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Investigational therapies for treating symptoms of lower extremity peripheral artery disease

Investigational therapies for treating symptoms of lower extremity peripheral artery disease
Authors:
Connie N Hess, MD, MHS
Marc P Bonaca, MD, MPH, FAHA, FACC
Section Editors:
Denis L Clement, MD, PhD
Mark A Creager, MD, FAHA, FACC, MSVM
Joseph L Mills, Sr, MD
John F Eidt, MD
Deputy Editor:
Kathryn A Collins, MD, PhD, FACS
Literature review current through: Jan 2024.
This topic last updated: Aug 05, 2022.

INTRODUCTION — Pharmacologic therapies under investigation that may become useful for patients with peripheral artery disease (PAD) to improve symptoms of claudication, with the added benefit of avoiding the need for revascularization, to promote healing of ischemic ulcers, or to alter perception of ischemic pain in patients who are poor candidates or who have failed revascularization attempts are reviewed here. The clinical use of these agents is not yet recommended.

For patients with claudication, evidence of benefit of pharmacologic agents for improving symptoms is available only for cilostazol and naftidrofuryl (not available in the United States) [1-4]. Statin therapy for PAD is associated with a reduction in limb events, including claudication, lower extremity revascularization, and critical limb ischemia, but evidence for the use of statins to improve PAD symptoms is not definitive [3]. Recommendations for these and other potentially beneficial pharmacologic agents are discussed separately. (See "Management of claudication due to peripheral artery disease", section on 'Beneficial' and "Management of claudication due to peripheral artery disease", section on 'Benefit not firmly established'.)

The best therapeutic option for patients with chronic limb-threatening ischemia manifesting as rest pain, ischemic ulceration, or gangrene is revascularization (percutaneous or surgical). However, many patients are poor candidates for revascularization due to severe medical comorbidities. (See "Management of chronic limb-threatening ischemia".)

Pharmacologic therapy aimed at reducing the risk for future cardiovascular events in patients with PAD, and that may also limit progression of disease, are reviewed elsewhere. (See "Overview of lower extremity peripheral artery disease" and "Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk".)

HOME EXERCISE PROGRAMS — The benefits of supervised exercise therapy are well documented, and the data on this therapy have led to approval in the United States by the Centers for Medicare & Medicaid Services (CMS) for reimbursement. However, these programs are not commonly available and may not be an option for many patients. As a result, there is interest in developing more efficient ways to deploy home-based exercise programs. (See "Management of claudication due to peripheral artery disease", section on 'Supervised versus unsupervised exercise'.)

Randomized trials comparing exercise regimens include a large study of 180 patients with claudication who were randomized into a 12-week exercise program [5]. Groups received supervised exercise, home-based exercise, or control. The results demonstrated improvement in treadmill exercise performance in both exercise groups with a greater improvement in six-minute walk distance in the home-based group compared with control [5]. A meta-analysis of 11 trials of structured home exercise that included 807 patients showed improvement in treadmill and six-minute walk test endpoints compared with controls not receiving an exercise program [6]. By contrast, a randomized trial of home-based exercise intervention that included a wearable activity monitor and telephone coaching did not improve walking performance more than usual care [7]. Another study evaluated a Group Mediated Cognitive Behavioral (GMCB) intervention, which was a behavioral component to enhance adherence to home-based walking exercise [8]. The combination of the behavioral intervention with home exercise was more effective in improving exercise performance than an attention control group [9].

PHARMACOLOGIC AGENTS — The pathophysiology of symptoms associated with ischemia is complex and provides multiple potential targets for novel drug therapies [10,11]. Potential future pharmacologic therapies that remain to be proven beneficial for the treatment of symptoms associated with lower extremity PAD are presented below. These therapies may be targeted either to symptoms of claudication or to more severe manifestations of ischemia, such as ischemic rest pain, ulceration, or gangrene.

Antiinflammatory therapies — Vascular inflammation has been associated with progression of atherosclerosis [12], and major adverse cardiovascular events [13,14]. Treatment of 38 patients with PAD for up to 12 months with the interleukin-1 beta antagonist canakinumab versus placebo did not alter plaque progression in the superficial femoral artery but did improve maximum and pain-free walking distances as early as three months [15]. Whether these findings are related to improved skeletal muscle perfusion and/or endothelial function as a result of reduced inflammation warrants additional investigation.

Closely related to inflammation is the process of efferocytosis, or the clearing of apoptotic cells by phagocytes. Impaired efferocytosis has been implicated in atherogenesis, and expansion of the necrotic core in atherosclerotic plaques may promote plaque vulnerability [16]. The antiefferocytic molecule CD47 has been demonstrated to be upregulated in atherosclerotic plaques [17]. Treatment of nine patients with lymphoma with the humanized anti-CD47 antibody magrolimab was shown to reduce vascular inflammation as measured by 18F-fluorodeoxyglucose uptake in the carotid artery [18]. The potential utility of this therapy in patients with atherosclerotic cardiovascular disease, including PAD, has yet to be examined.

Antioxidants — These treatments inhibit oxidation of other molecules, particularly in key mitochondrial metabolic pathways. A number of antioxidant therapies have been evaluated in patients with PAD; however, studies on walking performance have yielded mixed results, with positive studies showing only a modest beneficial effect, or no effect [10,19-23]. Antioxidants have also been evaluated for primary and secondary prevention of cardiovascular disease. (See "Vitamin intake and disease prevention", section on 'Antioxidants'.)

Polyphenols — Polyphenols are antioxidant phytochemicals found in plant-based foods.

Cocoa is a concentrated source of flavanols, which are a part of the polyphenol subgroup called flavonoids [24,25]. The subclass of flavanols found in cocoa are epicatechin and catechin derivatives. Cocoa can cause arterial dilatation by reducing oxidative stress and by increasing production of nitric oxide. Dark chocolate, in particular, can enhance arterial dilatation by lowering activation of NOX2, a catalytic subunit of NADPH oxidase. Despite these attractive mechanisms, a single consumption of dark chocolate had no effect on endothelial or microvascular function in patients with symptomatic PAD [26]. However, in a study of 20 PAD patients, dark, but not milk, chocolate improved maximal walking distance and maximal walking time [27]. The COCOA-PAD trial was a placebo-controlled pilot study of daily cocoa intake in PAD patients who were at least 60 years of age that showed improved six-minute walk distance at six-month follow-up as well as improved mitochondrial cytochrome c oxidase activity, increased capillary density, and improved calf muscle perfusion in patients receiving cocoa versus placebo [28].

There has been suggestion that Annurca apple polyphenols, which contain the same catechin-derived compounds found in cocoa, may provide benefit for patients with intermittent claudication. In a study of 180 patients with claudication, treatment for 24 weeks with Annurca apple extract significantly improved maximal walking distance, ankle-brachial index, and acceleration time compared with placebo [29]. However, these results should be considered preliminary and have not yet been replicated in other studies.

Endothelial-modulating agents — The endothelium regulates vascular tone, inhibits platelet aggregation and leucocyte attraction, and promotes angiogenesis through the release of vasoactive substances, including nitric oxide [30,31]. Nitric oxide (NO) is produced from the substrate L-arginine by three forms of nitric oxide synthase (NOS), with the majority from endothelial nitric oxide synthase using tetrahydrobiopterin (BH4) as a cofactor. Plasma nitrite can be reduced to NO under low oxygen conditions, such as ischemia, and thus may serve as a physiologic store of NO (figure 1) [32]. Patients with PAD have endothelial dysfunction and reduced NO bioavailability, forming the basis for investigation into strategies to increase NO activity in PAD patients.

Dietary nitrates — Oral consumption of inorganic nitrate can increase plasma nitrite levels [33-35]. Although the majority of inorganic nitrate is excreted in the urine, up to 25 percent is retained and stored in salivary glands. When saliva is secreted, oral bacteria reduce the nitrate to nitrite, which is swallowed and reabsorbed back into circulation. Dietary sources with high concentrations of nitrate include leafy green vegetables and beetroot. In healthy and athlete populations, dietary nitrate supplementation has shown benefit, including improved time trial performance, increased time to exhaustion, and decreased oxygen cost of exercise [36-38]. No impact of dietary nitrate has been found for improving power output, time trial time, or submaximal exercise efficiency among healthy subjects [39-42].

Exaggerated hemodynamic responses to physiologic stressors may be associated with hypertension and major adverse cardiac events (MACE) in aging populations [43,44]. In a placebo-controlled trial of 21 patients with PAD, dietary supplementation with sodium nitrate reduced exaggerated systolic blood pressure responses to sympatho-excitation using a cold pressor test [45]. Whether sodium nitrate supplementation is a novel strategy to reduce risk of hypertension and MACE in patients with PAD needs further investigation.

