Efficacy and Safety of Alprostadil in Patients with Peripheral Arterial Occlusive Disease Fontaine Stage IV: Results of a Placebo Controlled Randomised Multicentre Trial (ESPECIAL).

OBJECTIVES: The aim was to assess the efficacy and safety of alprostadil in patients with peripheral arterial occlusive disease (PAOD) Fontaine Stage IV. METHODS: This was a multinational, prospective, randomised, double blind, placebo controlled, parallel group trial. Patients with Stage IV PAOD were equally randomised to either 4 weeks of alprostadil treatment twice daily or to placebo treatment twice daily. The primary efficacy variables were the rate of complete healing of all necrosis and ulceration 12 weeks after the end of treatment and the frequency of major amputations 24 weeks after the end of treatment. RESULTS: A total of 840 patients were randomised between 2004 and 2013. At baseline, no major differences between treatment groups were found. The rate of "complete healing" was 18.4% in patients on alprostadil and 17.2% in patients on placebo. The rates of "major amputations" were 12.6% in patients on alprostadil and 14.6% in patients on placebo. The adjusted difference between alprostadil and placebo including their 95% confidence intervals was 1.1 (-4.0 to 6.3) for "complete healing" and -2.1 (-6.7 to 2.5) for "major amputations." In the subgroup of diabetic patients the rates of major amputations were numerically lower in the alprostadil than placebo group (10.6% vs. 17.4%). Within the total cohort a non-significant difference in "decrease in ulcer area ≥50%" was reached in 30.2% of patients on alprostadil and in 24.3% of patients on placebo at end of treatment. CONCLUSIONS: In this study, superiority of alprostadil over placebo could not be shown. Nevertheless, a slight numerical but not clinically relevant advantage for alprostadil emerged from the "area decrease of ulcers by ≥ 50%," indicating that a healing effect may have started. The results have to be considered in the light of several limitations in study design and conduct.

Treatment of chronic wounds.

Treatment of underlying diseases is of paramount importance due to the complex genesis of chronic wounds. This should be followed by a stage-adapted wound treatment, which usually consists of a phase-adapted wound debridement, ensued by a moist wound treatment. In case of epithelialization, a phase-specific shift to dry wound treatment should be performed. Despite the growing number of new wound dressings and therapeutics, current scientific data is incomplete, and evidence for the effectiveness of these wound dressings is only sparse. No significant advantage of one wound dressing over the other exists. The status of negative pressure treatment is still controversial, and no clear evidence is present. In order to achieve a permanent treatment success, causal therapy of venous obstructions and/or arterial disorders is of importance. Systematic and consistent compression therapy is of utmost significance when treating venous wounds.

[S3 guidelines for diagnostics and treatment of peripheral arterial occlusive disease]. / S3-Leitlinien zur Diagnostik und Therapie der peripheren arteriellen Verschlusskrankheit.

This report summarizes the most important aspects of the new German S3 guidelines for the diagnostics and treatment of peripheral arterial occlusive disease (PAOD) from March 2009. The guidelines include definitions and epidemiology of peripheral arterial occlusive disease, diagnostic methods including clinical and technical procedures as well as imaging methods, treatment by non-invasive, interventional and surgical methods and patient care during follow-up. In key messages recommendations are given which are graded corresponding to the scientific evidence concluded from the literature.

[Anticoagulation in the elderly]. / Antikoagulation im Alter.

The recommendations for anticoagulation in over 80 years old patients are based on the thromboembolic/bleeding risk relation. They add to the published recommendations for the specific indications. Low-molecular-weight heparin (LMWH) is used to prevent thromboembolism postoperatively. Compression stockings and/or intermittent pneumatic compression are used if bleeding risk is very high. The dose is increased starting at day two if the thromboembolic risk is very high. Bleeding and thromboembolic risks are re-evaluted daily. The antithrombotic therapy is adjusted accordingly. Prophylaxis of thromboembolism in patients with acute illnesses and bedrest is performed according postoperative care. Two-thirds of therapeutic doses of low-molecular-weight heparin are used to treat acute venous thromboembolism. Reduced renal function (creatinine clearance <30 ml/ min for most LMWHs or <20 ml/min for tinzaparin) should result in a further reduction of dose. Intensity and duration of prophylaxis of recurrent events with vitamin K antagonist or LMWH in malignancy follow current or herein described recommendations. Patients with atrial fibrillation are treated with vitamin K antagonists adjusted to an INR of 2-3 for prophylaxis of embolism. Further details of anticoagulant therapy should be in agreement with the national or international recommendations.

