Discover how we are teaming with leading healthcare professionals to advance the discussion and treatment for lymphatic, wound and circulatory disorders.
Superior Clinical, Quality of Life, Functional, and Health Economic Outcomes with Pneumatic Compression Therapy for Lymphedema
By: Desai SS, Shao M, Vascular Outcomes Collaborative
Pneumatic compression therapy is one of several options for the management of lymphedema. The lack of clarity around clinical outcomes, quality of life, cost of care, and its proper application, as a function of lymphedema complexity, limit its use in clinical practice. This is compounded by difficulties associated with insurance approval and uncertainty about the role of this modality in the treatment algorithm. The purpose of this study is to elucidate the healthcare economics and value of pneumatic compression therapy for lymphedema.
All patients who underwent treatment for lymphedema at a single institution were followed prospectively over a 2-year period. Patient demographics, comorbidities, treatment modality, and treatment efficacy were determined. Direct costs over the 2-year period, inclusive of hospitalization and device costs, SF-36 quality of life, and leg lymphedema complexity score (LLCS), were measured.
A total of 128 patients were enrolled over a period of 3 years for a total of 232 extremities treated for secondary lymphedema. Pneumatic compression therapy was utilized for all patients and led to a 28% decrease in absolute limb volume (P < 0.001), decrease in body mass index (BMI) (P < 0.001), significant improvement in SF-36 quality of life in 7 out of 8 domains (P < 0.001), and a significant improvement in LLCS (P < 0.001) at 1 year. A subsequent decrease in hospitalization for lymphedema-associated complications saved over $3,200 per patient per year.
Pneumatic compression therapy leads to improved clinical outcomes, quality of life, and functional status for clinically significant lymphedema. Significant per capita direct cost savings, a beneficial impact on pay for performance measures, and a reduction in lymphedema-related complications suggest that earlier adoption of this treatment modality may offer a superior value proposition to patients, physicians, hospitals, and the healthcare system.
Intermittent Pneumatic Compression Enhances the Treatment of Lymphedema
Standford University School of Medicine
By: Steven Reinberg
NEW YORK (Reuters Health) Dec 13, 2002 – Intermittent pneumatic compression (IPC) added to other elements of decongestive lymphatic therapy enhances the treatment of lymphedema associated with axillary lymph node dissection in breast cancer patients, researchers report in the December 1st issue of Cancer.
“Our study is the first prospective evaluation of the use of these pumps as
adjunctive therapy to the existing physiotherapies for breast cancer lymphedema, both in acute and maintenance management. We evaluated both efficacy and the potential for creating side effects,” Dr. Rockson explained.
Combined Modality Treatment of Lymphedema using the ReidSleeve and the BioCompression/Optiflow System.
Duke University School of Medicine (LM, JM), Healthtronix Lymphedema Management, Inc (NG, KA, DD, CH) and Peninsula Medical (RR, SM, AH, TR)
By: Renee Robinson, Lisa A Massa PT CLT, Jennifer Maddox, PT, Nancy Guillett, LMT, CLTLANA, Katherine Arsenault, MPT, CLT-LANA, Deborah Daugherty, MOT, CLT-LANA, Cheri Hoskins, Stephen Morgan, Ann Hafner and Tony Reid MD, Ph.D.
35 patients (16 upper extremity/19 lower extremity) with refractory lymphedema were enrolled on a longitudinal study using the ReidSleeve in combination with the BioCompression/Optiflow system. The primary objective of this study was to evaluate the effectiveness of this combined modality therapy. Patients wore the ReidSleeve at night and used the BioCompression pump with the ReidSleeve Optiflow insert for 2 sessions of 60 minutes during the day with class II compression stocking for the remainder of the day. Among patients with upper extremity edema, the reduction in lymphedema was 24.7, 53.8 and 80.2% at 4, 12 and 28 weeks. Linear regression analysis demonstrates a highly significant (p<0.001) reduction in arm edema during the course of treatment. A plateau phase occurred between weeks 4 and 8 weeks. Among patients with lymphedema edema of the lower extremity, the average reduction was 296, 646, 607, 484, 305, and 884 ml at 1, 2, 4, 8, 12 and 16 weeks respectively. These patients demonstrated marked reductions in lymphedema during the first 2 to 4 weeks followed by a period of relatively stable lymphedema until week 12 with a further decrease in average volume of lymphedema of 14496 cubic centimeters by week 16. Linear regression analysis demonstrates a significant (p<0.001) decrease in leg edema. The ReidSleeve used in combination with the BioCompression/Optiflow system provides effective management for upper and lower extremity lymphedema.
