Cilostazol for peripheral arterial disease - a position paper from the Italian Society for Angiology and Vascular Medicine.

Cilostazol is a quinolinone-derivative selective phosphodiesterase inhibitor and is a platelet-aggregation inhibitor and arterial vasodilator for the symptomatic treatment of intermittent claudication (IC). Cilostazol has been shown to improve walking distance for patients with moderate to severe disabling intermittent claudication who do not respond to exercise therapy and who are not candidates for vascular surgical or endovascular procedures. Several studies evaluated the pharmacological effects of cilostazol for restenosis prevention and indicated a possible effect on re-endothelialization mediated by hepatocyte growth factor and endothelial precursor cells, as well as inhibiting smooth muscle cell proliferation and leukocyte adhesion to endothelium, thereby exerting an anti-inflammatory effect. These effects may suggest a potential effectiveness of cilostazol in preventing restenosis and promoting the long-term outcome of revascularization interventions. This review aimed to point out the role of cilostazol in treating patients with peripheral arterial disease, particularly with IC, and to explore its possible role in restenosis after lower limb revascularization.

The Use and Impact of Cilostazol on Patients Undergoing Endovascular Peripheral Interventions.

BACKGROUND: Cilostazol is used for the treatment of intermittent claudication. The impact of cilostazol on the outcomes of peripheral vascular interventions (PVIs) remains controversial. This study assesses the use and impact of cilostazol on patients undergoing PVI for peripheral arterial disease (PAD). METHODS: The Vascular Quality Initiative (VQI) database files for PVI were reviewed. Patients with PAD who underwent PVI for chronic limb threatening-ischemia or claudication were included and divided based on the use of cilostazol preoperatively. After propensity matching for patient demographics and comorbidities, the short-term and long-term outcomes of the 2 groups (preoperative cilostazol use versus no preoperative cilostazol use) were compared. The Kaplan-Meier method was used to determine outcomes. RESULTS: A total of 245,309 patients underwent PVI procedures and 6.6% (N = 16,366) were on cilostazol prior to intervention. Patients that received cilostazol were more likely to be male (62% vs 60%; P < 0.001), White (77% vs. 75%; P < 0.001), and smokers (83% vs. 77%; P < 0.001). They were less likely to have diabetes mellitus (50% vs. 56%; P < 0.001) and congestive heart failure (14% vs. 23%; P < 0.001). Patient on cilostazol were more likely to be treated for claudication (63% vs. 40%, P < 0.001), undergo prior lower extremity revascularization (55% vs. 51%, P < 0.001) and less likely to have undergone prior minor and major amputation (10% vs. 19%; P < 0.001) compared with patients who did not receive cilostazol. After 3:1 propensity matching, there were 50,265 patients included in the analysis with no differences in baseline characteristics. Patients on cilostazol were less likely to develop renal complications and more likely to be discharged home. Patients on cilostazol had significantly lower rates of long-term mortality (11.5% vs. 13.4%, P < 0.001 and major amputation (4.0% vs. 4.7%, P = 0.022). However, there were no significant differences in rates of reintervention, major adverse limb events, or patency after PVI. Amputation-free survival rates were significantly higher for patients on cilostazol, after 4 years of follow up (89% vs. 87%, P = 0.03). CONCLUSIONS: Cilostazol is underutilized in the VQI database and seems to be associated with improved amputation-free survival. Cilostazol therapy should be considered in all patients with PAD who can tolerate it prior to PVI.

Mobile health technologies to improve walking distance in people with intermittent claudication.

