Prevention of Thromboembolism and Failed Healing During Lower Limb Immobilization - Multicenter Study With Adjuvant Intermittent Pneumatic Compression Therapy
Phase: NA
Conditions: Achilles Tendon Rupture, Ankle Fractures, Venous Thromboembolism
Sponsor: Karolinska University Hospital

STOP Leg Clots – Study Protocol 
1 
 
 
 
 
STOP Leg Clots  
- 
 
Swedish-international multicenter Trial of 
Outpatient Prevention of Leg Clots 
 
 
 
 
Prevention of thromboembolism and failed healing during lower 
limb immobilization –  
a multicenter study with adjuvant intermittent pneumatic 
compression therapy 
 
 
Date of document: 200901 
 
 
Identifiers: NCT03259204   Unique Protocol ID: 2017-00202 
 

STOP Leg Clots – Study Protocol 
2 
 
STOP Leg Clots - 
 
Swedish-international multicenter Trial of Outpatient Prevention of Leg Clots 
 
 
Prevention of thromboembolism and failed healing during lower limb immobilization –  
a multicenter study with adjuvant intermittent pneumatic compression therapy 
 
 
Purpose and Aims 
 
Complications related to lower limb immobilization, such as venous thromboembolism (VTE) 
and delayed healing, after musculoskeletal trauma and reconstructive surgery represent 
increasing problems. The National Health Service in England has identified prophylaxis of 
VTE as the number one prioritized intervention 1 2.  
 
As a result of trauma and post-operative lower limb immobilization and associated impaired 
neuro-vascular supply, patients exhibit an increased risk of VTE and hampered healing. 
Pharmacoprophylaxis for VTE in patients with lower-leg immobilization has, however, 
demonstrated low or non-effectiveness3 4 5. Thus, there is no consensus for prevention, and 
a need for novel treatment strategies 1 2 4. 
 
Our hypothesis is that leg immobilization calls for promoted blood circulation using adjuvant 
mechanical compression. This intervention, in the form of intermittent pneumatic 
compression (IPC) therapy, targets the primary cause of impaired neuro-vascular flow. IPC 
might reduce the risk of VTE and improve healing by respectively increasing the local supply 
of anticoagulants and healing mediators.  
 
We aim to demonstrate that adjuvant, outpatient IPC-therapy in lower-leg immobilized 
patients, compared to treatment-as-usual, reduces VTE-incidence and improves healing. 
This VTE-preventive intervention can without delay be adapted in daily health care in order to 
increase patient safety and reduce costs as compared to pharmacological alternatives. 
 
The primary outcome measure is the VTE-incidence at the end of immobilization, i.e. about 
at six weeks. Secondary outcome measures are patient-reported outcome assessed with 
validated scores, and effects on healing callus production with microdialysis and levels of 
profibrinolysis factors.  
 
 
Survey of the Field 
 
International guidelines offer opposing recommendations regarding VTE-prevention during 
leg-immobilization. The American College of Chest Physicians recommends no 
pharmacologic thromboprophylaxis, low molecular weight heparin (LMWH), due to the 
increased risk of bleeding in relation to the expected low effect of LMWH4. Furthermore, 
NICE, UK, recommends to consider offering LMHW to leg-immobilized patients after 
evaluating the risks of VTE and bleeding1. Thus, today the clinical practice of VTE prevention 
in leg-immobilization varies considerably 6 7, and lacks strong evidence5. 
 
The risk of VTE in association with trauma/surgery and leg-immobilization is high, with an 
estimated deep venous thrombosis (DVT) rate of 25% up to 50% after e.g. Achilles tendon 
rupture (ATR)8 9. Today it is known that also asymptomatic DVTs often may result in 
pulmonary embolism10. Pharmacologic thromboprophylaxis (LMWH) in patients with lower-

STOP Leg Clots – Study Protocol 
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leg immobilization has, however, shown to be low- or even non-effective in some studies5 7 3 4 
11. The latest meta-analysis of LMWH in leg-immobilized patients show only a moderate 
prevention on DVT because risk of bias and no preventive effect on pulmonary embolism5. 
Moreover, LMWH exerts adverse effects on the healing process12 and increases the risk of 
bleeding complications3 4. Thus, NHS, UK and SBU, Sweden have identified the need to 
develop safer and more efficient VTE-prophylaxis1 2 13. 
 
