Medical therapy for critical limb ischemia and the diabetic foot: an update.

Critical limb ischemia is the most severe manifestation of chronic peripheral artery disease (PAD). The goal of medical care is to provide symptomatic relief in patients who are unsuitable for percutaneous or surgical revascularization and to reduce systemic cardiovascular risk. PAD is a common manifestation of systemic atherosclerosis and is associated with significant morbidity and mortality. PAD represents a marker for premature cardiovascular events. Patients with PAD, even in the absence of a history of myocardial infarction or ischemic stroke, have approximately the same relative risk of death from cardiovascular causes as do patients with a history of coronary or cerebrovascular disease alone. The PARTNERS study demonstrated that patients with PAD were less likely to receive appropriate treatment for their atherosclerotic risk factors than those who were being treated for coronary artery disease. The long term prognosis of patients with PAD is significantly worse than for patients with coronary artery disease alone. Newer therapies are being investigated to treat patients with critical limb ischemia who are unsuitable candidates for revascularization, and these will be discussed briefly.

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.

"The challenge facing renal artery revascularization: what have we not proven and why we must"?

Endovascular renal artery stent therapy for atherosclerotic renal artery stenosis (RAS) is associated with excellent acute technical success, low complication rates and acceptable long-term patency. However, the clinical benefits to patients of renal artery stenting remain uncertain. To facilitate debate regarding the treatment of RAS, we need to understand the epidemiology, basic physiology and clinical consequences of renal artery stenosis. We must attempt to determine which patients are likely to benefit from renal artery stenting, assess the nuances of the percutaneous procedure and review the current literature pertaining to renal artery stenting.

Clinical endpoints in peripheral endovascular revascularization trials: a case for standardized definitions.

BACKGROUND: Endovascular therapy is a rapidly expanding option for the treatment of patients with peripheral arterial disease (PAD), leading to a myriad of published studies reporting on various revascularization strategies. However, these reports are often difficult to interpret and compare because they do not utilize uniform clinical endpoint definitions. Moreover, few of these studies describe clinical outcomes from a patients' perspective. METHODS AND RESULTS: The DEFINE Group is a collaborative effort of an ad-hoc multidisciplinary team from various specialties involved in peripheral arterial disease therapy in Europe and the United States. DEFINE's goal was to arrive at a broad based consensus for baseline and endpoint definitions in peripheral endovascular revascularization trials for chronic lower limb ischemia. In this project, which started in 2006, the individual team members reviewed the existing pertinent literature. Following this, a series of telephone conferences and face-to-face meetings were held to agree upon definitions. Input was also obtained from regulatory (United States Food and Drug Administration) and industry (device manufacturers with an interest in peripheral endovascular revascularization) stakeholders, respectively. The efforts resulted in the current document containing proposed baseline and endpoint definitions in chronic lower limb PAD. Although the consensus has inevitably included certain arbitrary choices and compromises, adherence to these proposed standard definitions would provide consistency across future trials, thereby facilitating evaluation of clinical effectiveness and safety of various endovascular revascularization techniques. CONCLUSION: This current document is based on a broad based consensus involving relevant stakeholders from the medical community, industry and regulatory bodies. It is proposed that the consensus document may have value for study design of future clinical trials in chronic lower limb ischemia as well as for regulatory purposes.

The safety and efficacy of the StarClose Vascular Closure System: the ultrasound substudy of the CLIP study.

BACKGROUND: The StarClose Vascular Closure System (Abbott Vascular, Redwood City, CA) features a nitinol clip that is designed to achieve closure of the femoral arteriotomy access site. The CLIP Study was performed to assess the safety and efficacy of StarClose when compared with standard manual compression following 5-6 French diagnostic or interventional percutaneous procedures. A substudy of this trial was designed to assess the utility of duplex ultrasonography to assess patency of the femoral artery and to determine access site complications (pseudoaneurysm, arteriovenous fistula, hematoma, deep vein thrombosis) in a multicenter prospective trial. This is the report of the duplex ultrasound (DUS) substudy of the CLIP trial. METHODS: A total of 17 U.S. sites enrolled 596 subjects with 483 subjects randomized at a 2:1 ratio to receive StarClose or manual compression of the arteriotomy after a percutaneous procedure. The study included roll-in (n = 113), diagnostic (n = 208), and interventional (n = 275) arms with a primary safety endpoint of major vascular complications through 30 days and a primary efficacy endpoint of postprocedure time to hemostasis. A substudy of the CLIP interventional arm evaluated DUS images of the closure site at five study sites, targeting 100 subjects at day 30 following hemostasis. The DUS protocol was devised and implemented by an independent vascular ultrasound core laboratory with extensive experience in vascular device trials. DUS inguinal region from 6 cm proximal to 6 cm distal to the arteriotomy puncture was performed. A qualitative examination was performed to determine the presence of iatrogenic vascular injuries: hematoma, pseudoaneurysm (PSA), arteriovenous fistula (AVF), and arterial/venous thrombosis or stenosis using 2-dimensional gray scale, color, and focused Doppler images. RESULTS: DUS of 96 subjects randomized to StarClose (n = 71) and compression (n = 25) were performed and evaluated. There was no evidence of hematoma, PSA, or AVF observed in the StarClose group. No StarClose subjects in the substudy had a PSA or AVF. All patients in the substudy demonstrated patency of the access site artery and vein without thrombosis or stenosis. Finally, in the entire study cohort, no clinically-driven DUS studies demonstrated iatrogenic vascular injury or vessel thrombosis in the StarClose treated patients. CONCLUSION: DUS, a safe and reliable method for determining the safety and efficacy of access site closure devices, is a reliable, safe, inexpensive and accurate method of assessing vascular access site complications in multicenter trials. In this substudy of the CLIP study, DUS found no statistical difference in access site complications between the StarClose and manual compression groups. Both groups maintained vessel patency without stenosis, thrombosis, hematoma, pseudoaneurysm, or AV fistula.