Anatomical distribution of tissue fluid and lymph in soft tissues of lower limbs in obstructive lymphedema—hints for physiotherapy
By: Waldemar L Olszewski, Pradeep Jain, Govinda Ambujam, Marzanna Zaleska, Marta Cakala
Knowledge of the exact location of tissue fluid (TF) and stagnant lymph (L) in lymphedema is indispensable to rational physiotherapy and specifically
defines where to apply external pressure and how much. We visualized the “TF&L” space in the skin and subcutaneous tissue of the foot, calf, and thigh
in various stages of lymphedema, using special staining techniques, in specimens obtained during lymphatic microsurgical procedures or tissue
debulking. With the collecting trunks obliterated, L was present only in the subepidermal lymphatics, whereas the bulk of mobile TF accumulated in the
spontaneously formed spaces in the subcutaneous tissue, around small veins, above and below the muscular fascia. Deformation of subcutaneous tissue by
free fluid led to formation of multiple interconnecting tissue channels. Thus, massaging of tissues can propel TF through the spontaneously formed tissue channels, but not the partially or totally obliterated lymph collectors. The subepidermal lymphatic network conducts only a small fraction of
L. Pneumatic compression therapy promoted formation of TF fluid channels.
Decongestive Lymphatic Therapy for Patients with
Breast Carcinoma-Associated Lymphedema
A Randomized, Prospective Study of a Role for Adjunctive Intermittent Pneumatic Compression
By: Andrzej Szuba, Ph.D., Rahda Achalu, M.D., Stanley G. Rockson, M.D.
BACKGROUND: Disruption of the lymphatic circulation through breast carcinoma-associated axillary lymph node dissection, with or without radiation therapy, reportedly is the most common cause of lymphedema in developed countries. There is no cure for breast carcinoma-associated lymphedema. Although intermittent pneumatic compression (IPC) has been acknowledged as a potential component of the multidisciplinary therapeutic strategy in the treatment of patients with breast carcinoma-associated lymphedema, prospective study of its adjunctive safety and efficacy is required.
METHODS: IPC was assessed as a component of the initial therapeutic regimen for newly treated patients with breast carcinoma-associated lymphedema. Twenty-three patients who had not previously been treated for lymphedema were randomized to receive either decongestive lymphatic therapy (DLT) alone or DLT with daily adjunctive IPC. Patients with stable, treated, breast carcinoma-associated lymphedema also were assessed in the maintenance phase of therapy. Twenty-
seven patients were randomized either to DLT alone or to DLT coupled with daily IPC. In both studies, objective assessment included serial measurement of volume
by water displacement, tissue tonometry to assess elasticity of the skin, and
goniometry to measure joint mobility.
RESULTS: During initial treatment, the addition of IPC to standard DLT yielded an additional mean volume reduction (45.3% vs. 26%; P 0.05). During maintenance DLT alone, there was a mean increase in volume (32.7 115.2 mL); with DLT and IPC, there was a mean volume reduction (89.5 195.5 mL; P 0.05). In both studies, IPC was tolerated well without detectable adverse effects on skin elasticity
or joint range of motion.
CONCLUSIONS. When IPC is used adjunctively with other, established elements of DLT, it provides an enhancement of the therapeutic response. IPC is well tolerated and remarkably free of complications. Cancer 2002;95:2260 –7.
© 2002 American Cancer Society.
Lymphedema: classification, diagnosis and therapy
By: Andrzej Szuba, Ph.D., Stanley G. Rockson, M.D.
Abstract: This review presents the diagnostic features, the pathophysiology and the available therapies for lymphedema. This disease is often able to be diagnosed by its characteristic clinical presentation, yet, in some cases, ancillary tests might be necessary to establish the diagnosis, particularly in the early stages of the disease and in edemas of mixed etiology. These diagnostic modalities are also useful in clinical studies.
