Intermittent Pneumatic Compression to Improve the Outcome of Revascularization for Severe Peripheral Artery Disease: a Pilot Study
Phase: NA
Conditions: Peripheral Arterial Disease
Sponsor: Indiana University

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Intermittent pneumatic compression to improve 
the outcome of revascularization for severe 
peripheral artery disease: a pilot study 
 
Identifiers: NCT04250675  
Unique Protocol ID: 1907961196 
 
 
 
 
 

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Table of Contents: 
 
Study Schema 
1.0 
Background 
2.0 
Rationale and Specific Aims 
3.0 
Inclusion/Exclusion Criteria 
4.0 
Enrollment/Randomization 
5.0 
Study Procedures 
6.0 
Reporting of Adverse Events or Unanticipated Problems involving Risk to 
Participants or Others 
7.0 
Study Withdrawal/Discontinuation 
8.0 
Statistical Considerations 
9.0 
Privacy/Confidentiality Issues 
10.0 Follow-up and Record Retention 
 
 

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1.0 
Background 
 
Peripheral artery disease (PAD) is characterized by atherosclerotic obstruction of the 
arteries in the lower extremities and affects approximately 10% of individuals older than 65 years. 
Patients with symptomatic PAD experience walking impairment and declines in physical 
performance and quality of life. At the extreme end of the clinical spectrum, patients with critical 
limb ischemia (CLI) have ischemic pain at rest and develop nonhealing or gangrenous wounds that 
might necessitate limb amputation. These patients with severe PAD require comprehensive 
medical management and effective limb revascularization to augment tissue oxygenation, promote 
wound healing and reduce pain. Endovascular and surgical interventions are considered in patients 
with PAD who have developed lifestyle-limiting claudication no longer responsive to conservative 
therapy and CLI. Patients with symptomatic PAD receiving intensive evidence-based therapies 
undergo peripheral revascularization frequently, with approximately 1 in 5 (19.3%) undergoing 
procedures at 3 years. Despite major technological advances in surgical and endovascular care, a 
significant number of patients with severe PAD that undergo revascularization procedures are 
readmitted because of persistent symptoms and loss of patency. Restenosis occurs frequently, 
within the first year after an intervention. There remains an urgent need for adjunctive therapies 
that aid in the improvement of tissue blood flow and consequently relieve pain and improve 
functional capacity in these patients. 
  
2.0 
Rationale and Specific Aims 
 
One emerging adjunctive therapy that has the potential to enhance the benefits of 
revascularization procedures for severe PAD is the application of intermittent pneumatic leg 
compressions (IPC). This is a non-invasive intervention, consisting of an air pump inside inflatable 
cuffs that are wrapped around the feet, ankles, and calves and 
worn for two hours daily. Every 20 second, the cuffs rapidly 
inflate, followed by rapid deflation. We and others have 
previously shown that exposure to IPC markedly enhances 
leg blood flow and vascular shear-stress in the arteries of the 
leg (2, 6, 7). Our preliminary work shows that 2 weeks of 
daily application of IPC enhances exercise tolerance in a 
model of PAD, in part by enhancing blood flow to collateral-
dependent tissues (4). IPC has also been shown to reduce 
amputation rates in patients with CLI without a 
revascularization option. The objective of this pilot study is 
to establish evidence to support the validity of IPC in 
improving the outcome of lower-extremity revascularization 
for severe PAD. Our central hypothesis is that the treatment with IPC will lead to greater 
improvements in leg hemodynamics as compared to a sham device. As a result, we anticipate that 
patients treated with IPC will report less rest pain, have enhanced walking endurance and improved 
calf muscle oxygenation resulting in a subsequent improvement in quality of life. To test this 
hypothesis, we propose the following specific aim: 
 
SPECIFIC AIM: Determine the effects of IPC following revascularization in patients diagnosed 
with severe PAD.  
Figure 1: Intermittent pneumatic 
compression device 

