Peripheral arterial disease (PAD) - A challenging manifestation of atherosclerosis.

The diagnosis of peripheral arterial disease (PAD) is not always evident as symptoms and signs may show great variation. As all grades of PAD are linked to both an increased risk for cardiovascular complications and adverse limb events, awareness of the condition and knowledge about diagnostic measures, prevention and treatment is crucial. This article presents in a condensed form information on PAD and its management.

Editor's choice. A randomized controlled trial of the fascia suture technique compared with a suture-mediated closure device for femoral arterial closure after endovascular aortic repair.

OBJECTIVES: The aim was to investigate whether the fascia suture technique (FST) can reduce access closure time and procedural costs compared with the Prostar technique (Prostar) in patients undergoing endovascular aortic repair and to evaluate the short- and mid-term outcomes of both techniques. METHODS: In this two center trial, 100 patients were randomized to access closure by either FST or Prostar between June 2006 and December 2009. The primary endpoint was access closure time. Secondary outcome measures included access related costs and evaluation of the short- and mid-term complications. Evaluation was performed peri- and post-operatively, at discharge, at 30 days and at 6 months follow up. RESULTS: The median access closure time was 12.4 minutes for FST and 19.9 minutes for Prostar (p < .001). Prostar required a 54% greater procedure time than FST, mean ratio 1.54 (95% CI 1.25-1.90, p < .001) according to regression analysis. Adjusted for operator experience the mean ratio was 1.30 (95% CI 1.09-1.55, p = .005) and for patient body mass index 1.59 (95% CI 1.28-1.96, p < .001). The technical failure rate for operators at proficiency level was 5% (2/40) compared with 28% (17/59) for those at the basic level (p = .003). The proficiency level group had a technical failure rate of 4% (1/26) for FST and 7% (1/14) for Prostar, p = 1.00, while corresponding rates for the basic level group were 27% (6/22) for FST and 30% (11/37) for Prostar (p = .84). There was a significant difference in cost in favor of FST, with a median difference of €800 (95% CI 710-927, p < .001). CONCLUSIONS: In aortic endovascular repair FST is a faster and cheaper technique than the Prostar technique.

Abdominal hypertension and decompression: the effect on peritoneal metabolism in an experimental porcine study.

OBJECTIVE: The aim of this study was to investigate the abdominal metabolic response and circulatory changes after decompression of intra-abdominal hypertension in a porcine model. METHODS: This was an experimental study with controls. Three-month-old domestic pigs of both sexes were anesthetized and ventilated. Nine animals had a pneumoperitoneum-induced IAH of 30 mmHg for 6 hours. Twelve animals had the same IAH for 4 hours followed by decompression, and were monitored for another 2 hours. Hemodynamics, including laser Doppler-measured mucosal blood flow, urine output, and arterial blood samples were analyzed every hour along with glucose, glycerol, lactate and pyruvate concentrations, and lactate-pyruvate (l/p) ratio, measured by microdialysis. RESULTS: Laser Doppler-measured mucosal blood flow and urine output decreased with the induction of IAH and showed a statistically significant resolution after decompression. Both groups developed distinct metabolic changes intraperitoneally on induction of IAH, including an increased l/p ratio, as signs of organ hypoperfusion. In the decompression group the intraperitoneal l/p ratio normalized during the second decompression hour, indicating partially restored perfusion. CONCLUSION: Decompression after 4 hours of IAH results in an improved intestinal blood flow and a normalized intraperitoneal l/p ratio.

Cloxacillin concentrations in serum, subcutaneous fat, and muscle in patients with chronic critical limb ischemia.

BACKGROUND: Patients suffering from critical limb ischemia (CLI) have poor wound healing in the ankle and foot areas. Secondary wound infections are frequent and often treated with prolonged courses of antibiotics. PURPOSE: This study set out to investigate to what extent the unbound fraction of 4 g of cloxacillin i.v. reaches its target organ in poorly vascularized tissues, i.e., the calf and foot of patients suffering from CLI. METHODS: Cloxacillin concentrations were measured by HPLC in serum and in microdialysis samples from skin and muscle of the lower part of the calf and as reference subcutaneously at the pectoral level in eight patients suffering from CLI (four males, four females, mean age 78 years, range 66-85 years) and in three healthy controls (two females, one male, mean age 67, range 66-68 years). RESULTS: In patients suffering from CLI, the tissue penetration of cloxacillin after a single 4 g dose was comparable to that of healthy controls, despite impaired blood circulation. CONCLUSIONS: The reduced blood flow in the peripheral vessels of the CLI patients presented here apparently is not the rate-limiting factor for delivery or tissue penetration of cloxacillin.