Oscillometric measurement of ankle-brachial index in patients with suspected peripheral disease: comparison with Doppler method.

QUESTION UNDER STUDY: Purpose was to validate accuracy and reliability of automated oscillometric ankle-brachial (ABI) measurement prospectively against the current gold standard of Doppler-assisted ABI determination. METHODS: Oscillometric ABI was measured in 50 consecutive patients with peripheral arterial disease (n = 100 limbs, mean age 65 +/- 6 years, 31 men, 19 diabetics) after both high and low ABI had been determined conventionally by Doppler under standardised conditions. Correlation was assessed by linear regression and Pearson product moment correlation. Degree of inter-modality agreement was quantified by use of Bland and Altman method. RESULTS: Oscillometry was performed significantly faster than Doppler-assisted ABI (3.9 +/- 1.3 vs 11.4 +/- 3.8 minutes, P <0.001). Mean readings were 0.62 +/- 0.25, 0.70 +/- 0.22 and 0.63 +/- 0.39 for low, high and oscillometric ABI, respectively. Correlation between oscillometry and Doppler ABI was good overall (r = 0.76 for both low and high ABI) and excellent in oligo-symptomatic, non-diabetic patients (r = 0.81; 0.07 +/- 0.23); it was, however, limited in diabetic patients and in patients with critical limb ischaemia. In general, oscillometric ABI readings were slightly higher (+0.06), but linear regression analysis showed that correlation was sustained over the whole range of measurements. CONCLUSIONS: Results of automated oscillometric ABI determination correlated well with Doppler-assisted measurements and could be obtained in shorter time. Agreement was particularly high in oligo-symptomatic non-diabetic patients.

[Diabetic foot syndrome from the perspective of angiology and diabetology]. / Das diabetische Fusssyndrom aus angiologisch-diabetologischer Sicht.

The diabetic foot syndrome (DFS) is one of the most significant complications of diabetes mellitus and frequently leads to amputation of the affected extremity. Cardiovascular mortality and morbidity of affected patients are still high and healed ulcers often recur. The pathogenesis of DFS is complex, clinical presentation is variable and management requires early expert assessment. Interventions should be directed towards infection, peripheral ischemia and pressure relief caused by peripheral neuropathy and limited joint mobility. Treatment includes wound clean-up, stage-oriented local wound management and the appropriate treatment of bacterial infection. Useful preventive measures are blood glucose control training of diabetics, regular foot care and the provision of appropriate footwear.

[Diabetic foot syndrome]. / Diabetisches Fusssyndrom.

Ulceration of the foot in diabetes is common and disabling and frequently leads to lower extremity amputation. Mortality and morbidity is still high and healed ulcers often recur. The pathogenesis of diabetic foot syndrome is complex, clinical presentation variable and management requires early expert assessment. Interventions should be directed at infection, peripheral ischemia and pressure relief caused by peripheral neuropathy and limited joint mobility. Treatment includes wound clean-up, stage-oriented local wound management, and the appropriate treatment of bacterial infection. Useful preventive measures are training of diabetics, regular foot care and the provision of appropriate footwear.

Design and rationale of a randomized, double-blind, placebo-controlled phase III study for autologous bone marrow cell transplantation in critical limb ischemia: the BONe Marrow Outcomes Trial in Critical Limb Ischemia (BONMOT-CLI).

BACKGROUND: Critical limb ischemia (CLI) is the end-stage of peripheral artery disease. Only about two thirds of patients with CLI can be revascularised, one third progresses to leg amputation with high associated morbidity and mortality. Therapeutic angiogenesis with bone marrow cells has shown promising improvement in less severe stages of peripheral ischemia. Our study evaluates the therapeutic value of bone marrow cell induced angiogenesis and arteriogenesis in severe, limb-threatening ischemia. PATIENTS AND METHODS: the BONe Marrow Outcome Trial in Critical Limb Ischemia (BONMOT-CLI) is a investigator-initiated, double-blinded, 1:1 randomized, placebo-controlled multi-centre study at 4 sites in Germany. Only patients with no option for revascularisation or after failed revascularisation will be included. A total of 90 patients is to be included. One arm with 45 subjects will be treated with a concentrate of autologous bone marrow cells which will be injected at 40 sites into the ischemic limb. In the placebo arm, study subjects will undergo a sham bone marrow punction and 40 saline injections. At three months, a combined primary endpoint of major amputation or persisting critical limb ischemia (no clinical or perfusion improvement) will be evaluated. Secondary endpoints are death, changes in perfusion, quality of life, walking distance, minor amputations, wound healing, collateral density and cancer incidence. Post-study follow-up is up to two years. CONCLUSIONS: The results of this first randomized placebo-controlled trial for autologous bone marrow cell therapy in CLI will clarify the value of this new therapeutic modality in a patient population with no other alternatives except major amputation.