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Patients will be enrolled in the study approximately 3 months after the revascularization 
procedure and will be randomly assigned to one of two groups: IPC or placebo pump. Patients will 
receive a commercially available IPC device (ArtAssist, ACI Medical, San Marcos, CA) and will 
be asked to apply the treatment to both legs at home for 2 hours daily during 3 consecutive months.  
Prior to the onset of the treatment and 1 and 3 months after daily home-based IPC , we will assess 
patient’s leg hemodynamics, rest pain, calf muscle oxygenation during exercise, walking 
endurance and quality of life. We expect beneficial changes in leg hemodynamics, reduced rest 
pain, increased levels of exercise tolerance, improved calf muscle oxygenation during exercise, 
and improved quality of life, (QOL) as assessed by responses to VascuQol and SF36 
questionnaires. The ankle-brachial index (ABI), the toe-brachial index (TBI), and rest pain will be 
assessed on the leg undergoing the revascularization procedure and the opposite leg. 
Transcutaneous PO2 (TcPO2) and calf muscle oxygenation will only be assessed in the leg 
undergoing revascularization.  
 
 
3.0 
Inclusion/Exclusion Criteria 
 
Inclusion criteria 
 
1) At least 18 years of age 
2) Evidence of significant obstructive disease for one or multiple lower extremity arteries, as 
identified by prior ABI, TBI, CT angiography, ultrasound, or MR imaging 
3) Completed endovascular or surgical revascularization of one or both lower extremities 
within the past 3 months (± 14 days) 
 
Exclusion criteria 
 
1) Chronic kidney disease (eGFR <30 by MDRD or Mayo or Cockcroft-Gault formula) 
2) Open and/or non-healing wounds in the areas covered by the IPC cuff 
3) Inability to walk on the treadmill 
4) Abnormal baseline treadmill stress test 
5) Walking limited by a symptom other than PAD 
6) Inability to independently and correctly position the IPC cuff on legs and feet 
7) Presence of any clinical condition that makes the patient unsuitable to participate in the 
trial 
8) Concern for inability of the patient to comply with study procedures and/or follow up 
(e.g., alcohol or drug abuse) 
9) Acute deep vein thrombosis (DVT) either suspected or diagnosed 
10) Uncontrolled infection 
11) Increased pain with ArtAssist device operating or with worsening skin tissue condition 
12) During episodes of inflammatory phlebitis or pulmonary embolism 
13) When increased venous or lymphatic return is undesirable including presumptive 
evidence of congestive heart failure 
 
 

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4.0 
Enrollment/Randomization 
 
Patients will be recruited by Dr. Raghu Motaganahalli and his associates at the Indiana 
University Health Methodist Hospital, Indiana University Health West Hospital and Indiana 
University Health Arnett. Patients that fulfill the inclusion criteria and are interested in 
participating in the protocol will receive detailed instructions about the experimental set-up and 
measurements and will be given a consent form. After providing consent, patients will be asked to 
complete the baseline assessment, including the assessment of leg hemodynamics, rest pain, calf 
muscle oxygenation during exercise, walking endurance and quality of life. Patients will be 
randomized into one of two groups: IPC (n=4) or placebo pump (n=4). Patients will receive an 
IPC device and will be asked to apply the treatment at home for 2 hours daily during 3 consecutive 
months. Outcomes will be reassessed 1 and 3 months after the onset of home-based treatment.  
 
