Meta-analysis of randomised controlled prostaglandin E1 studies in peripheral arterial occlusive disease stages III and IV.

BACKGROUND: The relevance of Prostaglandin El (PGE,) in the treatment of peripheral arterial occlusive disease stage III and IV was to be evaluated for the first time by a meta-analysis. PATIENTS AND METHODS: Altogether, 643 patients were analyzed from seven randomized, controlled PGE1 studies that were comparable with regard to patient selection, study design and endpoints. Of these, only placebo-controlled studies (n = 254) were included in the formal meta-analysis using the method of DerSimonian and Laird. Additionally, the response rate and the rate of adverse events were determined for the pooled groups of all studies. RESULTS: At the end of treatment, PGE1 showed a significantly better response (ulcer healing and/or pain reduction) as compared to placebo (47.8% for PGE1, vs. 25.2% for placebo, p = 0.0294). A significant difference in favor of PGE1 was also seen for the combined endpoint "major amputation or death" after 6-month follow-up (22.6% for PGE1 vs. 36.2% for placebo, p = 0.0150). The response rate (ulcer healing and/or pain relief) of the pooled treatment groups was 60.2% for PGE1, 25.2% for placebo, and 53.6% for iloprost. The adverse events rate of the pooled treatment groups showed good tolerability for PGE, with a rate of 39.6% in comparison to 73.9% for iloprost and 15.4% for placebo. CONCLUSION: For patients with peripheral arterial occlusive disease stage III or IV not eligible for arterial reconstruction, PGE1 therapy not only has significant beneficial effects over placebo on ulcer healing and pain relief but also increases the rate of patients surviving with both legs after 6-months follow-up.

[Therapy of venous thromboembolism with low-molecular-weight heparins]. / Therapie venöser Thromboembolien mit niedermolekularen Heparinen.

Low-molecular-weight heparins, nowadays already widely used for the prevention of thromboembolism, have now also become available for the treatment of deep-vein thrombosis. This article should serve to explain the rationale for this development and to demonstrate the clinically relevant advantages of the use of low-molecular-weight heparins. After briefly describing the characteristic properties of heparins the most relevant studies comparing the use of low-molecular-weight heparin versus unfractionated heparin for the treatment of thromboembolism are discussed. In conclusion, clinical trials suggest that low-molecular-weight heparins given subcutaneously can replace the hitherto standard intravenous application of unfractionated heparin in the initial treatment of deep-vein thrombosis, granting equal or even better efficacy and potentially lower rates of adverse side effects. Furthermore, the simplicity of this therapeutic regime allows for treatment of patients at home, thus offering patients mobility and also reducing the cost of treatment.

Randomized reliability study evaluating constant-load and graded-exercise treadmill test for intermittent claudication.

The aim of this randomized study was to compare the reliability of the treadmill test at constant-load (C-test, 3 km/hr; fixed grade of 12%) recommended in Germany with that of the graded-exercise test (G-test, 3 km/hr; increase in grade of 3.5% every 3 minutes) propagated in the United States. In 50 patients with an absolute claudication distance (ACD) in the C-test of between 50 and 400 m, the two treadmill tests were carried out in randomized order on one and the same day, and repeated on 3 days within 1 week. For the initial claudication distance (ICD), the intraclass correlation was 0.88 in the C-test and 0.87 in the G-test. For the ACD the coefficients were identical at 0.91. The within-subject variation (CVwithin) in the C-test and G-test was 25% and 27% for the ICD and for the ACD 24% and 21%, respectively. The between-subject variation was very similar with 72% and 73% (ICD) and with 78% and 68% (ACD). However, in ACDs below 100 m and between 100 to 150 m, the C-test showed significantly smaller coefficients of variation than the G-test: 13% vs 81% and 14% vs 50%, respectively. In conclusion, the results showed that both C-test and G-test are equally well reproducible.

Standardization of carotid ultrasound: a hemodynamic method to normalize for interindividual and interequipment variability.