BACKGROUND: Peripheral arterial disease (PAD) is the obstruction or narrowing of the large arteries of the lower limbs, which can result in impaired oxygen supply to the muscle and other tissues during exercise, or even at rest in more severe cases. PAD is classified into five categories (Fontaine classification). It may be asymptomatic or various levels of claudication pain may be present; at a later stage, there may be ulceration or gangrene of the limb, with amputation occasionally being required. About 20% of people with PAD suffer from intermittent claudication (IC), which is muscular discomfort in the lower extremities induced by exertion and relieved by rest within 10 minutes; IC causes restriction of movement in daily life. Treatment for people with IC involves addressing lifestyle risk factors. Exercise is an important part of treatment, but supervised exercise programmes for individuals with IC have low engagement levels and high attrition rates. The use of mobile technologies has been suggested as a new way to engage people with IC in walking exercise interventions. The novelty of the intervention, low cost for the user, automation, and ease of access are some of the advantages mobile health (mhealth) technologies provide that give them the potential to be effective in boosting physical activity in adults. OBJECTIVES: To assess the benefits and harms of mobile health (mhealth) technologies to improve walking distance in people with intermittent claudication. SEARCH METHODS: The Cochrane Vascular Information Specialist conducted systematic searches of the Cochrane Vascular Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, and CINAHL, and also searched the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) and ClinicalTrials.gov. The most recent searches were carried out on 19 December 2022. SELECTION CRITERIA: We included randomised controlled trials (RCTs) in people aged 18 years or over with symptomatic PAD and a clinical diagnosis of IC. We included RCTs comparing mhealth interventions to improve walking distance versus usual care (no intervention or non-exercise advice), exercise advice, or supervised exercise programmes. We excluded people with chronic limb-threatening ischaemia (Fontaine III and IV). DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Our primary outcomes were change in absolute walking distance from baseline, change in claudication distance from baseline, amputation-free survival, revascularisation-free survival. Our secondary outcomes were major adverse cardiovascular events, major adverse limb events, above-ankle amputation, quality of life, and adverse events. We used GRADE to assess the certainty of the evidence. MAIN RESULTS: We included four RCTs involving a total of 614 participants with a clinical diagnosis of IC. The duration of intervention of the four included RCTs ranged from 3 to 12 months. Participants were randomised to either mhealth or control (usual care or supervised exercise programme). All four studies had an unclear or high risk of bias in one or several domains. The most prevalent risk of bias was in the area of performance bias, which was rated high risk as it is not possible to blind participants and personnel in this type of trial. Based on GRADE criteria, we downgraded the certainty of the evidence to low, due to concerns about risk of bias, imprecision, and clinical inconsistency. Comparing mhealth with usual care, there was no clear evidence of an effect on absolute walking distance (mean difference 9.99 metres, 95% confidence interval (CI) -27.96 to 47.93; 2 studies, 503 participants; low-certainty evidence). None of the included studies reported on change in claudication walking distance, amputation-free survival, or revascularisation-free survival. Only one study reported on major adverse cardiovascular events (MACE) and found no clear difference between groups (risk ratio 1.37, 95% CI 0.07 to 28.17; 1 study, 305 participants; low-certainty evidence). None of the included studies reported on major adverse limb events (MALE) or above-ankle amputations. AUTHORS' CONCLUSIONS: Mobile health technologies can be used to provide lifestyle interventions for people with chronic conditions, such as IC. We identified a limited number of studies that met our inclusion criteria. We found no clear difference between mhealth and usual care in improving absolute walking distance in people with IC; however, we judged the evidence to be low certainty. Larger, well-designed RCTs are needed to provide adequate statistical power to reliably evaluate the effects of mhealth technologies on walking distance in people with IC.

Real-World Safety and Effectiveness of Controlled-Release Cilostazol in Patients with Symptomatic Peripheral Artery Disease.

BACKGROUND: Cilostazol is the only first-line medication for treating intermittent claudication, and the controlled-release (CR) formulation is associated with a lower prevalence of adverse events (AEs). OBJECTIVE: The objective of the study was to assess the safety and effectiveness of cilostazol CR in patients with symptomatic peripheral artery disease (PAD). METHODS: In this multicentre (113 sites), open-label, prospective observational study, we evaluated the real-world safety and effectiveness of cilostazol CR 200 mg once daily in patients with symptomatic PAD treated in routine clinical settings. The primary endpoint was the incidence and severity of AEs, and their causal relationship with cilostazol CR. The secondary endpoint was the effectiveness of the drug, as assessed by each patient's physician, for improving intermittent claudication. RESULTS: Among 2063 participants who received cilostazol CR for a mean duration of 88.6 days, 99 (4.80 %) experienced adverse drug reactions (ADRs), although no unexpected adverse reactions were observed. There was no significant difference in the incidence of ADRs according to patient demographics and comorbidities (all p > 0.05). The treatment was 'effective' in 1600 patients (78.93 %), although effectiveness significantly differed according to the patients' sex and the presence of comorbidities, including diabetes mellitus, hypertension, and coronary artery disease (all p < 0.01). CONCLUSIONS: This study demonstrated the tolerability and effectiveness of cilostazol CR treatment in patients with symptomatic PAD.

