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Hypoxia inducible factor (HIF) stabilization by HIF-prolyl hydroxylase (PHD) inhibitors may improve ischemic conditions such as peripheral artery disease (PAD). This multicenter, randomized, placebo-controlled study evaluated the safety and efficacy of GSK1278863 (an oral PHD inhibitor) in subjects with PAD. The study assessed two active treatment paradigms: single dosing and subchronic daily dosing (300 mg single dose and 15 mg daily for 14 days, respectively). Neither regimen improved exercise performance compared with placebo (change from baseline in the 6-minute walk test (6MWT; feet), (GSK1278863, placebo): single dose (–46, –44), p=0.96; repeat dose (9, 8), p=0.99; change in number of contractions to onset of claudication (goniometry): single dose (4, –1), p=0.053; repeat dose (–2, 1), p=0.08). A calf-muscle biopsy substudy showed no increases in mRNA or protein levels of HIF target genes. More subjects receiving GSK1278863 than placebo experienced adverse events, particularly following the 300 mg single dose. Thus, assessing the safety of GSK1278863 in this setting would require a larger population exposed to the agent for a longer duration. These data do not support a benefit of GSK1278863 in PAD using the regimens tested. ClinicalTrials.gov Identifier: NCT01673555 [ABSTRACT FROM AUTHOR]

Tirasemtiv (CK-2017357), a novel small-molecule activator of the fast skeletal muscle troponin complex, slows the rate of calcium release from troponin, thus sensitizing fast skeletal muscle fibers to calcium. In preclinical studies, tirasemtiv increased muscle force and delayed the onset and reduced the extent of muscle fatigue during hypoxia in vitro and muscle ischemia in situ. This study evaluated the effect of single doses of tirasemtiv on measures of skeletal muscle function and fatigability in patients with stable calf claudication due to peripheral artery disease (PAD). Sixty-one patients with an ankle–brachial index ≤0.90 in the leg with claudication received single double-blind doses of tirasemtiv 375 mg and 750 mg and matching placebo in random order about 1 week apart. After 33 patients were treated, the 750 mg dose was decreased to 500 mg due to adverse events and these dose groups were combined for analysis. On each study day, bilateral heel-raise testing was performed before and at 3 and 6 hours after dosing; a 6-minute walk test was performed at 4 hours after dosing. Claudicating calf muscle performance was increased at the highest dose and plasma concentration of tirasemtiv; however, the 6-minute walk distance decreased with both the dose and plasma concentration of tirasemtiv, possibly due to dose-related adverse events, particularly dizziness, that could impede walking ability. In conclusion, the mechanism of fast skeletal muscle troponin activation improved muscle function but not 6-minute walking distance in patients with claudication due to PAD. ClinicalTrials.gov Identifier: NCT01131013 [ABSTRACT FROM AUTHOR]

The article discusses the effectiveness of the treadmill walking performance in the treatment of patients with peripheral artery disease (PAD). Topics highlighted include the effect of the disease on the person's ability to walk, a description of the exercise method and the difference between the treadmill walking test and the 6-minute walk test.

Nitrite stores decrease after exercise in patients with peripheral artery disease (PAD) and diabetes represents decreased nitric oxide (NO) bioavailability that may contribute to endothelial dysfunction and limit exercise duration. The primary objective of this placebo-controlled study was the safety and tolerability of multiple doses of oral sodium nitrite in patients with PAD, predominantly with diabetes, over a period of 10 weeks. The primary efficacy endpoint was endothelial flow-mediated dilatation (FMD) and secondary efficacy endpoints included a 6-minute walk test and quality of life assessment. Of the 55 subjects, the most common side effects attributed to sodium nitrite were a composite of headache and dizziness occurring in 21% with the 40 mg dose and 44% with the 80 mg dose. There was no clinically significant elevation of methemoglobin. FMD non-significantly worsened in the placebo and 40 mg groups, but was stable in the 80 mg group. Diabetic patients receiving 80 mg had significantly higher FMD compared with the placebo and 40 mg groups. There was no significant change in 6-minute walk test or quality of life parameters over time compared to placebo. In conclusion, sodium nitrite therapy is well tolerated in patients with PAD. The possible clinical benefit of sodium nitrite should be studied in a larger and fully powered trial. [ABSTRACT FROM AUTHOR]