With respect to functional outcomes, in an early placebo-controlled trial, supplementation with beetroot juice increased plasma nitrite levels fivefold and increased claudication onset time and peak walk times during treadmill walking by 18 and 17 percent, respectively [34]. A placebo-controlled study of beetroot juice in conjunction with supervised exercise training in patients with intermittent claudication showed improvement in claudication onset time and six-minute walk distance with beetroot juice plus exercise compared with exercise alone [46,47]. The effect of beetroot juice on coronary blood flow and walking performance in PAD is also under study in the ongoing HeartBeet trial (NCT02553733), and a trial examining beetroot juice on endothelial function, walking capacity, leg function, and thermoregulation in PAD patients has completed enrollment but is still ongoing (NCT03506646).

Sodium nitrite — Nitrite is a first-order metabolite of nitric oxide. Following exercise, nitrite stores decrease in patients with PAD compared with healthy individuals [48,49]. Animal studies have suggested that sodium nitrite can promote new blood vessel growth, speed up wound healing, and prevent tissue necrosis. Studies showing that nitrite therapy may protect against ischemia-related heart and brain injury in cardiac arrest survivors have led to interest in using sodium nitrate to treat lower extremity ischemia [50,51].

In a safety and efficacy trial, 55 patients with PAD, predominantly with diabetes, were treated over a period of 10 weeks with either placebo (n = 18) or sodium nitrite twice daily, 40 mg (n = 19) or 80 mg (n = 18) [49]. The primary endpoint of endothelium-dependent, flow-mediated dilatation (FMD) was worse in the placebo and 40 mg groups (but not significantly different) and stable in the 80 mg group. Patients with diabetes receiving 80 mg had significantly higher FMD compared with the placebo and 40 mg groups. There were no significant changes in six-minute walk test or quality of life parameters over time compared with placebo. The most common side effects attributed to sodium nitrite were a composite of headache and dizziness occurring in 21 percent with the 40 mg dose and 44 percent with the 80 mg dose. There was no clinically significant elevation of methemoglobin [52].

Tetrahydrobiopterin (BH4) — BH4 is a cofactor for the production of nitric oxide by endothelial nitric oxide synthase. The effect of oral supplementation of BH4 versus placebo on peak walking time in patients with symptomatic PAD has been investigated in a phase 2 study (NCT00403494), but results have not yet been published.

L-arginine — Previous studies have reported mixed results regarding improved vascular function after supplementation with L-arginine in patients with cardiovascular disease [53-55]. In PAD, the effect of L-arginine on endothelial function was examined in the LargPAD trial, a phase 2A evaluation of catheter-directed L-arginine infusion into atherosclerotic superficial femoral arteries in 22 PAD patients undergoing lower extremity angiography. L-arginine infusion increased nitric oxide bioactivity and improved endothelial function, as measured by intravascular ultrasound and Doppler flow wire during acetylcholine-induced endothelium-dependent arterial relaxation [56].

In the Nitric Oxide in Peripheral Arterial Insufficiency (NO-PAIN) study, 133 subjects with intermittent claudication were randomly assigned oral L-arginine (3 g/day) or placebo for six months [57]. While L-arginine supplementation significantly increased plasma L-arginine levels, measures of NO availability were reduced or not improved compared with placebo. The functional endpoints of absolute claudication distance and initial claudication distance were numerically less improved, and flow-mediated dilatation was significantly reduced with L-arginine treatment compared with placebo. Thus, this treatment cannot be recommended at this time.

L-citrulline — Only approximately 1 percent of oral L-arginine supplementation is available for nitric oxide production, with the rest metabolized by the body [55]. Consequently, L-citrulline, which is a precursor of L-arginine, is also under consideration as a possible therapy for PAD. A placebo-controlled double-blind crossover trial in 25 older adults demonstrated increased femoral blood flow and vascular conductance during lower-limb exercise in older men [58]. Another placebo-controlled double-blind crossover study of oral L-citrulline examining vascular function measured by flow-mediated dilation and treadmill performance was completed, but results have not been published (NCT02521220).

Phosphodiesterase inhibitors — Phosphodiesterase (PDE) inhibitors cause vasodilation through a nitric oxide-cyclic guanosine monophosphate pathway, and the drugs have metabolic effects on triglyceride metabolism. Cilostazol is a PDE inhibitor with selective activity for the type III isozyme. Cilostazol has proven benefit for the treatment of claudication with Food and Drug Administration (FDA) approval for treatment of symptomatic PAD, with a black box warning to avoid its use in patients with heart failure. (See "Management of claudication due to peripheral artery disease", section on 'Cilostazol'.)

Other drugs in this class are no longer under investigation despite positive results for other drugs in this class such as NM-702 and K-134 [59,60].

Prostanoids — Prostaglandin, prostacyclin, and their analogs improve blood flow through direct vasodilation, antiplatelet, and other rheologic effects and have anti-inflammatory effects as well [61,62]. While some of these drugs remain under investigation, they have not been approved for treating the symptoms of PAD in the United States.

Agents previously investigated for the treatment of PAD include prostaglandin E1 (alprostadil) [61,63-66], the prostaglandin analog ecraprost [67,68], the prostacyclin epoprostenol (PGI2), as well as the prostacyclin analogs iloprost (inhalation, intravenous [IV] not available in the United States), beraprost (oral, not available in the United States) [69], taprostene, and treprostinil (inhalation, oral, subcutaneous, IV) [70-72]. Prostaglandin E1 (PGE1) and epoprostenol (PGI2) are structurally unstable. Their stable analogs have a longer duration of action and a more specific effect (in general) than their endogenous equivalents.

●Claudication – A systematic review and meta-analysis (Cochrane) identified 18 trials [61]. Four trials that compared PGE1 with placebo found significant improvements in treadmill exercise performance with PGE1 but not PGI2. However, the authors noted that the quality of individual trials was variable and results often unclear due to insufficient reporting information; the majority of trials did not report standard deviations for the primary outcomes.

●Chronic limb-threatening ischemia – In a systematic review and meta-analysis (Cochrane) [73], 15 trials compared various preparations of prostacyclin analogues with placebo. No differences were seen for cardiovascular mortality or overall amputation risk (minor and major) for patients receiving prostanoids compared with placebo. However, prostanoids may reduce rest pain (risk ratio [RR] 1.30, 95% CI 1.06-1.59) and improve ulcer healing (RR 1.24, 95% CI 1.04-1.48) compared with placebo. Adverse events were more frequent with prostanoids.

Ramipril — Ramipril is an angiotensin-converting enzyme (ACE) inhibitor. Ramipril has been associated with an increase in the biomarkers of angiogenesis/arteriogenesis and reduction in the markers of thrombosis, inflammation, and leukocyte adhesion. One small trial randomly assigned 33 subjects ramipril or placebo. After 24 weeks, ramipril improved maximum treadmill walking distance by an adjusted mean difference of 131 meters and mean pain-free distance by 122 meters [74]. Another randomized trial of 212 patients demonstrated no clinical benefit for patients treated with ramipril (study was subsequently retracted) [75]. In a systemic review and metaanalysis of four randomized clinical trials, there was no evidence for improvement of treadmill walking distance or ankle-brachial index (ABI) in patients with symptomatic PAD [76]. However, a phase 4 clinical trial investigating use of ramipril for the treatment of claudication is ongoing (NCT02842424).

Ranolazine — Ranolazine is approved for the treatment of angina pectoris, but there is little evidence for its use in treating PAD. In a small trial of 45 patients with intermittent claudication, patients were randomly assigned to ranolazine 1000 mg twice daily or placebo for four weeks. Ranolazine did not improve peak walking performance, but pain-free walking time was improved relative to baseline walking time, suggesting the possibility of a treatment effect. A follow-up study of supervised exercise and ranolazine compared with placebo enrolled 29 patients (NCT00914316) [77]. The study was terminated early in 2013 due to challenges in recruitment and retention, with unpublished results.

Glucagon-like peptide-1 (GLP-1) analogues — Semaglutide and liraglutide are GLP-1 analogues. In patients with type 2 diabetes mellitus at high cardiovascular risk, semaglutide significantly reduced the rate of major adverse cardiovascular events (MACE) compared with placebo in the SUSTAIN 6 trial [78]. Data presented from subgroup analyses from LEADER (placebo-controlled trial of liraglutide) and SUSTAIN 6 have demonstrated reductions in cardiovascular events associated with GLP-1 analogues in patients with and without PAD [79]. With respect to limb-specific outcomes, treatment with liraglutide in patients with diabetes at high cardiovascular risk was associated with a significant reduction in diabetic foot ulcer-related amputations compared with placebo [80]. The STRIDE trial of 800 participants randomized to semaglutide versus placebo is underway to determine whether semaglutide has any benefits for walking ability in those with diabetes and PAD (NCT04560998).