Peripheral artery disease: Update on etiology, pathophysiology, diagnosis and treatment.

Peripheral artery disease (PAD) is a condition related to atherosclerosis affecting >200 million people worldwide, and it increases cardiovascular morbidity (mainly from myocardial infarction and stroke) and mortality. Indeed, PAD patients are classified as patients at very high cardiovascular risk. The most common manifestation of PAD is intermittent claudication, which is associated with reduced mobility and leg pain. Nevertheless, asymptomatic PAD is the most frequent form of PAD worldwide; therefore, it remains underdiagnosed and undertreated. The major risk factors for PAD are smoking, diabetes mellitus, hyperlipidemia, hypertension, overweight/obesity, age, male sex, and black race. Hence, the first and most relevant approach in PAD treatment is lifestyle management, with measures such as smoking cessation, healthy diet, weight loss, and regular physical exercise. This should also be supported by an optimal pharmacological approach including lipid-lowering drugs, antihypertensive drugs, antidiabetic agents, and antithrombotics.

The addition of evolocumab to maximal tolerated statin therapy improves walking performance in patients with peripheral arterial disease and intermittent claudication (Evol-PAD study).

OBJECTIVE: To test the hypothesis that in patients with peripheral arterial disease (PAD) and claudication, treated with maximal tolerated statin therapy, the addition of a monthly subcutaneous injection of evolocumab for 6 months improves treadmill walking performance. BACKGROUND: Lipid lowering therapy improves walking parameters in patients with PAD and claudication. Evolocumab decreases cardiac and limb adverse events in patients with PAD; however, the effect of evolocumab on walking performance is not known. METHODS: We performed a double-blind, randomized, placebo-controlled study to compare maximal walking time (MWT) and pain free walking time (PFWT) in patients with PAD and claudication treated with monthly subcutaneous injections of evolocumab 420 mg (n = 35) or placebo (n = 35). We also performed measurements of lower limb perfusion, brachial flow mediated dilatation (FMD), carotid intima media thickness (IMT), and serum biomarkers of PAD disease severity. RESULTS: After six-months of treatment with evolocumab MWT increased by 37.7 % (87.5 ± 24 s) compared to 1.4 % (-21.7 ± 22.9 s) in the placebo group, p = 0.01. PFWT increased by 55.3 % (67.3 ± 21.2 s) in the evolocumab group compared to 20.3 % (8.5 ± 20.3 s) in the placebo group, p = 0.051. There was no difference in lower extremity arterial perfusion measurements. FMD increased by 42.0 ± 73.9 % (1.01 ± 0.7 %) in the evolocumab group and decreased by 16.29 ± 20.06 % (0.99 ± 0.68 %) in the placebo group (p < 0.001). IMT decreased by 7.16 ± 4.6 % (0.06 ± 0.04 mm) in the evolocumab group and increased by 6.68 ± 4.9 % (0.05 ± 0.03 mm) in the placebo group, (p < 0.001). CONCLUSIONS: The addition of evolocumab to maximal tolerated statin therapy improves maximal walking time in patients with PAD and claudication, increases FMD, and decreases IMT. CONDENSED ABSTRACT: Peripheral arterial disease (PAD) impairs quality of life by causing lower extremity intermittent claudication, rest pain, or amputation. Evolocumab is a monthly injectable monoclonal antibody medication that reduces cholesterol. In this study, we randomly treated patients with PAD and claudication, and on background statin therapy, with evolocumab or placebo, and found that evolocumab improves walking performance on a treadmill test by increasing maximal walking time. We also found that evolocumab decreases plasma MRP-14 levels, a marker of PAD severity.

MetfOrmin BenefIts Lower Extremities with Intermittent Claudication (MOBILE IC): randomized clinical trial protocol.