Available modalities include isotopic lymphoscintigraphy, indirect and direct lymphography, magnetic resonance imaging, computed tomography and ultrasonography. Lymphedema may be primary or secondary to the presence of other diseases and/or to the consequences of surgery. Primary lymphedema may occur at any phase of life but it most commonly appears at puberty. Secondary lymphedema is encountered more often. The most prevalent worldwide cause of lymphedema is filariasis, which is particularly common in south-east Asia. In the USA, postsurgical lymphedema of the extremity prevails. Complications of chronic limb lymphedema include recurrent cellulitis and lymphangiosarcoma.
Most patients are treated conservatively, by means of various forms of compression therapy, including complex physical therapy, pneumatic pumps and compressive garments. Volume reducing surgery is performed rarely. Lymphatic microsurgery is still in an experimental stage, although a few centers consistently report favorable outcomes.
Intermittent Pneumatic Compression Enhances Formation of Edema Tissue Fluid Channels in Lymphedema of Lower Limbs
By: Marzanna Zaleska, Waldemar L. Olszewski, Marta Cakala,
Jaroslaw Cwikla, and Tadeusz Budlewski
Background: In lymphedema, tissue fluid steadily accumulates in the subcutaneous space containing loose connective tissue. We documented previously that deformation of the structure of subcutaneous collagen bundles and fat by excess fluid leads to formation of ‘‘lakes’’ and interconnected channels with irregular shape. Since there is no force that could mobilize and propel stagnant fluid to the regions where lymphatics absorb and contract, this task should be taken over by external massage. The most effective in this respect seems to be the sequential intermittent pneumatic compression (IPC).
Aim: The aim of the study was to observe whether IPC would enhance and accelerate formation of tissue fluid channels.
Methods: Together with the Biocompression Systems (Moonachie, NJ), we designed a high pressure intermittent compression device and used in it our therapy protocol for patients with obstructive lymphedema of lower limbs. The study was carried out on 18 patients with lymphedema stages II–IV. The IPC was applied daily for 1–2 hours. The follow up time was 24–36 months. Lymphoscintigraphy and immunohistopathology of tissue biopsies were used for evaluation of channel formation process.
Results: The forced fluid flow brought about increase of the area of fluid channels in the thigh and groin, with a decrease in the calf. Concomitantly, with decrease of channel area in the calf, there was a decrease of calf circumference. No new lymphatic collectors were observed.
Conclusions: Compression of limb lymphedema tissues leads to formation of tissue channels as pathways for evacuation of edema fluid.
Effectiveness of Intermittent Pneumatic Compression
for the Treatment of Venous Ulcers in Subjects with
Secondary (Acquired) Lymphedema
Center for Curative and Palliative Wound Care,
Calvary Hospital, Bronx, NY
Department of Medicine, New York Medical College, Valhalla, NY
By: by Oscar M. Alvarez PhD, Martin Wendelken DPM, RN, Lee Markowitz DPM, Rachelle Parker MD and Christopher Comfort MD
Fifty-two subjects with secondary lymphedema, chronic venous insufficiency, and hard to heal lower leg ulceration (>1year old & >20cm2 surface area) were treated with either intermittent, gradient, pneumatic compression (IPC* n=27)
plus standard compression therapy or compression therapy alone (control). Compression therapy consisted of a non-adherent primary wound dressing plus a 4-layer compression bandage (4-LB** n=25). The mean age and size of the ulcers were 1.4 years and 31cm2 , respectively, and did not differ significantly between groups. IPC was performed using a 4-chamber pneumatic leg sleeve and gradient, sequential pump. All pumps were calibrated to a pressure setting of 50 mmHg on each subject, and treatments were for 1 hour, twice daily. evaluations were performed weekly to measure edema, local pain, degree of wound granulation, and wound healing (incidence of complete closure and rate of healing from wound surface area measurements).