Mechanical thromboprophylaxis (IPC) reduces VTE, is a cost-effective intervention in 
hospitalized patients, and is recommended by guidelines for surgical patients1 14. Whether 
IPC treatment applied during leg immobilization and performed in an outpatient setting can 
reduce the incidence of DVT is unknown. Therefore, mechanical thromboprophylaxis is not 
yet mentioned in guidelines for leg-immobilized patients. Recently, however, we published 
the first evidence that leg immobilized patients with ATR treated with adjuvant IPC exhibited 
a DVT-rate of 21% compared to 37% in the controls at 2 weeks. IPC intervention ended at 
two weeks, and thus at 6 weeks the DVT-rate was 50% in both groups9. 
 
Thus, it remains to show if prolonged adjuvant IPC therapy during the whole 6 weeks 
immobilization period could reduce the incidence of VTE in leg-immobilized patients, also in 
patients with fractures. Can the IPC treatment synchronously enhance the healing process 
so that it will lead to a long-term increased patient-reported outcome? Recent studies 
suggest that the increased neuro-vascular flow induced by IPC enhances the healing 
process15.  
 
 
Research question 
 
The primary research question is: 
• 
Does addition of IPC to patients with lower limb immobilization in routine care, reduce 
the incidence of VTE up to the end of immobilization, i.e. 6-8 weeks. 
 
Secondary questions are: 
• 
Can adjuvant IPC during leg immobilization enhance fracture/soft tissue healing and 
improve patient-reported outcome?  
• 
Does IPC reduce VTE incidence by upregulation of profibrinolysis?  
 
 
Variables and measures  
 
Primary outcome (binary), VTE, is defined as symptomatic or asymptomatic deep venous 
thrombosis (DVT) assessed at six weeks of immobilization by screening compression duplex 
ultrasound (CDU), or symptomatic pulmonary embolism detected by computer tomography. 
Assessors of CDU will be skilled ultrasonographists, masked to the treatment allocation9. The 
CDU-examination will document absence/presence of thrombus in the calf, popliteal and 
femoral veins separately, as previously described9. All positive examinations and those 
considered technically difficult will be reviewed by a specially trained vascular physician 
(blinded to the treatment allocation), who will establish the diagnosis and classify the 
examination result as absence or presence of thrombus. This will show the incidence of VTE 
in each group. 
 
We acknowledge that the CDU assessment of DVT will be the dependent measure of 
outcome since DVT is more common than pulmonary embolism. CDU screening (surrogate 
outcome), can be justified because of the clinical significance attributed to even 
asymptomatic DVTs, which today are known to cause a high rate of pulmonary embolism, 
affect the patient outcome16 and are treated by most clinicians with anticoagulant therapy10. 
To reliably confirm or refute an effect of IPC on survival or clinical pulmonary embolism a 

STOP Leg Clots – Study Protocol 
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randomized trial would require a sample size of several tens of thousands of patients; this is 
not currently possible.  
 
The secondary outcome measure is patient-reported outcome (PRO) assessed with reliable 
and validated rating-scales (0-100 points); EuroQol (EQ-5D-5L), the Achilles Tendon total 
Rupture Score (ATRS), foot and ankle outcome score (FAOS), and Olerud-Molander Ankle 
Score (OMAS) at 6 and 12 months. Data of both groups (IPC vs. no IPC) will be presented 
by mean, median, standard deviation, and range. EQ-5D-5L is a validated, generic health-
related quality of life measure consisting of five items each with a five-level answer 
possibility. Each combination of answers is converted into a health index score17. The EQ5D-
index is measured on an interval scale and, thus, analyzed with parametrical statistics. ATRS 
(ordinal scale) is a validated ATR PRO measure18, while OMAS (ordinal scale) and FAOS 
(ratio scale) are validated for ankle fractures19. Functional evaluation of the ATR-healing will 
be performed by the validated heel-rise test at one year post-injury18 16. Heel-rise height and 
work (continuous data) of both groups will be presented20. 
 
Callus production (continuous data) in ATR and ankle fracture (AF) patients will be assessed 
at six weeks using microdialysis followed by quantification of procollagens, which recently 
emerged as a method to assess tendon healing15 22 23. For fracture healing quantification of 
bone formation markers (alkaline phosphatase, osteocalcin, and pro-collagen type I 
propeptide) will be performed.  
  