BACKGROUND AND PURPOSE: Accurate carotid Doppler examination is an important issue in the light of large endarterectomy trials, but recommended cutoff values for detection of >70% stenosis vary widely. Standardization of diagnostic criteria should consider patient variation and instrument variability. METHODS: We prospectively analyzed various Doppler parameters in 44 patients undergoing carotid angiography to evaluate whether normalization through individual reference measurements from the common carotid artery or the distal internal carotid artery could improve accuracy. For assessment of interindividual and interequipment variability, we performed repeated measurements of 40 carotid arteries in 21 patients. Two color-coded duplex ultrasound systems were compared for machine variability estimation: Hewlett Packard SONOS 2500 and ATL Ultramark 9 HDI. RESULTS: Intrastenotic divided by distally recorded mean blood flow velocity (mean velocity ratio) showed the closest correlation with angiography: R2=0.93. Mean velocity ratio >5 was 97% sensitive and 98% specific for detection of >70% carotid stenosis. Intrastenotic blood flow velocities were significantly different between the 2 duplex systems (0.22+/-0.16 versus 0.17+/-0. 11 m/s; P<0.001), whereas mean velocity ratio values did not differ significantly. Interobserver variation expressed as 95% CI for predicted stenosis between 2 observers was 13.6% (peak systolic velocity) and 15.4% (mean velocity ratio). CONCLUSIONS: A mean velocity ratio using distal reference measurement in the internal carotid artery can normalize for interindividual and interequipment variability.

Restoring vascular nitric oxide formation by L-arginine improves the symptoms of intermittent claudication in patients with peripheral arterial occlusive disease.

BACKGROUND: Administration of L-arginine improves nitric oxide (NO) formation and endothelium-dependent vasodilation in atherosclerotic patients. OBJECTIVES: We investigated in this double-blind, controlled study whether prolonged intermittent infusion therapy with L-arginine improves the clinical symptoms of patients with intermittent claudication, as compared with the endothelium-independent vasodilator prostaglandin E1, and control patients. METHODS: Thirty-nine patients with intermittent claudication were randomly assigned to receive 2 x 8 g L-arginine/day, or 2 x 40 microg prostaglandin E1 (PGE1)/day or no hemodynamically active treatment, for 3 weeks. The pain-free and absolute walking distances were assessed on a walking treadmill at 3 km/h, 12% slope, and NO-mediated, flow-induced vasodilation of the femoral artery was assessed by ultrasonography at baseline, at 1, 2 and 3 weeks of therapy and 6 weeks after the end of treatment. Urinary nitrate and cyclic guanosine-3', 5'-monophosphate (GMP) were assessed as indices of endogenous NO production. RESULTS: L-Arginine improved the pain-free walking distance by 230+/-63% and the absolute walking distance by 155+/-48% (each p < 0.05). Prostaglandin E1 improved both parameters by 209+/-63% and 144+/-28%, respectively (each p < 0.05), whereas control patients experienced no significant change. L-Arginine therapy also improved endothelium-dependent vasodilation in the femoral artery, whereas PGE1 had no such effect. There was a significant linear correlation between the L-arginine/asymmetric dimethylarginine (ADMA) ratio and the pain-free walking distance at baseline (r=0.359, p < 0.03). L-Arginine treatment elevated the plasma L-arginine/ADMA ratio and increased urinary nitrate and cyclic GMP excretion rates, indicating normalized endogenous NO formation. Prostaglandin E1 therapy had no significant effect on any of these parameters. Symptom scores assessed on a visual analog scale increased from 3.51+/-0.18 to 83+/-0.4 (L-arginine) and 7.0+/-0.5 (PGE1; each p < 0.05), but did not significantly change in the control group (4.3+/-0.4). CONCLUSIONS: Restoring NO formation and endothelium-dependent vasodilation by L-arginine improves the clinical symptoms of intermittent claudication in patients with peripheral arterial occlusive disease.

Intra-arterial and intravenous administration of prostaglandin E1 cause different changes to skin microcirculation in patients with peripheral arterial occlusive disease.

BACKGROUND: Disturbed skin microcirculation in patients with peripheral arterial occlusive disease (PAOD) might be affected by prostaglandin E1 (PGE1). The purpose of this study was to investigate local skin perfusion at the forefoot and toe of PAOD patients during different modes of administration of PGE1. PATIENTS AND METHODS: In 17 patients with severe PAOD local intradermal haemoglobin oxygen saturation (SHB) and dermal vascular reserve capacity, transcutaneous oxygen pressure (tcPO2) and laser Doppler flux (LDF) were determined during intra-arterial (1.5 ng/kg body weight/min) and intravenous (6 ng/kg body weight/min) infusion of PGE1. RESULTS: SHB significantly increased at both locations during intravenous PGE1; intra-arterial administration significantly increased SHB in the skin of the forefoot only. Reserve capacity increased during intravenous administration and was markedly reduced during intra-arterial infusion. No significant changes were found regarding tcPO2 and LDF. CONCLUSIONS: These data suggest different therapeutic mechanisms for intra-arterial and intravenous administered of PGE1.

