Aspirin in peripheral arterial disease: breakthrough or pitfall?

BACKGROUND: This paper introduces a proof-of-concept trial in progress, supposedly providing new important information on anti-platelet drugs used in patients with peripheral arterial disease (PAD). The Arteriogenesis Competence Network (Art.Net.) of the Universities of Basel, Berlin, and Freiburg could show in animal models that Aspirin (ASA), in contrast to Clopidogrel, inhibits the formation of an appropriate collateral network (arteriogenesis). This trial is supposed to reproduce the animal data in man. MATERIALS AND METHODS: In a prospective, double-blind, parallel-group, bi-national (D, CH), multicentre trial, 250 patients will be randomised to either 100 mg ASA or 75 mg Clopidogrel once daily. Patients will then enter a three months structured rehabilitation programme with daily physical training supposed to induce arteriogenesis. The claudication distances will be tested as the primary endpoint at baseline, 6 weeks, and at 3 months. Also, the 24h physical activity profile of all patients will be electronically documented. CONCLUSIONS: This trial will provide information on potential disadvantages when using ASA in PAD patients. If data emerging from animal pharmacology can be reproduced in man, the present standard scheme of anti-aggregant treatment in PAD patients has to be reconsidered.

Quality of life improvement after hospital- based rehabilitation or home-based physical training in intermittent claudication.

BACKGROUND: The magnitude of potential changes in Quality-of-Life (QoL) after structured institution-based or home-based peripheral arterial disease (PAD) rehabilitation programs are largely unknown at present. This pilot study provides first QoL data after PAD rehabilitation or a home-based PAD training. PATIENTS AND METHODS: In a non-randomized, open-label pilot study three groups of out-patients were compared: group 1 (n = 18) PAD rehabilitation; group 2 (n = 17) PAD rehabilitation + clopidogrel 75 mg once daily; group 3 (n = 20) home-based training. The training period was 3 months, which was followed by a 3-month observation phase (without prescribed training). The institution-based rehabilitation program consisted of 3 training hours per week whereas patients training at home were instructed to walk for 1 hour per day on an outdoor track. QoL assessment was performed using MOS SF-36, PAVK-86 and PAD-WIQ questionnaires. RESULTS: At baseline background variables, demographics and claudication distances were comparable between groups. After three months of training the percentage changes for the initial and the absolute claudication distance (ICD, ACD) for groups 1, 2, and 3 amounted to 164%, 201%, 44% (ICD) and 83%, 131%, 5% (ACD), respectively. Statistically significant QoL improvements were recorded for physical functions, pain and disease related anxiety in all three study groups; statistically significant inter-group differences were not found. CONCLUSIONS: In sharp contrast to the development of the claudication distances the improvement in QoL, found after 3 months of training, was comparable and not consistently different between the groups.

Transatlantic Conference on Clinical Trial Guidelines in Peripheral Arterial Disease: clinical trial methodology. Basel PAD Clinical Trial Methodology Group.

Guidelines for the clinical development of drugs in peripheral arterial disease (PAD) have been issued by the Food and Drug Administration for the United States and by the regulatory agency of the European Union for Europe. With increasing globalization, transatlantic cooperation in drug research and development is essential for the future and would be substantially facilitated by the existence of transatlantic guidelines. A conference was held in Basel, Switzerland, in November 1997 to discuss the scientific background of the existing guidelines on the basis of published evidence and the extensive knowledge of clinical investigators and experienced regulators. The meeting was attended by 52 invited experts from the United States and Europe, as well as by representatives from the 2 regulatory authorities. The main conclusions from the meeting are presented and may serve as a reference for the future development of transatlantic guidelines for the evaluation of pharmacotherapy in PAD.

Acute deep vein thrombosis: early mobilization does not increase the frequency of pulmonary embolism.