5.0 
Study Procedures 
 
After enrollment, subjects will be asked to complete two experimental sessions for baseline 
testing. The procedures involved in each visit are listed on Table 1. Subjects will be asked to fast 
overnight and refrain from smoking or using alcohol for 4 hours prior to attending all experimental 
sessions. Subjects will be permitted to take their usual morning medication. Although fasting and 
refraining from tobacco, alcohol and exercise are desired for testing consistency, it will not be 
considered a protocol deviation if the subject does not follow these instructions prior to one of the 
study visits. On visit 1, demographic and anthropometric characteristics from participants will be 
initially recorded. Patients will be asked to report the pain in their legs using visual analog scale 
(VAS). The study coordinator will demonstrate how to operate the IPC pump on how to wear the 
legs cuffs. Participants will be given the opportunity to independently place the cuffs around their 
legs. Individuals that are unable to successfully complete this task without help will be excluded 
from the study. Participants will then perform a standard symptom-limited cardiopulmonary 
exercise test on a treadmill. A near-infrared spectroscopy (NIRS) system, which measures skeletal 
muscle oxygenation, will be placed on the calf of the most symptomatic leg. Participants with an 
abnormal baseline treadmill stress test, including signs of coronary ischemia and an exaggerated 
pressor response, will be excluded from the study. This session (Visit 1) will be performed at 
Methodist Hospital and is expected to last approximately 3 hours. 
At least 72 hrs after visit 1, subjects will be asked to return for visit 2. Participants will be 
asked to lay supine and a member of the Vascular Access Team (VAT) will draw a blood sample 
(20 mL) from one antecubital vein in the arm. Next, participants will undergo the bilateral 
assessment of the ankle-brachial index (ABI), the toe-brachial index (TBI) and transcutaneous 
PO2 (TcPO2) following standard of care practices. Patients will be asked to report the pain in their 
legs using visual analog scale (VAS). Patients will then be escorted to the exercise testing lab to 
undergo a graded, symptom-limited cardiopulmonary exercise test on a treadmill as described for 
visit 1. At the end of the session, subjects will be asked to fill out two questionnaires to assess 
generic (36-item Short-Form Health Survey) and disease-specific (Walking Impairment 
Questionnaire) quality of life. Next, patients will be trained on how to operate the IPC pump on 
how to wear the cuffs and will undergo a 15-min practice treatment session. At the end of the 
practice session, participants will be trained on: 1) how to wash and care for the inflatable cuffs, 
2) how to turn the pump on and off, 3) how to record usage time on a logbook. Participants will 
receive the ArtAssist device (ACI Medical Inc, San Marcos, CA, USA) for IPC application. This 
device applies compressions to both the calf and foot, at a pressure of 120 mmHg for 3 seconds 

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per cycle, and this continues for three cycles per minute with a 1-second delay between different 
segment inflation. Patients allocated to the control group will receive a sham device, that applies 
a pressure of 30 mmHg at the frequency specified above. Participants on both groups will be asked 
to apply the cuffs to both legs and use the device while seated for 2 hours daily for 3 months. This 
session (Visit 2) will be performed at IU’s Methodist Hospital and is expected to last 
approximately 4 hours. 
Patients in both groups will receive weekly telephone calls from the study coordinator to 
verify compliance and will receive a logbook to record their sessions. A timer built into the IPC 
unit, and inaccessible to patients, will also provide an estimate of the patients’ compliance with 
the treatment regimen. The logbook is intended to assist the participant keep track of the daily 
treatments; it will not be a protocol deviation if the logbook is not returned at the end of the 
treatments.  Compliance with daily treatment will be formally assessed and documented with the 
weekly phone call from the study team.  A protocol deviation will occur when either 3 consecutive 
home treatments are not performed or when 8 or more home treatments are not performed during 
the 3-month treatment period. 
 Outcomes will be reassessed after 1 month of treatment (end of week 4 ± 7 days) and at 
the completion of the intervention (end of week 12 ± 7 days). The protocol for these outcome 
visits will be similar to visit 2 as detailed in the table below. To ensure that the chronic rather than 
the acute effects of IPC are investigated, participants will be asked to interrupt the treatment 48 
hrs prior to the outcome sessions. Although interrupting the treatment 48 hours prior to the 
outcomes sessions is desired for testing consistency it will not be a protocol deviation if a subject 
does not interrupt the treatment as instructed. 
  