BACKGROUND: Peripheral artery disease (PAD) affects over 230 million people worldwide and is due to systemic atherosclerosis with etiology linked to chronic inflammation, hypertension, and smoking status. PAD is associated with walking impairment and mobility loss as well as a high prevalence of coronary and cerebrovascular disease. Intermittent claudication (IC) is the classic presenting symptom for PAD, although many patients are asymptomatic or have atypical presentations. Few effective medical therapies are available, while surgical and exercise therapies lack durability. Metformin, the most frequently prescribed oral medication for Type 2 diabetes, has salient anti-inflammatory and promitochondrial properties. We hypothesize that metformin will improve function, retard the progression of PAD, and improve systemic inflammation and mitochondrial function in non-diabetic patients with IC. METHODS: 200 non-diabetic Veterans with IC will be randomized 1:1 to 180-day treatment with metformin extended release (1000 mg/day) or placebo to evaluate the effect of metformin on functional status, PAD progression, cardiovascular disease events, and systemic inflammation. The primary outcome is 180-day maximum walking distance on the 6-min walk test (6MWT). Secondary outcomes include additional assessments of functional status (cardiopulmonary exercise testing, grip strength, Walking Impairment Questionnaires), health related quality of life (SF-36, VascuQoL), macro- and micro-vascular assessment of lower extremity blood flow (ankle brachial indices, pulse volume recording, EndoPAT), cardiovascular events (amputations, interventions, major adverse cardiac events, all-cause mortality), and measures of systemic inflammation. All outcomes will be assessed at baseline, 90 and 180 days of study drug exposure, and 180 days following cessation of study drug. We will evaluate the primary outcome with linear mixed-effects model analysis with covariate adjustment for baseline 6MWT, age, baseline ankle brachial indices, and smoking status following an intention to treat protocol. DISCUSSION: MOBILE IC is uniquely suited to evaluate the use of metformin to improve both systematic inflammatory responses, cellular energetics, and functional outcomes in patients with PAD and IC. TRIAL REGISTRATION: The prospective MOBILE IC trial was publicly registered (NCT05132439) November 24, 2021.

Moderate dose of dietary nitrate improves skeletal muscle microvascular function in patients with peripheral artery disease.

Peripheral artery disease (PAD) is an atherosclerotic disease characterized by compromised lower-extremity blood flow that impairs walking ability. We showed that a moderate dose of dietary nitrate in the form of beetroot juice (BRJ, 0.11 mmol/kg) can improve macrovascular function and maximal walking distance in patients with PAD. However, its impacts on the microcirculation and autonomic nervous system have not been examined. Therefore, we investigated the impacts of this dose of dietary nitrate on skeletal muscle microvascular function and autonomic nervous system function and further related these measurements to 6-min walking distance, pain-free walking distance, and exercise recovery in patients with PAD. Patients with PAD (n = 10) ingested either BRJ or placebo in a randomized crossover design. Heart rate variability, skeletal muscle microvascular function, and 6-min walking distance were performed pre- and post-BRJ and placebo. There were significant group × time interactions (P < 0.05) for skeletal muscle microvascular function, 6-min walking distance, and exercise recovery, but no changes (P > 0.05) in heart rate variability or pain-free walking distance were noted. The BRJ group demonstrated improved skeletal muscle microvascular function (∆ 22.1 ± 7.5 %·min-1), longer 6-min walking distance (Δ 37.5 ± 9.1 m), and faster recovery post-exercise (Δ -15.3 ± 4.2 s). Furthermore, changes in skeletal muscle microvascular function were positively associated with changes in 6-min walking distance (r = 0.5) and pain-free walking distance (r = 0.6). These results suggest that a moderate dose of dietary nitrate may support microvascular function, which is related to improvements in walking distance and claudication in patients with PAD.

Characterizing patient-reported claudication treatment goals to support patient-centered treatment selection and measurement strategies.

