Initial Claudication Distance Research Articles

The Effect of High-intensity Interval Training on Initial Claudication and Absolute Walking Distance in Peripheral Artery Disease Patient: A Case Report

The Effect of High-intensity Interval Training on Initial Claudication and Absolute Walking Distance in Peripheral Artery Disease Patient: A Case Report

Neuromuscular electrical stimulation as an adjunct to standard care in improving walking distances in intermittent claudication patients: the NESIC RCT

Background Peripheral arterial disease is common and associated with increased cardiovascular morbidity and mortality. While patients with peripheral arterial disease are known to benefit from supervised exercise therapy, it is not always available. Neuromuscular electrical stimulation devices may offer a similar benefit. A randomised controlled trial was required to ascertain whether such devices can benefit patients who receive supervised exercise therapy and those who do not. Objective(s) The primary objective was to assess the mean difference in absolute walking distance at 3 months in intermittent claudication patients receiving either a neuromuscular electrical stimulation device and local standard care (intervention), or local standard care alone (control). Design A pragmatic, multicentre, randomised controlled trial stratified by centre. Setting Secondary-care National Health Service hospitals in the United Kingdom. Participants Patients aged ≥18 years, with a diagnosis of intermittent claudication according to the Edinburgh Claudication Questionnaire and ankle–brachial pressure index (or stress test), without contraindications to neuromuscular electrical stimulation were deemed eligible to partake. Interventions Participants were randomised 1 : 1 to either local standard care or local standard care and neuromuscular electrical stimulation. Due to the nature of the intervention, it was unfeasible to blind the research nurse or participant to the study allocation. Main outcome measures The primary outcome measure was absolute walking distance measured by treadmill testing at 3 months. Secondary outcomes included change in initial claudication distance, quality of life, compliance with interventions and haemodynamic assessments. Results Two hundred patients underwent randomisation, with 160 patients having analysable primary outcome data for the intention-to-treat analysis intervention (n = 80); control (n = 80). As the data were right-censored, a Tobit regression model was used to analyse the primary outcome, utilising the square root of the absolute walking distance to accommodate the skewed data. However, as this made the data difficult to interpret, a Tobit regression model using raw absolute walking distance data was used as well. Neuromuscular electrical stimulation improved the difference in absolute walking distance at 3 months but this was not statistically significant (square root of absolute walking distance: 0.835 units, 95% confidence interval −0.67 to 2.34 units; p = 0.28/absolute walking distance raw data: 27.18 m, 95% confidence interval −26.92 to 81.28 m; p = 0.323). Supervised exercise therapy participants showed a markedly improved absolute walking distance compared with patients receiving best medical therapy only at 3 months (square root of absolute walking distance: 3.295 units 95% confidence interval 1.77 to 4.82; p < 0.001/absolute walking distance raw data: 121.71 m, 95% confidence interval 67.32 to 176.10; p ≤ 0.001). Neuromuscular electrical stimulation significantly improved absolute walking distance at 3 months for mild claudicants (square root of absolute walking distance: 2.877 units, 95% confidence interval 0.51 to 5.25; p = 0.019/absolute walking distance raw data: 120.55 m, 95% confidence interval 16.03 to 225.06; p = 0.03) compared to the control arm. This was an unplanned (post hoc) analysis. There were no clear differences in mechanistic measurements between the two treatment groups over the follow-up period. Serious adverse events were evenly reported between the two groups; all being classified as either not related or unlikely to be related to the study device. Limitations Absolute walking distance was used as the primary outcome measure; there was a large range of baseline distances in both groups with right-skewed distribution. We did not stratify by baseline absolute walking distance for the primary outcome analysis. Additionally, only 160 patients had analysable primary outcome data due to missing treadmill data. Conclusions Supervised exercise therapy is an effective treatment for intermittent claudication. Neuromuscular electrical stimulation appears to be beneficial as an adjunct to supervised exercise therapy and on its own in mild claudicants. Future work Further studies are needed to confirm the effectiveness of neuromuscular electrical stimulation in combination with supervised exercise therapy, and in mild to moderate claudicants in a larger sample size. Study registration This trial is registered as ISRCTN18242823. Funding This project was funded by the Efficacy and Mechanism Evaluation (EME) Programme, a Medical Research Council (MRC) and National Institute for Health and Care Research (NIHR) partnership (project number 15/180/68). This will be published in full in Efficacy and Mechanism Evaluation; Vol. 10, No. 2. See the NIHR Journals Library website for further project information. Infrastructure support for this research was provided by the NIHR Imperial Biomedical Research Centre (BRC) (with others, e.g. NIHR Imperial CRF, Imperial College ECMC, NIHR Imperial PSTRC, NIHR London MIC, etc.).

Effect of Dietary Supplements Which Upregulate Nitric Oxide on Walking and Quality of Life in Patients with Peripheral Artery Disease: A Meta-Analysis.