Visit 
# 
Time point  
Procedures 
1 
Baseline  
Consenting  
Rest pain measurement  
Demonstration of device operation and proper cuff 
placement 
Familiarization with Cardiopulmonary Treadmill test   
2 
Baseline 
Blood draw 
ABI, TBI and TCPO2 
Rest pain measurement  
Cardiopulmonary Treadmill test 
Quality of life questionnaires 
Familiarization with treatment 
3 
1 month 
Blood draw 
ABI, TBI and TCPO2 
Rest pain measurement  
Cardiopulmonary Treadmill test 
Quality of life questionnaires 
4 
3 months 
Blood draw 
ABI, TBI and TCPO2 
Rest pain measurement  
Cardiopulmonary Treadmill test 
Quality of life questionnaires 

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Table 1: Study timeline and experimental procedures that will be performed on each session 
 
Outcome Measures: 
 
Rest pain: Rest pain will be measured bilaterally with a 10-cm visual analog scale (VAS) at 
baseline and each follow-up visit. Patients will be instructed to place a mark on a line from 0 cm 
(no pain) to 10 cm (worst pain previously experienced) that would best describe the level of pain 
in the index limb during the previous 24 hours prior to examination. The distance from the 0-cm 
mark will then be measured and recorded. 
 
Cardiopulmonary Treadmill Exercise Test: Participants will perform a graded, symptom-limited 
exercise test on a treadmill following the Gardner protocol (treadmill speed of 2 mph, 0% grade 
with increments of 2% every 2 min), as described previously by our group (5). During the test, the 
microvascular oxygenation status of the gastrocnemius muscle of the leg undergoing 
revascularization will be continuously monitored using a near-infrared spectrometer (NIRS) (5). 
Gas exchange and ventilatory variables will be measured breath-by-breath during exercise and 
recovery using a computer-based system (5). 
 
Leg hemodynamics: The ankle-brachial index (ABI) and the toe-brachial index (TBI) will be 
measure bilaterally following standard of care practices. Transcutaneous PO2 (TcPO2) will be 
measured only in the leg undergoing revascularization.  
 
Quality of life assessment: Participants will be asked to fill out the the 36-item Short-Form Health 
Survey and the Vascular quality of life questionnaire (VascuQoL-6) health-related quality of life 
questionnaires. 
 
Biomarkers of coagulation and fibrinolysis: Blood levels of markers of coagulation and 
fibrinolysis will be measured in the Pathology laboratory using standard methods. 
 
 
Potential risks to subjects: 
 
Treadmill Cardiopulmonary Exercise Test: Intervention trials in PAD have demonstrated the 
ability of the graded treadmill exercise test to safely and robustly quantify changes associated with 
efficacious interventions (3). This test has been shown to be very safe, even in populations with 
underlying high-risk cardiovascular diagnosis (8), including patients with PAD (1). However, 
there is a chance that patients may experience chest pain, intolerable dyspnea, leg cramps, 
staggering, diaphoresis, and dizziness. The Treadmill Test will be conducted in the Heart Station 
where a Cardiologist is present 8AM to 5PM daily. Participants with an abnormal baseline 
treadmill stress test, including signs of coronary ischemia and an exaggerated pressor response, 
will be excluded from the study. 
 
IPC: There are no known side effects to IPC. It has been reported that patients with severe PAD 
may experience pain during initial exposure to the treatment.  
 

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Venous blood sampling: During blood sampling there is a risk of pain from the needle. Bleeding, 
local swelling, bruising and formation of a hematoma might also occur around puncture site.  
 
Measurement of calf muscle oxygenation: There are no risks associated with calf muscle 
oxygenation measurements. 
 
Rest pain measurement: There are no risks associated with rest pain measurements.  
 
 
6.0 
Reporting of Adverse Events or Unanticipated Problems involving Risk to 
Participants or Others 
 
If the patient is injured due to participation in this study, he/she will be instructed to contact the 
study investigators. Patients will also be advised to contact the Human Subject Office at Indiana 
University if they have questions about their rights while taking part in the study. 
 
7.0 
Study Withdrawal/Discontinuation 
 
Participation in this study is voluntary. Participants may choose not to participate or, if they agree to 
participate, they can withdraw their participation at any time without penalty or loss of benefits to 
which they are otherwise entitled.      
 