OBJECTIVE: Patient-reported outcomes (PRO) have been increasingly emphasized for peripheral artery disease (PAD). Patient-defined treatment goals and expectations, however, are poorly understood and might not be achievable or aligned with guidelines or clinical outcomes. We evaluated the patient-reported treatment goals among patients with claudication and the associations between patient characteristics, goals, and PAD-specific PRO scores. METHODS: Patients with a diagnosis of claudication were prospectively recruited. Patient-defined treatment goals and outcomes related to walking distance, duration, and speed were quantified using multiple-choice survey items. Free-text items were used to identify activities other than walking distance, duration, or speed associated with symptoms and treatment goals. The peripheral artery disease quality of life and walking impairment questionnaire instruments were included as PRO. The treatment goal categories were compared with the PRO percentile scores using 95% confidence intervals (CIs), categorical tests, and logistic regression models. Associations between the patient characteristics and PRO were evaluated using linear and ordinal logistic regression models. RESULTS: A total of 150 patients meeting the inclusion criteria were included in the present study. Of these 150 patients, 144 (96%) viewed the entire survey. Their mean age was 70.0 ± 11.3 years, and 32.9% were women. Most of the respondents had self-reported their race as White (n = 135), followed by Black (n = 3), Asian (n = 2), Native American (n = 2), and other/unknown (n = 2). Two participants self-reported Hispanic ethnicity. The primary treatment goals were an increased walking distance or duration without stopping (62.0%), the ability to perform a specific activity or task (23.0%), an increased walking speed (8.0%), or other/none of the above (7.0%). The specific activities associated with symptoms or goals included outdoor recreation (38.5%), labor-related tasks (30.7%), sports (26.9%), climbing stairs (23.1%), uphill walking (19.2%), and shopping (6%). Among the patients choosing an increased walking distance and duration as the primary goals, 64% had indicated that a distance of ≥0.5 mile (2640 ft) and 59% had indicated a duration of ≥30 minutes would be a minimum increase consistent with meaningful improvement. Increasing age was associated with lower odds of a distance improvement goal of ≥0.5 mile (odds ratio [OR], 0.68 per 5 years; 95% CI, 0.51-0.92; P = .012) or duration improvement goal of ≥30 minutes (OR, 0.76 per 5 years; 95% CI, 0.58-0.99; P = .047). Patient characteristics associated with PAD Quality of Life percentile scores included age, ankle brachial index, and gender. Ankle brachial index was the only patient characteristic associated with the walking impairment questionnaire percentile scores. CONCLUSIONS: Patients define treatment goals according to their desired activities and expectations, which may influence their goals and perceived outcomes. Patients' expectations of minimum increases in walking distance and duration consistent with meaningful improvement exceeded reported minimum important difference criteria for many patients and would not be captured using common clinic-based walking tests. Patient age was associated with both treatment goals and PRO scores, and the related floor and ceiling effects could influence sensitivity to PRO changes for younger and older patients, respectively. Heterogeneity in treatment goals supports consideration of tailored decision-making and outcomes informed by patient characteristics and perspectives.

Pentoxifylline in dermatology.

BACKGROUND: Pentoxifylline was initially marketed for use in patients with intermittent claudication due to chronic occlusive arterial disease of the extremities but has since been shown to have several off-label uses in dermatology. AIMS: The aim of this review is to increase awareness of the several applications of pentoxifylline in the field of dermatology. METHODS: A comprehensive PubMed search was conducted in May 2022 using the following phrases "dermatology" AND "pentoxifylline." Our search period spanned 34 years from 1988 to 2022. All available literature was reviewed. Reference lists of identified articles were included. Studies were excluded if they were not in English and if the study was out of scope. Eighty-one articles were included in this review. RESULTS: Pentoxifylline has been used to treat various dermatological conditions including peripheral vascular disease, vasculitis and vasculopathies, chilblains, pigmented purpuric dermatosis, granuloma annulare, necrobiosis, keloids, lichen sclerosis et atrophicus, scars, radiation-induced fibrosis, vitiligo, alopecia areata, leishmaniasis, and leprosy. CONCLUSIONS: Pentoxifylline's use in dermatology is growing. However, there are limited larger studies and randomized control trials on the use of pentoxifylline in dermatology and more investigation is needed to evaluate its use for many dermatologic conditions. Pentoxifylline's unique mechanism of action as well as its good tolerability, cost-effectiveness, and minimal drug interactions make it a convenient primary or adjunctive option in many dermatological conditions.

Real world data from a multi-centre study on the effects of cilostazol on pain symptoms and walking distance in patients with peripheral arterial disease.