Prostaglandin E1 in peripheral vascular disease: a PET study of muscular blood flow.

BACKGROUND: Increase of blood flow in the ischaemic leg is believed to represent the main action of prostaglandin E1 (PGE1) in the therapy of peripheral vascular disease (PVD). There is no reliable data in man concerning the amount of increase in muscular blood flow (MBF) of the calf, and the difference between intra-arterial and intravenous application. PATIENTS AND METHODS: We conducted a positron emission tomography (PET) study of MBF with 15O-water as flow tracer. Fifteen patients with PVD and three healthy volunteers were given 5 micrograms PGE1 intra-arterially over 50 min; PET scans were taken at 0, 25 and 50 min. Additionally, eight of the patients were investigated during an intravenous infusion of 40 micrograms PGE1 over 120 min; PET scans were taken at 0, 30, 60 and 120 min. RESULTS: Increase of muscular blood flow by intra-arterial PGE1 averaged 80%. A steal phenomenon was not observed. The amount of flow enhancement depended on whether or not the femoral artery was patent. During intravenous PGE1, muscular blood flow remained unchanged. CONCLUSIONS: In man, the pharmacodynamic profile of intra-arterial PGE1 differs clearly from intravenous PGE1. The flow-enhancing property is lost during metabolization in the lung. Since no difference exists between the therapeutic efficacy of intraarterial and intravenous PGE1, the impact on muscular blood flow is not as important as suggested previously.

Treadmill testing for evaluation of claudication: comparison of constant-load and graded-exercise tests.

OBJECTIVES: To compare the correlation and practicability of single-stage vs. graded treadmill protocols in the assessment of the absolute claudication distance (ACD). DESIGN: Randomized open study. MATERIAL AND METHODS: In 52 patients with peripheral arterial occlusive disease, the ACD on treadmill at 3 km/h and 12% grade (constant-load test = C-test) ranged form 50 to 400 m. The C-test and the graded-exercise test (walking on the treadmill at 3 km/h and 0% gradient for 3 min, with subsequent increase in gradient of 3.5% every 3 min = G-test) were carried out at random on the same day under standardized conditions. RESULTS: The ACD was higher in the G-test than in the C-test (360.4 +/- 208.8m vs. 166.5 +/- 93.6m; p < 0.001). The coefficients of variation were very similar (57.9% and 56.2%, respectively). In the subgroup of patients with an ACD of between 100 m and 150 m, a large difference was found both for the coefficient of variation (58.6% G-test, 9.6% C-test) and for the standard deviation (339.8 +/- 199.0m and 133.1 +/- 12.8m, respectively). CONCLUSIONS: For the assessment of the ACD in patients with severe claudication the C-test would seem to be more suitable than the G-test.

Circadian variation of skin perfusion in arterial occlusive disease.

BACKGROUND: Many physiological processes are subjected to circadian variation. We tested if circadian changes of skin perfusion can be detected by measuring laser Doppler flux (LDF) in the foot and if such variations are different in patients with peripheral arterial occlusive disease (PAOD). PATIENTS AND METHODS: LDF was recorded hourly during a 24-hour period in 10 healthy subjects and in 19 PAOD patients, 9 presenting with claudication (stage II according to Fontaine, ankle artery pressures (AP) 80 +/- 11 mmHg) and 10 with skin necrosis (stage IV, AP 42 +/- 29 mmHg). RESULTS: Circadian variability of LDF was significantly reduced in stage IV patients compared both with stage II patients and controls (p < 0.01). An increase in LDF could be observed early in the afternoon and, more pronounced, during the night, occurring to the same extent in healthy and PAOD patients in stage II (p < 0.001). In stage IV the increase in LDF was not significant and a decrease was observed in two patients. LDF and local skin temperature were correlated in controls and stage II patients (mean r = 0.69 +/- 0.12 and 0.7 +/- 0.14, respectively), but not in stage IV (mean r = 0.23 +/- 0.18). A further limitation of LDF variability and nocturnal increase was seen in the presence of diabetes. CONCLUSION: Circadian variations of skin blood flow are comparable in controls and patients with claudication but markedly reduced in patients with severe PAOD presenting with ulcers, in whom skin perfusion seems uncoupled from temperature regulation, possibly due to local factors causing continuous arteriolar vasodilation.

