Iris Baumgartner

Treatment of thromboangiitis obliterans (Buerger's disease) by intramuscular gene transfer of vascular endothelial growth factor: preliminary clinical results.

PURPOSE Thromboangiitis obliterans (TAO), or Buergers disease, a distinct form of vascular occlusive disease that afflicts the peripheral arteries of young smokers, is often characterized by an inexorable downhill course even in patients who discontinue smoking once a stage of critical limb ischemia associated with ulceration or gangrene is reached. As part of a phase I clinical trial to document the safety and efficacy of intramuscular gene transfer of naked plasmid DNA-encoding vascular endothelial growth factor (phVEGF165) in the treatment of critical limb ischemia, we treated TAO in 6 patients. METHODS Seven limbs in 6 patients (3 men, 3 women; mean age, 33 years; range, 33 to 51 years) who satisfied the criteria for TAO and had signs or symptoms of critical limb ischemia were treated twice, 4 weeks apart, with 2 or 4 mg of phVEGF165, which was administered by direct intramuscular injection at 4 arbitrarily selected sites in the ischemic limb. The gene expression was documented by enzyme-linked immunosorbent assay that was performed on peripheral blood samples. RESULTS The ulcers that were nonhealing for more than 1 month healed completely in 3 of 5 limbs after the intramuscular phVEGF165 gene therapy. Nocturnal rest pain was relieved in the remaining 2 patients, although both continue to have claudication. The evidence of the improved perfusion to the distal ischemic limb included an increase of more than 0.1 in the ankle brachial index in 3 limbs, an improved flow shown with magnetic resonance imaging in 7 of the 7 limbs, and newly visible collateral vessels shown with serial contrast angiography in 7 of the 7 limbs. The adverse consequences of the phVEGF165 gene transfer were limited to transient ankle or calf edema in 3 of the 7 limbs. Two patients with advanced distal forefoot gangrene ultimately required below-knee amputation despite the evidence of improved perfusion. A histologic section disclosed the classic pathologic findings of TAO. CONCLUSION Therapeutic angiogenesis with phVEGF165 gene transfer, if instituted before the development of forefoot gangrene, may provide a novel therapy for patients with advanced Buergers disease that is unresponsive to standard medical or surgical treatment methods.

Expert consensus document from the European Society of Cardiology on catheter-based renal denervation

Hypertension is highly prevalent and one of the most frequent chronic diseases worldwide.1 It has been suggested that over the next two decades up to 50% of the adult population will be diagnosed with hypertension, according to the standard guideline definitions.1 Despite the availability of many safe and effective antihypertensive drugs, control rates to target blood pressure remain low.2 Approximately 5–10% of all patients with high blood pressure are resistant to drug treatment defined as blood pressure >140/90 mmHg, >130–139/80–85 mmHg in diabetes mellitus or >130/80 mmHg in chronic kidney disease in the presence of three or more antihypertensives of different classes, including a diuretic, at maximal or the highest tolerated dose.3 Resistant hypertension is associated with an increased risk of cardiovascular events.4 Current non-invasive therapeutic strategies are mainly based on lifestyle interventions and pharmacological treatment, including mineralocorticoid receptor antagonists.3 Up until recently treatment options for patients with resistant hypertension were limited. Nowadays catheter-based renal denervation offers a new approach targeting the renal sympathetic nerves. Indeed, the technique has been shown to reduce sympathetic nerve activity,5 norepinephrine spillover6 as well as blood pressure7–9 in patients with resistant hypertension. Several national10–13 and international14 consensus documents from different societies have recently been published, with different degrees of involvement of interventionalists. This expert consensus document summarizes the view of an expert panel of the European Society of Cardiology and the European Association of Percutaneous Cardiovascular Interventions to provide guidance regarding …