This systematic review pooled evidence from randomised controlled trials (RCTs) on the effectiveness of dietary upregulators of nitric oxide (NO) in improving the walking and quality of life of patients with peripheral artery disease (PAD). RCTs examining the effect of dietary upregulators of NO in patients with PAD were included. The primary outcome was the maximum walking distance. Secondary outcomes were the initial claudication distance, the six-minute walking distance, quality of life, the ankle-brachial pressure index (ABI), adverse events and risk of mortality, revascularisation or amputation. Meta-analyses were performed using random effects models. The risk of bias was assessed using Cochrane's ROB-2 tool. Leave-one-out and subgroup analyses were conducted to assess the effect of individual studies, the risk of bias and intervention type on pooled estimates. Thirty-four RCTs involving 3472 participants were included. Seven trials tested NO donors, nineteen tested antioxidants, three tested NO synthase inducers and five tested enhancers of NO availability. Overall, the dietary supplements significantly improved the initial claudication (SMD 0.34; 95%CI 0.04, 0.64; p = 0.03) but not maximum walking (SMD 0.13; 95%CI -0.17, 0.43; p = 0.39) distances. Antioxidant supplements significantly increased both the maximum walking (SMD 0.36; 95%CI 0.14, 0.59; p = 0.001) and initial claudication (SMD 0.58; 95%CI 0.26, 0.90; p < 0.001) distances. The dietary interventions did not improve the physical function domain of the Short Form-36 (SMD -0.16; 95%CI -0.32, 0.00; p = 0.38), ABI or risk of adverse events, mortality, revascularisation or amputation. Dietary NO upregulators, especially antioxidants, appear to improve the initial claudication distance in patients with PAD. Larger high-quality RCTs are needed to fully examine the benefits and risks of these treatments. PROSPERO Registration: CRD42022256653.

The effect of resistance training on functional capacity in middle-aged to elderly individuals with peripheral artery disease: a meta-analysis.

Peripheral artery disease (PAD) is an ischemic disease of the lower limbs, caused by atherosclerotic plaques, leading to impairments in functional capacity and reduced quality of life. This meta-analysis aimed to assess the effect of 12-week and 24-week resistance training (RT) interventions on 6-minute walking distance (6WMD) and initial claudication distance (ICD) measured during a 6-minute walk test (6MWT). A meta-analysis was conducted in accordance with PRISMA guidelines, with an electronic search conducted using the online database of PUBMED. Methodological quality of all included studies was completed using a modified version of the Newcastle Ottawa Scale (NOS). The effect sizes (ES) of 6MWD and ICD were calculated, with the 12-week and 24-week interventions analyzed separately. An initial literature search yielded 1973 results that were consequently reduced to 7 studies to be included in the final meta-analysis. The pooled effect size for 6MWD for 12-week and 24-week interventions was ES=0.189 [95% CI: -0.074 to 0.451] P=0.159 and ES=0.298 [95% CI: -0.036 to 0.631] P=0.080 respectively. For ICD, ES=0.498 [95% CI: 0.000 to 0.995] P=0.050 and ES: 1.106 [95% CI: 0.120 to 0.428] P=0.001 respectively. Short-term RT interventions have a positive effect on functional capacity in middle-aged to elderly individuals with PAD. There was a greater effect on ICD compared to 6MWD, with 24-week interventions showing larger effects for both measures. Improvements in functional capacity in such populations confers significant potential for positive health outcomes.

Propionyl-L-carnitine for intermittent claudication.