OBJECTIVE: to assess the effects of cilostazol on pain-free walking distance in PAD patients with IC at 3 and 6 months in a real world, prospective, observational study. We included 1015 PAD patients presenting with IC (71.3% men, 93.5% white, mean age 69.2 ± 8.7 years). Patients were followed up for 6 months by their physicians. RESULTS: Cilostazol significantly increased pain-free walking distance by a median of 285 and 387 m at 3 and 6 months, respectively (p < 0.01 for all comparisons). This effect was significant for patients 50-74 years (but not for those aged ≥ 75 years) and independent of smoking status, changes in physical activity, comorbidities and concomitant medication for PAD (i.e., acetylsalicylic acid and clopidogrel). Furthermore, significant reductions were observed in systolic (from 139 ± 16 to 133 ± 14 mmHg; p < 0.001) and diastolic blood pressure (from 84 ± 9 mmHg to 80 ± 10 mmHg; p < 0.001). Smoking cessation and increased physical activity were reported by the majority of participants. In conclusion, cilostazol was shown to safely decrease pain symptoms and improve pain-free walking in PAD patients with IC in a real world setting. Benefits also occurred in terms of BP and lifestyle changes.

Systematic review the efficacy and safety of cilostazol, pentoxifylline, beraprost in the treatment of intermittent claudication: A network meta-analysis.

OBJECTIVE: To evaluate the efficacy and safety of cilostazol, pentoxifylline, beraprost for intermittent claudication due to lower extremity arterial occlusive disease. METHODS: Randomized controlled clinical trials were identified from PubMed, Scopus, EMbase, Cochrane Library, Web of Science, China National Knowledge Infrastructure, SinoMed, Wanfang and Chongqing VIP databases, from the database inception to 31/12/2021. The outcome measures were walking distance measured by treadmill (maximum and pain-free walking distance), ankle-brachial index and adverse events. The quality of included studies was assessed by the Cochrane bias risk assessment tool. A network meta-analysis was carried out with Stata 16.0 software. RESULTS: There were 29 RCTs included in the study, covering total 5352 patients. Cilostazol was ranked first for both maximum and pain-free walking distance, followed by beraprost and pentoxifylline. For cilostazol, pentoxifylline and beraprost, maximum walking distance increased by 62.93 95%CI(44.06, 81.79), 32.72 95%CI(13.51, 55.79) and 43.90 95%CI(2.10, 85.71) meters, respectively relative to placebo, and pain-free walking distance increased by 23.92 95%CI(11.24, 36.61), 15.16 95%CI(2.33, 27.99) and 19.78 95%CI(-3.07, 42.62) meters. For cilostazol, pentoxifylline, beraprost and cilostazol combined with beraprost, ankle-brachial index increased by 0.06 95%CI(0.04, 0.07), -0.01 95%CI(-0.08, 0.05), 0.18 95%CI(0.12, 0.23) and 0.23 95%CI(0.18, 0.27), respectively relative to placebo. The pentoxifylline and cilostazol was associated with a lower ratio of adverse events than beraprost and cilostazol combined with beraprost. CONCLUSION: Cilostazol, pentoxifylline and beraprost were all effective treatments for intermittent claudication; cilostazol with good tolerance was likely to be the most effective in walking distance, while beraprost and cilostazol combined with beraprost were more prominent in the ankle-brachial index.

Efficacy and safety of Actovegin in the treatment of intermittent claudication: results of an international, multicenter, placebo-controlled, randomized, phase IIIb clinical trial (APOLLO).

BACKGROUND: This study aimed to assess the efficacy and safety of Actovegin for the treatment of patients with Fontaine stage IIB peripheral arterial disease (PAD). METHODS: The study included 366 patients with Fontaine stage IIB PAD from 19 centers (Russia, Georgia, Kazakhstan). Placebo or Actovegin (1200 mg daily [QD]) were administered intravenously for two weeks, followed by a 10-week course of oral administration (placebo or Actovegin 1200 mg QD). The primary efficacy outcome was percentage change in the initial claudication distance (ICD) by week 12. Secondary outcomes included percent and absolute changes in ICD, absolute claudication distance (ACD) and changes in Quality of Life (QoL) assessed by the SF-36 Mental Health Score. RESULTS: The increase in ICD after 12 weeks of Actovegin treatment was 29.19% (LS mean [Actovegin vs. placebo]; 95% CI: 9.35-49.02; P=0.0041). The percentage increase in ICD at 24 weeks was 35.51% (LS mean; 95% CI: 10.96-60.05; P=0.0047), which correspond to an increase in absolute ICD of 41.22 m (LS mean; 95% CI: 16.77-65.66; P=0.0010). The percentage increase in ACD after 24 weeks was 36.47% compared with the baseline (LS mean; 95% CI: 10.07-62.88; P=0.0069), which corresponded to an absolute increase in ACD of 50.92 m (LS mean; 95% CI: 18.35-83.49; P=0.0023). A statistically significant improvement in QoL with Actovegin compared with placebo was demonstrated within 24 weeks (LS mean 2.28; 95% CI: 0.88-3.68; P=0.0015). Actovegin demonstrated an acceptable safety and tolerability profile with minor differences from placebo. CONCLUSIONS: The results of this 12-week course of Actovegin demonstrated its superiority over placebo in the increase in ICD and ACD at weeks 2, 12 and 24 from the start of treatment. Actovegin has an acceptable safety and tolerability profile.

