, Russian 
Federation, 12135) 
• Center 2 - Moscow Clinical Hospital no. 24 of the Moscow Health Department 
(10, Pistsovaya street, Moscow, Russian federation, 127015). 
 
Investigators: 
• Center 1: Eleanora Alencheva, MD, Ph.D. student at the Central State Medical 
Academy; 
• Center 2: Ekaterina Sautina, MD, Ph.D. student at the Pirogov Russian 
National Researching Medical University. 
Blinded experts: 
• Center 1: Victor Barinov, MD, Ph.D., Professor of the Central State Medical 
Academy certified for ultrasound diagnostic in 2011; 
• Center 2: Astanda Bargandzhiya, MD, Ph.D., Assistant at the Pirogov Russian 
National Researching Medical University, certified for ultrasound diagnostic 
in 2012.  
Data Monitoring Committee: 
• Leonid Laberko, MD, Ph.D., Professor of the Pirogov Russian National 
Researching Medical University; 
• Ilya Schastlivtsev, MD, Ph.D., Associated professor of the Pirogov Russian 
National Researching Medical University 
 
 
 
 
 
 
 


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IPC SUPER trial, May. 2016, v.1.1 
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