Propionyl-l-carnitine (PLC) may improve exercise performance in patients with peripheral artery disease, but results from clinical trials have been inconsistent. The safety and efficacy of PLC for treatment of claudication was evaluated by a systematic review and meta-analysis of clinical trials for which data were available through September 2010. Eighty-five studies were identified, of which 13 were randomized controlled trials. Owing to database availability for the six phase III studies carried out with PLC (1 g orally, twice daily), a patient-level meta-analysis was conducted as the primary analysis. Treadmill performance data from these six studies were harmonized to peak walking distance (PWD) on a 7% grade at a speed of 3 km/hour. PLC (n = 440) was associated with a net 16 meter improvement (95% CI, 8–20 meters) in PWD as compared with placebo (n = 427) in the primary analysis (p = 0.002). The effect of PLC was similar in subpopulations defined using clinical and demographic variables, with possible enhanced benefit in patients engaged in an exercise program or enrolled at study sites in Russia. The systematic review of the effect of PLCs on claudication identified seven additional randomized controlled trials for a total of 13 trials, which included 681 patients on placebo and 672 on PLC. This meta-analysis confirmed a 45 meter net improvement on PLC using a random-effects model. In conclusion, oral PLC is associated with a statistically significant increase in PWD in patients with claudication, which may be clinically relevant. [ABSTRACT FROM PUBLISHER]

The pathophysiology and time course of an individual converting from asymptomatic peripheral artery disease (PAD) to symptomatic claudication is unclear. The objectives of this study were: (1) to characterize the extent of atherosclerotic disease in individuals with an abnormal ankle–brachial index (ABI), but without claudication; and over 1 year of follow-up to (2) evaluate the progression of PAD using ultrasound imaging, (3) determine changes in the ABI and leg pain symptoms, and (4) correlate PAD progression with changes in the ABI and leg symptoms. We hypothesized that PAD progression would be associated with the development of claudication and changes in the ABI, 6-minute walk distance (6-MWD), and walking quality of life. Individuals with a reduced ABI but without typical intermittent claudication noted on community screening were invited to undergo baseline and 1-year follow-up assessment, including duplex ultrasound. The initial and repeat evaluations included measurement of the ABI, lower extremity duplex arterial mapping, and assessment of leg pain and functional status. Of the 50 people studied, 44 (88%) had significant atherosclerotic lesions in the lower extremity arteries, affecting 80 legs. A total of 33 of 50 individuals (66%) returned for the 1-year follow-up visit. On ultrasound examination, two of 18 normal legs developed PAD, and in 48 legs with PAD at baseline, 17 legs (35%) developed new or progressive lesions. Thirteen legs developed new claudication. Overall, there was no significant worsening in the ABI, 6-MWD, or the Walking Impairment Questionnaire (WIQ). However, legs with new lesions or lesion progression were significantly more likely to develop claudication, and the 13 legs (seven subjects) developing claudication showed a significant decline in the 6-MWD. In conclusion, these data indicate that a significant number of people with asymptomatic PAD show progression over 1 year, that such individuals are more likely to develop claudication, and that those developing claudication have a significant decrease in their 6-MWD. [ABSTRACT FROM AUTHOR]

The Walking Impairment Questionnaire (WIQ) is a frequently used questionnaire to evaluate patients with intermittent claudication on four subscales: pain severity, walking distance, walking speed and the ability to climb stairs. The aim of this study is to translate and validate the WIQ in Chinese. After translation and cultural adaptation of the WIQ, 134 patients with intermittent claudication completed the Chinese WIQ and European Quality of Life 5 Dimension (EQ-5D). Walking distances were determined by the 6-minute walk test (6MWT). Correlations between the WIQ, quality of life questionnaire and walking distances were calculated to determine validity. Reliability and internal consistency were determined using the intra-class correlation coefficient (ICC) and Cronbach’s alpha (α), respectively. Significant correlations were found between the WIQ score, initial claudication distance (ICD), absolute claudication distance (ACD) and all domains of the EQ-5D (all p ≤ 0.01). Test—retest reliability (ICC = 0.74) and the overall internal consistency determined (α = 0.90) showed good agreement. A lower WIQ score corresponded to shorter walking distances. In conclusion, this study showed that the Chinese version of the WIQ is a valid, reliable and clinically relevant instrument for assessing walking impairment in patients with intermittent claudication. [ABSTRACT FROM AUTHOR]

