Successful revascularization of chronic total occlusion of lower extremity arteries: a wire only and bail out use of re-entry device approach.

AIM: The management of progressive peripheral artery disease experienced a vast change in paradigms over the last decades for the benefit of minimal invasive therapy as a first-line strategy. With the constant development of new devices, materials and dedicated access strategies, more complex lesions can be managed but the limitations to successfully treat chronic total occlusions are still the challenge to re-enter the true lumen. The aim of this retrospective study was to investigate, if a "wire only" strategy leads to an acceptable success rate in a mixed cohort of CTO lesions and to what extend re-entry devices are used. METHODS: We retrospectively analyzed patients treated at the Vascular Center Berlin between 2011 and 2013 with chronic total occlusion out of a prospective conducted database (Endovascular MILestones - EMIL) for demographics, risk factors, co-morbidities, technical success rates, lesion characteristics and use of guidewires as well as re-entry systems. A total of 128 patients with 146 lesions, which represent a subgroup of all the cases performed in our center, following a predefined treatment algorithm for chronic total occlusions (CTOs), have been analyzed. RESULTS: We achieved a technical success in 133 (91.1%) of all cases following a "wire only" strategy. Out of 13 (8.9%) CTOs with technical failure in 7 (53.9%) CTOs a re-entry device (Off-Road®) with a 100% technical success has been used. In 91.1% of chronic total occlusion lesions the use of 2 wires only (88.7%) led to a successful recanalization. A "wire only" strategy followed by the use of a re-entry device as a bail out strategy, led to a total of 140 (96%) lesions to be successfully recanalized. CONCLUSION: In more than 90% of all cases with chronic total occlusion of peripheral lower extremity arteries, endovascular intervention has been successful following a "wire only" strategy. When deciding to use a re-entry device, in case of a failure of a proper wire re-entry at the reconstitution point, a technical success rate of 100% was achieved. Therefore following a strict wire algorithm and considering the use of a re-entry system as a bail out strategy will lead to a successful minimal invasive management of chronic total occlusion in nearly 100% of the cases with TASC II A - D lesions.

Therapeutic arteriogenesis in peripheral arterial disease: combining intervention and passive training.

The prevalence of peripheral arterial disease (PAD) is on the rise in an aging population, significantly affecting quality of life, morbidity and mortality. Besides medical treatment and surgical or interventional revascularization, supervised exercise programs are a primary treatment modality for PAD. Training may significantly increase pain-free walking time (+ 180 %) while avoiding the associated complications of (repeated) invasive revascularization. Training effects rely on an improvement of risk factor management, muscle function, economy of movement, hemorheology, vascular growth and collateral vessel growth. Exercise training upregulates pulsatile fluid shear stress on the vascular endothelium, prompting an improvement of endothelial function (eNOS, NO) and an outgrowth of preexistent collaterals (arteriogenesis) to functional conductance arteries outside the ischemic area at risk. However, the necessary intense minimum training intervals compromise patient compliance, and the impaired functional status of many PAD patients limits active exercise training. Strategies are necessary to a) increase training compliance, b) make the benefits of exercise training available to patients unable to exercise actively and c) therapeutically enhance the adaptive growth of biological bypasses (arteriogenesis). A modified form of “passive exercise training” derived from enhanced external counterpulsation (low-pressure ECP) which was originally developed for the therapy of heart failure, may prove to be an option for this group of patients. Therefore, this review article suggests a tailored combination therapy, consisting of a facilitating revascularization procedure to restore arterial inflow, succeeded by supervised exercise training, which has yielded promising therapeutic results in clinical trials. Further studies, using appropriate imaging methods and controls, are under way to (a) establish the efficacy of low-pressure EECP in PAD patients and (b) to directly correlate training-induced improvements of collateral flow to the functional improvements seen with exercise training.

[Peripheral arterial disease: secondary prevention, medical therapy, revascularization]. / Arterielle Verschlusskrankheit: Sekundärprävention, medikamentöse Therapie, Revaskularisierung.