Effects of a person-centred, nurse-led follow-up programme on adherence to prescribed medication among patients surgically treated for intermittent claudication: randomized clinical trial.

BACKGROUND: Management of intermittent claudication should include secondary prevention to reduce the risk of cardiocerebrovascular disease. Patient adherence to secondary prevention is a challenge. The aim of this study was to investigate whether a person-centred, nurse-led follow-up programme could improve adherence to medication compared with standard care. METHODS: A non-blinded RCT was conducted at two vascular surgery centres in Sweden. Patients with intermittent claudication and scheduled for revascularization were randomized to the intervention or control (standard care) follow-up programme. The primary outcome, adherence to prescribed secondary preventive medication, was based on registry data on dispensed medication and self-reported intake of medication. Secondary outcomes were risk factors for cardiocerebrovascular disease according to the Framingham risk score. RESULTS: Some 214 patients were randomized and analysed on an intention-to-treat basis. The mean proportion of days covered (PDC) at 1 year for lipid-modifying agents was 79 per cent in the intervention and 82 per cent in the control group, whereas it was 92 versus 91 per cent for antiplatelet and/or anticoagulant agents. The groups did not differ in mean PDC (lipid-modifying P = 0.464; antiplatelets and/or anticoagulants P = 0.700) or in change in adherence over time. Self-reported adherence to prescribed medication was higher than registry-based adherence regardless of allocation or medication group (minimum P < 0.001, maximum P = 0.034). There was no difference in median Framingham risk score at 1 year between the groups. CONCLUSION: Compared with the standard follow-up programme, a person-centred, nurse-led follow-up programme did not improve adherence to secondary preventive medication. Adherence was overestimated when self-reported compared with registry-reported.

Rivaroxaban with Aspirin Versus Aspirin for Peripheral Arterial Disease and Intermittent Claudication. Rationale and Design of the COMPASS CLAUDICATION Trial.

BACKGROUND: The COMPASS trial demonstrated that in patients with peripheral arterial disease, the combination of rivaroxaban and aspirin compared with aspirin reduces the risk of major adverse limb events, but it is not known whether this combination can also improve symptoms in patients with intermittent claudication. The primary objective of this study is to evaluate the effect of the combination on claudication distance. STUDY DESIGN: Eighty-eight patients with intermittent claudication will be randomized to receive rivaroxaban 2.5 mg twice daily plus aspirin 100 mg once daily or aspirin 100 mg once daily for 24 weeks. The primary outcome is the change in claudication distance from the baseline to 24 weeks, measured by 6 min walking test and treadmill test. The primary safety outcome is the incidence of major bleeding and clinically relevant non-major bleeding according to the International Society on Thrombosis and Hemostasis criteria. SUMMARY: The COMPASS CLAUDICATION trial will provide high-quality evidence regarding the effect of the combination of rivaroxaban and aspirin on claudication distance in patients with peripheral arterial disease.

Update on Cilostazol: A Critical Review of Its Antithrombotic and Cardiovascular Actions and Its Clinical Applications.