Objective: The pattern and distribution of arterial occlusions and stenoses in patients with critical limb ischemia presenting at two academic medical centers was described. Methods: From January 1998 to December 2006, 450 consecutive critical limb ischemia patients who underwent arteriography and infrainguinal revascularization at the University of Colorado Health Sciences Center or Southern Illinois University were retrospectively evaluated. Demographics, clinical morbidities, and Fontaine stage were recorded. The arterial tree was categorized into three groups: the aorta and iliac arteries (A-I); the common femoral, superficial femoral, and profunda femoral arteries (Fem); and the popliteal and tibial arteries (Pop-Tib). Arterial segments within groups were categorized as subcritical stenoses (patent or <50% stenoses), critical stenoses (single or multiple >50% stenoses), or occluded (segmental occlusions of any length). Patients with diabetes mellitus, end-stage renal disease, and Fontaine stage (III vs IV) were analyzed for differing disease patterns according to their chart history. Results: Occlusive disease was present in 5% in all arterial segments (A-I + Fem + Pop-Tib), in 1% in the A-I + Fem group, in 2% in the A-I + Pop-Tib group, in 3% in A-I group, in 4% in the Fem group, in 30% in the Fem + Pop-Tib group, and in 55% in the Pop-Tib group. Descriptive comparisons among subgroups demonstrated a 61% to 69% prevalence of popliteal and tibial occlusive patterns in patients with diabetes mellitus, end-stage renal disease, and Fontaine stage IV. Furthermore, 65% of patients with Pop-Tib occlusions had associated critical stenoses in the proximal arterial groups. Conclusion: More than half of critical limb ischemia patients undergoing infrainguinal revascularization have arterial occlusions in the popliteal or tibial arterial segments, or both, with associated critical stenoses in the femoral arterial segments, which is even greater in the subgroups with diabetes mellitus, end-stage renal disease, and Fontaine stage IV. Knowledge of such occlusive patterns is important for the development of novel infrainguinal endovascular and angiogenesis therapies for critical limb ischemia. [Copyright &y& Elsevier]

This study tested the hypothesis that patients with PAD have impaired health-related quality of life (HRQoL) to a degree similar to that of patients with other types of cardiovascular disease (other-CVD), and also evaluated the clinical features of PAD associated with impaired HRQoL. This was a cross-sectional study in 350 primary care practice sites nationwide with 6,499 participants. The reference group had no clinical or hemodynamic evidence of PAD or other-CVD; the PAD group had an ankle-brachial index < 0.90 or a prior history of PAD; the other-CVD group had a clinical history of cardiac or cerebral vascular disease (but no PAD), and the combined PAD-other-CVD group included both diagnoses. Individuals were assessed using four HRQoL questionnaires including the Walking Impairment Questionnaire (WIQ), Medical Outcomes Study SF-36 (SF-36), Cantril Ladder of Life and the PAD Quality of Life questionnaire. PAD patients had lower WIQ distance scores than the other-CVD group. Both the PAD and other-CVD groups had significantly lower SF-36 Physical Function scores compared with the reference group. The WIQ revealed that PAD patients were more limited by calf pain, whereas other-CVD patients were more limited by chest pain, shortness of breath and palpitations. In conclusion, in this nationwide study, one of the first to directly compare the HRQoL burden of CVD with that of PAD, the evaluation of PAD in office practice revealed a HRQoL burden as great in magnitude as in patients with other forms of CVD. [ABSTRACT FROM AUTHOR]