Patients with peripheral arterial disease have a high risk of cardiovascular morbidity and mortality. Thus, antiplatelet drugs, antidiabetic, antihypertensive and antilipemic agents should be administered early on. Smoking cessation has to be encouraged and supported. In case of significant reduction of walking distance with impaired quality of life structured and supervised exercise training as well as vasoactive substances have to be offered. If technically feasible and critically discussed with the patient revascularization procedures of the aorto-iliac and the femoro-popliteal segment may be performed. In patients with critical limb ischemia, all options for vascularisation have to be utilized as the main goal is limb salvage. As medication, only prostanoids have to be considered.

Complete ulcer healing as primary endpoint in studies on critical limb ischemia? A critical reappraisal.

OBJECTIVES: Although complete ulcer healing is the mandatory primary efficacy criterion in current European guidelines for drug trials in critical limb ischemia (CLI), the appropriateness of this endpoint has been questioned for some time. We carried out a systematic review to assess the value of this endpoint in studies on reconstructive measures, considered to be the standard of care for CLI. METHODS: A computerized literature search (1985-2005) was performed to track down clinical studies on endovascular and surgical interventions by using the search terms CLI and ulcer healing and their synonyms. RESULTS: 1,914 papers on revascularization in CLI were identified. Complete ulcer healing was reported in 17 studies (0.9%). Among these, there were no randomized controlled trials, five prospective cohorts on endovascular procedures, and six retrospective cohorts for endovascular and surgical procedures, respectively. If healing rates or time to ulcer healing were available, they differed greatly between the studies without consistent correlation to types of therapy. CONCLUSIONS: In past and current literature, complete ulcer healing is not a consistently reported criterion for success of revascularization in CLI. Thus, its appropriateness for efficacy assessment of drug studies in CLI patients has to be questioned.

[Are the TASC recommendations for diagnosis and treatment of PAOD still relevant?]. / Sind TASC-Kriterien in der Diagnostik und Therapie der pAVK noch relevant?

With regards to the rapid progress of interventional therapy in the treatment of PAOD the revision of the published guidelines (TASC Recommendations 2000) is more than necessary. The current options in therapy are modified constantly. Therefore, published recommendations might be not up-to-date. In consideration of the number of interventions and operations which are performed throughout Europe a trend towards less invasive treatment becomes apparent. Guidelines and recommendations from the Charing Cross and the ACC/AHA (ACC/AHA Guidelines for the Management of Patients With Peripheral Arterial Disease 2005) are reflecting this development. Regardless of the complexity of the planned procedure interventional treatment is almost always first choice therapy. A yearly revision of the actual guidelines would be useful, leading to an up-to-date modality. Although in the diagnostic pathway MRI and CTA gain more importance, the gold standard in diagnosis of PAOD remains the standardised measurement of the walking capacity, ankle-brachial index (ABI) and duplex ultrasound.

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.

A multicentre evaluation of the Medtronic AVE Flexible Iliac Bridge Stent in the iliac arteries (the first study).

PURPOSE: To investigate the short term and 6 month outcomes of a recently introduced iliac stent (the Medtronic AVE Flexible Iliac Bridge Stent). METHOD: One hundred and sixteen patients, 122 limbs from 6 European sites with atherosclerotic occlusive disease were included if they either had a full occlusion or there was a residual gradient >10 mmHg following PTA. Clinical, haemodynamic and Duplex outcomes were recorded to 6 months. RESULTS: After stent placement there was no residual stenosis >30 and 8.1% of segments had a residual resting gradient of >10 mmHg. There were three local complications and three deaths at 30 days. Primary patency at 30 days and 6 months was 94.1 and 82.7%. Marked clinical improvement occurred in 87.6 and 86.2% at 30 days and 6 months. CONCLUSION: The Medtronic AVE iliac stent has good 30 day and 6 months outcomes supporting the effective use of this device in occlusive disease.