Cilostazol, a phosphodiesterase III inhibitor, has vasodilating and antiplatelet properties with a low rate of bleeding complications. It has been used over the past 25 years for improving intermittent claudication in patients with peripheral artery disease (PAD). Cilostazol also has demonstrated efficacy in patients undergoing percutaneous revascularization procedures for both PAD and coronary artery disease. In addition to its antithrombotic and vasodilating actions, cilostazol also inhibits vascular smooth muscle cell proliferation via phosphodiesterase III inhibition, thus mitigating restenosis. Accumulated evidence has shown that cilostazol, due to its "pleiotropic" effects, is a useful, albeit underutilized, agent for both coronary artery disease and PAD. It is also potentially useful after ischemic stroke and is an alternative in those who are allergic or intolerant to classical antithrombotic agents (eg, aspirin or clopidogrel). These issues are herein reviewed together with the pharmacology and pharmacodynamics of cilostazol. Large studies and meta-analyses are presented and evaluated. Current guidelines are also discussed, and the spectrum of cilostazol's actions and therapeutic applications are illustrated.

No benefit of vorapaxar on walking performance in patients with intermittent claudication.

Background: The effect of pharmacologic agents in improving walking and quality of life measures in patients with intermittent claudication (IC) is variable. The objective of this study was to investigate the effect of the novel antithrombotic vorapaxar on symptom status in patients with IC. Methods: The study was a multicenter, randomized, placebo-controlled trial wherein patients with IC were treated with either vorapaxar or placebo in addition to a home exercise program for 6 months. Walking performance and quality of life were assessed by graded treadmill test (GTT) and 12-Item Short-Form Survey (SF-12), respectively, at baseline and at 6 months. A total of 102 subjects were randomized across 12 centers. Results: Of the subjects randomized, 66 completed all study assessments and comprised the dataset that was analyzed. After 6 months, there was no significant difference between the vorapaxar and placebo groups in walking performance, as reflected by the GTT, or in quality of life, as reflected by the SF-12. There were no severe bleeding events in either group. Conclusion: This study found no benefit of vorapaxar in patients with IC and reiterates the need for future drug therapy studies that expand the benefits of supervised exercise therapy in patients with IC. ClinicalTrials.gov Identifier: NCT02660866.

Cilostazol: a Review of Basic Mechanisms and Clinical Uses.

Primarily used in the treatment of intermittent claudication, cilostazol is a 2-oxyquinolone derivative that works through the inhibition of phosphodiesterase III and related increases in cyclic adenosine monophosphate (cAMP) levels. However, cilostazol has been implicated in a number of other basic pathways including the inhibition of adenosine reuptake, the inhibition of multidrug resistance protein 4, among others. It has been observed to exhibit antiplatelet, antiproliferative, vasodilatory, and ischemic-reperfusion protective properties. As such, cilostazol has been investigated for clinical use in a variety of settings including intermittent claudication, as an adjunctive for reduction of restenosis after coronary and peripheral endovascular interventions, and in the prevention of secondary stroke, although its widespread implementation for indications other than intermittent claudication has been limited by relatively modest effect sizes and lack of studies in western populations. In this review, we highlight the pleiotropic effects of cilostazol and the evidence for its clinical use.

Safety of home-based exercise for people with intermittent claudication: A systematic review.

Intermittent claudication (IC) is a classic symptom of peripheral artery disease, with first line treatment being supervised exercise therapy (SET). Despite this, SET is frequently underutilised, and adherence is often poor. An alternative option are home-based exercise programmes (HBEP). Although HBEPs are well tolerated, to the authors' knowledge, no research has assessed their safety. The aim of this review was to assess the safety of HBEPs in people living with IC. We performed an electronic search of the MEDLINE, CINAHL, and Cochrane Library databases. The main parameter of interest was complication rate, calculated as the number of related adverse events per patient-hours. Subanalysis was undertaken to determine differences in safety for studies that did and did not include pre-exercise cardiac screening, and for studies with exercise at low, moderate, and high levels of claudication pain. Our search strategy identified 8693 results, of which 27 studies were included for full review. Studies included 1642 participants completing 147,810 patient-hours of home-based exercise. Four related adverse events were reported, three of which were cardiac in origin, giving an all-cause complication rate of one event per 36,953 patient-hours. Three of these events occurred following exercise to high levels of claudication pain, and one occurred with pain-free exercise. One event occured in a study without cardiac screening. Based on the low number of related adverse events, HBEPs appear to be a safe method of exercise prescription for people with IC. Our results strengthen the rationale for providing alternative exercise options for this population. PROSPERO Registration No.: CRD42021254581.