Prostanoids, which promote vasodilation and reduce platelet aggregation, have been proposed as candidate therapies for intermittent claudication due to peripheral arterial disease (PAD). However, studies of these medications have yielded inconsistent results. This study tested the hypothesis that iloprost, an oral prostacyclin analogue, would improve walking distance and quality of life in patients with intermittent claudication. The study was a multi-center, randomized, double-blind, placebo-controlled trial comparing three doses of oral iloprost (50 μg, 100 μg, or 150 μg twice daily), pentoxifylline, or placebo in 430 patients with intermittent claudication. The primary outcome measure was improvement in absolute claudication distance (ACD) after 6 months. Secondary outcomes included initial claudication distance and quality of life assessment. Placebo increased ACD by 3.3%, and iloprost increased peak ACD by 7.7%, 8.8% and 11.2% at the 50 μg, 100 μg, and 150 μg twice-daily doses, respectively (all insignificant relative to placebo). Pentoxifylline increased ACD by 13.9% relative to placebo (p = 0.039). Neither iloprost nor pentoxifylline enhanced quality of life. These results indicate that oral iloprost is not effective in improving exercise performance or quality of life in patients with PAD who have intermittent claudication. [ABSTRACT FROM AUTHOR]

Office-based cardiovascular risk prediction continues to challenge practitioners in primary and secondary risk stratification settings. In patients with established peripheral arterial disease (PAD), the risk of cardiovascular events (i.e. death or morbidity due to coronary heart disease and/or cerebrovascular disease) is high, yet traditional risk factors and the ankle-brachial index (ABI) do not provide a complete secondary risk prediction. In this population, office-based cardiovascular risk stratification may be improved by surrogate markers of the systemic atherosclerotic burden, as well as markers of systemic inflammation. This review will evaluate the utility of the ABI, clinical stage of disease, and the emerging role of C-reactive protein (CRP) and other inflammatory markers in secondary risk prediction in PAD. Defining which patients are in the highest category of risk may direct health care providers to emphasize secondary preventive measures, and facilitate patient adherence to recommended medical therapies and smoking cessation. [ABSTRACT FROM AUTHOR]

Pharmacological and non-pharmacological interventions to improve function and quality of life in patients with claudication are being evaluated in clinical research trials. An important component of clinical development programs is assessing the safety of the intervention and monitoring for adverse impact of the therapy on research participants. The conduct of both of these safety assessments is facilitated by the ability to estimate the anticipated rates of cardiovascular events and death in the target population. To obtain estimates of these rates, data were abstracted from randomized, double-blind, placebo-controlled trials performed in patients with claudication and designed to show functional improvement, and which have been published since 1990. Patient-year exposures and the number of deaths, serious adverse events and cardiovascular serious adverse events in the placebo arms of these trials were tabulated, and summed event rates calculated. The mortality rate was 1.9 deaths per hundred patient-years (27 deaths observed in 1446 patient-years). The mortality rate in claudication trials is lower than that reported in natural history studies. Cardiovascular serious adverse events in claudication trials were observed at a rate of 8.5 per hundred patient-years (65 events in 762 patient-years). Thus, cardiovascular morbidity and mortality should be expected in clinical trials enrolling claudicants. The current analyses provide benchmark data for ensuring that development programs are large enough to allow meaningful safety conclusions, and to assist in data and safety monitoring of these trials. [ABSTRACT FROM AUTHOR]

Patients with peripheral arterial disease (PAD) who become symptomatic with claudication (approximately one-third of the population) have a marked impairment in exercise performance and overall functional capacity. Patients with claudication have a peak oxygen consumption measured during graded treadmill exercise testing that is 50% of that in age-matched normal subjects, and also report great difficulty in walking relatively short distances, even at a slow walking speed. The reduced walking capacity is associated with impairment in activities of daily living and quality of life. Thus, claudication is highly limiting to the physical functioning of daily activities. Improving mobility and improving the reduced quality of life are therefore major goals of treatment. Patients with PAD develop metabolic abnormalities in the skeletal muscles of the lower extremity. These abnormalities include impairment in ischemic muscle mitochondrial electron transport chain activity and accumulation of intermediates of oxidative metabolism (acylcarnitines). Patients with the greatest accumulation of muscle acylcarnitines have the most impaired exercise performance. Thus, claudication is not simply the result of reduced blood flow, and alterations in skeletal muscle metabolism are part of the pathophysiology of the disease. L-Carnitine and propionyl-L-carnitine may improve the metabolism and exercise performance of ischemic muscles. L-Carnitine in a dose of 2 grams twice daily improved treadmill performance, but propionyl-L-carnitine (an acyl form of carnitine) was more effective than L-carnitine in improving treadmill walking distance. In two multicenter trials of a total of 730 patients, initial and maximal treadmill walking distance improved more with propionyl-L-carnitine than placebo. The drug also improved quality of life and had minimal side effects as compared with placebo. Propionyl-L-carnitine has not been approved for use in the United States. [ABSTRACT FROM AUTHOR]