[Hemobahn-endoprosthesis: long-term experience (< or = 4 years follow-up) with percutaneous application in stenoses and occlusions of the superficial femoral artery]. / Hemobahn-Endoprothese: 4-Jahres-Erfahrungen mit der perkutanen Anwendung bei Stenosen und Verschlüssen der Arteria femoralis superficialis.

We tested the value of hemobahn-endoprosthesis in a prospective, nonrandomized, clinical trial in PAD-patients with femoral artery occlusive disease. During 4 years we placed in 52 patients (55 extremities) a total of 78 hemobahn-endoprostheses for treatment of stenoses (15%) or occlusions (85%) of femoral artery. The average length of the treated lesions was 11.6 cm, the mean length of the hemobahn-endoprosthesis was 15.9 cm, the average device diameter 6.1 mm. In 45% of the patients we used cross-over and in 55% ipsilateral antegrade technique. Fontaine's clinical stages were II b (89%), III (2%) and IV (9%); there were 15 diabetics. The average period of follow-up was 33 months (1-52 months). The primary/secondary patency rates after the first year (n = 50) were 64% vs. 78%, after 2 years (n = 46) 61% vs. 76%, after 3 years (n = 32) 53% vs. 66% and after 4 years (n = 14) 29% vs. 50%. After the first experiences in 1998 with 10 stent-occlusions in 14 treated extremities, indications were checked and thereafter hemobahn was only used in "ideal indications" as segments with a length of > or = 1 cm proximal and distal without any obstruction, no lesions in the popliteal artery, at least one open lower leg vessel and no severe calcifications. The primary/secondary patency rates were significantly better after exclusion of nonideal patients treated during the first year: Thus, primary/secondary patency rates were 76 % vs. 90% after first year (n = 32), 74 % vs. 89% after second year (n = 38) and 71% vs. 83% after third year (n = 24); after 4 years of 8 treated arteries 4 were primary and 7 were secondary open. Hemobahn-endoprostheses are suitable for treatment of long femoral artery occlusions. The medium patency rate in "ideal indications" is higher than that obtained by angioplasty with or without uncovered stents.

Leukocyte/endothelium activation and interactions during femoral percutaneous transluminal angioplasty.

Recent data suggest that leukocyte-endothelium activation/interactions are important for restenosis after percutaneous transluminal angioplasty (PTA). Ten patients with superficial femoral artery occlusive disease (stage Fontaine IIb) were examined after a percutaneous transluminal angioplasty (PTA) versus a preceding aortoangiography (AAG). Blood samples from corresponding femoral arteries and veins were obtained before, immediately after, and 4 hours after each procedure. The authors examined the ex vivo respiratory burst and leukocytic expression of adhesion molecules flowcytometrically, adhesion molecule plasma concentrations, and inflammatory mediators concentrations in plasma and in endotoxin-stimulated whole blood cultures by ELISA, and the leukocyte counts. After PTA, venous plasma concentrations of soluble (s)L-selectin (148.2 +/-14.7%, p<0.05 vs 100% baseline +/- sem), sP-selectin (130.7 +/-6.9%, p<0.01; sE-selectin (117.5 +/-8.3%, p<0.05 vs arterial), sLFA-3 (130.7 +/-15.8%, p<0.05) were increased. Expressions of L-selectin (93.0 +/-5.7%, p<0.05 vs arterial), CD11a (98.8 +/-3.8%, p=0.06), CD18 (96.9 +/-4.0%, p<0.05 vs arterial), and ICAM-1 (89.1 +/-7.7%, p<0.05) on polymorphonuclear neutrophils (PMN), and arteriovenous leukocyte counts (arterial: 103.5 +/-5.4%, venous: 91.1 +/-3.3%, p<0.05) decreased. Venous ex vivo secretions of oxygen radicals (141.4 +/-28.1%, p<0.05 vs AAG), PMN-elastase (173.7 +/-35.7%, p<0.05 vs AAG), and interleukin (IL)-8 (226.5 +/-56.4%, p<0.001; p<0.0001 vs AAG), as well as PMN-elastase (173.7 +/-35.7%, p<0.05 vs AAG) and tumor necrosis factor (TNF)-alpha plasma concentrations (124.1 +/-11.9%, p=0.06) rose. Four hours after PTA, a leukocytosis and exhausted TNF-alpha (69.8 +/-10.4%, p<0.05) and IL-8 secretions (72.4 +/-4.6%, p<0.01) occurred. PTA induced local leukocyte-endothelium activations (stronger ex vivo mediator productions) and interactions (decreased venous leukocyte counts, increased plasma concentrations, and decreased leukocytic expression of adhesion molecules) with the release of inflammatory mediators (higher plasma concentrations and exhaustions after 4 hours).