Intra-peritoneal microdialysis and intra-abdominal pressure after endovascular repair of ruptured aortic aneurysms.

OBJECTIVES: This study aims to evaluate intra-peritoneal (ip) microdialysis after endovascular aortic repair (EVAR) of ruptured abdominal aortic aneurysm (rAAA) in patients developing intra-abdominal hypertension (IAH), requiring abdominal decompression. DESIGN: Prospective study. MATERIAL AND METHODS: A total of 16 patients with rAAA treated with an emergency EVAR were followed up hourly for intra-abdominal pressure (IAP), urine production and ip lactate, pyruvate, glycerol and glucose by microdialysis, analysed only at the end of the study. Abdominal decompression was performed on clinical criteria, and decompressed (D) and non-decompressed (ND) patients were compared. RESULTS: The ip lactate/pyruvate (l/p) ratio was higher in the D group than in the ND group during the first five postoperative hours (mean 20 vs. 12), p = 0.005 and at 1 h prior to decompression compared to the fifth hour in the ND group (24 vs. 13), p = 0.016. Glycerol levels were higher in the D group during the first postoperative hours (mean 274.6 vs. 121.7 µM), p = 0.022. The IAP was higher only at 1 h prior to decompression in the D group compared to the ND group at the fifth hour (mean 19 vs. 14 mmHg). CONCLUSIONS: Ip l/p ratio and glycerol levels are elevated immediately postoperatively in patients developing IAH leading to organ failure and subsequent abdominal decompression.

Complete replacement of open repair for ruptured abdominal aortic aneurysms by endovascular aneurysm repair: a two-center 14-year experience.

OBJECTIVE: To present the combined 14-year experience of 2 university centers performing endovascular aneurysm repair (EVAR) on 100% of noninfected ruptured abdominal aortic aneurysms (RAAA) over the last 32 months. BACKGROUND: Endovascular aneurysm repair for RAAA feasibility is reported to be 20% to 50%, and EVAR for RAAA has been reported to have better outcomes than open repair. METHODS: We retrospectively analyzed prospectively gathered data on 473 consecutive RAAA patients (Zurich, 295; Örebro, 178) from January 1, 1998, to December 31, 2011, treated by an "EVAR-whenever-possible" approach until April 2009 (EVAR/OPEN period) and thereafter according to a "100% EVAR" approach (EVAR-ONLY period).Straightforward cases were treated by standard EVAR. More complex RAAA were managed during EVAR-ONLY with adjunctive procedures in 17 of 70 patients (24%): chimney, 3; open iliac debranching, 1; coiling, 8; onyx, 3; and chimney plus onyx, 2. RESULTS: Since May 2009, all RAAA but one have been treated by EVAR (Zurich, 31; Örebro, 39); 30-day mortality for EVAR-ONLY was 24% (17 of 70). Total cohort mortality (including medically treated patients) for EVAR/OPEN was 32.8% (131 of 400) compared with 27.4% (20 of 73) for EVAR-ONLY (P = 0.376). During EVAR/OPEN, 10% (39 of 400) of patients were treated medically compared with 4% (3 of 73) of patients during EVAR-ONLY. In EVAR/OPEN, open repair showed a statistically significant association with 30-day mortality (adjusted odds ratio [OR] = 3.3; 95% confidence interval [CI], 1.4-7.5; P = 0.004). For patients with no abdominal decompression, there was a higher mortality with open repair than EVAR (adjusted OR = 5.6; 95% CI, 1.9-16.7). In patients with abdominal decompression by laparotomy, there was no difference in mortality (adjusted OR = 1.1; 95% CI, 0.3-3.7). CONCLUSIONS: The "EVAR-ONLY" approach has allowed EVAR treatment of nearly all incoming RAAA with low mortality and turndown rates. Although the observed association of a higher EVAR mortality with abdominal decompression needs further study, our results support superiority and more widespread adoption of EVAR for the treatment of RAAA.

Insights on the role of diabetes and geographic variation in patients with critical limb ischaemia.