This study tested the hypothesis that avasimibe, an inhibitor of acyl coenzyme A-cholesterol acyltransferase (ACAT), would improve treadmill exercise performance in patients with claudication secondary to peripheral arterial disease (PAD). Four hundred and forty-two patients with PAD (ankle–brachial index in the index leg of ≤0.90 with a ≥20% reduction post-exercise) were enrolled from 39 centers in the USA. Patients were randomized to receive oral avasimibe 50 mg, 250 mg, 750 mg or placebo for a treatment period of 12 months. Changes from baseline in peak walking time (PWT) using a graded treadmill protocol were compared among groups after 6 and 12 months of treatment. Individual group comparisons were considered statistically significant if p < 0.0245 for the 50 mg and 250 mg groups and p < 0.001 for the 750 mg group. Patients randomized to the 50 mg group experienced a 0.76 min net increase over placebo in PWT, but this did not reach the pre-specified level of statistical significance (Hochberg procedure p = 0.027) using ANCOVA after 12 months of treatment after adjusting for multiple comparisons. This trend in PWT was supported by the changes in treadmill initial claudication time (ICT) (p = 0.026) and Walking Impairment Questionnaire (WIQ) walking distance score (p = 0.058). The 250 mg and 750 mg avasimibe dose groups failed to demonstrate an improvement in PWT over placebo after 6 months of treatment. In conclusion, while the ACAT inhibitor avasimibe did not show clear evidence of benefit on treadmill exercise performance in patients with PAD, the results add to our knowledge of the impact of treatments directed at atherosclerosis on functional endpoints. [ABSTRACT FROM AUTHOR]

Peripheral arterial disease is prevalent, associated with increased cardiovascular morbidity and mortality, and is underdiagnosed. Nevertheless, systematic efforts to provide early office-based peripheral arterial disease detection are not routinely implemented in office practice. The PARTNERS Program implemented the ankle–brachial index (ABI) measurement in primary care outpatient clinics in order to model practical dissemination of this technique and thus improve office-based peripheral arterial disease detection. The objective of this study was to identify clinician-defined factors that were perceived to foster acceptance of, or create barriers to, the use of the ABI in office practice. The ABI Utilization Survey was administered to primary care clinicians who participated in the PARTNERS Program, as well as to additional primary care clinicians who participated in the PARTNERS Preceptorship. The survey assessed six parameters: pre- and post-participation office ABI utilization; perceived clinical utility of the ABI; perceived value of the ABI data relative to other commonly used office disease detection methods; feasibility of implementing office-based ABI testing; definition of factors limiting utilization of the ABI in office practice; and the role of office staff in performing the ABI test. Survey data were obtained from 886 respondents. A total of 68% of respondents did not measure the ABI prior to participation in the PARTNERS Program. After Program participation, the frequency of office ABI use increased from 12% to 43% weekly and 13% to 39% monthly. The few participants who reported using the ABI only once a year (annually) did not significantly change after the program. Most clinicians believed that the ABI was useful in the diagnosis and management of both symptomatic (96%) and asymptomatic (89%) peripheral arterial disease. Moderate to major barriers to use of the ABI included time constraints (56%), lack of reimbursement (45%), and staff availability (45%). Nearly all (88%) clinicians believed that it was feasible to incorporate ABI into daily practice. Overall, most clinicians (57 – 75%) believed that ABI was equal to, or more useful, than other widely available and reimbursed screening tests in preserving their patients' health. In conclusion, the ABI was perceived by primary care clinicians to be a clinically useful diagnostic test. Limited reimbursement and time were identified as the primary barriers to its widespread use. Once learned, most clinicians stated that the ABI would continue to be frequently used in their office practice. The ABI is a simple peripheral arterial disease detection tool that can be successfully applied in primary care office practices. [ABSTRACT FROM AUTHOR]