Outpatient treatment for acute symptomatic deep vein thrombosis (DVT) was shown to be safe for most patients. However, little is known whether patients treated on an outpatient basis were ambulating or predominantly resting, a factor which may be decisive for the outcome. In the present study 129 DVT patients were randomized to either strict immobilization for 4 days or to ambulate for > or = 4 hours per day under supervision in order to show, whether the old concept of temporary immobilization is superior to early mobilization or not. The DVT diagnosis was based on duplex sonography; all patients were screened for PE at baseline and at day 4 by pulmonary ventilation-perfusion scanning, and were followed up for a total of 3 months. Clinically, changes in leg circumferences and leg pain were evaluated. The frequency of PE at baseline was 53.0% and 44.9% in the immobile and the mobile groups, respectively. During the 4 days observation period new PEs were found in 10.0% and in 14.4% of the immobilized and the ambulating patients (delta 4.4%; 95% CI -0.5 to 13.8; chi2 = 0.596, p = 0.44). The occurrence of new PE was related to the presence of PE at baseline but not to other potential predictors. The magnitude of a decrease in leg circumferences and leg pain was comparable in both groups. No patient died during the 4 day observation period. The total 3 month mortality rate was 3.9% (5 patients; 2 from the immobile, 3 from the ambulating group). All 5 patient suffered from malignancies. The results of this study show in accordance with the trial hypothesis that, regarding the frequency of PE, immobilization is not superior to early mobilization, suggesting that early mobilization is safe.

HWA 285 (propentofylline)--a new compound for the treatment of both vascular dementia and dementia of the Alzheimer type.

The pharmacological profile of HWA 285 favors its use in patients with both Alzheimer's disease (PDD) and/or vascular dementia (MID). Clinical trials showed clinically relevant, statistically significant efficacy in the domains of cognitive function, global function and activities of daily living (ADL) in both PDD and MID. HWA 285 had a prolonged symptomatic effect for at least 12 months, although therapeutic effects were seen already after the first 3 months of treatment. HWA 285 was very well tolerated for at least 1 year.

Platelets and cytokines in concert with endothelial activation in patients with peripheral arterial occlusive disease.

We tested the hypothesis whether circulating oncostatin-M (OSM), a cytokine that in vitro promotes fibrinogen biosynthesis and smooth muscle cell proliferation, or soluble CD40 ligand (CD40L; CD154), a leukocyte and platelet surface marker that stimulates endothelial cells, were associated: (a) with fibrinogen and other soluble cell adhesion molecules, such as P-selectin, vascular cell adhesion molecule-1 (VCAM-1), intercellular cell adhesion molecule-1 and platelet-endothelial cell adhesion molecule-1; or (b) with restenosis and platelet activation in 71 patients with peripheral arterial occlusive disease undergoing peripheral angioplasty (PTA). Platelet membrane activation markers (CD62P, CD63, activated GPIIb/IIIa) were immunologically measured at 0, 1, 24 and 48 h, and 3 and 6 months after PTA. Soluble cell adhesion molecules, endothelial markers and various hemostatic variables were measured before PTA. Of the patients, 42.3% developed restenosis within 6 months, defined as a >50% reduction of the lumen at the site of balloon dilatation. Soluble CD40L was not higher in the restenosis group. Interestingly, patients with high CD40L showed significantly higher soluble VCAM-1 (P < 0.01) and thrombomodulin (P < 0.01), as well as trends for higher soluble P- and E-selectin. Platelet activation was found uniformly increased mostly at 1 and 24 h, as well as at 3 and 6 months. OSM was measurable in 53.5% (6.9 +/- 9.4 pg/ml) of the patients and undetectable in the others. No differences in the rate of restenosis was found in these two groups, which did not differ with respect to fibrinogen (3.14 +/- 1.00 versus 3.21 +/- 0.70 g/l), or the other parameters. In conclusion, soluble CD40L is associated with higher endothelial biological markers that might implicate its involvement in endothelial activation. Platelet activation, probably intermittent, might play a significant role through the expression of CD40L as a source of activation signals to the endothelial cells. Free circulating OSM does not seem to correlate directly with fibrinogen or with other acute phase reaction proteins, the synthesis of which it could influence in vitro. This might well not mean, however, that OSM lacks this activity in vivo.

How useful are acceleration- and deceleration-based Doppler indices? A trial on patients with percutaneous transluminal angioplasty.

The usefulness of indices commonly used in Doppler sonography is limited; the aim of this study was to investigate if inclusion of systolic acceleration and deceleration patterns in Doppler indices will result in practical diagnostic advantages. Systolic delay time index (SDTI) and height-width index (HWI) are compared to Gosling's pulsatility index (PI) and to PI-based damping factors (DF) in patients with isolated lesions in the distal superficial femoral artery before and after percutaneous transluminal angioplasty (PTA). Before PTA, all indices distal to the lesion differ significantly from proximal indices. After successful PTA, none of the indices is able to detect the PTA outcome with sufficient sensitivity. The additionally defined curve broadening index (CBI) shows a 100% sensitivity for detecting PTA success in the examined patient population.