BACKGROUND: Patients with critical limb ischaemia (CLI) unsuitable for revascularisation have a high rate of amputation and mortality (30% and 25% at 1 year, respectively). Localised gene therapy using plasmid DNA encoding acidic fibroblast growth factor (NV1FGF, riferminogene pecaplasmid) has showed an increased amputation-free survival in a phase II trial. This article provides the rationale, design and baseline characteristics of CLI patients enrolled in the pivotal phase III trial (EFC6145/TAMARIS). METHODS: An international, double-blind, placebo-controlled, randomised study composed of 525 CLI patients recruited from 170 sites worldwide who were unsuitable for revascularisation and had non-healing skin lesions was carried out to evaluate the potential benefit of repeated intramuscular administration of NV1FGF. Randomisation was stratified by country and by diabetic status. RESULTS: The mean age of the study cohort was 70 ± 10 years, and included 70% males and 53% diabetic patients. Fifty-four percent of the patients had previous lower-extremity revascularisation and 22% had previous minor amputation of the index leg. In 94% of the patients, the index leg had distal occlusive disease affecting arteries below the knee. Statins were prescribed for 54% of the patients, and anti-platelet drugs for 80%. Variation in region of origin resulted in only minor demographic imbalance. Similarly, while diabetic status was associated with a frequent history of coronary artery disease, it had little impact on limb haemodynamics and vascular lesions. CONCLUSIONS: Clinical characteristics and vascular anatomy of CLI patients with ischaemic skin lesions who were unsuitable for revascularisation therapy show little variations by region of origin and diabetic status. The findings from this large CLI cohort will contribute to our understanding of this disease process. This study is registered with ClinicalTrials.gov, number NCT00566657.

Results of the randomized, placebo-controlled clopidogrel and acetylsalicylic acid in bypass surgery for peripheral arterial disease (CASPAR) trial.

OBJECTIVE: Dual antiplatelet therapy with clopidogrel plus acetylsalicylic acid (ASA) is superior to ASA alone in patients with acute coronary syndromes and in those undergoing percutaneous coronary intervention. We sought to determine whether clopidogrel plus ASA conferred benefit on limb outcomes over ASA alone in patients undergoing below-knee bypass grafting. METHODS: Patients undergoing unilateral, below-knee bypass graft for atherosclerotic peripheral arterial disease (PAD) were enrolled 2 to 4 days after surgery and were randomly assigned to clopidogrel 75 mg/day plus ASA 75 to 100 mg/day or placebo plus ASA 75 to 100 mg/day for 6 to 24 months. The primary efficacy endpoint was a composite of index-graft occlusion or revascularization, above-ankle amputation of the affected limb, or death. The primary safety endpoint was severe bleeding (Global Utilization of Streptokinase and Tissue plasminogen activator for Occluded coronary arteries [GUSTO] classification). RESULTS: In the overall population, the primary endpoint occurred in 149 of 425 patients in the clopidogrel group vs 151 of 426 patients in the placebo (plus ASA) group (hazard ratio [HR], 0.98; 95% confidence interval [CI], 0.78-1.23). In a prespecified subgroup analysis, the primary endpoint was significantly reduced by clopidogrel in prosthetic graft patients (HR, 0.65; 95% CI, 0.45-0.95; P = .025) but not in venous graft patients (HR, 1.25; 95% CI, 0.94-1.67, not significant [NS]). A significant statistical interaction between treatment effect and graft type was observed (P(interaction) = .008). Although total bleeds were more frequent with clopidogrel, there was no significant difference between the rates of severe bleeding in the clopidogrel and placebo (plus ASA) groups (2.1% vs 1.2%). CONCLUSION: The combination of clopidogrel plus ASA did not improve limb or systemic outcomes in the overall population of PAD patients requiring below-knee bypass grafting. Subgroup analysis suggests that clopidogrel plus ASA confers benefit in patients receiving prosthetic grafts without significantly increasing major bleeding risk.

The next 10 years in the management of peripheral artery disease: perspectives from the 'PAD 2009' Conference.

OBJECTIVES: To briefly inform on the conclusions from a conference on the next 10 years in the management of peripheral artery disease (PAD). DESIGN OF THE CONFERENCE: International participation, invited presentations and open discussion were based on the following issues: Why is PAD under-recognised? Health economic impact of PAD; funding of PAD research; changes of treatment options? Aspects on clinical trials and regulatory views; and the role of guidelines. RESULTS AND CONCLUSIONS: A relative lack of knowledge about cardiovascular risk and optimal management of PAD patients exists not only among the public, but also in parts of the health-care system. Specialists are required to act for improved information. More specific PAD research is needed for risk management and to apply the best possible evaluation of evidence for treatment strategies. Better strategies for funding are required based on, for example, public/private initiatives. The proportion of endovascular treatments is steadily increasing, more frequently based on observational studies than on randomised controlled trials. The role of guidelines is therefore important to guide the profession in the assessment of most relevant treatment.

ESVS guidelines. Invasive treatment for carotid stenosis: indications, techniques.