[Gene therapy and stem cell transplantation in PAD]. / Gen- und autologe Stammzelltherapie bei pAVK mit chronischer Extremitätenischämie. Aktueller Stand.

Therapeutic angiogenesis is a novel promising strategy that uses angiogenic factors and stem cell transplantation to increase blood perfusion in ischaemic lower limbs. In preliminary studies short term safety and feasibility of gene therapy by recombinant protein administration or gene transfer were proven. Early reports mostly fail to show an convincing efficacy. In the largest placebo-controlled study of therapeutic angiogenesis in severe PAD reported to date, the plasmid-based fibroblast growth factor was safe and significantly reduced amputation rates. The data suggest the efficacy of the angiogenic therapy and provide the basis for further larger trials to confirm these first results.

[The diabetic foot]. / Prophylaxe und Therapie beim diabetischen Fusssyndrom.

As a means of achieving a reduction in the amputation rate in patients with a diabetic foot syndrome, the early diagnosis and specialized treatment of peripheral circulatory disorders is of eminent importance. Treatment includes pressure relief, wound cleanup and stage-oriented local wound management, measures to improve circulation, and the appropriate treatment of bacterial infection. Useful preventive measures include the training of diabetics, regular foot care, and the provision of appropriate footwear.

Does calculation of ankle brachial pressure index need revision?

Peripheral arterial disease (PAD) is a commonly encountered but a commonly under-diagnosed condition in clinical practice. Ankle brachial pressure index (ABI) is a widely used procedure in its detection. It is also a very good prognostic marker not only of PAD but also of mortality. According to the current guidelines ABI of a side i.e. either the left or the right, is the quotient of the higher of the systolic blood pressures (SBP) of the two ankle arteries of that limb (either the anterior tibial artery or the posterior tibial artery) and the higher of the two brachial SBP of upper limbs. With the currently existing method of ABI calculation, considering only the higher of the SBP of the two ankle arteries, a distal stenosis of the ankle arterial system with the lower SBP, may be missed. We suggest a modification to the currently existing of calculating ABI. The method has been termed by us as the low ankle pressure method. In this method the lowest ankle pressure between the two ankle arteries of a particular side is to be the numerator and the denominator could be the same as before. A study or a series of studies comparing our proposed method with the current one are needed to test its clinical utility.

Correlation between rheological parameters and erythrocyte velocity in nailfold capillaries in patients with diabetes mellitus.

Increased rheological parameters and disturbances of capillary perfusion are often observed in both types of diabetes. It is assumed that these alterations might be involved in the development and progression of diabetic microangiopathy. It has been shown elsewhere, that erythrocyte rigidity, erythrocyte and platelet aggregation, plasma viscosity and leucocyte adhesion are increased. By methods of microcirculation capillary perfusion can be investigated and in vivo no significant alterations can be found at rest. During reactive hyperemia flow reduction diminishes capillary perfusion in various organs. In this presentation hemorheological parameters and erythrocyte velocity in nailfold capillaries are investigated in both types of diabetes under various conditions. Plasma viscosity and spontaneous platelet aggregation are often increased, especially in patients with diabetes type 2 and in diabetic foot lesions. Improvement of the metabolic situation by insulin application reduces the elevated parameters and improves capillary perfusion. Long-term type 1 diabetics tend to show increased rheological factors and reduced capillary perfusion. Although an association between some hemorheological parameters and capillary perfusion seems to exist, a strong correlation cannot be found.

Epidemiology of peripheral arterial disease.