Physiological flow variations in the periorbital arteries in Zambian Africans. A screening with bidirectional Doppler ultrasound.

Directional Doppler sonography with direct evaluation of the extracranial carotid artery system and scanning of the periorbital arteries has been performed in 49 black Zambian hypertensive patients and in 19 controls without cardiovascular risk factors. Direct evaluation of the extracranial carotid artery system did not show any abnormalities. In contrast to this periorbital Doppler examination revealed positive findings with retrograde flow direction in the supratrochlear artery in 19% and 21% of all examined carotids in the hypertension and control group, respectively. Compared to direct carotid angiography, 66% of the positive supratrochlear and 13% of the positive supraorbital findings in the hypertensive patient group could be shown to be false positive results. As a possible explanation of this high incidence of a retrograde flow direction in periorbital arteries a different flow physiology in the ophthalmic artery of black Zambians compared to Caucasians is discussed.

Assessment of collateral perfusion: a pharmacodynamic study with buflomedil hydrochloride.

The aim of the study was to assess the influence of Buflomedil hydrochloride on collateral function. Ten patients with isolated superficial femoral occlusions were investigated twice by duplex sonography with measurement sites at the common femoral artery (CF) and the popliteal artery (PA). After the second scan 200 mg of Buflomedil hydrochloride were infused; the infusion was followed by a third duplex examination. Endpoints assessed included the arterial diameter (D(CF), D(PA)), the systolic peak velocity (Vmax), the mean velocity of the maximum envelope (Vmean m.e.), the intensity weighted time average mean velocity (Vmean i.w.), the maximum reverse flow velocity (Vrev), the end-diastolic velocity (Venddiast), the calculated volume flow (Q), the pulsatility and the resistance indices (PI, RI), and PI and RI based segmental damping factors (DF(PI), DF(RI)). For the CF measurement site the infusion of Buflomedil hydrochloride resulted in a significant reduction in Vrev and PI (p<0.05), whereas trends in the opposite direction (increase) were observed for both measures of Vmean and for Q (0.1

Doppler-based diagnosis of restenosis after femoropopliteal percutaneous transluminal angioplasty: sensitivity and specificity of the ankle/brachial pressure index versus changes in absolute pressure values.

The aim of this study was to investigate the sensitivity and specificity of changes of the ankle/brachial pressure index (ABI) and changes in absolute ankle pressure values to detect restenosis in patients who underwent femoropopliteal percutaneous transluminal angioplasty (PTA). In total, 171 patients were followed up prospectively for 12 months; sensitivity and specificity of Doppler-based diagnosis were calculated with duplex scanning as the gold standard. The criteria for restenosis were: (1) a loss of 50% of the ABI increase or (2) loss of 50% of the absolute ankle systolic pressure, gained by PTA. For both criteria, different cut-off points (minimum increase of ABI or ankle pressure gained by PTA) were evaluated. The overall sensitivity and specificity of the ABI criterion was 67% and 80%, respectively. The introduction of cut-off points (the minimum ABI increase gained by PTA), ranging between > or = 0.13 and > or = 0.35, did not markedly improve the results. The overall sensitivity and specificity of the absolute ankle pressure criterion again was poor (59% and 81%). With the introduction of cut-off points (the minimum increase of absolute ankle pressure gained by PTA) ranging between > or = 15 mm Hg and > or = 20 mm Hg, the sensitivity and specificity of the criterion improved to acceptable 92% and 96%, respectively. It is concluded, that in the long-term follow-up of PTA patients, the "loss of 50% ankle pressure" criterion will detect restenosis with reasonable accuracy in those patients, in whom an increase in systolic ankle pressure > or = 20 mm Hg is warranted.

Drug-induced changes of the flow pulse contour recorded by directional CW-Doppler devices: a possible estimation of changes in vascular characteristic impedance and peripheral resistance.