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

This study evaluated the efficacy and safety of intramuscular administration of NV1FGF, a plasmid-based angiogenic gene delivery system for local expression of fibroblast growth factor 1 (FGF-1), versus placebo, in patients with critical limb ischemia (CLI). In a double-blind, randomized, placebo-controlled, European, multinational study, 125 patients in whom revascularization was not considered to be a suitable option, presenting with nonhealing ulcer(s), were randomized to receive eight intramuscular injections of placebo or 2.5 ml of NV1FGF at 0.2 mg/ml on days 1, 15, 30, and 45 (total 16 mg: 4 × 4 mg). The primary end point was occurrence of complete healing of at least one ulcer in the treated limb at week 25. Secondary end points included ankle brachial index (ABI), amputation, and death. There were 107 patients eligible for evaluation. Improvements in ulcer healing were similar for use of NV1FGF (19.6%) and placebo (14.3%; P = 0.514). However, the use of NV1FGF significantly reduced (by twofold) the risk of all amputations [hazard ratio (HR) 0.498; P = 0.015] and major amputations (HR 0.371; P = 0.015). Furthermore, there was a trend for reduced risk of death with the use of NV1FGF (HR 0.460; P = 0.105). The adverse event incidence was high, and similar between the groups. In patients with CLI, plasmid-based NV1FGF gene transfer was well tolerated, and resulted in a significantly reduced risk of major amputation when compared with placebo.This study evaluated the efficacy and safety of intramuscular administration of NV1FGF, a plasmid-based angiogenic gene delivery system for local expression of fibroblast growth factor 1 (FGF-1), versus placebo, in patients with critical limb ischemia (CLI). In a double-blind, randomized, placebo-controlled, European, multinational study, 125 patients in whom revascularization was not considered to be a suitable option, presenting with nonhealing ulcer(s), were randomized to receive eight intramuscular injections of placebo or 2.5 ml of NV1FGF at 0.2 mg/ml on days 1, 15, 30, and 45 (total 16 mg: 4 x 4 mg). The primary end point was occurrence of complete healing of at least one ulcer in the treated limb at week 25. Secondary end points included ankle brachial index (ABI), amputation, and death. There were 107 patients eligible for evaluation. Improvements in ulcer healing were similar for use of NV1FGF (19.6%) and placebo (14.3%; P = 0.514). However, the use of NV1FGF significantly reduced (by twofold) the risk of all amputations [hazard ratio (HR) 0.498; P = 0.015] and major amputations (HR 0.371; P = 0.015). Furthermore, there was a trend for reduced risk of death with the use of NV1FGF (HR 0.460; P = 0.105). The adverse event incidence was high, and similar between the groups. In patients with CLI, plasmid-based NV1FGF gene transfer was well tolerated, and resulted in a significantly reduced risk of major amputation when compared with placebo.

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

BACKGROUND Patients with critical limb ischaemia have a high rate of amputation and mortality. We tested the hypothesis that non-viral 1 fibroblast growth factor (NV1FGF) would improve amputation-free survival. METHODS In this phase 3 trial (EFC6145/TAMARIS), 525 patients with critical limb ischaemia unsuitable for revascularisation were enrolled from 171 sites in 30 countries. All had ischaemic ulcer in legs or minor skin gangrene and met haemodynamic criteria (ankle pressure <70 mm Hg or a toe pressure <50 mm Hg, or both, or a transcutaneous oxygen pressure <30 mm Hg on the treated leg). Patients were randomly assigned to either NV1FGF at 0·2 mg/mL or matching placebo (visually identical) in a 1:1 ratio. Randomisation was done with a central interactive voice response system by block size 4 and was stratified by diabetes status and country. Investigators, patients, and study teams were masked to treatment. Patients received eight intramuscular injections of their assigned treatment in the index leg on days 1, 15, 29, and 43. The primary endpoint was time to major amputation or death at 1 year analysed by intention to treat with a log-rank test using a multivariate Cox proportional hazard model. This trial is registered with ClinicalTrials.gov, number NCT00566657. FINDINGS 259 patients were assigned to NV1FGF and 266 to placebo. All 525 patients were analysed. The mean age was 70 years (range 50-92), 365 (70%) were men, 280 (53%) had diabetes, and 248 (47%) had a history of coronary artery disease. The primary endpoint or components of the primary did not differ between treatment groups, with major amputation or death in 86 patients (33%) in the placebo group, and 96 (36%) in the active group (hazard ratio 1·11, 95% CI 0·83-1·49; p=0·48). No significant safety issues were recorded. INTERPRETATION TAMARIS provided no evidence that NV1FGF is effective in reduction of amputation or death in patients with critical limb ischaemia. Thus, this group of patients remains a major therapeutic challenge for the clinician. FUNDING Sanofi-Aventis, Paris, France.

Lower-extremity edema associated with gene transfer of naked DNA encoding vascular endothelial growth factor.