SNF472 — Vascular calcification involves the deposition of calcium phosphate hydroxyapatite crystals into the arterial intima or media. Medial calcification, including smaller subcutaneous arteries, has been observed in approximately three-quarters of patients with PAD. Advanced chronic kidney disease is a common comorbid condition among patients with PAD and is associated with increased risk for cardiovascular death compared with the general population [81]. Some of this risk is attributed to higher prevalence of traditional cardiovascular risk factors, such as diabetes mellitus and hypertension, in patients with chronic kidney disease. However, vascular calcification related to accelerated atherosclerosis and deranged mineral metabolism leading to arteriosclerosis is one of the strongest predictors of cardiovascular risk and has been associated with cardiovascular morbidity and mortality, as well as all-cause mortality in renal patients [82,83]. SNF472 is an inhibitor of vascular calcification that directly targets the deposition of solid calcium (hydroxyapatite) in the cardiovascular system. SNF472 has received orphan drug status and was previously shown to attenuate progression of coronary artery calcium and aortic valve calcification in patients with end-stage kidney disease receiving hemodialysis [84]. SNF472 is being investigated for the treatment of calciphylaxis in patients with end-stage kidney disease in an ongoing phase 3 study (NCT04195906).

Factor Xa inhibition — The combination of low-dose anticoagulation and antiplatelet therapy, so-called dual pathway inhibition, has been shown to be beneficial in preventing ischemic events in patients with PAD. The COMPASS trial demonstrated significant reductions in MACE and major adverse limb events with rivaroxaban 2.5 mg twice daily plus aspirin versus aspirin alone in 27,395 patients with stable atherosclerotic cardiovascular disease, including chronic PAD [85]. VOYAGER PAD also showed significant reduction in severe cardiovascular and limb events with this same regimen among 6564 patients undergoing endovascular or surgical lower extremity revascularization for symptomatic PAD [86]. Another trial of dual pathway inhibition studying apixaban 2.5 mg twice daily plus aspirin versus clopidogrel plus aspirin among 200 patients with PAD and critical limb ischemia undergoing infrapopliteal endovascular revascularization is planned [87]. However, this study is unlikely to provide robust data on efficacy and safety to support use of this combination in this clinical setting.

Lipoprotein(a) reduction — Lipoprotein(a) is a low-density lipoprotein particle with proatherogenic, proinflammatory, and prothrombotic effects that has been associated with development of atherosclerotic cardiovascular disease, including PAD, and poor cardiovascular prognosis [88,89]. Lipoprotein(a) apheresis reduces levels of lipoprotein(a) and has been shown to reduce risk of cardiovascular events among patients with coronary artery disease [90-93]. Among patients with PAD, small observational studies have demonstrated apheresis is associated with reductions in MACE, coronary and noncoronary artery revascularization procedures, and leg pain, and increases in mean walking distance and resting ABI [91,94,95]. The efficacy of apheresis in PAD has not yet been proven with randomized trials, however.

No approved pharmacologic therapies that specifically target lipoprotein(a) are available. However, proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) and inclisiran, a small interfering RNA that inhibits hepatic synthesis of PCSK9, have been shown to reduce lipoprotein(a) levels by approximately 25 percent [96]. Treatment with PSCK9i was demonstrated to reduce risk of PAD events among patients with atherosclerotic cardiovascular disease, with the reduction in risk associated with both baseline lipoprotein(a) and LDL-C levels [97]. A hepatocyte-directed antisense oligonucleotide, AKCEA-APO(a)-LRx, was shown to significantly reduce lipoprotein(a) levels among patients with established cardiovascular disease [98]. Two studies examining small interfering RNAs directed against Apo(a) in patients with atherosclerotic cardiovascular disease and elevated lipoprotein(a) levels are planned or have begun enrollment (NCT04270760, NCT04606602).

Icosapent ethyl — Icosapent ethyl (IPE) is a purified and stable eicosapentaenoic acid ethyl ester that lowers triglyceride levels [99]. It may also have anti-inflammatory and antioxidative properties [100]. REDUCE-IT showed benefit of IPE versus placebo in patients with established cardiovascular disease or diabetes and other risk factors in reducing cardiovascular death, nonfatal myocardial infarction, coronary revascularization, or unstable angina [101]. In a subgroup analysis of REDUCE-IT, patients with PAD were at higher risk for first and total events, and IPE versus placebo provided consistent cardiovascular benefit in patients with or without PAD for first (p interaction = 0.58) and total (p interaction = 0.78) events [102].

Fenofibrates — Diabetes mellitus (DM) is a frequent comorbid condition in patients with PAD and is one of the most common causes of nontraumatic lower-extremity amputation. In the fenofibrate intervention and event lowering in diabetes (FIELD) study, treatment of 9.795 patients with type 2 DM with fenofibrate versus placebo was associated with a lower risk of any amputation (HR 0.64, 95% CI 0.44-0.94). Use of fibrates to improve limb outcomes in patients with PAD has not been reported.

STEM CELL THERAPY — Stem cell therapy involves the transplantation of hematopoietic or bone marrow stem cells to stimulate blood vessel growth and new blood vessel formation [103-105]. Adult stem cells are thought to be present in most, but not all, tissues and to persist throughout life. (See "Overview of stem cells" and "Hematopoietic cell transplantation (HCT): Sources of hematopoietic stem/progenitor cells" and "Overview of hematopoietic stem cells".)

Bone marrow-derived, adipose-derived stem cell therapy [106-110] and placenta-derived [111] stem cells have been studied for the treatment of PAD [112-115]. Bone marrow can be obtained by direct aspiration. Subcutaneous injection of granulocyte-macrophage colony stimulating factor (GM-CSF) can be used to mobilize mononuclear cells from the bone marrow, which can then be collected in the peripheral blood [116-118]. Flow cytometry has also been used to detect cells that express high levels of the aldehyde dehydrogenase activity, and such aldehyde dehydrogenase bright cell populations have been sorted from bone marrow and peripheral blood and used to treat patients with claudication and chronic limb-threatening ischemia [119-121].

A trial using aldehyde dehydrogenase bright cells for the treatment of claudication has been completed [121]. Although intramuscular injection of these cells was safe and feasible, there was no improvement in peak walking time or difference in physiologic magnetic resonance imaging-derived end points. Another approach was to give patients GM-CSF alone or in combination with supervised exercise training [122]. While exercise training worked as expected, GM-CSF did not improve exercise performance.

A 2011 Cochrane review that limited analysis to intramuscular transplantation of mononuclear cells (excluding intraarterial injection) identified two small trials (n = 57) [112]. An updated 2014 review found no additional studies deemed of sufficient quality to merit inclusion [123]. Each of the included studies found a significantly smaller proportion of participants in the stem cell therapy group requiring amputation. One trial compared stem cell therapy to standard therapy, while the other compared mobilized peripheral mononuclear cells with daily intravenous prostaglandin E1 injections (control group) [124]. Pain, ankle-brachial index (mean increase 0.13 versus 0.02), and pain-free walking distance (mean increase 306 versus 79 meters) were significantly improved compared with the PGE1 group. The rate of healing of ischemic ulcers was increased in the stem cell therapy group (14 of 18 versus 7 of 18).

A systematic review and meta-analysis [125] evaluated outcomes of randomized and observational studies of autologous cell therapy in patients with limb-threatening ischemia or PAD without revascularization options [124,126-136]. Although cell therapy appeared to decrease rest pain and amputation risk and increase ankle-brachial index, the efficacy was not significant after limiting the analysis to randomized placebo-controlled studies, and efficacy was not present after excluding randomized controlled studies with high risk of bias. The results of several subsequent small studies have been reported [116-118,137-145]. A later meta-analysis reported significant improvement in ulcer healing and reductions in any amputation and pain with stem cell therapy but no difference in major limb salvage [146]. The use of stem cells primarily for the treatment of chronic limb-threatening ischemia and "no option" patients remains an active area of interest with several study protocols in progress or completed but not published (NCT03304821, NCT01745744, NCT03968198).

THERAPEUTIC ANGIOGENESIS — The term "angiogenesis" broadly refers to formation of new vessels. The goal of therapeutic angiogenesis is to induce development of new arterial vessels to improve perfusion of ischemic tissue. The main processes leading to new vessel formation are described elsewhere. (See "Therapeutic angiogenesis for management of refractory angina".)

A number of angiogenic growth factors stimulate blood vessel growth and can be administered as recombinant protein or naked DNA via intra-arterial or intramuscular injection [147]. Preclinical studies suggested that angiogenic growth factors can stimulate the development of collateral arteries [148,149]. Early studies evaluating the safety and efficacy in patients with PAD had variable results [150-153].

A later systematic review [154] identified 12 trials performed between 2003 and 2011, 3 in patients with claudication [155-157], 9 in patients with chronic limb-threatening ischemia [158-165], and 1 with both [166]. Various angiogenic factors were used, including vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), hepatocyte growth factor (HGF), developmental endothelial locus-1 (Del-1), and hypoxia-inducible factor-1 alpha (HIF-1alpha). A meta-analysis did not find any significant treatment effect overall, or for claudication or for chronic limb-threatening ischemia, with respect to the rate of amputation, ulcer healing, or all-cause mortality.