Changes of dermal haemoglobin oxygenation and concentration in healthy subjects and in patients with peripheral arterial occlusive disease during and after acute ischemia.

BACKGROUND: Oxygen saturation (SHB) and concentration (CHB) of dermal haemoglobin play an important role in the nutrition of the skin. In patients with severe peripheral arterial occlusive disease (PAOD) they are reduced at the forefoot. We investigated the changes of the named parameters during an acute ischemia and during reactive hyperemia using an occlusion test. PATIENTS AND METHODS: Dermal reflection spectra were conducted from the forefoot of 11 healthy subjects and 39 patients with peripheral arterial occlusive disease of various stages at rest, during, and after an arterial occlusion at the thigh. Using a multicomponent analysis SHB and CHB were calculated iteratively. The halftime of the post-occlusive increase of SHB (post-occlusive recovery halftime PORHT) and the relation of post- to pre-occlusive CHB (post-occlusive reactive hyperemia PORH) were calculated to estimate the dynamic of the post-occlusive inflow of blood. TcPO2 (37 degrees C) was additionally determined at the forefoot. RESULTS: In patients from stage III and IV all resting values were lower compared to controls. TcPO2 decreased in all persons to 0 mm Hg during the occlusion, SHB was between 0 and 10%, while CHB remained unchanged. In healthy subjects and in patients with claudication the post-occlusive values exceeded the preocclusive ones, while in some patients with higher stages of the disease this could not be found. There was a marked, on the stage of the disease depending difference in the post-occlusive course between controls and patients: in healthy subjects it took only 5.5 +/- 4.8 s until SHB reached half of the maximum value, in patients from the stage IIa group 26.8 +/- 16.9 s (p < 0.001) was measured while in stage III and IV the value was 132 +/- 75 s (p < 0.001). CONCLUSIONS: During ischemia a decrease of the haemoglobin oxygen saturation (SHB) and tcPO2 was found. Haemoglobin concentration (CHB) remained constant, hence a significant shift of blood from skin to muscle did not take place. PORHT was selectively dependent on the stage of the disease. The occlusion manoeuvre enhances the significance of reflection photometry in PAOD.

Nailfold capillaroscopy and laser Doppler fluxmetry for evaluation of Raynaud's phenomenon: how valid is the local cooling test?

BACKGROUND: Since there is a need for an objective parameter of microcirculation in follow-up of patients with Raynaud's syndrome we evaluated the reproducibility of the reaction to a cold exposure test with nailfold capillaroscopy and laser Doppler fluxmetry during a winter period. PATIENTS AND METHODS: 10 healthy subjects and 16 patients with primary Raynaud's syndrome were evaluated with nailfold capillaroscopy and laser Doppler fluxmetry of the finger tips during and after a standardized cold exposure stress test. The measurements were repeated in the controls within 2 weeks, in the patient population twice within 24 weeks. RESULTS: In the healthy controls the percentage of capillaries with flow stop was stable (r = 0.785) and the duration of flow stop was reproducible (r = 0.993). Both parameters were significantly lower in controls than in the patients. The flow stop durations in patients varied intra-individually to a great extent between the different weeks without any significant correlation. For all calculated laser Doppler perfusion and time parameters we did not find any significant differences between controls and patients nor any consistent correlations in the intra-individual comparison within the different weeks for both, controls and patients. CONCLUSION: Nailfold capillaroscopy during cold exposure is able to discriminate between healthy persons and patients with primary Raynaud's syndrome, but seems to be of minor value for follow-up evaluation of patients because of intraindividual variations. Laser Doppler fluxmetry is invalid for both purposes when using the applied cold exposure test.

[Cellular mechanisms of endothelial endothelin synthesis]. / Zelluläre Mechanismen der endothelialen Endothelinsynthese.