The median time to wound closure by 9 months was 141 days for the IPC treated group and 211 days for the control group (P= 0.031). The rate of healing was 0.8±0.4 mm/day for the control group and 2.1±0.8 mm/day for the group treated with IPC (P<0.05). When compared to subject treated with standard care, the group treated with IPC reported less pain at each evaluation point for the first 6 weeks of the trial. At week 2 and 3, the visual analog pain scores were significantly lower for the IPC-treated group (P<0.05). These results suggest that IPC is a valuable adjunct to compression therapy in the management of large or painful venous ulcers. ClinicalTrials. Gov ID: NCT01079299
Effect of High-Pressure, Intermittent Pneumatic Compression (HPIPC) for the Treatment of Peripheral Arterial Disease (PAD) and Critical Limb Ischemia (CLI) in Patients without a Surgical Option
Center Curative and Palliative Wound Care, Calvary Hospital, Bronx, NY
Department of Medicine, New York Medical College, Valhalla, NY
By: Oscar M. Alvarez PhD,1, 2 Martin Wendelken DPM, RN1, Lee Markowitz DPM1 and Christopher Comfort MD
Thirty-four subjects with symptomatic PAD or CLI (claudication pain, resting pain, numbness and lower leg/foot ulceration) were randomized into 2 treatment groups. Eighteen received treatment with HPIPC (60 minutes twice daily for 16weeks) and 16 subjects received standard care consisting of an exercise regimen (walking for 20 minutes twice daily for 16 weeks). The HPIPC device delivers bilateral pressures of 120mmHg. Cycle times provide sequential compression for 4 seconds (+/-0.5 sec.) followed by a 16 second rest period (+/-3.0 sec.), resulting in a 20 second cycle or 3 cycles per minute. The primary endpoint was peak walking time (PWT, time to maximally tolerated claudication pain). Secondary endpoints included: change in resting ABIs, ulcer healing, relief of resting/wound pain, and quality of life index (QOL). Age (73.7 vs. 72.7),baseline PWTs (1-6 minutes) and risk factors were similar in both treatment groups. At 4 weeks the percent change from baseline in PWT, did not vary significantly between treatment groups (17.8% for HPIC and 17% for standard care). After 8 weeks the percent change in PWT for the HPIPC group was 41%compared to 32% for the group receiving standard care (p=0.062). At the week-16 time point the percent change from baseline in PWT was significantly different between treatment arms (35.5% for the standard care group and 54.7% for the group receiving HPIPC [p=0.043]). The mean reduction in wound surface area was 57% and 71% at 12 and 16 weeks respectively for the HPIPC group compared to 45% and 56% for the control group. The HPIPC group reported significantly greater pain relief at the 12 week (p=0.044) and 16 week (p=0.038)time points.
Improving Limb Salvage in Critical Ischemia with Intermittent Pneumatic Compression: A Controlled Study with 18-month Follow Up
By: Steven J. Kavros, DPM, Konstantinos T. Deils, MD, MS, PhD, FRCSI, EBSQvasc, Norman S. Turner, MD, Anthony E. Voll, RN, Davis A. Liedl, RN, Peter Gloviczki, MD, and Thom W. Rooke, MD, Rochester, Minn
Background: Intermittent pneumatic compression (IPC) is an effective method of leg inflow enhancement and amelioration of claudication in patients with peripheral arterial disease. This study evaluated the clinical efficacy of IPC in patients with chronic critical limb ischemia, tissue loss, and non-healing wounds of the foot after limited foot surgery (toe or transmetatarsal amputation) on whom additional arterial revascularization had been exhausted.
Methods: Performed in a community and multidisciplinary health care clinic (1998 through 2004), this retrospective study comprises 2 groups. Group 1 (IPC group) consisted of 24 consecutive patients, median age 70 years (interquartile range [IQR], 68.7-71.3) years, who received IPC for tissue loss and non-healing amputation wounds of the foot attributable to critical limb ischemia in addition to wound care. Group 2 (control group) consisted of 24 consecutive patients, median age 69 years (IQR, 65.7-70.3 years), who received wound care for tissue loss and non-healing amputation wounds of the foot due to critical limb ischemia, without use of IPC. Stringent exclusion criteria applied. Group allocation of patients depended solely on their willingness to undergo IPC therapy. Vascular assessment included determination of the resting ankle-brachial pressure index, transcutaneous oximetry (TcPO(2)), duplex graft surveillance, and foot radiography. Outcome was considered favorable if complete healing and limb salvage occurred, and adverse if the patient had to undergo a below knee amputation subsequent to failure of wound healing. Follow-up was 18 months. Wound care consisted of weekly débridement and biologic dressings. IPC was delivered at an inflation pressure of 85 to 95 mm Hg, applied for 2 seconds with rapid rise (0.2 seconds), 3 cycles per minute; three 2-hourly sessions per day were requested. Compliance was closely monitored.