Anticoagulation: the present and future.

Thrombin is a central bioregulator of coagulation and is therefore a key target in the therapeutic prevention and treatment of thromboembolic disorders, including deep vein thrombosis and pulmonary embolism. The current mainstays of anticoagulation treatment are heparins, which are indirect thrombin inhibitors, and coumarins, such as warfarin, which modulate the synthesis of vitamin K-dependent proteins. Although efficacious and widely used, heparins and coumarins have limitations because their pharmacokinetics and anticoagulant effects are unpredictable, with the risk of bleeding and other complications resulting in the need for close monitoring with their use. Low-molecular-weight heparins (LMWHs) provide a more predictable anticoagulant response, but their use is limited by the need for subcutaneous administration. In addition, discontinuation of heparin treatment can result in a thrombotic rebound due to the inability of these compounds to inhibit clot-bound thrombin. Direct thrombin inhibitors (DTI) are able to target both free and clot-bound thrombin. The first to be used was hirudin, but DTIs with lower molecular weights, such as DuP 714, PPACK, and efegatran, have subsequently been developed, and these agents are better able to inhibit clot-bound thrombin and the thrombotic processes that take place at sites of arterial damage. Such compounds inhibit thrombin by covalently binding to it, but this can result in toxicity and nonspecific binding. The development of reversible noncovalent DTIs, such as inogatran and melagatran, has resulted in safer, more specific and predictable anticoagulant treatment. Oral DTIs, such as ximelagatran, are set to provide a further breakthrough in the prophylaxis and treatment of thrombosis.

[Hemobahn endoprosthesis: experience with percutaneous placing in the arteria femoralis superficialis]. / Hemobahn-Endoprothese. Erfahrungen mit der perkutanen Anwendung in der Arteria femoralis superficialis.

The self-expanding Polytetrafluoroethylene-lined nitinolstent Hemobahn offers from its design a prophylaxis for re-occlusion after angioplasty of long femoral artery occlusions. During the last two years we placed in 33 patients at 35 extremities a total of 53 Hemobahns. Fontaine's clinical stages were: 30 x IIb, 1 x III and 4 x IV. The treated lesions were femoral stenoses (3x) and occlusions (32x with mean distance 12 cm). Follow-up-visits were after 3, 6 and 12 months. The mean ankle-brachial-index changed from 0.49 to 0.85, post-interventional Fontaine's stages were: 24 x I, 5 x IIa, 2 x IIb and 4 x IV. The primary inhospital patency rate was 91%. After 3 months all primary/secondary patency rates were: 77%/87%, after 6 months 62%/85% and after 1 year 40%/67%. Causes for re-occlusions were a poor "run off", calcifications and multiple vessel lesions. The results for "ideal indications" were much better. Such "ideal indications" applied to: > or = 1 cm "healthy" proximal and distal vascular segments, missing lesions in the popliteal artery, at least one open lower leg vessel and no severe calcifications. The primary/secondary patency rate was inhospital 100% (n = 23), after 3 months 95/100%, after 6 months 85/100% and after 1 year 80/100%. Side effects were local haematoma, pain in the prosthesis and temporarily temperature reactions. Sonographically no re-stenoses at the limb ends were observed. Hemobahn-endoprostheses are suited for therapy of long femoral artery occlusions. The medium patency rate of "ideal indications" is higher than that of angioplasty with or without uncovered stents.