OTHER THERAPIES — A variety of factors can limit the successful performance of recommended exercise therapy regimens in patients with PAD. Other therapies aimed at overcoming some of the limitations have been investigated and include spinal cord stimulation, transcutaneous nerve stimulation, heat therapy, pneumatic compression therapy, and extracorporeal shockwave therapy. The quality of evidence for these therapies is overall low and as such, these therapies cannot be recommended. The available studies are reviewed briefly below.

Spinal cord stimulation — Initial uncontrolled studies suggested that spinal cord stimulation (SCS) was effective for pain relief and might prevent or delay amputation and improve limb survival [167,168]. A systematic review identified six studies involving 450 patients [169]. The risk of limb loss after 12 months was significantly lower in the spinal cord stimulation group (risk ratio [RR] 0.71, 95% CI 0.56-0.90). Overall, there were no significant differences in ulcer healing. Complications of spinal cord stimulation consisted of implantation problems, changes in stimulation requiring reintervention, and, less frequently, infections of the lead or pulse generator pocket. The benefits of SCS must be considered against the possibility of harm due to mostly mild complications and the additional cost of the device and implantation.

Nerve stimulation — Neuromuscular electrical stimulation (NMES) has been explored as an adjunct to reduce PAD symptoms as well as for improving exercise therapy [170]. NMES causes muscle contraction as well as sensory stimulation [171-174], and in patients with PAD, NMES to the lower legs has also been reported to cause vasodilatation [175]. In a pilot trial that randomly assigned 42 patients to footplate NMES and supervised exercise (ie, combined therapy) or supervised exercise therapy alone for six weeks, initial claudication distance was 46 percent greater in the combined therapy group, but maximum claudication distance was similar between the groups, indicating no benefit on peak exercise performance [174]. Intermittent claudication questionnaire scores were also improved for the combined therapy group. Other clinically important outcomes (eg, PAD progression) were not evaluated. Another study evaluating NMES in the management of patients with claudication has competed but has not yet published results (NCT03446027).

In addition to NMES, the effects of transcutaneous electrical nerve stimulation (TENS), which only induces sensory stimulation and mainly provides analgesia, is also under investigation in PAD patients. The TENS-PAD study is an ongoing placebo-controlled, double-blind, multicenter randomized trial that will assess the effect of TENS on the primary outcome of pain-free walking distance in 100 patients with PAD and claudication [176]. Other studies of TENS in PAD patients with claudication are also ongoing or have not yet published results (NCT03462472, NCT03204825, NCT03512912).

Pneumatic compression — Intermittent pneumatic compression (IPC) appears to improve walking ability and ankle-brachial indices in PAD patients with claudication, with effects maintained 12 months after cessation of therapy [177-179]. Mechanisms for this benefit include drainage of veins of the foot and calf, depending on the level of compression, with an increase in the arteriovenous pressure gradient and enhanced arterial inflow [178], as well as the potential promotion of arterial collateralization [177].

Intermittent negative pressure therapy — Intermittent vacuum therapy alternately applies negative pressure and atmospheric pressure to the lower extremities. Outcomes of studies evaluating intermittent negative pressure therapy are conflicting. A randomized comparison of intermittent vacuum therapy plus lifestyle changes versus lifestyle changes alone in 48 patients with PAD showed no difference in toe pressures, walking capacity, claudication symptoms, physical activity, or self-rated health between treatment groups [180]. In a Dutch study, walking distance was similar between those randomly assigned to intermittent vacuum therapy (-50 mBar [-37.5 mmHg]) or control (-5 mBar [-4 mmHg]), and both groups had a similar improvement in quality of life at 6- and 12-week follow-up [181]. Thus, intermittent vacuum therapy did not confer any additional beneficial effects in patients with intermittent claudication undergoing a standardized supervised exercise therapy program. In another trial in which intermittent vacuum therapy (-40 mmHg) was applied for one hour twice daily for two weeks, mean walking distance was modestly increased for intermittent vacuum therapy compared with controls, although not significant [182].

Heat therapy — Passive heat therapy has also been reported to improve lower limb perfusion, enhance vascular function, and reduce blood pressure in PAD patients, potentially via alterations in arterial shear stress [183-185]. In a small sham-controlled randomized study, leg heat therapy reduced systolic blood pressure and plasma levels of endothelin-1, and there was a trend for increased peak walking time (911±69 sec vs 954±77 sec, p = 0.059). Heat therapy is currently under investigation among PAD patients with claudication in other ongoing studies (NCT03435835, NCT02770547, NCT03763331).

Extracorporeal shockwave therapy — Extracorporeal shockwave therapy (ESWT) is a relatively novel therapy for treating patients with PAD. Historically, ESWT has been used in orthopedics for delayed bone healing and in wound care [186,187]. In ischemic heart disease, ESWT has shown promise for reducing angina [188], improving left ventricular ejection fraction in ischemic cardiomyopathy [189], and improving myocardial perfusion on thallium scintography [190].

For patients with PAD, several studies have shown improvements in lower limb blood flow and walking ability with ESWT [191-194]. Although the studies were small, a systematic review of five studies of ESWT in symptomatic PAD found significant improvements in pain-free walking distance and maximum walking distance [195]. The exact mechanisms by which ESWT achieves these results is unclear but is thought to be related to mechanotransduction, whereby mechanical stimuli are transformed into chemical signals and angiogenesis [196]. A trial examining the effect of ESWT on the primary outcome of maximum walking distance in claudication has been completed, but results are not yet available (NCT02652078).

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Occlusive carotid, aortic, renal, mesenteric, and peripheral atherosclerotic disease".)

SUMMARY AND RECOMMENDATIONS

●Claudication – Therapies under investigation for claudication are aimed at improving ambulation to avoid the need for revascularization (see 'Pharmacologic agents' above). Among the many pharmacologic agents studied for the treatment of patients with claudication, convincing evidence of benefit is available only for cilostazol and naftidrofuryl. These and other potentially beneficial pharmacologic agents are discussed elsewhere. (See "Management of claudication due to peripheral artery disease", section on 'Pharmacologic therapy to improve walking'.)

●Chronic limb-threatening ischemia – The best therapeutic option for patients with severe peripheral artery disease (PAD; ie, chronic limb-threatening ischemia manifesting as rest pain, ischemic ulceration, or gangrene) is revascularization (percutaneous or surgical). Therapies under investigation for treating chronic limb-threatening ischemia, primarily for patients who are poor candidates for revascularization due to severe medical comorbidities, are aimed at promoting healing of ischemic ulcers or altering the perception of ischemic pain. The clinical use of these agents is not yet recommended. (See 'Pharmacologic agents' above and 'Stem cell therapy' above and 'Therapeutic angiogenesis' above and 'Other therapies' above.)

ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges William R Hiatt, MD, now deceased, who contributed to an earlier version of this topic review.

The UpToDate editorial staff acknowledges Emile R Mohler, III, MD (deceased), who contributed to an earlier version of this topic review.