Ultrasound Doppler sonography using directional continuous wave Doppler devices is an inexpensive, simple tool used worldwide for the diagnosis and hemodynamic assessment of patients with peripheral vascular disease (PVD). In addition to pressure evaluation, the interpretation of Doppler velocity pulses has become routine within the last years. However, spontaneous variations in characteristic impedance of muscular arteries or in peripheral resistance will lead to respective variations of arterial reflection coefficients, with consequent changes of the arterial flow pulse reflection pattern and flow pulse contour. The authors studied peripheral Doppler wave forms in 20 volunteers after buccal administration of 1.6 mg of glyceryl trinitrate (GTN) and i.a. (femoral) injection of 30 mg tolazoline hydrochloride. Velocity pulse changes due to artificially introduced variation in peripheral resistance (reactive hyperemia, total arterial blockade) were compared to those induced by above maneuvers. An isolated decrease in characteristic impedance of muscular arteries without alteration of the peripheral resistance is characterized by an increase in the amplitudes of foreward as well as the reverse flow phase of the Doppler signal, with predominant increase of the early diastolic reverse flow phase and subsequent decrease in mean velocity. In contrast, isolated changes in peripheral resistance are reflected mainly by subsequent variations of the reverse flow phase amplitude of the Doppler signals.

The pre-stenotic Doppler shift signature.

In two series of measurements the Doppler shift signatures of 10 healthy volunteers were studied at varying distances proximal to a total reflection site, in order to describe parameters which are predictive for downstream lesions. Characteristic changes both in amplitude and time parameters were found; the most marked changes being the abolishment of a DC-component for monophasic signatures, the development or the augmentation of early diastolic reverse flow amplitudes together with a highly significant reduction in the signatures' systolic deceleration time. Maximum changes however tended to be localized at 2 to 4 centimeters upstream from the reflection site. Further upstream propagation was limited. Hence the time course of a Doppler signature and particularly its systolic deceleration should be taken into account in addition to the known resistance indices, if downstream lesions shall be predicted from upstream Doppler signatures. The limited upstream propagation of pre-stenotic Doppler signature changes restricts its diagnostic value to vascular segments where the region adjacent to a lesion is routinely scanned; thus diagnostic benefit can be expected for extracranial carotid artery disease but hardly for peripheral (lower limb) lesions.

Unusual cause of intermittent claudication.

Spontaneous dissection of a peripheral artery is a rare event. We report a case of a spontaneous, non-atherosclerotic and non-aneurysmal dissection limited to the external iliac artery in a 60-year-old woman who was admitted with a left calf claudication. Non-invasive examination documented signs of leg ischemia due to a floating wall dissection of the external iliac artery. After medical treatment over eight weeks the dissection membrane had been adapted to the vessel wall. A similar case of a spontaneous dissection limited to the external iliac artery, followed by a spontaneous healing has not been reported in the literature.

Symptomatic vascular complications after vascular closure device use following diagnostic and interventional catheterisation.

BACKGROUND: Haemostatic puncture closure devices for rapid and effective hemostasis after arterial catheterisation are a comfortable alternative to manual compression. Implanting a collagen plug against the vessel wall may become responsible for other kind of vascular injuries i.e. thrombotic or stenotic lesions and peripheral embolisation. The aim of this paper is to report our clinically relevant vascular complications after Angio-Seal and to discuss the results in the light of the current literature. PATIENTS AND METHODS: We report the symptomatic vascular complications in 17 of 7376 patients undergoing diagnostic or therapeutic catheterisation between May 2000 and March 2003 at the University Hospital Basel. RESULTS: Most patients presented with ischaemic symptoms, arterial stenoses or occlusions and thrombotic lesions (n = 14), whereas pseudoaneurysms were extremely rare (n = 3). Most patients with ischaemic lesions underwent vascular surgery and all patients with a pseudoaneurysm were successfully treated by ultrasound-guided compression. CONCLUSIONS: Severe vascular complications after Angio-Seal are rare, consistent with the current literature. There may be a shift from pseudoaneurysms to ischaemic lesions.

[Unilateral swelling of the leg]. / Die einseitige Beinschwellung.

Unilateral swelling of the leg is a common problem in general practice. The spectrum of underlying diseases is broad and does include venous and lymphatic disorders but also less frequent diseases such as Baker cysts and Sudeck's dystrophia. In the majority of cases a diagnosis can be made based on the patients history, the clinical findings and some specific laboratory and/or instrumental investigations. Selected cases however, require the attention of the vascular specialist.