Underestimation of 24-hour hypotensive efficacy of nifedipine GITS versus enalapril: ambulatory recording as an adjunct to clinical blood pressure measurement.

AIMS: Short-acting calcium entry blockers should be used primarily in slow-release form. Furthermore, studies of the antihypertensive efficacy of drugs can be negatively influenced by between 15% and 30% of the enrolled patients not being hypertensive according to ambulatory blood pressure (BP) measurement. Thus, a randomized double-blind multicenter parallel-group study was conducted to compare the effect of nifedipine GITS (gastrointestinal therapeutic system) with enalapril. METHODS AND RESULTS: After a 2-week placebo run-in period, 186 patients with a sitting diastolic BP > or = 95 mmHg were enrolled for an 8-week treatment period. They received 30-60 mg nifedipine GITS or 5-10 mg enalapril. Diastolic BP fell comparably from 99 to 87 mmHg (p < 0.01) in the nifedipine GITS group, and from 100 to 88 mmHg (p < 0.01) in the enalapril group. The increase in BP 2 h before waking, however, was suppressed significantly more by nifedipine. Furthermore, this study highlighted the existence of "whitecoat" hypertension in a number of patients, especially when clinical BP was used to identify hypertension. Of the patients who had been identified as hypertensive before randomization by standardized BP measurement, 53 (28.5%) were identified as non-hypertensives by 24-h BP monitoring. This led to an underestimation of the efficacy of the antihypertensive therapy. CONCLUSION: Nifedipine GITS as well as enalapril are comparably effective antihypertensive drugs.

Captopril test: time over?

OBJECTIVE: The role of non-invasive tests for the detection of renovascular hypertension is still a matter of controversy. The 'captopril test' is widely used; its clinical usefulness, however, remains questionable. The aim of the current study was therefore to report our own experience and to review the published data on the diagnostic significance of the test. PATIENTS AND METHODS: Data from 485 hypertensive patients who underwent a captopril test in consecutive order at our institution were analysed retrospectively. After a 30-min resting period in the supine position 50 mg of captopril was given orally. Blood was collected before and 90 min after dosage for the determination of plasma renin concentration (normal range 3.5-8.0 ng/ml/h). An increase by 100% or more of the baseline value was considered a positive response. Blood pressure was recorded at baseline and at 90 min. RESULTS: A positive response was present in 62 patients; further diagnostic work-up revealed significant renal artery stenosis in 11 of these patients. In the 423 patients with a negative response renal artery stenosis was found in three cases. With some limitations of retrospective analyses in mind, sensitivity and specificity of the test were calculated as 79% and 89%, respectively. No severe complication occurred during the test. CONCLUSION: Our data on the diagnostic indices and the safety of the captopril test are in good agreement with most published series. Altogether, available data suggest that the captopril test has a limited diagnostic accuracy as a screening test for the detection of renovascular hypertension. New radiologic non-invasive techniques with greater diagnostic value are therefore likely to challenge the clinical role of the test in the future.

Clonidine suppression test revisited.

BACKGROUND: The diagnosis of pheochromocytoma may be difficult because the clinical picture is variable. OBJECTIVE: The purpose of this paper is to report our experience and to review the published data on the diagnostic significance and risks of the clonidine suppression test in the diagnosis of pheochromocytoma. PATIENTS AND METHODS: 114 patients were evaluated for pheochromocytoma using the clonidine suppression test. RESULTS: The diagnosis was established in four patients. Overall accuracy of the test in our own series was 98% when the normal response to clonidine was defined as total plasma catecholamines of less than 500 ng/L, or less than 70% of the baseline value. No serious complication was noted. CONCLUSION: Our data and the published series demonstrate that the clonidine suppression test is accurate and safe in patients with suspected pheochromocytoma.