Results: Baseline differences in demography, cardiovascular risk factors (diabetes mellitus, smoking, hypertension, dyslipidemia, renal impairment), and severity of peripheral arterial disease (ankle-brachial indices, TcPO(2), prior arterial reconstruction) were not significant. The types of local foot amputation that occurred in the two groups were not significantly different. In the control group, foot wounds failed to heal in 20 patients (83%) and they underwent a below knee amputation; the remaining four (17%, 95% confidence interval [CI], 0.59%-32.7%) had complete healing and limb salvage. In the IPC group, 14 patients (58%, 95% CI, 37.1%-79.6%) had complete foot wound healing and limb salvage, and 10 (42%) underwent below knee amputation for non-healing foot wounds. Wound healing and limb salvage were significantly better in the IPC group (P < .01, chi(2)). Compared with the IPC group, the odds ratio of limb loss in the control group was 7.0. On study completion, TcPO(2) on sitting was higher in the IPC group than in the control group (P = .0038).
Conclusion: IPC used as an adjunct to wound care in patients with chronic critical limb ischemia and non-healing amputation wounds/tissue loss improves the likelihood of wound healing and limb salvage when established treatment alternatives in current practice are lacking. This controlled study adds to the momentum of IPC clinical efficacy in critical limb ischemia set by previously published case series, compelling the pursuit of large scale multicentric level 1 studies to substantiate its actual clinical role, relative indications, and to enhance our insight into the pertinent physiologic mechanisms.
Sequential Compression Biochemical Device in Patients with Critical Limb Ischemia and Nonreconstructable Peripheral Vascular Disease
By: Sherif Sultan, MD, FRCS, Nader Hamada, MRCS, MCH, Esraa Soylu, MBBCh, Anne Fahy, MPPM, Niamh Hynes, MD, MCRS, and Wael Tawfick, MRCSI, Galway, Ireland
Objective: Critical limb ischemia (CLI) patients who are unsuitable for intervention face the dire prospect of primary amputation. Sequential compression biomechanical device (SCBD) therapy provides a limb salvage option for these patients. This study assessed the outcome of SCBD in severe CLI patients who otherwise would face an amputation. Primary end points were limb salvage and 30-day mortality. Secondary end points were hemodynamic outcomes (increase in popliteal artery flow and toe pressure), ulcer healing, quality-adjusted time without symptoms of disease or toxicity of treatment (Q-TwiST), and cost-effectiveness.
Methods: From 2004 to 2009, we assessed 4538 patients with peripheral vascular disease (PVD). Of these, 707 had CLI, 518 underwent intervention, and 189 were not suitable for any intervention. A total of 171 patients joined the SCBD program for 3 months.
Results: All patients were Rutherford category >4. Median follow-up was 13 months. Mean toe pressure increased from 39.9 to 55.42 mm Hg, with a mean difference in toe pressure of 15.49 mm Hg (P ? .0001). Mean popliteal flow increased from 35.44 to 55.91 cm/s, with mean difference in popliteal flow of 20.47 cm/s (P < .0001). Mortality at 30 days was 0.6%. Median amputation-free survival was 18 months. Limb salvage at 3.5 years was 94%. Freedom from major adverse clinical events (MACE) at 4.5 years was 62.5%. We treated 171 patients with SCBD at a cost of €681,948, with an estimated median per-patient cost of treatment with SCBD of €3988.
Conclusion: SCBD therapy is a cost-effective and clinically efficacious solution in CLI patients with no option of revascularization. It provides adequate limb salvage and ameliorated amputation-free survival while providing relief of rest pain without any intervention.
Intermittent pneumatic compression (IPC) is an effective method of leg inflow enhancement and amelioration of claudication in patients with peripheral arterial disease. This study evaluated the clinical efficacy of IPC in patients with chronic critical limb ischemia, tissue loss, and non-healing wounds of the foot after limited foot surgery (toe or transmetatarsal amputation) on whom additional arterial revascularization had been exhausted.