Slowed pulmonary O2 uptake (&Vdot;o2) kinetics in peripheral arterial disease (PAD) have been attributed to impaired limb blood flow and/or peripheral muscle metabolic abnormalities. Although PAD results from atherosclerotic occlusive disease in the arteries to the lower extremities, systemic abnormalities affecting whole body O2 delivery or vascular function in PAD could also partially explain the exercise impairment. To date, the effects of these systemic abnormalities have not been evaluated. To test the hypothesis that the slowed pulmonary &Vdot;o2 kinetics in PAD reflects local and not systemic abnormalities, Vo2 kinetics were evaluated after the onset of constant-load exercise of the upper and lower limbs in PAD patients and healthy controls (Con). Ten PAD patients and 10 Con without significant cardiopulmonary dysfunction performed multiple transitions from rest to moderate-intensity arm ergometry and treadmill exercise to assess their &Vdot;o2 kinetic responses. Reactive hyperemic (RH) blood flow was assessed in the arms and legs as a measure of endothelial function. Compared with Con, PAD &Vdot;o2 kinetic phase 2 time constants were prolonged during treadmill exercise (PAD 34.3 &plusmn: 9.2 s vs. Con 19.6 &plusmn: 3.5 s; P < 0.01) but not arm exercise (PAD 38.5 &plusmn: 7.5 s vs. Con 32.5 &plusmn: 9.0 s; P > 0.05). RH blood flow was significantly reduced in the legs (PAD 20.7 &plusmn: 8.3 vs. Con 46.1 &plusmn: 17.1 ml·100 ml-1·min-1; p < 0.01) and arms of PAD subjects (PAD 34.0 &plusmn: 8.6 vs. Con 50.8 &plusmn: 12.2 ml·100 ml-1·min-1; p < 0.01) compared with Con, but RH limb flow was not correlated with arm or treadmill &Vdot;o2 kinetic responses in either group. In summary, slowed pulmonary &Vdot;o2 kinetics in PAD patients occur only with exercise of the lower limbs affected by the arterial occlusive disease process and are not slowed with exercise of the unaffected upper extremities compared with controls. Furthermore, the slowed pulmonary&Vdot;o2 kinetics of the lower extremity could not be explained by any abnormalities in resting cardiac or pulmonary function and were not related to the magnitude of reduction in limb vascular reactivity. [ABSTRACT FROM AUTHOR]

OBJECTIVES: To assess whether cilostazol, a phosphodiesterase III inhibitor, improves treadmill and community-based walking ability and health-related quality of life (HQL) in patients with intermittent claudication resulting from peripheral arterial disease (PAD). DESIGN: Retrospective meta-analysis of data pooled from six Phase 3, multicenter, double-blind, placebo-controlled, parallel-group, randomized studies. SETTING: Patients were recruited from outpatient ambulatory medical care facilities. PARTICIPANTS: Patients' (n = 1,751) mean age ± standard deviation was 65 ± 9, and they had a history of PAD for 6 months or longer and an ankle brachial index (ABI) of 0.90 or less. INTERVENTION: Cilostazol 50 mg bid or 100 mg bid for 12, 16, or 24 weeks. MEASUREMENTS: ABI; maximal walking distance (MWD); pain-free walking distance on a graded and constant-load treadmill; and HQL, measured using the Walking Impairment Questionnaire (WIQ) and the Medical Outcomes Study Short Form-36 (SF-36). RESULTS: Maximal treadmill walking distance improved more in both cilostazol groups than in the placebo group (both P < .0001). WIQ and SF-36 physical summary scores improved significantly more with cilostazol than with placebo (for instance, WIQ distance score, P < .0001 and SF-36 physical summary score, P < .0001, comparing persons taking cilostazol with controls). Improved MWD correlated with improvements in WIQ (correlation with distance score, r = 0.34, P < .0001) and SF-36 physical summary scores (r = 0.29, P < .0001). CONCLUSIONS: Treatment with cilostazol was associated with greater improvements in community-based walking ability and HQL in patients with intermittent claudication than treatment with placebo. These improvements correlated with increased MWD. This analysis of effects of cilostazol on improving walking ability in persons with claudication is the first cilostazol study focused on community-based measures of functional status and HQL. Questionnaires... [ABSTRACT FROM AUTHOR]

Examines the occurrence of basic fibroblast growth factor (bFGF)-related proteinuria for intermittent claudication in patients with peripheral arterial disease. Intravenous administration of bFGF; Association of limb blood flow with exercise; Ways of improving claudication symptoms.

