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.

[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.

[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.

[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.

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.

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.

[Treatment of the acute coronary syndrome in Germany: experiences in a German cluster of the GRACE registry]. / Behandlung des akuten Koronarsyndroms in Deutschland: Erfahrungen eines deutschen Clusters des GRACE-Registers.

BACKGROUND: The acute coronary syndrome (ACS) remains a major cause of mortality and morbidity in the western world. The Global Registry of Acute Coronary Events (GRACE) documents inpatients with all types of ACS and a follow-up at three months in Germany and worldwide. METHODS: The data of the German Cluster Detmold were compared with data from the worldwide GRACE registry (31,070 patients). Data from 849 patients with ST-elevation myocardial infarction (STEMI), non-ST elevation myocardial infarction (NSTEMI) and unstable angina (UA) were collected from October 2001 to September 2005 in eight participating hospitals in the GRACE2 Cluster Detmold. RESULTS: Compared with the worldwide GRACE data the patients in the Cluster Detmold had longer pre-hospital admission times (STEMI patients < 1 h: 13.9 % vs. 17.0 %; p < 0.05); more frequent interventions (PCI 60.1 % vs. 48.7%; p < 0.001) and less thrombolysis (17.9 vs. 42.5%; p < 0.001) in STEMI patients; more frequent use of platelet inhibitors (clopidogrel and ticlopidine, 93.4 % vs. 89.4%; p < 0.001) and unfractionated heparin (69.8 % vs. 36.5; p < 0.001), and less frequent use of low molecular weight heparin (31.1 % vs. 51.2%; p < 0.001); more frequent use of RAS blocking agents (80.2 vs. 66.6, p < 0.001) and beta blockers (87.4 vs. 78.8, p < 0.001) and less frequent use of lipid lowering agents (23.5 vs. 72.5%; p < 0.001). CONCLUSIONS: Current management of ACS in Germany closely follows the recommendations of the German society of Cardiology. Differences in practice may account for the observed substantially lower event rates in Germany during hospitalization, but there is still room for improvement in the pre-hospital phase und in the degree to which pharmacotherapy is used for secondary prevention.

[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.

[Diabetes, heart surgery and the peripheral arteries]. / Diabetes, Herzchirurgie und periphere Gefässe.

Peripheral arterial disease (PAD) is an under-recognized and underestimated complication of diabetes. Prevalence of PAD in diabetic patients is 25-30%. The main reason for underreporting is the largely asymptomatic nature of PAD in diabetes. It is important to diagnose PAD as soon as possible because PAD is an important marker for systemic atherosclerosis. Patients with claudication have approximately a 30% five-year mortality rate. PAD patients die 10 years earlier than patients without this atherothrombotic disease. About 70% of the PAD patients die from coronary heart disease, 5-11% die from stroke. PAD and diabetes are comorbid conditions and are associated with the risk of death from coronary artery bypass graft surgery. The prevalence of diabetes in patients who undergo cardiac surgery is 30% and the prevalence of PAD is 18%. The presence of PAD in diabetic patients had a similar 2-fold increase in the annual incidence of death compared with diabetic patients without PAD. The theory that diabetes and PAD together is associated with small vessel disease may play a role in the cause of the higher long-term mortality seen in at least two studies (Circulation 2004; suppl II: II/41-II/44).

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.

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.

[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.

[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.

[Repeated attacks of pain in the nipple of a pregnant woman. Unusual manifestation of Raynaud's phenomenon]. / Anfallsartige Brustwarzenschmerzen bei einer schwangeren Patientin. Ungewöhnliche Manifestation eines Raynaud-Phänomens.

HISTORY AND FINDINGS: A 38-year-old woman, in her 13th week of pregnancy, presented for angiological investigation of repeated episodes of pain in the right index finger. She also reported painful paleness of the right nipple evoked particularly by cold. This was her fifth pregnancy; she had miscarried twice. The nipple pain occurred spasmodically and in three phases, while the left nipple was unaffected. The attacks lasted c. 15 min, progressing from an ischemic to a hyperemic phase, accompanied by unbearable pain. When first examined there was circumscribed, purplish network-patterned discoloration of the right hand with blackened discoloration of the distal nail-bed of the index finger. INVESTIGATIONS: Duplex-sonography revealed patency of the large arteries of the arm and hand. Transesophageal echocardiography showed a persistent foramen ovale and echo-density suspected to be a right atrial thrombus. Laboratory tests demonstrated anticardiolipin antibodies, suggesting an antiphospholipid syndrome. TREATMENT AND COURSE: On administration of low-molecular heparin, its dosage weight-adjusted, and 100 mg aspirin daily the discoloration of the finger quickly disappeared, but Raynaud's syndrome remained unchanged until she had stopped breast feeding (left breast only) after 8 months. A healthy girl had been delivered by cesarean section in the 39th week, weighing 3100 g. There were no further thromboembolic complications. CONCLUSION: This very rare case of Raynaud's phenomenon in a nipple was associated with an anti-phospholipid syndrome.

[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.