Renal artery stent revascularization with embolic protection in patients with ischemic nephropathy.

A prospective analysis of renal artery stent revascularization with distal embolic protection in a high-risk patient population with ischemic nephropathy is presented. A total of 63 patients (median age 70.2 years, range 54-86 years) had significant atherosclerotic stenosis of 83 renal arteries documented on pre-procedural imaging. All patients had baseline chronic renal insufficiency with a documented deterioration in renal function in the 6 months before revascularization. The endovascular technique used in all patients involved primary passage of an embolic filter into the distal main renal artery followed by primary stent deployment with a balloon expandable stainless steel stent. The filter baskets were recaptured and contents submitted for pathological analysis. At 6 months post-intervention, 97% of patients demonstrated stabilization or improvement in renal function. Only 3% of patients had an inexorable decline in renal function, unchanged by the intervention. After a mean follow up of 16.0 months (6-27), 94% of patients demonstrated stabilization or improvement in renal function. One patient suffered an acute post-procedural deterioration in renal function. In total, 60% of the filter baskets contained embolic material. This study confirms the technical feasibility of renal artery stent deployment with adjuvant embolic protection. The excellent results for renal preservation at 6 months post-intervention also suggest that a distal embolic protection device may improve the impact of percutaneous renal revascularization on progressive deterioration in renal function. The postulated mechanism is through the prevention of atheromatous embolization and the embolic yield from the distal filters supports this hypothesis. Patients most likely to receive the greatest benefit are those with mild baseline chronic renal insufficiency and a recent decline in renal function.

Tibioperoneal (outflow lesion) angioplasty can be used as primary treatment in 235 patients with critical limb ischemia: five-year follow-up.

BACKGROUND: In a prospective, nonrandomized, consecutive series of tibioperoneal vessel angioplasty (TPVA), critical limb ischemia (CLI) patients' data were analyzed with regard to immediate and follow-up success. METHODS AND RESULTS: TPVA was successful in 270 of 284 critically ischemic limbs (95%), with 167 limbs (59%) requiring dilatation of 333 ipsilateral inflow obstructions to access and successfully dilate 486 of 529 (92%) tibioperoneal lesions. A clinical success (relief of rest pain or improvement of lower-extremity blood flow) was attained in 270 limbs at risk (95%). Clinical 5-year follow-up of 215 of 221 successful CLI patients (97%) with 266 successfully revascularized limbs revealed that bypass surgery occurred in 8% and significant amputations in 9% of limbs; 91% of the limbs were salvaged. The cohort's probability of survival was 56%: 58% for Fontaine class III and 33% for class IV patients. Class III compared with class IV patients had significantly (P<0.05) fewer surgical bypasses (3% versus 16%) and amputations: above-knee, 1% versus 4%; below-knee, 3% versus 12%; and transmetatarsal, <1% versus 21%. CONCLUSIONS: TPVA, often in combination with inflow lesions, is an effective primary treatment for critical limb ischemia. The poor cumulative survival reflects the existence of severe comorbidities, which could potentially be affected by aggressive and effective cardiovascular diagnostic and therapeutic strategies.

Haploinsufficiency for one COL3A1 allele of type III procollagen results in a phenotype similar to the vascular form of Ehlers-Danlos syndrome, Ehlers-Danlos syndrome type IV.