Presents a study to assess the feasibility of detecting peripheral arterial disease (PAD) in primary care clinics, patient and physician awareness of PAD, and intensity of risk factor treatment and use of antiplatelet therapies in primary care clinics. Design and setting; Patients; Main outcome measures; Results; Conclusions.

Tests the hypothesis that peripheral arterial disease (PAD) is associated with specific defects in skeletal muscle electron transport activity in human patients. Relative decreases in nicotinamide adenine dinucleotide dehydrogenase and ubiquinol-cytochrome c oxidoreductase activities; Mitochondrial content in skeletal muscle of PAD patients and controls.

Supervised, hospital-based exercise rehabilitation programs are effective for improving functional status for patients with claudication due to peripheral arterial occlusive disease. However, it has been suggested that unsupervised, home-based exercise programs, which have been relatively little evaluated, would be equally efficacious as compared with hospital-based programs. The authors tested the hypothesis that a hospital-based exercise rehabilitation program would improve treadmill exercise performance more than a home-based program. Of 20 consecutively enrolled patients with claudication, 10 were randomly placed into a supervised, hospital-based program and 10 into an unsupervised, home-based program for a three-month period. Exercise performance was evaluated by treadmill testing using a graded protocol. In addition, functional status was evaluated by the Walking Impairment Questionnaire (WIQ) and the Medical Outcomes Study SF-20 questionnaire (MOS). Patients in the hospital-based program were treated with treadmill walking three times a week for one hour/visit. Patients in the home-based program were instructed to walk at least three times a week and were contacted weekly to provide encouragement and to record compliance with the program. Patients in the hospital-based group improved peak walking time by 137%, pain-free walking time by 150%, and peak oxygen consumption by 19% (all P<0.05). Patients reported an improved walking distance and speed according to WIQ data (both P<0.05). In addition, the MOS physical functioning score in the hospital-based group improved by 20 percentage points (P<0.05). In contrast, patients in the home-based program did not improve exercise performance measured on the treadmill. Improvement in the ability to walk on the treadmill was greater in the hospital-based than the home-based program (P<0.05). The ability to walk distances was the only questionnaire measure that improved in persons who received the home-based program (P<0.05). Preliminary results suggest that a supervised, hospital-based program is more effective for improving treadmill exercise performance than an unsupervised, home-based program. [ABSTRACT FROM AUTHOR]

Many patients with peripheral arterial disease (PAD) undergo peripheral bypass surgery to relieve the symptom of intermittent claudication. However, measurement of graft patency alone, assessed by change in ankle blood pressure, may not adequately reflect the improvement in functional status following the operation. Fourteen patients with moderately severe intermittent claudication were evaluated before and after bypass surgery to assess changes in hemodynamics (by resting ankle-brachial indices-ABIs), exercise performance (by a graded treadmill protocol), and community-based walking ability (by a questionnaire that characterizes self-reported walking speed and distance). Six weeks after surgery, resting ABIs improved in surgical patients (from 0.56 ± 0.09 to 0.93 ± 0.16, P < 0.05). Peak treadmill walking time improved from 6.2 ± 5.9 to 11.8 ± 7.1 min (90%), peak oxygen consumption from 15.5 ± 6.5 to 19.1 ± 8.5 mL/kg/min (23%), and pain-free walking time from 1.5 ± 0.4 to 6.0 5.5 min (290%). Questionnaire scores for walking distance improved by 203% and for walking speed by 130% (all P < 0.05). After twelve weeks, improvements other than pain-free walking time were maintained. Changes in peak treadmill performance or questionnaire scores were not correlated with the initial ABI, changes in ABI six or twelve weeks after surgery, or the type or extent of bypass surgery. The results demonstrate that surgical treatment of PAD, indicated for the relief of intermittent claudication, improves exercise performance and self-reported community-based walking ability. The change in functional status of the patient is an important outcome of surgery that cannot be predicted from routine noninvasive testing alone and should be measured directly. [ABSTRACT FROM AUTHOR]

The article discusses the recommendation indicated in the guideline from the American Heart Association and American College of Cardiology for management of patients with peripheral artery disease (PAD). Details on the benefit of antiplatelet therapy with aspirin or clopidogrel on the reduction of myocardial infarction, stroke and vascular death in patients with symptomatic PAD is offered.