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  143. Gupta PK, Chullikana A, Parakh R, et al. A double blind randomized placebo controlled phase I/II study assessing the safety and efficacy of allogeneic bone marrow derived mesenchymal stem cell in critical limb ischemia. J Transl Med 2013; 11:143.
  144. Arici V, Perotti C, Fabrizio C, et al. Autologous immuno magnetically selected CD133+ stem cells in the treatment of no-option critical limb ischemia: clinical and contrast enhanced ultrasound assessed results in eight patients. J Transl Med 2015; 13:342.
  145. Franz RW, Shah KJ, Pin RH, et al. Autologous bone marrow mononuclear cell implantation therapy is an effective limb salvage strategy for patients with severe peripheral arterial disease. J Vasc Surg 2015; 62:673.
  146. Gao W, Chen D, Liu G, Ran X. Autologous stem cell therapy for peripheral arterial disease: a systematic review and meta-analysis of randomized controlled trials. Stem Cell Res Ther 2019; 10:140.
  147. Shimamura M, Nakagami H, Taniyama Y, Morishita R. Gene therapy for peripheral arterial disease. Expert Opin Biol Ther 2014; 14:1175.
  148. Kalka C, Masuda H, Takahashi T, et al. Vascular endothelial growth factor(165) gene transfer augments circulating endothelial progenitor cells in human subjects. Circ Res 2000; 86:1198.
  149. Takeshita S, Zheng LP, Brogi E, et al. Therapeutic angiogenesis. A single intraarterial bolus of vascular endothelial growth factor augments revascularization in a rabbit ischemic hind limb model. J Clin Invest 1994; 93:662.
  150. Lederman RJ, Mendelsohn FO, Anderson RD, et al. Therapeutic angiogenesis with recombinant fibroblast growth factor-2 for intermittent claudication (the TRAFFIC study): a randomised trial. Lancet 2002; 359:2053.
  151. Baumgartner I, Pieczek A, Manor O, et al. Constitutive expression of phVEGF165 after intramuscular gene transfer promotes collateral vessel development in patients with critical limb ischemia. Circulation 1998; 97:1114.
  152. Rajagopalan S, Mohler ER 3rd, Lederman RJ, et al. Regional angiogenesis with vascular endothelial growth factor in peripheral arterial disease: a phase II randomized, double-blind, controlled study of adenoviral delivery of vascular endothelial growth factor 121 in patients with disabling intermittent claudication. Circulation 2003; 108:1933.
  153. De Haro J, Acin F, Lopez-Quintana A, et al. Meta-analysis of randomized, controlled clinical trials in angiogenesis: gene and cell therapy in peripheral arterial disease. Heart Vessels 2009; 24:321.
  154. Hammer A, Steiner S. Gene therapy for therapeutic angiogenesis in peripheral arterial disease - a systematic review and meta-analysis of randomized, controlled trials. Vasa 2013; 42:331.
  155. Creager MA, Olin JW, Belch JJ, et al. Effect of hypoxia-inducible factor-1alpha gene therapy on walking performance in patients with intermittent claudication. Circulation 2011; 124:1765.
  156. Rajagopalan S, Mohler E 3rd, Lederman RJ, et al. Regional Angiogenesis with Vascular Endothelial Growth Factor (VEGF) in peripheral arterial disease: Design of the RAVE trial. Am Heart J 2003; 145:1114.
  157. Grossman PM, Mendelsohn F, Henry TD, et al. Results from a phase II multicenter, double-blind placebo-controlled study of Del-1 (VLTS-589) for intermittent claudication in subjects with peripheral arterial disease. Am Heart J 2007; 153:874.
  158. Belch J, Hiatt WR, Baumgartner I, et al. Effect of fibroblast growth factor NV1FGF on amputation and death: a randomised placebo-controlled trial of gene therapy in critical limb ischaemia. Lancet 2011; 377:1929.
  159. Kusumanto YH, van Weel V, Mulder NH, et al. Treatment with intramuscular vascular endothelial growth factor gene compared with placebo for patients with diabetes mellitus and critical limb ischemia: a double-blind randomized trial. Hum Gene Ther 2006; 17:683.
  160. Rajagopalan S, Olin J, Deitcher S, et al. Use of a constitutively active hypoxia-inducible factor-1alpha transgene as a therapeutic strategy in no-option critical limb ischemia patients: phase I dose-escalation experience. Circulation 2007; 115:1234.
  161. Nikol S, Baumgartner I, Van Belle E, et al. Therapeutic angiogenesis with intramuscular NV1FGF improves amputation-free survival in patients with critical limb ischemia. Mol Ther 2008; 16:972.
  162. Powell RJ, Simons M, Mendelsohn FO, et al. Results of a double-blind, placebo-controlled study to assess the safety of intramuscular injection of hepatocyte growth factor plasmid to improve limb perfusion in patients with critical limb ischemia. Circulation 2008; 118:58.
  163. Powell RJ, Goodney P, Mendelsohn FO, et al. Safety and efficacy of patient specific intramuscular injection of HGF plasmid gene therapy on limb perfusion and wound healing in patients with ischemic lower extremity ulceration: results of the HGF-0205 trial. J Vasc Surg 2010; 52:1525.
  164. Shigematsu H, Yasuda K, Iwai T, et al. Randomized, double-blind, placebo-controlled clinical trial of hepatocyte growth factor plasmid for critical limb ischemia. Gene Ther 2010; 17:1152.
  165. Anghel A, Taranu G, Seclaman E, et al. Safety of vascular endothelial and hepatocyte growth factor gene therapy in patients with critical limb ischemia. Curr Neurovasc Res 2011; 8:183.
  166. Mäkinen K, Manninen H, Hedman M, et al. Increased vascularity detected by digital subtraction angiography after VEGF gene transfer to human lower limb artery: a randomized, placebo-controlled, double-blinded phase II study. Mol Ther 2002; 6:127.
  167. Horsch S, Claeys L. Epidural spinal cord stimulation in the treatment of severe peripheral arterial occlusive disease. Ann Vasc Surg 1994; 8:468.
  168. Mingoli A, Sciacca V, Tamorri M, et al. Clinical results of epidural spinal cord electrical stimulation in patients affected with limb-threatening chronic arterial obstructive disease. Angiology 1993; 44:21.
  169. Ubbink DT, Vermeulen H. Spinal cord stimulation for non-reconstructable chronic critical leg ischaemia. Cochrane Database Syst Rev 2013; :CD004001.
  170. Anderson SI, Whatling P, Hudlicka O, et al. Chronic transcutaneous electrical stimulation of calf muscles improves functional capacity without inducing systemic inflammation in claudicants. Eur J Vasc Endovasc Surg 2004; 27:201.
  171. Ellul C, Formosa C, Gatt A, et al. The Effectiveness of Calf Muscle Electrostimulation on Vascular Perfusion and Walking Capacity in Patients Living With Type 2 Diabetes Mellitus and Peripheral Artery Disease. Int J Low Extrem Wounds 2017; 16:122.
  172. Tsang GM, Green MA, Crow AJ, et al. Chronic muscle stimulation improves ischaemic muscle performance in patients with peripheral vascular disease. Eur J Vasc Surg 1994; 8:419.
  173. Abraham P, Mateus V, Bieuzen F, et al. Calf muscle stimulation with the Veinoplus device results in a significant increase in lower limb inflow without generating limb ischemia or pain in patients with peripheral artery disease. J Vasc Surg 2013; 57:714.
  174. Babber A, Ravikumar R, Onida S, et al. Effect of footplate neuromuscular electrical stimulation on functional and quality-of-life parameters in patients with peripheral artery disease: pilot, and subsequent randomized clinical trial. Br J Surg 2020; 107:355.
  175. Loubser PG, Cardus D, Pickard LR, McTaggart WG. Effects of unilateral, low-frequency, neuromuscular stimulation on superficial circulation in lower extremities of patients with peripheral vascular disease. Med Instrum 1988; 22:82.
  176. Besnier F, Sénard JM, Grémeaux V, et al. The efficacy of transcutaneous electrical nerve stimulation on the improvement of walking distance in patients with peripheral arterial disease with intermittent claudication: study protocol for a randomised controlled trial: the TENS-PAD study. Trials 2017; 18:373.
  177. Delis KT, Nicolaides AN, Wolfe JH, Stansby G. Improving walking ability and ankle brachial pressure indices in symptomatic peripheral vascular disease with intermittent pneumatic foot compression: a prospective controlled study with one-year follow-up. J Vasc Surg 2000; 31:650.
  178. Delis KT, Nicolaides AN. Effect of intermittent pneumatic compression of foot and calf on walking distance, hemodynamics, and quality of life in patients with arterial claudication: a prospective randomized controlled study with 1-year follow-up. Ann Surg 2005; 241:431.
  179. Kakkos SK, Geroulakos G, Nicolaides AN. Improvement of the walking ability in intermittent claudication due to superficial femoral artery occlusion with supervised exercise and pneumatic foot and calf compression: a randomised controlled trial. Eur J Vasc Endovasc Surg 2005; 30:164.
  180. Afzelius P, Molsted S, Tarnow L. Intermittent vacuum treatment with VacuMed does not improve peripheral artery disease or walking capacity in patients with intermittent claudication. Scand J Clin Lab Invest 2018; 78:456.
  181. Hageman D, Fokkenrood HJP, van Deursen BAC, et al. Randomized controlled trial of vacuum therapy for intermittent claudication. J Vasc Surg 2020; 71:1692.
  182. Hoel H, Pettersen EM, Høiseth LØ, et al. A randomized controlled trial of treatment with intermittent negative pressure for intermittent claudication. J Vasc Surg 2021; 73:1750.
  183. Tei C, Shinsato T, Miyata M, et al. Waon therapy improves peripheral arterial disease. J Am Coll Cardiol 2007; 50:2169.
  184. Shinsato T, Miyata M, Kubozono T, et al. Waon therapy mobilizes CD34+ cells and improves peripheral arterial disease. J Cardiol 2010; 56:361.
  185. Thomas KN, van Rij AM, Lucas SJ, Cotter JD. Lower-limb hot-water immersion acutely induces beneficial hemodynamic and cardiovascular responses in peripheral arterial disease and healthy, elderly controls. Am J Physiol Regul Integr Comp Physiol 2017; 312:R281.
  186. Xu ZH, Jiang Q, Chen DY, et al. Extracorporeal shock wave treatment in nonunions of long bone fractures. Int Orthop 2009; 33:789.
  187. Dumfarth J, Zimpfer D, Vögele-Kadletz M, et al. Prophylactic low-energy shock wave therapy improves wound healing after vein harvesting for coronary artery bypass graft surgery: a prospective, randomized trial. Ann Thorac Surg 2008; 86:1909.
  188. Schmid JP, Capoferri M, Wahl A, et al. Cardiac shock wave therapy for chronic refractory angina pectoris. A prospective placebo-controlled randomized trial. Cardiovasc Ther 2013; 31:e1.
  189. Nishida T, Shimokawa H, Oi K, et al. Extracorporeal cardiac shock wave therapy markedly ameliorates ischemia-induced myocardial dysfunction in pigs in vivo. Circulation 2004; 110:3055.
  190. Fukumoto Y, Ito A, Uwatoku T, et al. Extracorporeal cardiac shock wave therapy ameliorates myocardial ischemia in patients with severe coronary artery disease. Coron Artery Dis 2006; 17:63.
  191. Belcaro G, Cesarone MR, Dugall M, et al. Effects of shock waves on microcirculation, perfusion, and pain management in critical limb ischemia. Angiology 2005; 56:403.
  192. Tara S, Miyamoto M, Takagi G, et al. Low-energy extracorporeal shock wave therapy improves microcirculation blood flow of ischemic limbs in patients with peripheral arterial disease: pilot study. J Nippon Med Sch 2014; 81:19.
  193. Serizawa F, Ito K, Kawamura K, et al. Extracorporeal shock wave therapy improves the walking ability of patients with peripheral artery disease and intermittent claudication. Circ J 2012; 76:1486.
  194. Ciccone MM, Notarnicola A, Scicchitano P, et al. Shockwave therapy in patients with peripheral artery disease. Adv Ther 2012; 29:698.
  195. Cayton T, Harwood A, Smith GE, Chetter I. A Systematic Review of Extracorporeal Shockwave Therapy as a Novel Treatment for Intermittent Claudication. Ann Vasc Surg 2016; 35:226.
  196. Raza A, Harwood A, Totty J, et al. Extracorporeal Shockwave Therapy for Peripheral Arterial Disease: A Review of the Potential Mechanisms of Action. Ann Vasc Surg 2017; 45:294.
Topic 94161 Version 29.0