8.0 
Statistical Considerations 
 
The results obtained in this pilot experiment will allow us to demonstrate the feasibility of 
recruitment, randomization and intervention implementation and will provide the necessary data 
to support pursuit of a larger randomized clinical trial. Walking tolerance, limb hemodynamics 
and muscle oxygenation parameters will be compared between groups with two-way repeated-
measures ANOVA, followed by Tukey's post hoc test when appropriate. We estimate that 4 
subjects per group are needed to show feasibility and to provide support to our hypothesis that 
repeated exposure to IPC improves leg hemodynamics and reduces leg pain in patients with severe 
PAD recovering from peripheral revascularization. 
 
9.0 
Privacy/Confidentiality Issues 
 
Information produced by this study will be stored in the investigator’s file and identified by a code 
number only. The code key connecting the patient’s name to specific information about the patient 
will be kept in a separate, secure location. Information contained in the patient’s records may not 
be given to anyone unaffiliated with the study in a form that could identify the patient without their 
written consent, except as required by law.   
The results of this study may be published in a medical book or journal or used for teaching 
purposes. However, the patients’ name or other identifying information will not be used in any 
publication or teaching materials without their specific permission.   
 
The patient’s name and social security number will be given to the business office for facilitating 
payment, but will not be used for any other purposes.  
 

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10.0 Follow-up and Record Retention 
 
Records relating to this study will be retained for at least 7 years after completion of the research. 
Paper records will be shredded and recycled.  Records stored on a computer hard drive will be 
erased using commercial software applications designed to remove all data from the storage 
device.  
 
 
References: 
 
1. 
Brass EP, Cooper LT, Morgan RE, and Hiatt WR. A phase II dose-ranging study of the 
phosphodiesterase inhibitor K-134 in patients with peripheral artery disease and claudication. J 
Vasc Surg 55: 381-389 e381, 2012. 
2. 
Delis KT, Nicolaides AN, Labropoulos N, and Stansby G. The acute effects of 
intermittent pneumatic foot versus calf versus simultaneous foot and calf compression on popliteal 
artery hemodynamics: a comparative study. J Vasc Surg 32: 284-292, 2000. 
3. 
Hiatt WR, Rogers RK, and Brass EP. The treadmill is a better functional test than the 6-
minute walk test in therapeutic trials of patients with peripheral artery disease. Circulation 130: 
69-78, 2014. 
4. 
Roseguini BT, Arce-Esquivel AA, Newcomer SC, Yang HT, Terjung R, and Laughlin 
MH. Intermittent pneumatic leg compressions enhance muscle performance and blood flow in a 
model of peripheral arterial insufficiency. J Appl Physiol (1985) 112: 1556-1563, 2012. 
5. 
Roseguini BT, Hirai DM, Alencar MC, Ramos RP, Silva BM, Wolosker N, Neder JA, 
and Nery LE. Sildenafil improves skeletal muscle oxygenation during exercise in men with 
intermittent claudication. Am J Physiol Regul Integr Comp Physiol 307: R396-404, 2014. 
6. 
Roseguini BT, Sheldon R, Stroup A, Bell JW, Maurer D, Crist BD, Laughlin MH, and 
Newcomer SC. Impact of chronic intermittent external compressions on forearm blood flow 
capacity in humans. Eur J Appl Physiol 111: 509-519, 2011. 
7. 
Sheldon RD, Roseguini BT, Thyfault JP, Crist BD, Laughlin MH, and Newcomer SC. 
Acute impact of intermittent pneumatic leg compression frequency on limb hemodynamics, 
vascular function, and skeletal muscle gene expression in humans. J Appl Physiol (1985) 112: 
2099-2109, 2012. 
8. 
Skalski J, Allison TG, and Miller TD. The safety of cardiopulmonary exercise testing in 
a population with high-risk cardiovascular diseases. Circulation 126: 2465-2472, 2012.