Mutations in the COL3A1 gene that encodes the chains of type III procollagen result in the vascular form of Ehlers-Danlos syndrome (EDS), EDS type IV, if they alter the sequence in the triple-helical domain. Although other fibrillar collagen-gene mutations that lead to allele instability or failure to incorporate proalpha-chains into trimers-and that thus reduce the amount of mature molecules produced-result in clinically apparent phenotypes, no such mutations have been identified in COL3A1. Furthermore, mice heterozygous for Col3a1 "null" alleles have no identified phenotype. We have now found three frameshift mutations (1832delAA, 413delC, and 555delT) that lead to premature termination codons (PTCs) in exons 27, 6, and 9, respectively, and to allele-product instability. The mRNA from each mutant allele was transcribed efficiently but rapidly degraded, presumably by the mechanisms of nonsense-mediated decay. In a fourth patient, we identified a point mutation, in the final exon, that resulted in a PTC (4294C-->T [Arg1432Ter]). In this last instance, the mRNA was stable but led to synthesis of a truncated protein that was not incorporated into mature type III procollagen molecules. In all probands, the presenting feature was vascular aneurysm or rupture. Thus, in contrast to mutations in genes that encode the dominant protein of a tissue (e.g., COL1A1 and COL2A1), in which "null" mutations result in phenotypes milder than those caused by mutations that alter protein sequence, the phenotypes produced by these mutations in COL3A1 overlap with those of the vascular form of EDS. This suggests that the major effect of many of these dominant mutations in the "minor" collagen genes may be expressed through protein deficiency rather than through incorporation of structurally altered molecules into fibrils.

Therapeutic thrombin injection of pseudoaneurysms: a multicenter experience.

The standard non-invasive treatment of pseudoaneurysms has been ultrasound-guided compression (UGC). Problems with UGC include pain at the site of compression, long compression times and incomplete closure. Each of these difficulties is exacerbated with large pseudoaneurysms. Recently, ultrasound-guided injection of pseudoaneurysms with thrombin has gained popularity. The goal of this study was to report a multicenter registry using this technique and in so doing detail the clinical utility and safety of this emerging procedure. The medical records of all patients diagnosed with pseudoaneurysm in the vascular laboratory who underwent thrombin injection over the past year were reviewed for patient characteristics and clinical outcome. There were 91 patients (55 male) with a mean age of 69 years. Three patients also had an arteriovenous fistula. The majority of patients were receiving one or more antiplatelet agents and/or anticoagulants. All patients underwent pseudoaneurysm injection with bovine thrombin. The mean aneurysm diameter was 3.3 cm, with a range of 1.5-6.3 cm. Successful thrombosis of the pseudoaneurysm was achieved in 89/91 (98%) of cases. Anticoagulation with heparin was used in one of the unsuccessful cases. In two cases, UGC was used to close a small active region that did not completely thrombose after thrombin injection. There were two patients who had recurrence of pseudoaneurysm the day after successful injection and thrombosis of the pseudoaneurysm. There were no local complications after injection; however, one patient suffered a pulmonary embolus that was thought to be unrelated to the procedure. In conclusion, thrombin injection for the treatment of pseudoaneurysms is safe and effective, even in patients receiving anticoagulation. This procedure should be considered as the initial therapeutic approach for peripheral pseudoaneurysms.

Clinical evaluation and options for infrainguinal atherosclerosis therapy: when to intervene?

Cardiologists have gained considerable experience and expertise in the diagnosis and management of coronary artery disease. Interventional therapy has now become a standard cornerstone of therapy for coronary artery disease, and endoluminal stents are being used in over 70% of all coronary interventions. Diagnosis and treatment of peripheral arterial disease (PAD) has recently gained momentum. In the past, vascular surgeons and interventional radiologists were the classic caregivers for PAD patients, with an interest in deciding between intervention or no intervention. In addition, the majority of PAD patients had few medical resources since many medical specialists did not view PAD as important for many reasons, such as: (1) few effective options for the management of patients with PAD, (2) PAD did not represent a significant health hazard to patients, (3) few patients actually suffered from PAD, and (4) patients did not view PAD as a significant limitation in their quality of life. Over the past decade, a new medical specialty, vascular medicine, had dedicated itself to the comprehensive management of these complex patients. Vascular medicine specialists are predominantly internists and cardiologists. These physicians not only view PAD as an important medical issue, they understand the increasing prevalence of PAD among the "baby-boomer" generation, the shortened life-expectancy of patients with PAD, and the marked reduction in the quality of life among PAD patients. Most importantly, vascular medicine physicians are now aware of several effective options for patients with PAD.

Hypertension and renal artery stenosis: a complex clinical scenario.