Endothelin-1 is a vasoactive peptide produced by endothelial cells. Endothelin-1 exerts potent vasoconstrictory effects upon vascular smooth muscle cells, and it may play a role in the pathogenesis of several cardiovascular disorders such as atherosclerosis and ischemic conditions. Besides the investigation of its biological effects, knowledge about cellular mechanisms of the synthesis, signal transduction pathway(s) and receptor-mediated actions on target cells is mandatory for the development of pharmacological strategies in the treatment of cardiovascular disease. In this review cellular mechanisms of endothelial endothelin-1 synthesis and release are discussed.

[Physiology and pathophysiology of the endothelin system in cardiovascular diseases]. / Zur Physiologie und Pathophysiologie des Endothelin-Systems bei kardiovaskulären Erkrankungen.

The endothelins are a family of potent vasoconstrictors and mitogenic agents. Since the isolation of ET-1 in 1988 the worldwide scientific research interest has mushroomed, resulting in considerable knowledge about molecular biology, biochemistry and pharmacological actions of these peptides. A body of evidence has parallelly emerged pointing to their role in some physiological phenomena as well as in the pathophysiology of cardiovascular disease. The future therapeutic use of anti-endothelin strategies may offer clinical benefit in many of these conditions.

Vital capillary microscopy of skin areas at the forefoot of diabetic patients using intraarterial injection of Na-fluorescein.

A modified technique of vital capillary microscopy with intraarterial application of Na-fluorescein has been introduced in the study of nutritional skin microcirculation to assess skin microcirculation of different diabetic patients, comprising one group without neurocutaneous complications (group 2; n = 9), one suffering only from neuropathy (group 3; n = 9) and one with trophic skin lesions in the contralateral foot (group 4; n = 8), all without macroangiopathy, compared to healthy controls (group 1; n = 9). Femoroarterial injection of small boli (10 mg) of Na-fluorescein allowed repeated investigation of the dye appearance times (AT) and capillary-filling times of forefoot skin capillaries within small periods of time before, during and after reactive hyperemia. At rest, AT was significantly shorter in patients of group 4 (16.8 +/- 4.4 s; p < 0.05) compared with groups 1-3 (34.3 +/- 12.8; 31.7 +/- 11.7 and 35.9 +/- 15.3 s). Fifteen seconds after the end of arterial occlusion, dye propagation to the skin was markedly accelerated in groups 1-3 (19.8 +/- 14.0; 14.4 +/- 7.6 and 18.7 +/- 10.6 s, respectively; p < 0.001), but prolonged in group 4 (18.4 +/- 7.4 s). After 10 min, the values at rest were reestablished. No differences between the four groups were found concerning capillary density and morphology. It is concluded that the development of skin lesions in diabetic patients without significant macroangiopathy may be favored by hyperperfusion and impaired vasoregulation. Intraarterial dye injection presents a valuable tool to assess dynamic alterations of the microcirculation at the level of skin capillaries.

Improvement in the quality of life after i.v. PGE1 therapy for intermittent claudication.

BACKGROUND: Increasingly and justifiably, clinical studies are now being expected to investigate the influence of therapeutic measures also on the quality of life of the patient. PATIENTS AND METHODS: Since no data on the variability of changes in the quality of life of the patient following PGE1 treatment are so far available, the initial investigation was designed as an uncontrolled pilot study. 104 patients (median age 64.5 years) with a maximum of walking distance on the treadmill (3 km/12%) of 50-250 m were included and given a daily intravenous infusion of 60 micrograms PGE1 (Prostavasin) over a period of 4 weeks excluding weekends. This was followed by a treatment-free follow-up period of 3 months. Changes in the quality of life were recorded with both the newly developed disease-specific questionnaire PAVK-86, and the generic questionnaire SF 36; in addition, the pain-free and maximum walking distances on the treadmill were also established prior to and immediately following treatment, as also at the end of the follow-up period. RESULTS: The quality of life was significantly improved in all dimensions (functional status, complaints, pain, mood, anxiety, social life, treatment expectations) in addition to a marked increase in the median pain-free walking distance from 77 to 108 m (p < 0.001) and the maximum walking distance from 118 to 171 m (p < 0.001). At the end of the 3-month observation period, the improvement was essentially still demonstrable. CONCLUSION: The study has shown for the first time that treatment with intravenous PGE1 brings about not only the already known increase in the walking distance, but also a clinically relevant and significant improvement in the patient's quality of life.