Vascular endothelial growth factor (VEGF) was discovered as a tumor-secreted factor that augments vascular permeability (1). The permeability-enhancing effect of VEGF has been estimated to be 50 times greater than that of histamine (2). After identification of the effects of VEGF on microvascular permeability, Leung (3) and Keck (4) and their colleagues demonstrated that VEGF may promote endothelial cell proliferation and migration. These findings led to preclinical animal studies (5-7) and human studies (8-10) that established that VEGF may promote angiogenesis in cases of limb ischemia. We prospectively evaluated 90 patients with peripheral artery disease who underwent gene transfer of naked plasmid DNA encoding the 165amino acid isoform of VEGF (phVEGF165) for clinical evidence of enhanced vascular permeability. The primary results of these trials have been reported in preliminary form elsewhere (9-12). Methods Between December 1994 and July 1999, 90 patients (mean age SD, 59 19 years) underwent gene transfer of phVEGF165 as therapeutic angiogenesis (13) or to prevent restenosis after angioplasty (14). The protocols for these trials were approved by the institutional review board and institutional biosafety committee of St. Elizabeths Medical Center, the Recombinant DNA Advisory Committee of the National Institutes of Health, and the Food and Drug Administration. Informed consent was obtained from all patients treated. Intra-arterial gene transfer was performed in 40 patients. Of these patients, 28 with claudication underwent phVEGF165 gene transfer after superficial femoral artery angioplasty; 4 patients with lower-extremity pain at rest and 8 patients with gangrene were treated to promote angiogenesis in the ischemic limb. Plasmid doses were 100 g (1 patient), 500 g (1 patient), 1000 g (13 patients), 2000 g (22 patients), and 4000 g (3 patients). Intramuscular gene transfer was performed in 50 patients, of whom 13 were treated for pain at rest and 37 presented with established gangrene. Five patients underwent treatment of the contralateral limb 3 or more months after treatment of the initial limb. Patients received 1000 g (n =10), 2000 g (n =19), 3000 g (n =11), and 4000 g (n =10) of phVEGF165. Edema was scored jointly by two observers as follows: 0, no edema; 1, edema limited to the foot; 2, edema involving the foot and ankle; 3, edema involving the calf; 4, more than the three preceding symptoms (Figure). Figure. Representative examples of lower-extremity edema ( asterisks ) according to clinical grade in four patients who underwent intramuscular gene transfer of naked plasmid DNA encoding vascular endothelial growth factor. Venous blood samples were analyzed by using enzyme-linked immunosorbent assay at baseline and weekly up to 4 weeks after the initial gene transfer, as described elsewhere (8). Data are reported as the mean (SE). The relation between nominal variables was calculated by using the Fisher exact test (2 2 contingency table). All statistical tests were two-tailed. A P value less than 0.05 indicated statistical significance. Results Development of Edema Transient lower-extremity edema was observed after gene transfer of phVEGF165 in 31 of 90 (34%) patients. Edema was graded as 1 in 9 patients, 2 in 13 patients, 3 in 6 patients, and 4 in 3 patients. In 3 of 90 (3.3%) patients, edema developed in both limbs after gene transfer of phVEGF165. All 3 patients had critical limb ischemia in both lower extremities. Relation of Edema to Tissue Integrity The incidence of peripheral edema differed among all subgroups. Peripheral edema developed significantly less frequently in patients without compromised tissue integrity than in patients with ischemic ulcers or gangrene. Peripheral edema associated with gene transfer was observed in 0 of 28 (0%) patients with claudication, 4 of 17 (24%) patients with pain at rest, and 27 of 45 (60%) patients with gangrene (Table). Results of the Fisher exact test showed that the incidence of edema differed significantly among all patient groups. Specifically, edema was less common in patients with claudication than in those with pain at rest (P =0.016) or ischemic ulcers (P <0.001) and was less common in patients with pain at rest than in those with ischemic ulcers (P =0.017). Table. Frequency of Peripheral Edema after Intra-Arterial and Intramuscular Administration of Naked Plasmid DNA Encoding Vascular Endothelial Growth Factor Intra-Arterial Compared with Intramuscular Gene Transfer Peripheral edema was observed after both intra-arterial and intramuscular gene transfer (Table). After intra-arterial gene transfer, peripheral edema occurred in 0 of 28 (0%) patients with claudication, 1 of 4 (25%) patients with pain at rest, and 4 of 8 (50%) patients with established gangrene. After intramuscular gene transfer, peripheral edema occurred in 3 of 13 (23%) patients with pain at rest and 23 of 37 (62%) patients with gangrene. The difference between the incidence of