References

1 : Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II).

2 : Antithrombotic therapy for peripheral artery occlusive disease: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition).

3 : 2016 AHA/ACC Guideline on the Management of Patients With Lower Extremity Peripheral Artery Disease: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.

4 : 2017 ESC Guidelines on the Diagnosis and Treatment of Peripheral Arterial Diseases, in collaboration with the European Society for Vascular Surgery (ESVS).

5 : Step-monitored home exercise improves ambulation, vascular function, and inflammation in symptomatic patients with peripheral artery disease: a randomized controlled trial.

6 : Meta-analysis of clinical trials examining the benefit of structured home exercise in patients with peripheral artery disease.

7 : Effect of a Home-Based Exercise Intervention of Wearable Technology and Telephone Coaching on Walking Performance in Peripheral Artery Disease: The HONOR Randomized Clinical Trial.

8 : Home-based walking exercise intervention in peripheral artery disease: a randomized clinical trial.

9 : Effects of a home-based walking intervention on mobility and quality of life in people with diabetes and peripheral arterial disease: a randomized controlled trial.

10 : Intermittent claudication: new targets for drug development.

11 : Adjunctive pharmacotherapies for intermittent claudication--NICE guidance.

12 : Effect of interleukin 1βinhibition in cardiovascular disease.

13 : Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease.

14 : Inflammation and cardiovascular diseases: lessons from seminal clinical trials.

15 : A randomized, placebo-controlled trial of canakinumab in patients with peripheral artery disease.

16 : 2021 Jeffrey M. Hoeg Award Lecture: Defining the Role of Efferocytosis in Cardiovascular Disease: A Focus on the CD47 (Cluster of Differentiation 47) Axis.

17 : CD47-blocking antibodies restore phagocytosis and prevent atherosclerosis.

18 : Effect of CD47 Blockade on Vascular Inflammation.

19 : Vitamin E for intermittent claudication.

20 : Daily supplementation with (n-3) PUFAs, oleic acid, folic acid, and vitamins B-6 and E increases pain-free walking distance and improves risk factors in men with peripheral vascular disease.

21 : Antioxidants in peripheral arterial disease.

22 : Effect of glutathione infusion on leg arterial circulation, cutaneous microcirculation, and pain-free walking distance in patients with peripheral obstructive arterial disease: a randomized, double-blind, placebo-controlled trial.

23 : Evaluation of trans sodium crocetinate on safety and exercise performance in patients with peripheral artery disease and intermittent claudication.

24 : Inflammation and Chlamydia pneumoniae infection correlate with the severity of peripheral arterial disease.

25 : Dark chocolate: consumption for pleasure or therapy?

26 : Dark chocolate and vascular function in patients with peripheral artery disease: a randomized, controlled cross-over trial.

27 : Dark chocolate acutely improves walking autonomy in patients with peripheral artery disease.

28 : Cocoa to Improve Walking Performance in Older People With Peripheral Artery Disease: The COCOA-PAD Pilot Randomized Clinical Trial.

29 : Effect of Annurca Apple Polyphenols on Intermittent Claudication in Patients With Peripheral Artery Disease.

30 : The endothelium and its role in regulating vascular tone.

31 : The vascular endothelium and human diseases.

32 : Nitric oxide: link between endothelial dysfunction and inflammation in patients with peripheral arterial disease of the lower limbs.

33 : Inorganic nitrate supplementation lowers blood pressure in humans: role for nitrite-derived NO.

34 : Dietary nitrate supplementation enhances exercise performance in peripheral arterial disease.

35 : Nitrite: A Physiological Store of Nitric Oxide and Modulator of Mitochondrial Function.

36 : Nitrate supplementation's improvement of 10-km time-trial performance in trained cyclists.

37 : Dietary nitrate supplementation reduces the O2 cost of walking and running: a placebo-controlled study.

38 : Dietary nitrate supplementation reduces the O2 cost of low-intensity exercise and enhances tolerance to high-intensity exercise in humans.

39 : No improvement of repeated-sprint performance with dietary nitrate.

40 : Influence of acute dietary nitrate supplementation on 50 mile time trial performance in well-trained cyclists.

41 : Dietary nitrate does not enhance running performance in elite cross-country skiers.

42 : Beetroot juice supplementation does not improve performance of elite 1500-m runners.

43 : Cold pressor test as a predictor of hypertension.

44 : Prognostic value of abnormal vasoreactivity of epicardial coronary arteries to sympathetic stimulation in patients with normal coronary angiograms.

45 : Sodium nitrate supplementation improves blood pressure reactivity in patients with peripheral artery disease.

46 : Combined Dietary Nitrate and Exercise Intervention in Peripheral Artery Disease: Protocol Rationale and Design.

47 : Beet the Best?

48 : Chronic sodium nitrite therapy augments ischemia-induced angiogenesis and arteriogenesis.

49 : Sodium nitrite in patients with peripheral artery disease and diabetes mellitus: safety, walking distance and endothelial function.

50 : Nitrite therapy is neuroprotective and safe in cardiac arrest survivors.

51 : Nitrite therapy after cardiac arrest reduces reactive oxygen species generation, improves cardiac and neurological function, and enhances survival via reversible inhibition of mitochondrial complex I.

52 : Nonautocatalytic methemoglobin formation by sodium nitrite under aerobic and anaerobic conditions.

53 : L-arginine transporters in cardiovascular disease: a novel therapeutic target.

54 : L-arginine therapy in acute myocardial infarction: the Vascular Interaction With Age in Myocardial Infarction (VINTAGE MI) randomized clinical trial.

55 : Nitric oxide synthase inhibition and oxidative stress in cardiovascular diseases: possible therapeutic targets?

56 : The LargPAD Trial: Phase IIA evaluation of l-arginine infusion in patients with peripheral arterial disease.

57 : L-arginine supplementation in peripheral arterial disease: no benefit and possible harm.

58 : Does l-citrulline supplementation improve exercise blood flow in older adults?

59 : The novel phosphodiesterase inhibitor NM-702 improves claudication-limited exercise performance in patients with peripheral arterial disease.

60 : A phase II dose-ranging study of the phosphodiesterase inhibitor K-134 in patients with peripheral artery disease and claudication.

61 : Prostanoids for intermittent claudication.

62 : Prostanoids for critical limb ischaemia.

63 : Efficacy and Safety of Alprostadil in Patients with Peripheral Arterial Occlusive Disease Fontaine Stage IV: Results of a Placebo Controlled Randomised Multicentre Trial (ESPECIAL).

64 : Randomized, double-blind, placebo-controlled study evaluating the efficacy and safety of AS-013, a prostaglandin E1 prodrug, in patients with intermittent claudication.

65 : [Severe intermittent claudication: PGE1 treatment. A 40-week registry, efficacy and costs].