VTE-preventive mechanisms will be analyzed at the six week visit by assessments of 
profibrinolysis and coagulation as well as by blood-flow quantification using ultrasound24. 
Overall hemostatic potential (OHP), D-dimer, plasminogen activator inhibitor-1 (PAI-1), 
endogen trombin potential, trombin antitrombin complex, plasmin antiplasmin complex, tissue 
plasminogen activator/PAI complex will be assessed at Karolinska Institutet, Coag. Unit, Ass. 
Prof. J. Antovic. Peak femoral blood velocity will be calculated using custom ultrasound 
software and compared with baseline values, while microcirculation and tissue oxygenation 
will be assessed by near-infrared spectroscopy (INVOS®)25 24. These explanatory continuous 
data will be compared between the groups. 
 
Further patient data that will be analyzed as secondary outcome measures at 2 and 6 weeks 
are adherence to allocated treatment and adverse events related to IPC. Adverse events 
(binary) that will be registered are 1) Any damage to the skin of the legs including infection. 
2) Any reasons for prematurely stopping the IPC. 3) Any fall associated with significant injury 
occurring within 6 weeks of enrollment. The frequency of the adverse events of each group 
will be presented9. 
 
Health economic analyses, together with Karolinska Institutet, LIME, Med. dr. Peter Lindgren, 
of the trial treatment effects will involve a within-trial evaluation of cost effectiveness 
integrated into a decision-analytic model of longer run costs and health effects. 
 
Study Design (PICO) 
“STOP leg clots” is an international, multicentre prospective randomized, controlled, parallel 
group trial with blinded assessment of the outcome. The allocation ratio is 1:1. The study has 
an Ethical review board approval 2016/1753-31 and is registered at clinicaltrials.gov. 
 
Patients: At least 20 hospitals in a minimum of twelve regions have accepted to participate, 
and this captures a study population, which is representative of Sweden. The included 
patients, ATR and ankle fractures, are representative of, and constitute a large part of the 
population with lower limb immobilization. Moreover, patients with ATR and AF have 

STOP Leg Clots – Study Protocol 
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demonstrated low- or non-effectiveness of LMHW prophylaxis also in relation to the risk of 
bleeding complications3 4. Therefore, there is a need for an alternative prophylaxis with 
documented effects.  
 
In the perspective that different hospitals have different clinical traditions/indications for 
surgery of ATR and AF we have chosen to include both operated and non-operated ATR/AF, 
since both groups are equally served by VTE prophylaxis. Earlier studies have shown a just 
as high incidence of VTE in non-operated as in operated ATR/AF 6, further indicating a 
benefit of demonstrating a VTE risk reduction in both operated/non-operated lower limb 
immobilized patients. Surgery vs. no surgery will be accounted for in the statistical analysis. 
 
Intervention: There is a need for new VTE prophylactic methods, especially in lower limb 
immobilized patients. IPC has been demonstrated cost effective both as adjuvant and versus 
no pharmacoprophylaxis in hospitalized patients by NICE. However, in an outpatient setting 
there are yet only recent short-term data of the efficacy of IPC. There is a need for data on 
the efficacy of IPC during long-term leg immobilization to inform guidelines. 
 
The intervention, addition of IPC to routine care, will be administered in the emergency 
department or in the outpatient clinic. Patients will during the six weeks of lower limb 
immobilization receive bilateral calf IPC (Venaflow Elite, DJO LLC, Vista, CA, USA) applied 
under an orthosis (Aircast® AirSelect Elite, DJO LLC, Vista, CA, USA). This IPC-system 
delivers rapid inflation and graduated sequential compression. The IPC device is mobile and 
should therefore not restrict patient mobilization, but can be taken off if the patient wants to 
mobilize independently. The patients will be instructed to apply the IPC-therapy continuously, 
both day and night. Compliance with the treatment will be registered by both the patient and 
by the device9. American College of Chest Physicians recommend that efforts should be 
made to achieve 18 h of daily compliance with IPC in hospitalized patients17. However, there 
are no recommendations for mobile outpatients. Outpatients were in our recent study 
recommended at least 6h daily therapy, and in this study we will increase the 
recommendation to 10h/daily. Graduated compression stockings are part of IPC-care and 
these should be applied and worn under the IPC sleeves on both legs. IPC will be 
discontinued if the patient declines to continue IPC or had adverse effects of the IPC that 
warrants removal. At the 2 and 6 weeks visit the orthosis will be removed by a nurse and the 
patient will be examined by an orthopaedic surgeon (masked to the treatment allocation), 
who will document compliance and adverse events. At the 6 weeks visit the patient will also 
be sent for CDU-examination, which will document the main outcome. Patients will during the 
six weeks leg immobilization be weight-bearing with crutches or non-weight-bearing with 
crutches according to the preference of the orthopedic surgeon (masked to the treatment 
allocation). Weight-bearing will be recorded and accounted for in the statistical analysis. 
 