Peripheral arterial disease (PAD) is a manifestation of systemic atherosclerosis. Intermittent claudication is a symptomatic form of PAD that is characterized by pain in the lower limbs caused by chronic occlusive arterial disease. This pain develops in a limb during exercise and is relieved with rest. Propionyl-L-carnitine (PLC) is a drug that may alleviate the symptoms of PAD through a metabolic pathway, thereby improving exercise performance. The objective of this review is to determine whether propionyl-L-carnitine is efficacious compared with placebo, other drugs, or other interventions used for treatment of intermittent claudication (e.g. exercise, endovascular intervention, surgery) in increasing pain-free and maximum walking distance for people with stable intermittent claudication, Fontaine stage II. The Cochrane Vascular Information Specialist searched the Cochrane Vascular Specialised Register, CENTRAL, MEDLINE, Embase, and CINAHL databases and the World Health Organization International Clinical Trials Registry Platform and the ClinicalTrials.gov trials register to July 7, 2021. We undertook reference checking and contact with study authors and pharmaceutical companies to identify additional unpublished and ongoing studies. Double-blind randomized controlled trials (RCTs) in people with intermittent claudication (Fontaine stage II) receiving PLC compared with placebo or another intervention. Outcomes included pain-free walking performance (initial claudication distance - ICD) and maximal walking performance (absolute claudication distance - ACD), analyzed by standardized treadmill exercise test, as well as ankle brachial index (ABI), quality of life, progression of disease, and adverse events. Two review authors independently selected trials, extracted data, and evaluated trials for risk of bias. We contacted study authors for additional information. We resolved any disagreements by consensus. We performed fixed-effect model meta-analyses with mean differences (MDs) and 95% confidence intervals (CIs). We graded the certainty of evidence according to GRADE. We included 12 studies in this review with a total number of 1423 randomized participants. A majority of the included studies assessed PLC versus placebo (11 studies, 1395 participants), and one study assessed PLC versus L-carnitine (1 study, 26 participants). We identified no RCTs that assessed PLC versus any other medication, exercise, endovascular intervention, or surgery. Participants received PLC 1 grams to 2 grams orally (9 studies) or intravenously (3 studies) per day or placebo. For the comparison PLC versus placebo, there was a high level of both clinical and statistical heterogeneity due to study size, participants coming from different countries and centres, the combination of participants with and without diabetes, and use of different treadmill protocols. We found a high proportion of drug company-backed studies. The overall certainty of the evidence was moderate. For PLC compared with placebo, improvement in maximal walking performance (ACD) was greater for PLC than for placebo, with a mean difference in absolute improvement of 50.86 meters (95% CI 50.34 to 51.38; 9 studies, 1121 participants), or a 26% relative improvement (95% CI 23% to 28%). Improvement in pain-free walking distance (ICD) was also greater for PLC than for placebo, with a mean difference in absolute improvement of 32.98 meters (95% CI 32.60 to 33.37; 9 studies, 1151 participants), or a 31% relative improvement (95% CI 28% to 34%). Improvement in ABI was greater for PLC than for placebo, with a mean difference in improvement of 0.09 (95% CI 0.08 to 0.09; 4 studies, 369 participants). Quality of life improvement was greater with PLC (MD 0.06, 95% CI 0.05 to 0.07; 1 study, 126 participants). Progression of disease and adverse events including nausea, gastric intolerance, and flu-like symptoms did not differ greatly between PLC and placebo. For the comparison of PLC with L-carnitine, the certainty of evidence was low because this included a single, very small, cross-over study. Mean improvement in ACD was slightly greater for PLC compared to L-carnitine, with a mean difference in absolute improvement of 20.00 meters (95% CI 0.47 to 39.53; 1 study, 14 participants) or a 16% relative improvement (95% CI 0.4% to 31.6%). We found no evidence of a clear difference in the ICD (absolute improvement 4.00 meters, 95% CI -9.86 to 17.86; 1 study, 14 participants); or a 3% relative improvement (95% CI -7.4% to 13.4%). None of the other outcomes of this review were reported in this study. When PLC was compared with placebo, improvement in walking distance was mild to moderate and safety profiles were similar, with moderate overall certainty of evidence. Although In clinical practice, PLC might be considered as an alternative or an adjuvant to standard treatment when such therapies are found to be contraindicated or ineffective, we found no RCT evidence comparing PLC with standard treatment to directly support such use.

Physical Activity Impacts Walking Distances and Energy Consumption of Patients with Peripheral Artery Disease

Lower extremity peripheral artery disease (PAD) is attributed to buildup of atherosclerotic plaques preventing adequate blood flow, leading to pain during walking, and ultimately physical inactivity. Normal day-to-day levels of physical activity may impact the distance a subject can walk before claudication pain onset, as well as their energy consumption capabilities. This study compared walking performance (initial claudication distance (ICD) and absolute claudication distance (ACD)), and energy consumption (EC) between active and inactive subjects with PAD. The distinction between groups was made using previous research that declared the average PAD patient walks 3586 steps/day. Ten subjects were classified as active (□3586 average steps/day) and sixteen participants as inactive (<3586 steps/day) based on a 7-day accelerometer measurement. The Gardner progressive treadmill test was used to asses ICD, ACD, and EC. EC was measured using a metabolic cart and calculated from the second minute of walking and the last minute prior to stopping due to claudication pain. The average ICD and ACD for the active group were 130.6±106.7 meters and 306.0±184.7 meters, respectively and 143.8±119.0 meters and 248.0±156.0 meters, respectively for the inactive group. The average EC for the second minute and last minute were 9.6±1.9 mlkg-1min-1 and 11.5±2.4 mlkg-1min-1 respectively for active group and 7.0±3.1 mlkg-1min-1 and 8.1±3.8 mlkg-1min-1 respectively for inactive group. The data suggests that the active group had better walking performance and greater energy consumption indicating increased efficiency of oxygen transport and extraction capability in the leg muscles.

Influence of Peripheral Transluminal Angioplasty Alongside Exercise Training on Oxidative Stress and Inflammation in Patients with Peripheral Arterial Disease

In patients with intermittent claudication, exercise training ameliorates inflammation by reducing oxidative stress. A total of 41 patients with intermittent claudication (Rutherford 3) were included in the study (with 21 patients treated by endovascular revascularization (ER), and 20 patients without ER). All patients were referred to home-based exercise training. Absolute and initial claudication distance (ACD, ICD) and ABI (ankle–brachial index) were measured. ROS (reactive oxygen species) formation was measured using the luminol analogue L-012. Follow-up was performed after 3 months. ROS production after NOX2 (NAPDH oxidase 2) stimulation showed a significant reduction in both groups at follow-up (PTA group: p = 0.002, control group: p = 0.019), with a higher relative reduction in ROS in the PTA group than in the control group (p = 0.014). ABI measurements showed a significant increase in the PTA (peripheral transluminal angioplasty) group (p = 0.001), but not in the control group (p = 0.127). Comparing both groups at follow-up, ABI was higher in the PTA group (p = 0.047). Both groups showed a significant increas ACD and ICD at follow-up (PTA group: ACD: p = 0.001, ICD: p < 0.0001; control group: ACD: p = 0.041, ICD: p = 0.002). There was no significant difference between both groups at follow-up (ACD: p = 0.421, ICD: p = 0.839). Endovascular therapy in combination with exercise training leads to a lower leukocyte activation state with a reduced NOX2-derived ROS production paralleled by an improved ABI, ACD and ICD. Our data support the strategy to combine exercise training with preceding endovascular therapy.