66 : Prostanoids for chronic critical leg ischemia. A randomized, controlled, open-label trial with prostaglandin E1. The ICAI Study Group. Ischemia Cronica degli Arti Inferiori.

67 : Adjunctive parenteral therapy with lipo-ecraprost, a prostaglandin E1 analog, in patients with critical limb ischemia undergoing distal revascularization does not improve 6-month outcomes.

68 : Parenteral therapy with lipo-ecraprost, a lipid-based formulation of a PGE1 analog, does not alter six-month outcomes in patients with critical leg ischemia.

69 : A randomized trial of iloprost in patients with intermittent claudication.

70 : Trial of a novel prostacyclin analog, UT-15, in patients with severe intermittent claudication.

71 : Treprostinil sodium (Remodulin), a prostacyclin analog, in the treatment of critical limb ischemia: open-label study.

72 : The prostacyclin analog, treprostinil sodium, provides symptom relief in severe Buerger's disease--a case report and review of literature.

73 : Prostanoids for critical limb ischaemia.

74 : Randomized clinical trial of angiotensin-converting enzyme inhibitor, ramipril, in patients with intermittent claudication.

75 : Effect of ramipril on walking times and quality of life among patients with peripheral artery disease and intermittent claudication: a randomized controlled trial.

76 : Do angiotensin converting enzyme inhibitors improve walking distance in patients with symptomatic lower limb arterial disease? A systematic review and meta-analysis of randomised controlled trials.

77 : Do angiotensin converting enzyme inhibitors improve walking distance in patients with symptomatic lower limb arterial disease? A systematic review and meta-analysis of randomised controlled trials.

78 : Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes.

79 : Liraglutide and semaglutide reduce cardiovascular events in patients with type 2 diabetes and peripheral arterial disease

80 : The Impact of Liraglutide on Diabetes-Related Foot Ulceration and Associated Complications in Patients With Type 2 Diabetes at High Risk for Cardiovascular Events: Results From the LEADER Trial.

81 : Clinical epidemiology of cardiovascular disease in chronic renal disease.

82 : Arterial calcifications, arterial stiffness, and cardiovascular risk in end-stage renal disease.

83 : Vascular calcification in chronic kidney disease: role of disordered mineral metabolism.

84 : Slowing Progression of Cardiovascular Calcification With SNF472 in Patients on Hemodialysis: Results of a Randomized Phase 2b Study.

85 : Rivaroxaban with or without Aspirin in Stable Cardiovascular Disease.

86 : Rivaroxaban in Peripheral Artery Disease after Revascularization.

87 : Rationale and design for the study Apixaban versus ClopidoGRel on a background of aspirin in patient undergoing InfraPoPliteal angioplasty for critical limb ischemia: AGRIPPA trial.

88 : Low-density lipoproteins cause atherosclerotic cardiovascular disease: pathophysiological, genetic, and therapeutic insights: a consensus statement from the European Atherosclerosis Society Consensus Panel.

89 : Role of lipoprotein (a) in peripheral arterial disease.

90 : Longitudinal cohort study on the effectiveness of lipid apheresis treatment to reduce high lipoprotein(a) levels and prevent major adverse coronary events.

91 : Lipoprotein apheresis in patients with maximally tolerated lipid-lowering therapy, lipoprotein(a)-hyperlipoproteinemia, and progressive cardiovascular disease: prospective observational multicenter study.

92 : Lipoprotein Apheresis for Lipoprotein(a)-Associated Cardiovascular Disease: Prospective 5 Years of Follow-Up and Apolipoprotein(a) Characterization.

93 : Most significant reduction of cardiovascular events in patients undergoing lipoproteinapheresis due to raised Lp(a) levels - A multicenter observational study.

94 : Lipoprotein apheresis in patients with peripheral artery disease and hyperlipoproteinemia(a).

95 : Lipoprotein apheresis in patients with peripheral artery disease and lipoprotein(a)-hyperlipoproteinemia: 2-year follow-up of a prospective single center study.

96 : Lipoprotein(a), PCSK9 Inhibition, and Cardiovascular Risk.

97 : Peripheral Artery Disease and Venous Thromboembolic Events After Acute Coronary Syndrome: Role of Lipoprotein(a) and Modification by Alirocumab: Prespecified Analysis of the ODYSSEY OUTCOMES Randomized Clinical Trial.

98 : Lipoprotein(a) Reduction in Persons with Cardiovascular Disease.

99 : Efficacy and safety of eicosapentaenoic acid ethyl ester (AMR101) therapy in statin-treated patients with persistent high triglycerides (from the ANCHOR study).

100 : Icosapent ethyl, a pure ethyl ester of eicosapentaenoic acid: effects on circulating markers of inflammation from the MARINE and ANCHOR studies.

101 : Cardiovascular Risk Reduction with Icosapent Ethyl for Hypertriglyceridemia.

102 : Benefits of Icosapent Ethyl in Patients with Prior Peripheral Artery Disease: REDUCE-IT PAD

103 : Angiographic demonstration of neoangiogenesis after intra-arterial infusion of autologous bone marrow mononuclear cells in diabetic patients with critical limb ischemia.

104 : Vascular disease and stem cell therapies.

105 : Autologous bone-marrow mononuclear cell implantation reduces long-term major amputation risk in patients with critical limb ischemia: a comparison of atherosclerotic peripheral arterial disease and Buerger disease.

106 : Safety and effect of adipose tissue-derived stem cell implantation in patients with critical limb ischemia: a pilot study.

107 : Phase I trial: the use of autologous cultured adipose-derived stroma/stem cells to treat patients with non-revascularizable critical limb ischemia.

108 : Application of adipose-derived stem cells in critical limb ischemia.

109 : Atorvastatin treatment of rats with ischemia-reperfusion injury improves adipose-derived mesenchymal stem cell migration and survival via the SDF-1α/CXCR-4 axis.

110 : Adipose mesenchymal stromal cells isolated from type 2 diabetic patients display reduced fibrinolytic activity.

111 : The role of placental-derived adherent stromal cell (PLX-PAD) in the treatment of critical limb ischemia.

112 : Local intramuscular transplantation of autologous mononuclear cells for critical lower limb ischaemia.

113 : Safety and efficacy of autologous cell therapy in critical limb ischemia: a systematic review.

114 : Autologous bone marrow-derived cell therapy in patients with critical limb ischemia: a meta-analysis of randomized controlled clinical trials.

115 : Cell therapy for peripheral artery disease.

116 : Effect of progenitor cell mobilization with granulocyte-macrophage colony-stimulating factor in patients with peripheral artery disease: a randomized clinical trial.

117 : Progenitor cell release plus exercise to improve functional performance in peripheral artery disease: the PROPEL Study.

118 : START Trial: a pilot study on STimulation of ARTeriogenesis using subcutaneous application of granulocyte-macrophage colony-stimulating factor as a new treatment for peripheral vascular disease.

119 : Concise review: aldehyde dehydrogenase bright stem and progenitor cell populations from normal tissues: characteristics, activities, and emerging uses in regenerative medicine.

120 : Bone marrow-derived aldehyde dehydrogenase-bright stem and progenitor cells for ischemic repair.

121 : Evaluation of Cell Therapy on Exercise Performance and Limb Perfusion in Peripheral Artery Disease: The CCTRN PACE Trial (Patients With Intermittent Claudication Injected With ALDH Bright Cells).

122 : Effect of Granulocyte-Macrophage Colony-Stimulating Factor With or Without Supervised Exercise on Walking Performance in Patients With Peripheral Artery Disease: The PROPEL Randomized Clinical Trial.

123 : Local intramuscular transplantation of autologous mononuclear cells for critical lower limb ischaemia.

124 : Autologous transplantation of granulocyte colony-stimulating factor-mobilized peripheral blood mononuclear cells improves critical limb ischemia in diabetes.

125 : Autologous Cell Therapy for Peripheral Arterial Disease: Systematic Review and Meta-Analysis of Randomized, Nonrandomized, and Noncontrolled Studies.

126 : Therapeutic angiogenesis for patients with limb ischaemia by autologous transplantation of bone-marrow cells: a pilot study and a randomised controlled trial.

127 : Targeting nonhealing ulcers of lower extremity in human through autologous bone marrow-derived mesenchymal stem cells.

128 : Therapeutical potential of autologous peripheral blood mononuclear cell transplantation in patients with type 2 diabetic critical limb ischemia.

129 : Therapeutical potential of autologous peripheral blood mononuclear cell transplantation in patients with type 2 diabetic critical limb ischemia.

130 : Therapeutical potential of autologous peripheral blood mononuclear cell transplantation in patients with type 2 diabetic critical limb ischemia.

131 : Granulocyte colony-stimulating factor: a noninvasive regeneration therapy for treating atherosclerotic peripheral artery disease.

132 : Intraarterial administration of bone marrow mononuclear cells in patients with critical limb ischemia: a randomized-start, placebo-controlled pilot trial (PROVASA).