Effect of Intermittent Pneumatic Compression of Foot and Calf on Walking Distance, Hemodynamics, and Quality of Life Patients with Arterial Claudication A Prospective
Randomized Controlled Study with 1-Year Follow-Up
By: Konstantinos T. Delis, MD, MS, PhD, FRCSI, EBSQvasc, and Andrew N. Nicolaides, MS, FRCS(Ed), FRCS
Background Data: Perioperative mortality, graft failure, and angioplasty limitations militate against active intervention for claudication. With the exception of exercise programs, conservative treatments yield modest results. Intermittent pneumatic compression [IPC] of the foot used daily for 3 months enhances the walking ability and pressure indices of claudicants. Although IPC applied to the foot and calf together is hemodynamically superior to IPC of the foot, its clinical effects in claudicants remain undetermined. Objective: This prospective randomized controlled study evaluates the effects of IPC on the walking ability, peripheral hemodynamics, and quality of life [QOL] in patients with arterial claudication.
Methods: Forty-one stable claudicants, meeting stringent inclusion and exclusion criteria, were randomized to receive either IPCfoot?calf and aspirin [75 mg] (Group 1; n = 20), or aspirin [75 mg] alone (Group 2; n = 21), with stratification for diabetes and smoking. Groups matched for age, sex, initial [ICD] and absolute [ACD] claudication distances, pressure indices [ABI], popliteal artery flow, and QOL with the short-form 36 Health Survey Ques- tionnaire (SF-36). IPCfoot?calf (120 mm Hg, inflation 4 seconds X 3 impulses per minute, calf inflate delay 1 second) was used for 5 months, >2.5 hours daily. Both groups were advised to exercise unsupervised. Evaluation of patients, after randomization, included the ICD and ACD, ABI, popliteal artery flow with duplex and QOL* at baseline*, 1/12, 2/12, 3/12, 4/12, 5/12* and 17/12. Logbooks allowed compliance control. Wilcoxon and Mann-Whitney corrected [Bonferroni] tests were used.
Results: At 5/12 median ICD, ACD, resting and post-exercise ABI had increased by 197%, 212%, 17%, and 64%, respectively, in Group 1 (P ? 0.001), but had changed little (P ? 0.1) in Group 2; Group 1 had better ICD, ACD, and resting and post-exercise ABI than Group 2. Inter- and intragroup popliteal flow differences at 5/12 were small. QOL had improved significantly in Group 1 but not in Group 2; QOL in the former was better than in Group 2. QOL in Group 1 was better than in Group 2 at 5/12. IPC was complication free. IPC compliance was >82% at 1 month and >85% at 3 and 5 months. ABI and walking benefits in Group 1 were maintained a year after cessation of IPC treatment.
Conclusions: IPC emerged as an effective, high-compliance, complication-free method for improving the walking ability and pressure indices in stable claudication, with a durable outcome. These changes were associated with a significant improvement in all aspects of QOL evaluated with the SF-36. Despite some limited benefit noted in some individuals, unsupervised exercise had a nonsignificant impact overall.
Integrity of Venoarteriolar Reflex Determines Level of Microvascular Skin Flow Enhancement with Intermittent Pneumatic Compression
By: Marc Husmann, MD, Torsten Willenberg, MD, Hak Hong Keo, MD, Silviana Spring, MD, Evi Kalodiki, MD, PhD, and Kostas T. Delis, MSc, MD, MS, PhD, Bern, and Zurich, Switzerland; and London, United Kingdom
Objective: To investigate whether intermittent pneumatic compression (IPC) augments skin blood flow through transient suspension of local vasoregulation, the veno-arteriolar response (VAR), in healthy controls and in patients with peripheral arterial disease (PAD).
Methods: Nineteen healthy limbs and twenty-two limbs with PAD were examined. To assess VAR, skin blood flow (SBF) was measured using laser Doppler fluxmetry in the horizontal and sitting positions and was defined as percentage change with postural alteration. On IPC application to the foot, the calf, or both, SBF was measured with laser Doppler fluxmetry, the probe being attached to the pulp of the big toe. Results: Baseline VAR was higher in the controls than in patients with PAD. In both groups SBF was significantly higher with IPC than at rest. A higher percentage increase with IPC was demonstrated in the controls than in subjects with PAD, for each one of the three different IPC modes investigated with IPC was demonstrated. The SBF enhancement with IPC correlated with VAR for all three compression modes.
Conclusion: The integrity of the veno-arteriolar response correlates with the level of skin blood flow augmentation generated with intermittent pneumatic compression, indicating that this may be associated with a transient suspension of the auto-regulatory vasoconstriction both in healthy controls and inpatients with PAD.