Comparator: Since there are no documented highly effective therapies for DVT reduction 
during leg immobilization, and guidelines vary regarding prophylaxis, we chose to use 
treatment-as-usual as a comparator, regardless of LMHW use or not3 4. Based on our 
calculations less 10% of the patients will receive LMHW in clinical practice and our power 
calculations has taken this into account. NICE has stated that LMWH is not a feasible 
general treatment, especially health economically, during six weeks for all patients with leg 
immobilization. One review, including 1,490 patients from six randomized trials, showed a 
small reduction in DVTs using LMHW8. However, they concluded that more research is 
needed to develop more effective and safe thromboprophylactic treatments. Moreover, since 
a study with LMHW as a comparator would necessitate too many patients - this was not an 
option. The main research question remains: Is adjuvant IPC more effective than routine care 
for reducing the incidence of VTE in patients during lower limb immobilization? The usage of 
no general VTE-prevention in the comparator group is moreover justified since a DVT-
screening will be performed on all patients. LMWH vs. no LMWH will be accounted for in the 
statistical analysis. If a VTE is detected we will follow clinical guidelines and initiate 

STOP Leg Clots – Study Protocol 
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pharmacological VTE-treatment. 
 
The comparator, routine care, lower limb immobilization will be administered by normal 
routine in the emergency department or in the outpatient clinic. Routine care include that the 
lower limb will be immobilized in an orthosis or a below-knee plaster cast according to local 
routines. At the 2 and 6 weeks visit the orthosis/plaster cast will be removed by a nurse who 
will document compliance. Subsequently, the patient will be examined by an orthopaedic 
surgeon (masked to the treatment allocation), who will document adverse events. At the 6-8 
weeks visit the patient will also be sent for CDU-examination, which will document the main 
outcome. Patients will during the six weeks leg immobilization be weight-bearing with 
crutches or non-weight-bearing with crutches according to the preference of the orthopedic 
surgeon (blinded to the treatment group). Weight-bearing will be recorded and accounted for 
in the statistical analysis. 
 
Outcome: The primary outcome, VTE at 6 weeks post-immobilization, will best be assessed 
by screening CDU of DVTs. CDU is rapidly becoming the investigation of choice to confirm 
the diagnosis of DVT since it is non invasive. It is acceptable to patients, can easily be 
repeated several times and uses equipment, which is widely available. Thus consent, accrual 
and adherence in a trial are likely to be more easily achieved than with alternatives. 
 
The primary outcome will be validated by the explanatory outcome of VTE-prevention, 
assessed by quantification of blood flow, profibrinolysis and coagulation factors from blood 
serum taken by a study nurse at the 6 weeks visit. 
 
A long-term effect of IPC on VTE and healing will be confirmed by the secondary patient-
reported outcome measures (PROM). We have data suggesting that an asymptomatic DVT 
affects PROM at 1 year16. The PROM will be assessed by the patient filling in the validated 
questionnaires (EQ-5D-5L, ATRS, FAOS, OMAS) at the 1 year visit at the physiotherapist, 
who will also perform the functional evaluations, i.e. heel-rise tests. If any patient will miss 
the 1 year visit, the questionnaires will be sent home to the patient. 
 
An IPC effect on tissue healing will be corroborated by assessment of callus production. 
Callus production in ATR and AF patients is assessed at 6 weeks by microdialysis followed 
by quantification of procollagens15. 
 
To further control that the outcome measures are registered correctly, independent data 
monitoring and help with data management will be performed by eg. Karolinska Trial Alliance 
(KTA). Major outcome events (including serious adverse events believed to be due to 
treatment) will be supplied. All data will be reported using an online system registration at 
Karolinska Institutet called RedCap, which is a validated patient reporting tool used at over 
300 universities.  
 
Trial Organization: The Steering Committee will consist of Paul Ackermann (PI), Bengt 
Eriksson (VTE expert), Lasse Lapidus (VTE expert), Fausto Labruto (Radiologist, 
compression Doppler ultrasound), Gunnar Edman (Statistician), Luigi Belcastro (coordinating 
study nurse), Kenneth Jonsson (bone healing), Jon Karlsson (expert on patient-reported 
outcome), and Therese Djärv (Patient representative).  
 