Cilostazol for intermittent claudication.

Peripheral arterial disease (PAD) affects between 4% and 12% of people aged 55 to 70 years, and 20% of people over 70 years. A common complaint is intermittent claudication(exercise-induced lower limb pain relieved by rest).Thesepatients have a three- to six-fold increase in cardiovascular mortality. Cilostazol is a drug licensed for the use of improving claudication distance and, if shown to reduce cardiovascular risk,could offer additional clinical benefits. This is an update of the review first published in 2007. To determine the effect of cilostazolon initial and absolute claudication distances, mortality and vascular events in patients with stable intermittent claudication. The Cochrane Vascular Information Specialist searched the Cochrane Vascular Specialised Register, CENTRAL, MEDLINE, Embase, CINAHL, and AMED databases, and the World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov trials registries, on 9 November 2020. We considered double-blind, randomised controlled trials (RCTs) of cilostazol versus placebo, or versus other drugs used to improve claudication distance in patients with stable intermittent claudication. Two authors independently assessed trials for selection and independently extracted data. Disagreements were resolved by discussion. We assessed the risk of bias with the Cochrane risk of bias tool. Certainty of the evidence was evaluated using GRADE. For dichotomous outcomes, we used odds ratios (ORs) with corresponding 95% confidence intervals (CIs) and for continuous outcomes we used mean differences (MDs) and 95% CIs. We pooled data using a fixed-effect model, or a random-effects model when heterogeneity was identified. Primary outcomes were initial claudication distance (ICD) and quality of life (QoL). Secondary outcomes were absolute claudication distance (ACD), revascularisation, amputation, adverse events and cardiovascular events. We included 16 double-blind, RCTs (3972 participants) comparing cilostazol with placebo, of which five studies also compared cilostazol with pentoxifylline. Treatment duration ranged from six to 26 weeks. All participants had intermittent claudication secondary to PAD. Cilostazol dose ranged from 100 mg to 300 mg; pentoxifylline dose ranged from 800 mg to 1200 mg. The certainty of the evidence was downgraded by one level for all studies because publication bias was strongly suspected. Other reasons for downgrading were imprecision, inconsistency and selective reporting. Cilostazol versus placebo Participants taking cilostazol had a higher ICD compared with those taking placebo (MD 26.49 metres; 95% CI 18.93 to 34.05; 1722 participants; six studies; low-certainty evidence). We reported QoL measures descriptively due to insufficient statistical detail within the studies to combine the results; there was a possible indication in improvement of QoL in the cilostazol treatment groups (low-certainty evidence). Participants taking cilostazol had a higher ACD compared with those taking placebo (39.57 metres; 95% CI 21.80 to 57.33; 2360 participants; eight studies; very-low certainty evidence). The most commonly reported adverse events were headache, diarrhoea, abnormal stools, dizziness, pain and palpitations. Participants taking cilostazol had an increased odds of experiencing headache compared to participants taking placebo (OR 2.83; 95% CI 2.26 to 3.55; 2584 participants; eight studies; moderate-certainty evidence).Very few studies reported on other outcomes so conclusionson revascularisation, amputation, or cardiovascular events could not be made. Cilostazol versus pentoxifylline There was no difference detected between cilostazol and pentoxifylline for improving walking distance, both in terms of ICD (MD 20.0 metres, 95% CI -2.57 to 42.57; 417 participants; one study; low-certainty evidence); and ACD (MD 13.4 metres, 95% CI -43.50 to 70.36; 866 participants; two studies; very low-certainty evidence). One study reported on QoL; the study authors reported no difference in QoL between the treatment groups (very low-certainty evidence). No study reported on revascularisation, amputation or cardiovascular events. Cilostazol participants had an increased odds of experiencing headache compared with participants taking pentoxifylline at 24 weeks (OR 2.20, 95% CI 1.16 to 4.17; 982 participants; two studies; low-certainty evidence). Cilostazol has been shown to improve walking distance in people with intermittent claudication. However, participants taking cilostazol had higher odds of experiencing headache. There is insufficient evidence about the effectiveness of cilostazol for serious events such as amputation, revascularisation, and cardiovascular events. Despite the importance of QoL to patients, meta-analysis could not be undertaken because of differences in measures used and reporting. Very limited data indicated no difference between cilostazol and pentoxifylline for improving walking distance and data weretoo limited for any conclusions on other outcomes.

Use of the walking impairment questionnaire as a measure of functional assessment.