lower-extremity edema after intra-arterial gene transfer (5 of 40 patients [12.5%]) compared with intramuscular gene transfer (26 of 55 patients [52%]) was statistically significant (P <0.001) only when patients with claudication were included in the intra-arterial gene transfer group. When comparison of intra-arterial and intramuscular gene transfer was limited to patients in whom either method was used to treat pain at rest or gangrene, the incidence of edema did not differ significantly (5 of 12 patients [42%] compared with 26 of 50 patients [52%], respectively; P >0.2). Development of edema was unrelated to the dose of phVEGF165. Time to Development of Edema Clinically apparent peripheral edema usually developed within 3 weeks after intra-arterial or intramuscular gene transfer. Development of edema corresponded temporally to an increase in circulating levels of VEGF, consistent with the time course of gene expression (2 to 3 weeks) established for this plasmid in preclinical animal studies (7, 10). No differences were observed for intra-arterial compared with intramuscular gene transfer with regard to the time to development of edema or increased serum levels of VEGF. Despite the temporal relation between the increase in serum VEGF levels and development of peripheral edema, no correlation was observed between the absolute peak level of VEGF and the appearance of peripheral edema. Similarly, no relation was seen between the absolute or relative increase in serum VEGF levels from baseline to peak levels and the presence or absence of edema. Neither the magnitude (scores of 1 to 4) nor the probability of lower-extremity edema could be predicted by an individual VEGF level. Recurrent Edema, Treatment, and Hospitalization Development of peripheral edema was usually consistent among patients treated more than once. All patients who developed edema after the first gene transfer developed edema on subsequent injections, whereas no patient in whom edema failed to develop after the first gene transfer experienced edema on repeated gene transfer. Treatment was usually initiated on an outpatient basis and consisted of oral diuretics. Patients most commonly received furosemide, bumetanide, or hydrochlorothiazide or a combination of these agents. Edema was promptly attenuated after administration of diuretics and resolved completely within 2 to 4 weeks after initiation of therapy. In five patients, diuretics were administered intravenously during hospital admission; in none of these five patients was edema the principal indication for hospitalization. Four of the five patients were admitted for initiation of antibiotic treatment for suspected osteomyelitis, and one patient was admitted for control of ischemic pain at rest. Vascular Endothelial Growth FactorEnhanced Vascular Permeability and Evidence of Angiogenesis Evidence of augmented collateral vessel development, including an increase in the anklebrachial or toebrachial index to a value greater than 0.1, newly visible collateral vessels on follow-up serial angiography, or marked improvement of ischemic gangrene and disappearance of ischemic rest pain, was seen in 43 of the 57 patients treated for critical limb ischemia. The relation between development of edema and evidence of enhanced angiogenesis was not statistically significant (P >0.2). Discussion Our findings show that VEGF may augment vascular permeability in humans. The fact that edema failed to develop in patients with claudication but was observed in nearly half of the patients with resting ischemia suggests that the permeability-enhancing effects of VEGF are directly or indirectly potentiated by tissue ischemia. Ischemic damage to the integrity of the microcirculation may directly potentiate the effect of VEGF. Similar loss of microcirculatory integrity in patients with critical limb ischemia frequently leads to edema after conventional revascularization; in that setting, successful bypass surgery leads to augmented blood flow, which, when superimposed on a damaged endothelial substrate, allows excess fluid transudation and, subsequently, development of clinically apparent edema. The potent vasodilating effects of VEGF, previously shown to be a potent stimulus for release of nitric oxide (15), together with vasoactive metabolites released from ischemic tissues may compound this effect. These mechanisms may have contributed to the development of bilateral edema in three patients with critical limb ischemia involving both lower extremities. In the absence of ischemia at rest, however, even the potent permeability-enhancing effects of VEGF were insufficient to cause clinically apparent edema. Systemic administration of VEGF in a rabbit model of hind-limb ischemia was shown to cause selective neovascularization of the ischemic but not normally vascularized areas of the limb (5, 16). The localized biological effect observed in these experimental models, in which angiogenesis was selectively targeted to hy