The European Society for Vascular Surgery brought together a group of experts in the field of carotid artery disease to produce updated guidelines for the invasive treatment of carotid disease. The recommendations were rated according to the level of evidence. Carotid endarterectomy (CEA) is recommended in symptomatic patients with >50% stenosis if the perioperative stroke/death rate is <6% [A], preferably within 2 weeks of the patient's last symptoms [A]. CEA is also recommended in asymptomatic men <75 years old with 70-99% stenosis if the perioperative stroke/death risk is <3% [A]. The benefit from CEA in asymptomatic women is significantly less than in men [A]. CEA should therefore be considered only in younger, fit women [A]. Carotid patch angioplasty is preferable to primary closure [A]. Aspirin at a dose of 75-325 mg daily and statins should be given before, during and following CEA. [A] Carotid artery stenting (CAS) should be performed only in high-risk for CEA patients, in high-volume centres with documented low peri-operative stroke and death rates or inside a randomized controlled trial [C]. CAS should be performed under dual antiplatelet treatment with aspirin and clopidogrel [A]. Carotid protection devices are probably of benefit [C].

Endovascular repair of the ruptured abdominal aortic aneurysm.

The present knowledge on endovascular repair of ruptured abdominal aortic aneurysms (rAAA) prevents firm conclusions when to use this method in comparison to open repair. This review article briefly summarizes results from case series, and discusses how to achieve reliable information despite the absence of randomized controlled trials. At present a careful conclusion might be that dedicated centers with an adequate organization and reasonably high volume of abdominal aortic aneurysm (AAA) should use detailed registry protocols to achieve experience and data to create an as reliable basis as possible for future recommendations.

Systemic white blood and endothelial cell response after revascularization of critical limb ischemia is only influenced in case of ischemic ulcers.

AIM: The aim of this study was to study the inflammatory response to open revascularization of an ischemic leg in terms of activation of white blood cells (WBC), platelets and endothelial cells. DESIGN: prospective study. METHODS: Venous samples from 21 patients suffering critical limb ischemia (CLI) were drawn before, and 4 weeks after (20 patients) revascularization. Total WBC, differentiated WBC, and platelets were counted. Expression of CD11b/CD18 on granulocytes and monocytes and CD41 on platelets was measured by flow cytometry. Soluble endothelial markers (sICAM-1, sVCAM-1, sE-selectin and sP-selectin) were analysed with ELISA. RESULTS: WBC and granulocyte count decreased in the subgroup of patients with ulcer and gangrene but no change in activation of WBC was recorded. The endothelial marker sICAM-1 decreased while VCAM-1 increased following surgery, most evident in the subgroup with ulcers and gangrene. CONCLUSIONS: This study shows that revascularization of CLI does not significantly influence the inflammatory response in patients with rest pain only, but a limited response of down regulation was found in the ulcer/gangrene patients probably as an effect of healing ulcers.

Arteriogenic gene therapy in patients with unreconstructable critical limb ischemia: a randomized, placebo-controlled clinical trial of adenovirus 5-delivered fibroblast growth factor-4.

The objectives of this study were to assess the safety and potential clinical efficacy of adenovirus-delivered fibroblast growth factor-4 (Ad5FGF-4) by intramuscular injection into patients with critical limb ischemia (CLI). This study was a double-blind, randomized, placebo-controlled study with escalating dose groups of 2.87 x 10(8) to 2.87 x 10(10) viral particles. Thirteen patients with CLI were randomized to receive active drug (n = 10) or placebo (n = 3). Safety evaluations and efficacy parameters (ankle-brachial index, digital subtraction angiograms, magnetic resonance imaging, and scintigraphy) were performed at baseline and for 12 weeks after treatment. Injections of Ad5FGF-4 were generally well tolerated and considered safe. Transfection efficacy at these concentrations may have been limited or local. The small sample size did not allow any firm conclusions regarding clinical efficacy but a trend toward more and slightly larger blood vessels was observed in the angiograms. It is concluded that intramuscular injection of Ad5FGF-4 into CLI patients seemed safe, but transfection efficacy was limited at the assessed doses. Conclusions regarding clinical efficacy are impossible to draw from this small patient cohort.

Axillofemoral bypass reconstructions in sixty-one patients with leg ischemia.

During a 5-year period, 61 axillofemoral bypass operations have been performed in patients regarding as poor risks for conventional bifurcations procedures with arteriosclerotic occlusive disease and in patients with graft infections. Velour-Dacron grafts and expanded polytetrafluoroethylene (PTFE)-grafts have been used. The results are encouraging with a 3 year graft patency rate of 75% and a 3 year limb salvage rate of 90%. The expanded PTFE graft is a suitable graft for this purpose, and the use of axillofemoral bypass grafting is recommended as an alternative to the conventional aortoiliac/femoral bypass graft when dealing with high risk patients and patients with graft infections.