Background: A significant consequence of peripheral arterial disease (PAD) is an impaired functional capacity and deteriorated quality of life. Therefore, our study aimed to investigate the usefulness of a symptom questionnaire and walk tests for the determination of the functional capacity of patients with intermittent claudication. Patients and methods: The study included 53 patients (38 males) with stable claudication distance (50-300m). A detailed history and physical examination, ankle-brachial index (ABI), treadmill exercise test, and 6-minute walk test were performed and compared to walking impairment questionnaire (WIQ). Results: Claudication distance reported from patients' history and 6-minute walk test were significantly correlated with ABI (p=0.033, p=0.044). There were no significant correlations between ABI and treadmill walk test or WIQ. Results of WIQ were significantly correlated with the history and the most of performed walk tests: treadmill initial and maximal claudication distance (p=0.004 and 0.012, respectively) and 6-minute walk test (p=0.026). 6-minute walk test was correlated with maximal claudication distance of treadmill (p=0.018), but not with an initial claudication distance. Conclusions: The validity of WIQ is comparable to walk tests and represents the useful technique for the investigation of the functional capacity of patients with PAD. A self-report based on WIQ enables a longer period of observation. It should be routinely used as a basic diagnostic tool for the estimation of the functional capacity of PAD patients with stable intermittent claudication.

Intermittent Administration of Nitroglycerin Sublingual Powder Compared with Placebo in Outpatients with Peripheral Artery Disease: Results of a Randomised Proof of Concept Study

Treatment of peripheral artery disease (PAD), Fontaine Stage IIb with vasoactive substances is of limited efficacy and does not last beyond the active treatment. Glyceryl trinitrate (GTN) is a vasodilating agent that relaxes vascular smooth muscle cells. The aim was to prove the concept that GTN sublingual powder has sustained clinical efficacy and adequate safety in these patients. This was a multicentre, randomised, double blind, placebo controlled, forced titration, proof of concept study (phase IIa). Patients had a treadmill test at baseline, after 12 weeks of GTN/placebo administration, and at 19 and 26 weeks (without treatment). Primary objectives were an increase in initial claudication distance (ICD) and absolute claudication distance (ACD) at 12 weeks. Ninety-five patients were screened and 73 randomised, of which 53 patients completed the 12 week treatment phase (GTN 26, placebo 27). At a baseline ICD of 59.2±32.8m (GTN) and 57.5±39.7m (placebo), GTN led to a placebo corrected ICD increase of 23.2% vs. baseline (p=.35). Baseline ACD was 105.3±52.9m (GTN) and 106.1±95.0m (placebo), and GTN led to a placebo corrected increase of 3.6% (p=.44), with substantial interindividual variation. The change in claudication distance was greater in patients with an ICD of ≥50m at baseline (ΔICD 29.3%; p=.19), and an ACD≥100m (ΔACD 8.5%; p=.40). The effect lasted beyond the active treatment period as shown by a 49.3% increase in ICD (p=.31) and a 20.6% increase in ACD (p=.21) by week 26. GTN sublingual powder was well tolerated. Intermittent treatment with nitroglycerin sublingual powder may represent a potential treatment option for patients with PAD stage Fontaine IIb, with an immediate and a sustained effect. The observed increases in ACD and ICD were however not statistically significant in this phase IIa proof of concept study. Further studies are required.

Impact Of An Ankle-foot Orthosis On Physical Activity In Patients With Peripheral Artery Disease

Patients with peripheral artery disease (PAD) are sedentary due to claudication pain in the lower extremities. Our research has documented an inability of the ankle plantarflexors to generate normal push-off during walking. An ankle-foot orthosis (AFO) to offset push-off deficiency may improve physical activity levels and walking distances in patients with PAD. PURPOSE: To compare step count (SC), peak activity index (PAI), initial claudication distances (ICD), and absolute claudication distances (ACD) before and after an AFO intervention. METHODS: Six patients with PAD (Age: 71.7 ± 9.3 years; Body Mass Index: 27.5 ± 5.5 kg/m2) were enrolled in the study. They underwent measurements of SC and PAI over a week using an accelerometer. ICD and ACD were determined while subjects performed the Gardner treadmill protocol without wearing AFOs. All measures were assessed before and after the three month AFO intervention. Signed Rank tests were performed to determine differences following the intervention. RESULTS: ACD was significantly increased following the AFO intervention (p=0.046). Mean ACD was 312 ± 169 meters at baseline and increased to 364 ± 194 meters after the three month AFO intervention. Measures before and after the AFO intervention of SC (2422 ± 1166 steps/day and 2349 ± 1112 steps/day), PAI (34 ± 13 steps/min and 30 ± 7 steps/min), and ICD (187 ± 111 meters and 173 ± 138 meters) were not significantly different. CONCLUSION: The preliminary results of this study indicated that the AFO intervention improves the ACD in patients with PAD while walking without AFO. Future work should increase the number of subjects and determine whether physical activity intensity levels (light, moderate, and vigorous) changed after AFO intervention. Supported by NIH Grant HD090333-01. We acknowledge Alex Dzewaltowski, Cody Anderson, and Kaeli Samson for supporting this study.

Sulodexide improves pain-free walking distance in patients with lower extremity peripheral arterial disease: A systematic review and meta-analysis.