The long-term multicenter observational study of dabigatran treatment in patients with atrial fibrillation (RELY-ABLE) study

Background— During follow-up of between 1 and 3 years in the Randomized Evaluation of Long-term Anticoagulation Therapy (RE-LY) trial, 2 doses of dabigatran etexilate were shown to be effective and safe for the prevention of stroke or systemic embolism in patients with atrial fibrillation. There is a need for longer-term follow-up of patients on dabigatran and for further data comparing the 2 dabigatran doses. Methods and Results— Patients randomly assigned to dabigatran in RE-LY were eligible for the Long-term Multicenter Extension of Dabigatran Treatment in Patients with Atrial Fibrillation (RELY-ABLE) trial if they had not permanently discontinued study medication at the time of their final RE-LY study visit. Enrolled patients continued to receive the double-blind dabigatran dose received in RE-LY, for up to 28 months of follow up after RE-LY (median follow-up, 2.3 years). There were 5851 patients enrolled, representing 48% of patients originally randomly assigned to receive dabigatran in RE-LY and 86% of RELY-ABLE–eligible patients. Rates of stroke or systemic embolism were 1.46% and 1.60%/y on dabigatran 150 and 110 mg twice daily, respectively (hazard ratio, 0.91; 95% confidence interval, 0.69–1.20). Rates of major hemorrhage were 3.74% and 2.99%/y on dabigatran 150 and 110 mg (hazard ratio, 1.26; 95% confidence interval, 1.04–1.53). Rates of death were 3.02% and 3.10%/y (hazard ratio, 0.97; 95% confidence interval, 0.80–1.19). Rates of hemorrhagic stroke were 0.13% and 0.14%/y. Conclusions— During 2.3 years of continued treatment with dabigatran after RE-LY, there was a higher rate of major bleeding with dabigatran 150 mg twice daily in comparison with 110 mg, and similar rates of stroke and death. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00808067.

Drug-Eluting Balloon Versus Standard Balloon Angioplasty for Infrapopliteal Arterial Revascularization in Critical Limb Ischemia 12-Month Results From the IN.PACT DEEP Randomized Trial

BACKGROUND Drug-eluting balloons (DEB) may reduce infrapopliteal restenosis and reintervention rates versus percutaneous transluminal angioplasty (PTA) and improve wound healing/limb preservation. OBJECTIVES The goal of this clinical trial was to assess the efficacy and safety of IN.PACT Amphirion drug-eluting balloons (IA-DEB) compared to PTA for infrapopliteal arterial revascularization in patients with critical limb ischemia (CLI). METHODS Within a prospective, multicenter, randomized, controlled trial with independent clinical event adjudication and angiographic and wound core laboratories 358 CLI patients were randomized 2:1 to IA-DEB or PTA. The 2 coprimary efficacy endpoints through 12 months were clinically driven target lesion revascularization (CD-TLR) and late lumen loss (LLL). The primary safety endpoint through 6 months was a composite of all-cause mortality, major amputation, and CD-TLR. RESULTS Clinical characteristics were similar between the 2 groups. Significant baseline differences between the IA-DEB and PTA arms included mean lesion length (10.2 cm vs. 12.9 cm; p = 0.002), impaired inflow (40.7% vs. 28.8%; p = 0.035), and previous target limb revascularization (32.2% vs. 21.8%; p = 0.047). Primary efficacy results of IA-DEB versus PTA were CD-TLR of 9.2% versus 13.1% (p = 0.291) and LLL of 0.61 ± 0.78 mm versus 0.62 ± 0.78 mm (p = 0.950). Primary safety endpoints were 17.7% versus 15.8% (p = 0.021) and met the noninferiority hypothesis. A safety signal driven by major amputations through 12 months was observed in the IA-DEB arm versus the PTA arm (8.8% vs. 3.6%; p = 0.080). CONCLUSIONS In patients with CLI, IA-DEB had comparable efficacy to PTA. While primary safety was met, there was a trend towards an increased major amputation rate through 12 months compared to PTA. (Study of IN.PACT Amphirion™ Drug Eluting Balloon vs. Standard PTA for the Treatment of Below the Knee Critical Limb Ischemia [INPACT-DEEP]; NCT00941733).

Cardiovascular risk factor control and outcomes in peripheral artery disease patients in the Reduction of Atherothrombosis for Continued Health (REACH) Registry.