Background: In patients with symptomatic peripheral artery disease with a history of limb revascularization, the optimal antithrombotic regimen for long-term management is unknown.Methods: The EUCLID trial (Examining Use of Ticagrelor In PAD) randomized 13 885 patients with peripheral artery disease to treatment with ticagrelor 90 mg twice daily or clopidogrel 75 mg daily. Patients were enrolled based on an abnormal ankle-brachial index ≤0.80 or a previous lower extremity revascularization. This analysis focuses on the 7875 (57%) patients enrolled based on the previous lower extremity revascularization criterion. Patients could not be enrolled within 30 days of most recent revascularization, and patients with an indication for dual antiplatelet therapy were excluded. The primary efficacy end point was a composite of cardiovascular death, myocardial infarction, or ischemic stroke. The primary safety end point was major bleeding.Results: Patients with a previous revascularization had a mean age of 66 years, 73% were male, and the median baseline ankle-brachial index was 0.78. After adjustment for baseline characteristics, patients enrolled based on previous revascularization had similar rates of the primary composite end point (hazard ratio [HR] 1.10, 95% confidence interval [CI] 0.98-1.23, P=0.12) and statistically significantly higher rates of myocardial infarction (HR 1.29, 95% CI 1.08-1.55, P=0.005) and acute limb ischemia (HR 4.23, 95% CI 2.86-6.25, P<0.001) when compared with patients enrolled based on ankle-brachial index criteria. No differences in ticagrelor- versus clopidogrel-treated patients were found for the primary efficacy end point (11.4% vs 11.3%; HR 1.01, 95% CI 0.88-1.15; P=0.90), all-cause mortality (9.2% vs 9.2%; HR 0.99, 95% CI 0.86-1.15; P=0.93), acute limb ischemia (2.5% vs 2.5%; HR 1.03, 95% CI 0.78-1.36; P=0.84), or major bleeding (1.9% vs 1.8%; HR 1.15, 95% CI 0.83-1.59; P=0.41). The median duration of follow-up was ≈30 months.Conclusions: After adjustment for baseline characteristics, patients enrolled based on previous revascularization for peripheral artery disease had higher rates of myocardial infarction and acute limb ischemia, with similar composite rates of cardiovascular death, myocardial infarction, and stroke when compared with patients enrolled based on the ankle-brachial index criterion. No significant differences were found between ticagrelor and clopidogrel for reduction of cardiovascular or acute limb events.Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01732822. [ABSTRACT FROM AUTHOR]

Presents an article on peripheral arterial disease (PAD), which is an important manifestation of systemic atherosclerosis. Severity of PAD which is associated with the risk of myocardial infarction, ischemic stroke, and death; Major risk factors of PAD; Undertreatment of patients with PAD with regard to use of lipid-lowering and antiplatelet drugs as compared with patients with coronary artery disease.

The lack of consistent definitions and nomenclature across clinical trials of novel devices, drugs, or biologics poses a significant barrier to accrual of knowledge in and across peripheral artery disease therapies and technologies. Recognizing this problem, the Peripheral Academic Research Consortium, together with the U.S. Food and Drug Administration and the Japanese Pharmaceuticals and Medical Devices Agency, has developed a series of pragmatic consensus definitions for patients being treated for peripheral artery disease affecting the lower extremities. These consensus definitions include the clinical presentation, anatomic depiction, interventional outcomes, surrogate imaging and physiological follow-up, and clinical outcomes of patients with lower-extremity peripheral artery disease. Consistent application of these definitions in clinical trials evaluating novel revascularization technologies should result in more efficient regulatory evaluation and best practice guidelines to inform clinical decisions in patients with lower extremity peripheral artery disease. [ABSTRACT FROM AUTHOR]