Peripheral arterial disease is associated with very high cardiovascular risk. The main symptom is intermittent claudication, which strongly affects the quality of life. Therefore, treatment goals in peripheral arterial disease consist of the reduction of cardiovascular events and the relief of symptoms. An increase in pain-free walking distance, evaluated based on the Initial Claudication Distance, was also a strong positive prognostic factor in patients with peripheral arterial disease. Our objective was to reassess whether sulodexide is effective in improving Initial Claudication Distance. For this, we searched the literature according to the PRISMA checklist for double blind clinical trials assessing the improvement in the Initial Claudication Distance after 90 days of standard therapeutic regimen with sulodexide in adult patients with peripheral arterial disease. We found and assessed for bias in 11 studies eligible for review and meta-analysis. Data extracted from those studies favoured the sulodexide group, showing an overall difference in Initial Claudication Distance of +68.9 (CI 95%; ± 11.9 m) at the end of treatment (p < 0.001). According to this review, sulodexide is effective in improving Initial Claudication Distance and consequently the quality of life in patients with peripheral arterial disease. Further studies are needed to assess the effects of this drug on disease progression in asymptomatic patients with peripheral arterial disease.

Long-term efficacy of a home-based training program coupled to education for patients with intermittent claudication

There are emerging evidences of efficacy of home-based exercise programs for peripheral artery disease (PAD) patients who suffer from intermittent claudication (IC), especially when they are coupled with educational programs (HEP - EPs). We have previously reported the positive one-year results of a specific 3 months home-based exercise program combined with therapeutic education. In this work, we aimed to evaluate the long-term effect of this program (24 months) in walking distance improvement. The secondary objective of the study was to evaluate the long-term results of our program for patients with aorto-iliac lesions. Patients with an ankle-brachial index (ABI) below 0.9 in at least one limb, and an absolute claudication distance (ACD) ≤ 500 meters, were included in the study. During the first three months, patient participated to an educational program with educational workshop, and a weekly telephone coaching. In educational session patients were assisted in delimiting walking objectives. Functional parameters were evaluated at 0, 12, and 24 months. Between Feb 2014 and Jan 2019, 112 and 39 PAD patients with IC completed the 12- and 24-month follow-up, respectively. More than a third of the population (42 patients) had significant aorto-iliac artery lesions. In both the overall population and the group of patients with aorto-iliac lesions, the mean initial claudication distance (ICD) increased by 3 times and the mean absolute claudication distance (ACD) by 2, compared to baseline values at 24-month follow-up ( Fig. 1 ). The results of our study indicate that home-based training combined with therapeutic educational programs for patients with PAD who suffer from IC, have a clear long-term beneficial effect in walking performance at 24 months. Patients with aorto-iliac disease can benefit equally from this program than patients with femoral lesions.

Efficacy and Feasibility of Pain management and Patient Education for Physical Activity in Intermittent claudication (PrEPAID): protocol for a randomised controlled trial

BackgroundPhysical activity (PA) improves functional capacity and quality of life and provides secondary prevention benefits in individuals with peripheral arterial disease (PAD) and intermittent claudication (IC). However, pain and patient lack of knowledge are key barriers to the uptake of, and adherence to, PA recommendations. This trial will test the efficacy and feasibility of a non-invasive pain management intervention with and without patient education to improve PA in individuals with PAD and IC.MethodsThis is a randomised, controlled assessor-blinded feasibility trial with four parallel groups. Eighty adults with PAD and IC will be randomly assigned 1:1:1:1 to Active TENS (transcutaneous electrical nerve stimulation), Placebo TENS, Active TENS + Patient education or Placebo TENS + Patient education groups. All groups will continue to receive usual care over the intervention period. Participants randomised to Active TENS will receive a TENS device (preset at 120 Hz, 200 μs) and will be instructed to use the device daily at home or elsewhere for 6 weeks with a patient-determined intensity of “strong but comfortable”. Placebo TENS group participants will receive the same model of TENS device and instructions for use as those in the active group, except that the stimulation dose will be safely altered to produce non-therapeutic, ineffective stimulation. Participants randomised to patient education will receive a one-off 3-h workshop of structured group education (four to five persons in each group) and three sets of twice-weekly phone calls. Efficacy outcomes will be assessed at baseline, after 6 weeks of intervention and at 3 months follow-up. Absolute claudication distance using the Gardner treadmill protocol will be assessed as the primary outcome. Secondary outcomes will assess initial claudication distance, daily PA and patient-reported outcomes including quality of life, pain self-efficacy, depression, disease perception and walking impairment pain intensity and quality. Feasibility outcomes will assess rates of recruitment, retention and adherence. Focus groups with participants at the end of the trial will explore the acceptability of the interventions.DiscussionThis trial will determine the efficacy and feasibility of using a low-cost, CE-marked non-invasive pain management modality delivered with or without a patient-centred education intervention to improve PA in individuals with PAD and IC.Trial registrationClinicalTrials.gov, NCT03204825. Registered on 2 July 2017.