Peripheral arterial disease (PAD) is not an uncommon but a commonly neglected condition by many medical practitioners. It is a disease that threatens not only the limb but also life itself! Atherosclerosis is the commonest cause of PAD in the western nations. The cardinal symptom is intermittent claudication (IC) but majority of the patients are asymptomatic. Ankle-brachial pressure index (ABI) is an effective screening tool for PAD. A diminished ABI (< 0.9) is a definite sign of PAD. Its prevalence steadily increases with age. In Germany almost a fifth of the patients aged over 65 years suffer from it. With increasing life expectancy the prevalence of PAD is on the increase. PAD is a manifestation of diffuse and severe atherosclerosis. It is a strong marker of cardiovascular disease; a very strong association exists between PAD and other atherosclerotic disorders such as coronary artery disease (CAD) and cerebrovascular disease (CVD). PAD is an independent predictor of high mortality in patients with CAD. Smoking, diabetes mellitus and advancing age are the cardinal risk factors. A relatively small number of PAD patients lose limbs by amputation. Most paitients with PAD die of either heart attacks or strokes and they die of the former conditions far earlier than controls. PAD still remains an esoteric disease and there is a significant lack of awareness of this condition by many physicians, and therefore under-diagnosed and underestimated. Measures to promote awareness of PAD among physicians and the society in general are needed. Since most patients are asymptomatic and carry potentially significant morbidity and mortality risks, screening for PAD should be made a routine practice at primary care level.

The role of microcirculatory techniques in patients with diabetic foot syndrome.

BACKGROUND: Diabetic foot syndrome (DFS) is a frequent complication of long-standing diabetes mellitus, occurring in 10 to 30 percent of all diabetics with a vital risk for the affected limb and high mortality rates. Macroangiopathy, diabetic polyneuropathy and infections are trigger factors for DFS. Recent results imply a pathogenic role of functional and structural microcirculatory changes. The exact role of microangiopathy and the value of microcirculatory diagnostic methods in DFS have not yet been defined. PATIENTS AND METHODS: 78 patients with DFS (28 type I, 50 type II diabetics, mean age 63 years) were evaluated with video capillary microscopy, transcutaneous partial oxygen tension (tcpO2) measurement and laser Doppler fluxmetry (LDF) at the forefoot of the affected leg at admission and after revascularisation. Mean hospital stay was 28 +/- 11.7 days. Patients were stratified according to the etiology of DFS in patients with neuropathic lesions, macroangiopathic ulcers and mixed neuropathic-angiopathic lesions. RESULTS: All groups had impaired microcirculation, and significant differences between groups were found in respect to capillary density. Reactive hyperemia, LDF pattern and tcpO2 did not differ significantly. Microcirculatory examinations did not yield additional information to clinical and Doppler sonographic results. CONCLUSION: In clinical practice, the role of microcirculation evaluation techniques for diabetic foot syndrome is limited.

Comparison of haemostatic parameters in arterial and venous blood from patients with peripheral arterial occlusive disease.

BACKGROUND: Several studies proved the co-existence of peripheral arterial occlusive disease (PAOD) and hypercoagulability. However, in practice coagulation parameters are mainly determined from venous blood samples. In this study several coagulation parameters in arterial and venous blood were examined for differences and the validity of coagulation parameters determined in venous blood was investigated. PATIENTS AND METHODS: In 22 patients with peripheral artery disease venous and arterial blood samples from vessels of the diseased leg were examined for the concentration of thrombine-antithrombine III-complex (TAT), prothrombin fragments (F1 and F2) and D-dimers, and results were compared. RESULTS: Mean concentrations of TATs and prothrombin fragments F1 and F2 were significantly higher in arterial than in venous blood. TAT-complex was the most sensitive parameter for quantification of thrombin generation. D-dimer levels did not differ in arterial and venous blood. TAT and F1 and F2 concentrations in arterial and venous blood did not correlate in individual patients whereas D-dimer concentration did. CONCLUSION: The determination of TAT and F1 + F2 in venous blood does not adequately reflect the degree of the local coagulation activation in the arterial system. As indicators for hypercoagulability, D-Dimer values are less sensitive than F1 + 2, but venous D-dimer concentrations mirror arterial levels.

[Standardization of nailfold capillary microscopy in routine diagnosis]. / Standardisierung der Nagelfalz-Kapillarmikroskopie in der Routinediagnostik.

BACKGROUND: Nailfold capillary microscopy is scientifically established and recognized as a diagnostic tool in clinical routine. It is, however, practiced in only a few centres. METHODS: But since a more widespread use of the method is to be expected for the near future, a consensus-meeting was held, where all German-speaking clinicians and scientists, involved in capillary microscopy, were invited. Here, the technical procedure and the most important morphological parameters were evaluated and defined according to practical clinical aspects. RESULTS AND CONCLUSION: The main task of the consensus-meeting was to develop a standard evaluation sheet, accompanied by an explanation sheet. This standard evaluation sheet focuses on semiquantitative registration of morphological parameters like density, dilation, avascular fields, perivascular edema, microbleeding, torsion, atypical capillaries and giant capillaries. This standard evaluation sheet is to be validated by determining the inter-observer-variance. Later-on an illustrated practical guideline will be published.