133 : The role of amputation as an outcome measure in cellular therapy for critical limb ischemia: implications for clinical trial design.

134 : Comparison of bone marrow mesenchymal stem cells with bone marrow-derived mononuclear cells for treatment of diabetic critical limb ischemia and foot ulcer: a double-blind, randomized, controlled trial.

135 : Cellular therapy with Ixmyelocel-T to treat critical limb ischemia: the randomized, double-blind, placebo-controlled RESTORE-CLI trial.

136 : Cell therapy, a new standard in management of chronic critical limb ischemia and foot ulcer.

137 : Effect of repetitive intra-arterial infusion of bone marrow mononuclear cells in patients with no-option limb ischemia: the randomized, double-blind, placebo-controlled Rejuvenating Endothelial Progenitor Cells via Transcutaneous Intra-arterial Supplementation (JUVENTAS) trial.

138 : Therapeutic outcomes of transplanting autologous granulocyte colony-stimulating factor-mobilised peripheral mononuclear cells in diabetic patients with critical limb ischaemia.

139 : Randomized, double-blind pilot study of transendocardial injection of autologous aldehyde dehydrogenase-bright stem cells in patients with ischemic heart failure.

140 : A randomized, controlled study of autologous therapy with bone marrow-derived aldehyde dehydrogenase bright cells in patients with critical limb ischemia.

141 : Short- to mid-term results using autologous bone-marrow mononuclear cell implantation therapy as a limb salvage procedure in patients with severe peripheral arterial disease.

142 : Therapeutic angiogenesis in patients with severe limb ischemia by transplantation of a combination stem cell product.

143 : A double blind randomized placebo controlled phase I/II study assessing the safety and efficacy of allogeneic bone marrow derived mesenchymal stem cell in critical limb ischemia.

144 : Autologous immuno magnetically selected CD133+ stem cells in the treatment of no-option critical limb ischemia: clinical and contrast enhanced ultrasound assessed results in eight patients.

145 : Autologous bone marrow mononuclear cell implantation therapy is an effective limb salvage strategy for patients with severe peripheral arterial disease.

146 : Autologous stem cell therapy for peripheral arterial disease: a systematic review and meta-analysis of randomized controlled trials.

147 : Gene therapy for peripheral arterial disease.

148 : Vascular endothelial growth factor(165) gene transfer augments circulating endothelial progenitor cells in human subjects.

149 : Therapeutic angiogenesis. A single intraarterial bolus of vascular endothelial growth factor augments revascularization in a rabbit ischemic hind limb model.

150 : Therapeutic angiogenesis with recombinant fibroblast growth factor-2 for intermittent claudication (the TRAFFIC study): a randomised trial.

151 : Constitutive expression of phVEGF165 after intramuscular gene transfer promotes collateral vessel development in patients with critical limb ischemia.

152 : Regional angiogenesis with vascular endothelial growth factor in peripheral arterial disease: a phase II randomized, double-blind, controlled study of adenoviral delivery of vascular endothelial growth factor 121 in patients with disabling intermittent claudication.

153 : Meta-analysis of randomized, controlled clinical trials in angiogenesis: gene and cell therapy in peripheral arterial disease.

154 : Gene therapy for therapeutic angiogenesis in peripheral arterial disease - a systematic review and meta-analysis of randomized, controlled trials.

155 : Effect of hypoxia-inducible factor-1alpha gene therapy on walking performance in patients with intermittent claudication.

156 : Regional Angiogenesis with Vascular Endothelial Growth Factor (VEGF) in peripheral arterial disease: Design of the RAVE trial.

157 : Results from a phase II multicenter, double-blind placebo-controlled study of Del-1 (VLTS-589) for intermittent claudication in subjects with peripheral arterial disease.

158 : Effect of fibroblast growth factor NV1FGF on amputation and death: a randomised placebo-controlled trial of gene therapy in critical limb ischaemia.

159 : Treatment with intramuscular vascular endothelial growth factor gene compared with placebo for patients with diabetes mellitus and critical limb ischemia: a double-blind randomized trial.

160 : Use of a constitutively active hypoxia-inducible factor-1alpha transgene as a therapeutic strategy in no-option critical limb ischemia patients: phase I dose-escalation experience.

161 : Therapeutic angiogenesis with intramuscular NV1FGF improves amputation-free survival in patients with critical limb ischemia.

162 : Results of a double-blind, placebo-controlled study to assess the safety of intramuscular injection of hepatocyte growth factor plasmid to improve limb perfusion in patients with critical limb ischemia.

163 : Safety and efficacy of patient specific intramuscular injection of HGF plasmid gene therapy on limb perfusion and wound healing in patients with ischemic lower extremity ulceration: results of the HGF-0205 trial.

164 : Randomized, double-blind, placebo-controlled clinical trial of hepatocyte growth factor plasmid for critical limb ischemia.

165 : Safety of vascular endothelial and hepatocyte growth factor gene therapy in patients with critical limb ischemia.

166 : Increased vascularity detected by digital subtraction angiography after VEGF gene transfer to human lower limb artery: a randomized, placebo-controlled, double-blinded phase II study.

167 : Epidural spinal cord stimulation in the treatment of severe peripheral arterial occlusive disease.

168 : Clinical results of epidural spinal cord electrical stimulation in patients affected with limb-threatening chronic arterial obstructive disease.

169 : Spinal cord stimulation for non-reconstructable chronic critical leg ischaemia.

170 : Chronic transcutaneous electrical stimulation of calf muscles improves functional capacity without inducing systemic inflammation in claudicants.

171 : The Effectiveness of Calf Muscle Electrostimulation on Vascular Perfusion and Walking Capacity in Patients Living With Type 2 Diabetes Mellitus and Peripheral Artery Disease.

172 : Chronic muscle stimulation improves ischaemic muscle performance in patients with peripheral vascular disease.

173 : Calf muscle stimulation with the Veinoplus device results in a significant increase in lower limb inflow without generating limb ischemia or pain in patients with peripheral artery disease.

174 : Effect of footplate neuromuscular electrical stimulation on functional and quality-of-life parameters in patients with peripheral artery disease: pilot, and subsequent randomized clinical trial.

175 : Effects of unilateral, low-frequency, neuromuscular stimulation on superficial circulation in lower extremities of patients with peripheral vascular disease.

176 : The efficacy of transcutaneous electrical nerve stimulation on the improvement of walking distance in patients with peripheral arterial disease with intermittent claudication: study protocol for a randomised controlled trial: the TENS-PAD study.

177 : Improving walking ability and ankle brachial pressure indices in symptomatic peripheral vascular disease with intermittent pneumatic foot compression: a prospective controlled study with one-year follow-up.

178 : Effect of intermittent pneumatic compression of foot and calf on walking distance, hemodynamics, and quality of life in patients with arterial claudication: a prospective randomized controlled study with 1-year follow-up.

179 : Improvement of the walking ability in intermittent claudication due to superficial femoral artery occlusion with supervised exercise and pneumatic foot and calf compression: a randomised controlled trial.

180 : Intermittent vacuum treatment with VacuMed does not improve peripheral artery disease or walking capacity in patients with intermittent claudication.

181 : Randomized controlled trial of vacuum therapy for intermittent claudication.

182 : A randomized controlled trial of treatment with intermittent negative pressure for intermittent claudication.

183 : Waon therapy improves peripheral arterial disease.

184 : Waon therapy mobilizes CD34+ cells and improves peripheral arterial disease.

185 : Lower-limb hot-water immersion acutely induces beneficial hemodynamic and cardiovascular responses in peripheral arterial disease and healthy, elderly controls.

186 : Extracorporeal shock wave treatment in nonunions of long bone fractures.

187 : Prophylactic low-energy shock wave therapy improves wound healing after vein harvesting for coronary artery bypass graft surgery: a prospective, randomized trial.

188 : Cardiac shock wave therapy for chronic refractory angina pectoris. A prospective placebo-controlled randomized trial.

189 : Extracorporeal cardiac shock wave therapy markedly ameliorates ischemia-induced myocardial dysfunction in pigs in vivo.

190 : Extracorporeal cardiac shock wave therapy ameliorates myocardial ischemia in patients with severe coronary artery disease.

191 : Effects of shock waves on microcirculation, perfusion, and pain management in critical limb ischemia.

192 : Low-energy extracorporeal shock wave therapy improves microcirculation blood flow of ischemic limbs in patients with peripheral arterial disease: pilot study.

193 : Extracorporeal shock wave therapy improves the walking ability of patients with peripheral artery disease and intermittent claudication.

194 : Shockwave therapy in patients with peripheral artery disease.

195 : A Systematic Review of Extracorporeal Shockwave Therapy as a Novel Treatment for Intermittent Claudication.

196 : Extracorporeal Shockwave Therapy for Peripheral Arterial Disease: A Review of the Potential Mechanisms of Action.

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