Venous Return Assist Devices for Intermittent Claudication: A Randomized Controlled Trial Utilizing a Sham Comparator

Objectives: To determine whether an intermittent mechanical compression device (Venowave) effects walking distance in patients with intermittent claudication as compared to placebo, as well as to review the published literature on the topic. Design: Randomized, cross-over, blinded trial of an intermittent mechanical compression device (Venowave), compared with a sham compression device. Setting: Hamilton Health Sciences, Hamilton, Canada. Participants: 27 patients with severe peripheral limb ischemia, as identified by at least one of: i) ABI<0.4; ii) ACD<200 m (Fontaine stage IIb); iii) toe-brachial index<0.5; or iv) toe pressure<40 mmHg or rest pain due to arterial ischemia. Main Outcome Measures: The primary outcome measure was Absolute Claudication Distance (ACD) while walking on a treadmill. Secondary outcome measures included Initial Claudication Distance (ICD), walk time measured in minutes, and a modified version of the Walking Impairment Questionnaire (WIQ). Results: There was no significant difference in ACD (mean difference: 14.1 m; 95% CI: -31.6 m-59.9 m; p=0.53) or ICD (mean difference: 5.9 m; 95% CI: -26.3 m-14.5 m; p=0.55) between active and sham devices. Mean walk time was identical between active and sham devices (5.6 minutes (2.1) vs. 5.6 minutes (2.0); p=0.99). The modified WIQ score was higher in the active group compared with the sham group (mean difference 2.1 m; 95% CI: 0.3 m-3.9 m; p=0.03). Conclusion: In patients with moderate to severe intermittent claudication, the Venowave device did not increase walking distance when used immediately prior to and during measured effort. This is the first study to use a sham device as a comparator in this specific context.

Three-curve rocker-soled shoes and gait adaptations to intermittent claudication pain: A randomised crossover trial

BackgroundIntermittent claudication (IC) is a symptom of peripheral arterial disease where a cramp-like leg pain is exhibited during walking, which affects gait and limits walking distance. Specifically-designed rocker-soled shoes were purported to mechanically unload the calf musculature and increase walking distances until IC pain. Research questionsDo three-curve rocker-soled shoes increase walking distance and what are the biomechanical differences during pain-free walking and IC pain-induced walking, when compared with control shoes? MethodsFollowing NHS ethical approval, 31 individuals with claudication (age 69 ± 10 years, stature 1.7 ± 0.9 m, mass 83.2 ± 16.2 kg, ankle-brachial pressure index 0.55 ± 0.14) were randomised in this cross-over trial. Gait parameters whilst walking with rocker-soled shoes were compared with control shoes at three intervals of pain-free walking, at onset of IC pain (initial claudication distance) and when IC intensifies and prevents them walking any further (absolute claudication distance). Two-way repeated measures ANOVA were performed on gait variables. ResultsWhen compared with control shoes, rocker-soled shoes reduced ankle power generation (mean 2.1 vs 1.6 W/kg, respectively; p = 0.006) and altered sagittal kinematics of the hip, knee and ankle. However, this did not translate to a significant increase in initial (138 m vs 146 m, respectively) or absolute (373 m vs 406 m, respectively) claudication distances. In response to IC pain, similar adaptations in temporal-spatial parameters and the sagittal kinematics were observed between the shoe types. SignificanceThe three-curved rocker shoes, in their current design, do not augment gait sufficiently to enhance walking distance, when compared with control shoes, and therefore cannot be recommended for the intermittent claudication population.Clinical Reg No. (ClinicalTrials.gov): NCT02505503.

Calf Muscle Oxygen Saturation during 6-Minute Walk Test and Its Relationship with Walking Impairment in Symptomatic Peripheral Artery Disease

Impaired microcirculation is associated with poor walking capacity in symptomatic peripheral artery disease (PAD) patients during treadmill test; however, this test does not simulate the efforts of daily walking of these patients. Thus, the aim of the study was to describe the microcirculation responses during a 6-minute walk test (6MWT) and to analyze the relationship between microcirculation indicators and walking impairment in symptomatic PAD patients. Thirty-four patients were included (mean age=67.6±11.2 years). Their clinical characteristics were collected, and they performed a 6MWT, in which the initial claudication distance (ICD) and total walking distance (TWD) were recorded. During and after the 6MWT, calf muscle oxygen saturation (StO2) parameters were monitored continuously to measure microcirculation behavior. The association between calf muscle StO2 parameters and walking impairment were analyzed by Pearson or Spearman correlations. Walking impairment was not associated with any StO2 parameters during exercise. In contrast, after 6MWT, recovery time of StO2 (r=-0.472, P=0.008) and recovery time to maximal StO2 (r=-0.402, P=0.019) were negatively correlated with ICD. Furthermore, the distance walked under claudication symptoms (ΔTWD-ICD) was positively correlated with recovery time to maximal StO2 (r=0.347, P=0.048). In symptomatic PAD patients, shorter ICD values during a 6MWT are associated with a delayed recovery in calf muscle StO2 after exercise. Calf muscle StO2 parameters decrease subtly during 6MWT, suggesting that the degree of ischemia in the calf muscle during ground walking, simulating efforts of the daily walking, is relatively low.