[DRG-based cost analysis of inpatient conservative treatment of stage III/IV peripheral arterial occlusive disease]. / DRG-basierte Kostenanalyse zur stationären konservativen Behandlung der PAVK Stadium III/IV.

UNLABELLED: DRG-based cost analysis of inpatient conservative treatment of PAD stage III/IV BACKGROUND: In a prospective study carried out by the German Society of Angiology and the DRG Competence Center, Munich, the question was investigated whether the costs of conservative treatment of patients with PAOD stage III/IV (DRG F65) are adequately represented within the current G-DRG system. METHODS UND PATIENTS: Between September 1 and December 16, 2002, a total of 704 patients with DRG F65 (peripheral vascular diseases) were evaluated at 8 angiologic centers in Germany. Apart from the length of hospital stay, the total costs (cost equivalents) were calculated using a method developed by the DRG Research Group at the University of Münster. Moreover, the study population was compared with a German calculation sample for the DRGs F65A/B, as published by InEK. RESULTS: As it turned out, conservatively treated patients with PAOD stage III or IV (DRGs F65A/B) cause significantly (p < 0.001) higher costs and have significantly (p < 0.001) greater lengths of hospital stay than patients who were also assigned to DRG F65 because of other vascular diseases. At the same time it became clear that angiologic centers treat twice as many patients with critical limb ischemia in comparison with the German average. The reimbursement hitherto estimated by InEK covers not even half the cost actually produced by conservative treatment of PAD stage III/IV. CONCLUSION: To ensure a performance-related reimbursement, a new basis DRG for patients with PAD stage III/IV has to be created, as has ben proposed by the German Society of Angiology. Otherwise, adequate conservative therapy in accordance with existing guidelines, of patients who cannot be treated surgically or interventionally will not be possible any more in the future.

[Deep venous thrombosis of the leg. Will it be acute ambulatory therapy in the future?]. / Tiefe Beinvenenthrombose. Akuttherapie in Zukunft ambulant?

Early diagnosis and treatment of deep venous thrombosis (DVT) in the leg is of decisive importance, in particular in view of the potentially life-threatening complication of pulmonary embolism. The establishment of the diagnosis if often difficult since in the early stage symptoms may be non-existent or few (50%). The most important therapeutic measure is compression. Acute medication is initiated within the first 24 hours with unfractionated conventional heparin administered as a continuous i.v. infusion or intermittent s.c. injections. An initial bolus injection is followed by continuous infusion of 30,000-40,000 units of heparin. More recent data show that low-molecular-weight heparins are as effective as conventional heparin and are easier to apply, making acute treatment on an ambulatory basis feasible. Conversion to anticoagulation treatment is effected with gradually increasing doses, and must overlap heparin for at least 4-5 days. The duration of treatment is determined by the nature of the thrombosis, with recommendations ranging from 3 to 12 months. A shortened in-hospital treatment with early mobilization is considered to be of benefit to the patient.

[Characteristics of diagnosis of peripheral arterial occlusive disease in diabetic patients. This pitfall should be avoided]. / Besonderheiten der pAVK-Diagnostik bei Diabetikern. Diese Fallstricke sollten Sie meiden.

Doppler pressure measurement with determination of the ankle-arm indices, and duplex ultrasonography, together form the basis of the diagnostic investigation of the vascular system in diabetics. MR angiography and arteriography are not screening methods in suspected peripheral blood flow disorders. MR angiography should be applied only when findings are unclear and the therapeutic consequences uncertain. Invasive therapeutic measures (angioplasty, vascular surgery, amputation) must still be preceded by intra-arterial digital subtraction angiography as the method of choice.

[Diagnosis of arterial vascular diseases with duplex sonography. Often better than angiography]. / Diagnostik arterieller Gefässerkrankungen mit der Duplexsonographie. Oft besser als die Angiographie.

Color-coded duplex ultrasonography has decisively improved the noninvasive diagnostic possibilities in angiology. It is side effect-free, repeatable whenever required and, in experienced hands, can be performed within a reasonable time. In contrast, arterial angiography is a purely diagnostic but invasive procedure with an associated complication rate of 0.5% [25]. Color-coded duplex ultrasonography is an effective and inexpensive diagnostic method. The overall cost of such an examination is about 120 euros [25]; this contrasts with overall costs of 939 euros for MR angiography, and 1297 euros for an intra-arterial angiography.