[What does 31 phosphorus magnetic resonance spectroscopy measure?A validation in healthy probands]. / Was leistet die 31Phosphor-Kernspinspektroskopie? Eine Validierung an gesunden Probanden.

With 31P nuclear magnetic resonance spectroscopy skeletal muscle metabolism can be measured noninvasively. Aim of this study was to investigate intraindividual reproducebility, interindividual variability, and the correlation of the NMR parameters PCr, alpha-, beta-, gamma-ATP to graded exercise. Reproducebility and variability of PCr values were comparabel to changes of the pH value. Alpha-, beta-, gamma-ATP did not change during measurements. Correlations between the workload and the changes of the NMR parameters were rare. It was found that the intraindividual reproducebility is low and the interindividual variability is high. No systematic correlation between the NMR parameters and the workload could be seen. The termination of exercise in healthy volunteers is not explained by energy depletion but due to other mechanisms. There is no evidence that 31P NMR spectroscopy presents remarkable advantages for clinical purposes compared to well established diagnostic methods.

The pentoxifylline experience: exercise testing reconsidered.

This paper critically reviews the methodology used in clinical trials in chronic occlusive arterial disease (COAD) stage II (intermittent claudication) patients. The reasons for choosing internationally accepted standard treadmill settings as well as its limitations are discussed. Emphasis is put on the discussion of valid trial endpoints such as hemodynamic surrogates and clinically oriented parameters. Reasons for a spontaneous and treatment-unrelated improvement in claudication distance are elucidated, and variables which may be used for the definition of patient subsamples showing a high frequency of a pronounced treatment response (treatment responder populations) are presented. The magnitude of claudication distance improvement that might be considered clinically relevant is discussed in the light of the European Union guidelines for clinical trials in COAD patients. Results achieved with pentoxifylline are presented in context with all variables mentioned above.

The reliability of leg circumference assessment: a comparison of spring tape measurements and optoelectronic volumetry.

The purpose of this study was to compare the reliability of repeated spring tape measurements with optoelectronic volumeter measurements for the assessment of lower leg circumferences. The limb circumferences at mid-calf and ankle level of both legs were measured three times using a spring tape measure as well as an optoelectronic volumeter. In all, 30 healthy volunteers participated in the study. Test reliability and repeatability were described through the process-related and between-subject variances and variance-derived parameters such as the reliability coefficient (intraclass correlation coefficient, RC), the relative precision (RP), and the coefficient of repeatability (CR). A higher value for the RC and a lower value for the RP indicate that the test variability is predominantly due to between-subject variance and not to test process-related variance. RCs for both methods, independent of whether measurements were taken at calf or at ankle level, always exceeded 0.95. RPs were in the same order of magnitude for both methods but lower for measurements at calf than at ankle level (range: RPcalf 6.36-8.74%; range: RPankle 12.49-18.56%). CRs for both methods were low and of comparable magnitude (CR range: 4.8-7.7), although slightly smaller for the spring tape. When measurement results from the spring tape and the volumeter were compared, results achieved with the volumeter were significantly longer than those from the spring tape (p<0.05). Results from both methods were linearly in good agreement and there was no proportional bias; differences shown were due to a significant constant bias regarding the volumeter. Circumference measurements taken by spring tape and by optoelectronic volumetry are both characterized by a comparably high reliability. However, these methods cannot be used in an interchangeable way because a constant bias exists for volumetry, resulting in significantly larger circumferences compared with those measured using the spring tape.

[Changes in the ultrasound power spectrum due to concentric stenoses of the femoral artery of the dog]. / Veränderungen des Ultraschall Power-Spektrums durch konzentrische Stenosen in der Femoralarterie des Hundes.

An artificial stenosis model consisting of a revolving centric cylinder with six boreholes (10-60% diameter reduction) was implanted in the superficial femoral artery of anaesthezised beagles (n = 10). Range gated pulsed Doppler signals were recorded at 7 sites between three diameters upstream to ten diameters downstream the Angle corrected parameters derived from the contour of spectral lines between 3 and 21dB on both sides of mode frequency were calculated for different time windows. Two groups of dogs could be distinguished. Group A showed marked downstream power spectrum changes which did not correlate to the degree of stenosis. In Group B, in contrast, the degree of power spectral disturbances correlated to the degree of stenosis. It was suggested that partial thrombosis of the stenoses during measurement provides an acceptable explanation for the missing correlation in Group A.