Hypertension remains the most common reason for patients to visit physicians in the United States. Although awareness of hypertension among patients continues to increase, adequate control of hypertension remains poor. In addition, as the population of patients with hypertension ages, atherosclerosis becomes increasingly prevalent. Atherosclerotic renal artery stenosis is the most common secondary cause of hypertension and can cause hypertension to be difficult to control. Atherosclerotic renal artery stenosis may also result in chronic renal insufficiency. The physician must be aware of the clinical scenarios in which renal artery stenosis may occur, methods of diagnosis, and indications for intervention.

Carotid artery disease: natural history, diagnosis, and therapy.

Stroke remains a major complication of atherosclerotic cerebrovascular disease, with extracranial carotid occlusive disease accounting for nearly one-third of all events. Although historical symptoms and physical examination findings are important, objective testing with carotid duplex ultrasonography and magnetic resonance arteriography represent the foundation for therapeutic decision making. Contrast arteriography is playing a decreasing role in the evaluation of patients with carotid artery disease. Options for therapy, based on the presence or absence of symptoms and degree of stenosis, include antiplatelet therapy with cardiovascular risk factor modification, carotid endarterectomy, and more recently, endovascular therapy.

In vivo crushing of an aortic stent enables endovascular repair of a large infrarenal aortic pseudoaneurysm.

PURPOSE: To report an unusual approach to endovascular exclusion of a large aortic pseudoaneurysm. METHODS AND RESULTS: A 63-year-old male had an unsuccessful endovascular repair of an aortic anastomotic pseudoaneurysm that left an expanded, uncovered Palmaz stent lying obliquely within the aorta. After nearly 3 years, the pseudoaneurysm enlarged to 7 cm, and the patient became symptomatic. Repair of the pseudoaneurysm was accomplished by crushing the indwelling stent to allow placement of a stent-graft. CONCLUSIONS: Malpositioned stents that are hindering an endoluminal procedure may be crushed against the arterial wall in vivo to facilitate passage of endovascular instruments or devices.

The acute outcome of tibioperoneal vessel angioplasty in 417 cases with claudication and critical limb ischemia.

A non-randomized, consecutive series of 417 first procedure tibioperoneal vessel angioplasty (TPVA) cases were analyzed to determine if angioplasty were an alternative revascularization technique for critical limb ischemia (CLI) and claudicants patients. TPVA was performed on 312 patients (70% male; age 66 +/- 10 years) with success attained in 406/417 cases (96%) of 605/657 lesions (92%): [461/469 stenoses (98%) and 144/188 occlusions (77%) *(P < 0.05)]. Claudication and CLI patients had similar rates of success. In claudication patients clinical success was 130/133 (98%); lesion success was 197/208 (92%); stenosis was 148/151 (98%); and occlusion was 49/57 (86%). In CLI patients clinical success was 270/284 (95%); lesion success was 408/449 (91%); stenosis was 313/318 (98%); and occlusion was 95/131 (73%). We conclude that TPVA is an effective revascularization technique for obstructed tibioperoneal vessels, with excellent success in stenotic (98%) and reasonable results in occluded vessels (77%). These data demonstrate TPVA effectiveness in CLI patients and in carefully selected claudicants with appropriate indications (severe, lifestyle limiting claudication) and readily amenable anatomy, and TPVA for CLI patients appears to be an effective revascularization technique.

A model for collaboration in quality improvement projects: implementing a weight-based heparin dosing nomogram across an integrated health care delivery system.

BACKGROUND: At Aurora Health Care, an integrated delivery system based in Milwaukee, a system-level clinical quality improvement department was established in 1995 to facilitate collaboration on clinical quality improvement (QI) initiatives. THE COLLABORATIVE MODEL: A model was developed to use expertise within the system and avoid unnecessary duplication of efforts, while maintaining buy-in for the project's interventions at the point of service delivery. It was believed that a single team could design the improvement efforts or guidelines, and then work at a more local level with a different group of people to implement the processes. APPLYING THE MODEL TO THE HEPARIN QI PROJECT: Anticoagulation with heparin is considered the mainstay of treatment for pulmonary embolism and deep venous thrombosis. However, a large gap was found between present anticoagulation practices and published best practice in regards to achieving a key process measure. To reduce the overall time to achieving effective anticoagulation, a system-level team created an intervention primarily consisting of a preprinted order sheet, including the weight-based heparin dosing nomogram, and an education plan for physicians and other health care professionals. Significant improvement was observed at all pilot sites with overall rates of adequate anticoagulation within the first 24 hours improving from 73% to 95%. DISCUSSION: The system was able to standardize care at four of its five major hospitals and provide for better patient outcomes to a larger segment of the community, and then to replicate the heparin project to four additional sites during a six-month period. This model has been successfully applied to other quality improvement projects.