National collaborators from 12 regions in Sweden, 23 hospitals, have already agreed to 
participate in this multicenter study. Stockholm region: Karolinska University Hospital Solna 
and Huddinge, Danderyd Hospital, Stockholm South General Hospital, Södertälje and 
Norrtälje Hospital. Uppsala region: Uppsala University Hospital. Östergötland region: 
Linköping University Hospital. Gotland region: Visby lasarett. Skåne region: Skåne University 
Hospital in Lund and in Malmö. Halland region: Kungsbacka Hospital. Västra Götalands 
region: Sahlgrenska University Hospital, Östra Hospital, Kungälv Hospital. Värmland region: 

STOP Leg Clots – Study Protocol 
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Karlstad Central Hospital. Gävleborg Region: Gävle and Bollnäs Hospital. Västerbotten 
region: University Hospital Umeå. Örebro: University Hospital Örebro, Karlskoga lasarett, 
Lindesberg lasarett. Jönköping region: Eksjö Hospital. 
 
International collaborators from Rizzoli hospital in Bologna, Italy have shown interest to 
participate. 
 
Estimated sample size and power 
 
We plan to include at least 1400 patients, with 10% drop-out accounted for, although our 
earlier study demonstrated a 5.3% drop-out9. Many patients will in clinical routine receive 
LMWH, which is accounted for. This gives the trial 90% power (alpha 0.05) to identify an 
absolute risk reduction of 8% (28% vs. 20%) and relative risk reduction of 29% in primary 
outcome. The expected relative risk reduction is higher, 40%, and the minimum clinical 
relevant absolute risk reduction in primary outcome between the groups is 4% based on 
recent studies9 26. 
 
The frequency of our primary outcome is given from recent studies showing a 50% rate of 
CDU-verified DVTs after ATR and 25% rate after ankle fracture (AF)9 27. This gives a total 
DVT-rate of 33% when including two AF for every ATR. As extra precautions we reduced the 
expected total DVT-rate from 33% to 28% and reduced the relative risk reduction from 40% 
to 30%.  
 
The 1400 included patients will consist of at least 400 ATR- and at least 1000 AF-patients, 
with the same drop out as above. For subgroup analyses (ATR / AF) this gives the trial 80% 
power (alpha 0.05) to detect a 30% relative risk reduction and an absolute risk reduction of 
8% (25% vs. 17%) for AF and 15% (50% vs. 35%) for ATR in primary outcome. 
 
The mean inclusion per hospital is (one)-two AF each week and one ATR every second 
week, which totals at least a mean of 75 patients/hospital/year9. With 1,5 patients included 
per week per each hospital (20 hospitals registered), we will finish inclusion within one year. 
 
For the secondary patient-reported outcomes, the trial has more than 95% power (alpha 
0.05) to identify a clinically relevant difference, which at one year is 10 points difference on 
the rating scales (0-100)20. For the explanatory VTE-preventive mechanisms (blood serum 
test) and collagen production (microdialysis) earlier studies demonstrate that a sample size 
of 100 gives 90% power to detect significant differences between groups, which will save 
expenses. 
 
Treatment compliance of the patients, which was 91% in our earlier study, will be registered 
both by the IPC-device and by the patient. Patients will daily register the number of hours 
that IPC was used.  
 
 
Material: Patient selection – population, sample 
 
Male and female patients aged between 18 and 75 years with an acute injury requiring lower-
leg immobilization, i.e. acute unilateral ATR or isolated AF, in a hospital setting will be 
eligible. The exclusion criteria will be: inability to give informed consent; planned follow-up at 
another hospital; renal failure; heart failure with pitting oedema; thrombophlebitis; 
malignancy; peripheral vascular disease; haemophilia/thrombophilia and pregnancy 9. 
 
The randomising clinician or nurse will screen for eligible patients as soon after their 
presentation to hospital as possible. To minimize differences between hospitals, patients will 
be eligible for inclusion if treatment starts within 10 days after the injury. IPC-prophylaxis for 

STOP Leg Clots – Study Protocol 
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DVT may have greater effect if started early after injury, but these potential differences will 
also be considered below. The responsible clinician collects the baseline data necessary to 
complete a randomization form. He/she then will randomize patients via a central, web-based 
service (RedCap) by giving the baseline data (which are then stored securely) and receives 
the treatment allocation at the end of the session.  
 