Revascularization of popliteal and below-knee arteries with polytetrafluoroethylene.

The expanded polytetrafluoroethylene (PTFE) graft (Gore-tex) is the most frequently used synthetic graft when an alternative to autologous saphenous vein is required. Early results have been encouraging. In the present paper we report on 6 years of results from 153 above-knee (AK) femoropopliteal bypass grafts, 74 below-knee (BK) femoropopliteal bypass grafts, and 54 femorotibial/peroneal bypass grafts. The main indication for the vascular reconstruction was severe ischemia. Preventive antibiotics were given to 95% of the patients. Minimum observation time was 1 year after implantation. There was no operative death. Graft infection was seen in less than 5% of patients. The 6-year cumulative limb salvage rate was 87% for patients with severe ischemia in the AK femoropopliteal bypass group, 59% for those in the BK femoropopliteal bypass group, and 57% for those in the femorotibial/peroneal bypass group. The graft patency rate was 88% at 2 years and 78% at 6 years for the AK femoropopliteal bypass group, for whom the operative indication was disabling claudication, and 81% and 68%, respectively, when the indication for the vascular procedure was severe ischemia. The cumulative graft patency rate was 53% and 43% at 2 and 6 years, respectively, after implantation of BK femoropopliteal bypass grafts and 43% and 39% for femorotibial/peroneal bypass procedures. The expanded PTFE (Gore-tex) graft seems therefore to be a good alternative when an autologous vein is not available, even for reconstructions well below the knee joint.

Streptokinase treatment of deep venous thrombosis and the postthrombotic syndrome. Follow-up evaluation of venous function.

The conditions of 35 patients with deep venous thrombosis treated with streptokinase were reevaluated after a mean of 29 months with clinical examination, venous plethysmography, foot volumetry, phlebography (28 patients) and femoral vein pressure measurement (24 patients). At follow-up, 25 patients (71%) had symptoms and 22 (63%) had signs of venous insufficiency. Plethysmography was abnormal in 29 patients (83%) and foot volumetry in 25 (72%). Only two (6%) of the patients had normal plethysmography and foot volumetry and were free from symptoms and signs. No leg ulcer or severe postthrombotic syndrome was found. Phlebography showed that no patient had a normal deep venous system. Six of earlier thrombotic iliac veins (38%) and femoral veins 14 (48%), respectively, remained occluded. Increased femoral venous pressure, more pronounced during and after exercise, was found when iliac vein was diseased. Our results emphasize the importance of functional evaluation of the patient with a postthrombotic leg.

Rebound increase of PAI-1 following local intra-arterial rt-PA infusion, a possible cause of reocclusion.

We studied systemic changes in the plasminogen activating system induced by local intra-arterial infusion of recombinant t-PA (rt-PA) in ten patients with arterial occlusion. The arterial infusion of rt-PA resulted in an immediate increase of t-PA activity and antigen in venous plasma. Concomitantly the plasma was depleted of PAI-1 activity with a moderate decrease of PAI-1 antigen, presumably due to immediate complexing of rt-PA by PAI-1 and gradual elimination of the rt-PA/PAI-1 complex from the circulation. Activation of plasminogen in the circulation was reflected by the occurrence of fibrinogen/fibrin degradation products. This rapid systemic activation of the fibrinolytic system at local intra-arterial administration of rt-PA might be due to the opening of small collaterals or backward flow through open arteries, allowing rt-PA to enter the general circulation. The disappearance of detectable PAI-1 activity during rt-PA infusion was followed by a rebound effect with a significant increase of PAI-1 antigen. As this increase may have contributed to the reocclusion which occurred in four patients, it might be advisable to replace heparin by rt-PA at a lower dosage in the immediate phase following rt-PA infusion.

The late results after axillo-femoral bypass grafts in patients with leg ischaemia.

The late results--up to six years--after axillo-femoral bypass reconstruction are reported for 85 patients with leg ischaemia who were regarded as poor-risk patients for aortic bypass surgery, or who had aortic graft infection. Velour-Dacron grafts and expanded polytetrafluoroethylene (PTFE, Gore-Tex)--grafts have been used. The cumulative patency rate (life table) six years after graft implantation was 64% (PTFE-grafts) and 58% (Velour-Dacron grafts). The corresponding cumulative limb salvage rate six years after graft implantation was 88% when PTFE grafts were used and 77% when Velour-Dacron grafts were used. Our results demonstrate that axillo-femoral reconstruction is a useful procedure with a good patency rate 6 years after implantation. This procedure should be considered when dealing with poor risk patients with severe leg ischaemia.