OBJECTIVES To examine differences in risk factor (RF) management between peripheral artery disease (PAD) and coronary artery (CAD) or cerebrovascular disease (CVD), as well as the impact of RF control on major 1-year cardiovascular (CV) event rates. METHODS The REACH Registry recruited >68000 outpatients aged >or=45 years with established atherothrombotic disease or >or=3 RFs for atherothrombosis. The predictors of RF control that were evaluated included: (1) patient demographics, (2) mode of PAD diagnosis, and (3) concomitant CAD and/or CVD. RESULTS RF control was less frequent in patients with PAD (n=8322), compared with those with CAD or CVD (but no PAD, n=47492) [blood pressure; glycemia; total cholesterol; smoking cessation (each P<0.001)]. Factors independently associated with optimal RF control in patients with PAD were male gender (OR=1.9); residence in North America (OR=3.5), Japan (OR=2.5) or Latin America (OR=1.5); previous coronary revascularization (OR=1.3); and statin use (OR=1.4); whereas prior leg amputation was a negative predictor (OR=0.7) (P<0.001). Optimal RF control was associated with fewer 1-year CV ischemic symptoms or events. CONCLUSIONS Patients with PAD do not achieve RF control as frequently as individuals with CAD or CVD. Improved RF control is associated with a positive impact on 1-year CV event rates.

Novel cell-free strategy for therapeutic angiogenesis: in vitro generated conditioned medium can replace progenitor cell transplantation

Background Current evidence suggests that endothelial progenitor cells (EPC) contribute to ischemic tissue repair by both secretion of paracrine factors and incorporation into developing vessels. We tested the hypothesis that cell-free administration of paracrine factors secreted by cultured EPC may achieve an angiogenic effect equivalent to cell therapy. Methodology/Principal Findings EPC-derived conditioned medium (EPC-CM) was obtained from culture expanded EPC subjected to 72 hours of hypoxia. In vitro, EPC-CM significantly inhibited apoptosis of mature endothelial cells and promoted angiogenesis in a rat aortic ring assay. The therapeutic potential of EPC-CM as compared to EPC transplantation was evaluated in a rat model of chronic hindlimb ischemia. Serial intramuscular injections of EPC-CM and EPC both significantly increased hindlimb blood flow assessed by laser Doppler (81.2±2.9% and 83.7±3.0% vs. 53.5±2.4% of normal, P<0.01) and improved muscle performance. A significantly increased capillary density (1.62±0.03 and 1.68±0.05/muscle fiber, P<0.05), enhanced vascular maturation (8.6±0.3 and 8.1±0.4/HPF, P<0.05) and muscle viability corroborated the findings of improved hindlimb perfusion and muscle function. Furthermore, EPC-CM transplantation stimulated the mobilization of bone marrow (BM)-derived EPC compared to control (678.7±44.1 vs. 340.0±29.1 CD34+/CD45− cells/1×105 mononuclear cells, P<0.05) and their recruitment to the ischemic muscles (5.9±0.7 vs. 2.6±0.4 CD34+ cells/HPF, P<0.001) 3 days after the last injection. Conclusions/Significance Intramuscular injection of EPC-CM is as effective as cell transplantation for promoting tissue revascularization and functional recovery. Owing to the technical and practical limitations of cell therapy, cell free conditioned media may represent a potent alternative for therapeutic angiogenesis in ischemic cardiovascular diseases.

A prospective randomized multicenter comparison of balloon angioplasty and infrapopliteal stenting with the sirolimus-eluting stent in patients with ischemic peripheral arterial disease: 1-year results from the ACHILLES trial.

OBJECTIVES The study investigated the efficacy and safety of a balloon expandable, sirolimus-eluting stent (SES) in patients with symptomatic infrapopliteal arterial disease. BACKGROUND Results of infrapopliteal interventions using balloon angioplasty and/or bare stents are limited by a relatively high restenosis rate, which could be potentially improved by stabilizing the lesion with a SES. METHODS Two hundred patients (total lesion length 27 ± 21 mm) were randomized to infrapopliteal SES stenting or percutaneous transluminal balloon angioplasty (PTA). The primary endpoint was 1-year in-segment binary restenosis by quantitative angiography. RESULTS Ninety-nine and 101 patients (mean age 73.4 years; 64% diabetics) were randomized to SES and PTA, respectively (8 crossover bailout cases to SES). At 1 year, there were lower angiographic restenosis rates (22.4% vs. 41.9%, p = 0.019), greater vessel patency (75.0% vs. 57.1%, p =0.025), and similar death, repeat revascularization, index-limb amputation rates, and proportions of patients with improved Rutherford class for SES versus PTA. CONCLUSIONS SES implantation may offer a promising therapeutic alternative to PTA for treatment of infrapopliteal peripheral arterial disease.