The randomisation form should be filed in the patient’s medical notes, along with one copy of 
the signed informed consent form and patient brochure. The patient should receive a patient 
brochure along with a signed copy of the consent form. Copies should also be kept in the site 
file. The treatment allocation will be blinded for the assessors of outcome; i.e. 
ultrasonographists doing the CDU, physiotherapists or nurses performing the patient 
reported outcomes. The IPC-therapy will, due to its nature, not be blinded to the patient and 
the clinician applying the therapy. 
 
 
 
Statistical analysis plan (Gunnar Edman, statistician) 
 
All analyses will be based on intention to treat. We will analyze patients in the groups they 
are randomized to, regardless of treatment received. A patient might be withdrawn because 
of severe non-adherence or withdrawal of consent by the patient. For binary outcomes (e.g. 
occurrence of a primary or secondary outcome OR not), outcomes will be presented as odds 
ratios and 95% confidence intervals, adjusted using logistic regression for the factors used in 
the minimization algorithm and weight-bearing. We will calculate absolute reductions in risk 
from these values, as presented in the reference with similar study design26. 
 
Group differences for ordinal secondary outcome data, such as the patient-reported data 
(ATRS and OMAS), will be analyzed by nonparametric tests20. Group differences for EQ5D-
5L (index scale), FAOS (ratio scale) and continuous secondary outcome data will be 
analyzed by t-tests if the data are normally distributed, and using an appropriate 
nonparametric test otherwise.  
 
Subgroup analyses will be performed to determine whether certain types of patients might 
gain greater or less benefit from IPC. We will estimate the effect of treatment allocation on 
the primary outcome subdivided by key baseline variables and adjusted for the other factors 
included in the minimization algorithm. Subgroup analyses will be performed by observing 
the change in log-likelihood when the interaction between the treatment and the subgroup is 
added into a logistic regression model. We will determine whether there is significant 
heterogeneity between these subgroups. The following preplanned subgroup analyses will 
be performed: 
 
Is IPC more effective in patients at higher risk of DVT? It seems likely that patients at 
higher risk of DVT might gain greater benefit from IPC than those at lower risk. Patients with 
ATR exhibit higher risk of DVT than patients with AF, and patients aged ≥ 40 years exhibit 
almost fivefold higher odds of developing DVT9. Moreover, prior history of DVT, weight-
bearing, and surgery are likely to affect the risk of DVT. Therefore, we will undertake 
subgroup analyses of the effect of allocation to IPC on the primary outcome among patients 
with and without at least one of these factors at baseline. 
 
Analysis of impact of delay in applying IPC? There is often a delay in presenting or being 
treated with a lower limb injury (ATR/AF) and therefore this can lead to a delay in applying 
VTE prophylaxis. Moreover, patients may even suffer a VTE before treatment is initiated. 
Thus, we hypothesize that IPC will reduce the frequency of the primary outcome to a greater 

STOP Leg Clots – Study Protocol 
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extent among patients enrolled early compared to later. We will therefore examine the effect 
of treatment among patients enrolled early versus later after injury. 
 
Compliance and duration of treatment with IPC? IPC compliance was 91% in our recent 
trial, but has usually been used for a relatively short time on perioperative patients and in 
outpatients. There is a concern that IPC may not be used for the whole six weeks or that it 
will not be applied continuously. We will therefore carry out additional analyses in order to 
determine how IPC- compliance affects the primary outcome.  
 
Economic analyses: Economic analysis of the trial treatment effects will involve a within-
trial evaluation of cost effectiveness integrated into a decision-analytic model of longer run 
costs and health effects. The within-trial analysis will be conducted on an intention-to-treat 
basis. The primary health endpoints will be VTE times adjusted for patient reported outcome.  
A societal perspective will be taken for assessing costs of patient´s care during the six-week 
immobilization. Patient-specific hospital resource use will be measured. The net direct 
medical cost will include a cost estimate of IPC capital/equipment (and staffing implications) 
and the averted costs arising from the effects of IPC on expected DVT/PE incidence. 
Probabilistic sensitivity analysis will also be used to assess the hospital cost distributions. 
 
Specific intermediate objectives 
 
The Steering Committee will meet every 4th month. Milestones at these meetings will consist 
of an inclusion rate of at least 200 patients/4 months, adequate data monitoring by 
Karolinska Trial Alliance and that the primary outcome has been reported in more than 80% 
of the patients. If the inclusion rate drops significantly below 200 patients, then more 
hospitals will be included in the study. These milestones will be reported to the Swedish 
Research Council. 
 
 
 
 
 
 
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