Evaluation of the effect of Noclaud® on maximum walking distance without pain in patients diagnosed with second stage peripheral artery disease according to the Fontaine classification

Introduction. Medicinal product Noclaud®, containing cilostazol, was approved in Poland on 19.03.2014 without performing a study on its effectiveness in polish population. The aim of this study was to evaluate the efficacy of Noclaud® in the therapy of intermittent claudication (the second stage according to Fontaine classification) in patients with peripheral artery disease (PAD), in whom lifestyle modifications and supervised exercise programs did not alleviate the symptoms. Material and methods. Non-interventional, multi-center, open, post-registration observational study on Noclaud® effectiveness was conducted on 1680 patients with PAD (second stage according to the Fontaine). The assessment of Noclaud® effectiveness included changes in the initial and total claudication distances and changes in ankle-brachial index (ABI). Adverse effects were recorded. Results. Administration of Noclaud® resulted in an increase in the initial claudication distance by 88 (95% CI: 76–100) and 125 (106–145) m after 3 and 6 months, respectively, and the total claudication distance by 121 (99–142) and 148 (119–177) m after 3 and 6 months, respectively. Also during the six minute walk test, distances increased by 64 (57–72) and 104 (93–114) m after 3 and 6 months, respectively. ABI increased by 0.04 (0.03–0.05), and the percentage of patients with ABI < 0.9 decreased significantly (from 90.3 to 72.5%; p < 0.001). However, the percentage of patients with ABI < 0.4 did not change (1.2 vs. 0.9%). Conclusions. Medicinal product Noclaud® increases claudication distance in patients with second grade peripheral artery disease, according to the Fontaine classification. The administration of this drug has only minor effects on the ankle-brachial index.

Transcutaneous Electrical Nerve Stimulation Improves Walking Performance in Patients With Intermittent Claudication.

The purpose of this study was to investigate the effects of 2 types of transcutaneous electrical nerve stimulation (TENS) on walking distance and measures of pain in patients with peripheral arterial disease (PAD) and intermittent claudication (IC). In a phase 2a study, 40 participants with PAD and IC completed a graded treadmill test on 2 separate testing occasions. Active TENS was applied to the lower limb on the first occasion; and placebo TENS, on the second. The participants were divided into 2 experimental groups. One group received high-frequency TENS; and the other, low-frequency TENS. Measures taken were initial claudication distance, functional claudication distance, and absolute claudication distance. The McGill Pain Questionnaire (MPQ) vocabulary was completed at the end of the intervention, and the MPQ-Pain Rating Index score was calculated. Four participants were excluded from the final analysis because of noncompletion of the experimental procedure. Median walking distance increased with high-frequency TENS for all measures (P < .05, Wilcoxon signed rank test, all measures). Only absolute claudication distance increased significantly with low-frequency TENS compared with placebo (median, 179-228; Ws = 39; z = 2.025; P = .043; r = 0.48). No difference was observed between reported median MPQ-Pain Rating Index scores: 21.5 with placebo TENS and 21.5 with active TENS (P = .41). Transcutaneous electrical nerve stimulation applied to the lower limb of the patients with PAD and IC was associated with increased walking distance on a treadmill but not with any reduction in pain. Transcutaneous electrical nerve stimulation may be a useful adjunctive intervention to help increase walking performance in patients with IC.

Adaptation of external counterpulsation based on individual shear rate therapy improves endothelial function and claudication distance in peripheral artery disease.

External counterpulsation therapy enhances blood flow and was shown to improve endothelial function and quality of life in coronary artery disease patients. However, high pressures of up to 300 mmHg may lead to malperfusion of the ischaemic limb. To improve the clinical outcome of patients with peripheral artery disease (PAD), we adjusted external counterpulsation and developed a novel non-invasive approach termed individual shear rate therapy (ISRT). In the present study, 14 patients with a Fontaine stage IIb and femoral-popliteal PAD underwent 30 hours of ISRT over 5 weeks. For ISRT, individual treatment pressures that do not exceed 160 mmHg were assessed by Doppler flow parameters during counterpulsation (individual shear rate diagnosis) in order to enhance and maximise peripheral perfusion. The study aimed to enhance peripheral perfusion and evaluate the primary clinical endpoint endothelial function, as well as to perform preliminary analysis of the ankle brachial index (ABI) and walking distance. Doppler flow measurements in the lower limb (ankle) validated that maximum blood flow velocity during systole and acceleration doubled during ISRT. Study results demonstrated that long-term ISRT significantly increased flow-mediated dilation (FMD) in the brachial artery (0.13+/- 0.09 mm to 0.38+/- 0.05 mm; p < 0.05), while nitromediated dilation (0.36+/- 0.10 mm to 0.45+/- 0.08 mm) remained and common femoral artery FMD did not reach statistical significance (0.38+/- 0.08 mm to 0.67+/- 0.19 mm; p<0.05). Initial claudication distance considerably improved for all patients after 30 hours of ISRT (92.6 +/- 8.2 metres to 280+/- 101.3 metres, p<0.05), just like the absolute claudication distance, which showed a more than 2.5-fold increase (167.8+/- 18.1 metres to 446.7+/- 133.3 metres; p<0.05). The ABI did not improve (0.58+/- 0.03 to 0.65+/- 0.04). Our data demonstrate that long-term ISRT is a potential novel non-invasive treatment to improve endothelial function and absolute pain-free walking distance for PAD patients.