Intermittent Administration of Nitroglycerin Sublingual Powder Compared with Placebo in Outpatients with Peripheral Artery Disease: Results of a Randomised Proof of Concept Study.

OBJECTIVE: Treatment of peripheral artery disease (PAD), Fontaine Stage IIb with vasoactive substances is of limited efficacy and does not last beyond the active treatment. Glyceryl trinitrate (GTN) is a vasodilating agent that relaxes vascular smooth muscle cells. The aim was to prove the concept that GTN sublingual powder has sustained clinical efficacy and adequate safety in these patients. METHODS: This was a multicentre, randomised, double blind, placebo controlled, forced titration, proof of concept study (phase IIa). Patients had a treadmill test at baseline, after 12 weeks of GTN/placebo administration, and at 19 and 26 weeks (without treatment). Primary objectives were an increase in initial claudication distance (ICD) and absolute claudication distance (ACD) at 12 weeks. RESULTS: Ninety-five patients were screened and 73 randomised, of which 53 patients completed the 12 week treatment phase (GTN 26, placebo 27). At a baseline ICD of 59.2 ± 32.8 m (GTN) and 57.5 ± 39.7 m (placebo), GTN led to a placebo corrected ICD increase of 23.2% vs. baseline (p = .35). Baseline ACD was 105.3 ± 52.9 m (GTN) and 106.1 ± 95.0 m (placebo), and GTN led to a placebo corrected increase of 3.6% (p = .44), with substantial interindividual variation. The change in claudication distance was greater in patients with an ICD of ≥50 m at baseline (ΔICD 29.3%; p = .19), and an ACD ≥ 100 m (ΔACD 8.5%; p = .40). The effect lasted beyond the active treatment period as shown by a 49.3% increase in ICD (p = .31) and a 20.6% increase in ACD (p = .21) by week 26. GTN sublingual powder was well tolerated. CONCLUSION: Intermittent treatment with nitroglycerin sublingual powder may represent a potential treatment option for patients with PAD stage Fontaine IIb, with an immediate and a sustained effect. The observed increases in ACD and ICD were however not statistically significant in this phase IIa proof of concept study. Further studies are required.

Impact of diabetes on outcome in critical limb ischemia with tissue loss: a large-scaled routine data analysis.

BACKGROUND: Patients with diabetes concomitant to critical limb ischemia (CLI) represent a sub-group at particular risk. Objective of this analysis is to evaluate the actual impact of diabetes on treatment, outcome, and costs in a real-world scenario in Germany. METHODS: We obtained routine-data on 15,332 patients with CLI with tissue loss from the largest German health insurance, BARMER GEK from 2009 to 2011, including a follow-up until 2013. Patient data were analyzed regarding co-diagnosis with diabetes with respect to risk profiles, treatment strategy, in-hospital and long-term outcome including costs. RESULTS: Diabetic patients received less overall revascularizations in Rutherford grades 5 and 6 (Rutherford grade 5: 45.0 vs. 55.5%; Rutherford grade 6: 46.5 vs. 51.8; p < 0.001) and less vascular surgery (Rutherford grade 5: 13.4 vs. 23.4; Rutherford grade 6: 19.7 vs. 29.6; p < 0.001), however more often endovascular revascularization in Rutherford grade 6 (31.0 vs. 28.1; p = 0.004) compared to non-diabetic patients. Diabetes was associated with a higher observed ratio of infections (35.3 vs. 23.5% Rutherford grade 5; 44.3 vs. 27.4% Rutherford grade 6; p < 0.001) and in-hospital amputations (13.0 vs. 7.3% Rutherford grade 5; 47.5 vs. 36.7% Ruth6; p < 0.001). Diabetes further increased the risk for amputation during follow-up [Rutherford grade 5: HR 1.51 (1.38-1.67); Rutherford grade 6: HR 1.33 (1.25-1.41); p < 0.001], but not for death. CONCLUSIONS: Diabetes increases markedly the risk of amputation attended by higher costs in CLI patients with tissue loss (OR 1.67 at Rutherford 5, OR 1.53 at Rutherford 6; p < 0.001), but is associated with lower revascularizations. However, in Rutherford grades 5 and 6, concomitant diabetes does not further worsen the overall poor survival.

German guideline on the diagnosis and treatment of peripheral artery disease - a comprehensive update 2016.

The prevalence of peripheral artery disease (PAD) is increasing worldwide and is strongly age-related, affecting about 20 % of Germans over 70 years of age. Recent advances in endovascular and surgical techniques as well as clinical study results on comparative treatment methods strengthened the need for a comprehensive review of the published evidence for diagnosis, management, and prevention of PAD. The interdisciplinary guideline exclusively covers distal aorta and atherosclerotic lower extremity artery disease. A systematic literature review and formal consensus finding process, including delegated members of 22 medical societies and two patient self-support organisations were conducted and supervised by the Association of Scientific Medical Societies in Germany, AWMF. Three levels of recommendation were defined, A = "is recommended/indicated", B = "should be considered", C = "may be considered", means agreement of expert opinions due to lack of evidence. Altogether 294 articles, including 34 systematic reviews and 98 RCTs have been analysed. The key diagnostic tools and treatment basics have been defined. In patients with intermittent claudication endovascular and/or surgical techniques are treatment options depending on appropriate individual morphology and patient preference. In critical limb ischaemia, revascularisation without delay by means of the most appropriate technique is key. If possible and reasonable, endovascular procedures should be applied first. The TASC classification is no longer recommended as the base of therapeutic decision process due to advances in endovascular techniques and new crural therapeutic options. Limited new data on rehabilitation and follow-up therapies have been integrated. The article summarises major new aspects of PAD treatment from the updated German Guidelines for Diagnosis and Treatment of PAD. Limited scientific evidence still calls for randomised clinical trials to close the present gap of evidence.

The Diagnosis and Treatment of Peripheral Arterial Vascular Disease.

BACKGROUND: In peripheral arterial occlusive disease (PAOD), arterial stenosis or occlusion impairs perfusion in the territory of the distal portion of the aorta and the iliac and leg arteries. In Germany, the prevalence of PAOD rises with age, reaching 20% among persons over age 70. METHODS: This guideline was prepared by a collaboration of 22 medical specialty societies and two patient self-help organizations on the basis of pertinent publications that were retrieved by a systematic search in PubMed for articles that appeared from 2008 to April 2014, with a subsequent update to May 2015. RESULTS: 294 articles were assessed, including 34 systematic reviews and 98 randomized controlled trials (RCTs). The diagnostic assessment of PAOD is based on physical examination, blood pressure at the ankles, and color-coded duplex ultrasonography (grade A recommendation). Other tomographic imaging methods can be used for suitable indications. The main elements of the treatment of PAOD are the control of cardiovascular risk factors and structured vascular exercise (grade A recommendation). Acetylsalicylic acid and statins are the main drugs for symptomatic PAOD (grade A recommendation). Patients with claudication and correlated structural findings can undergo an endo - vascular or open surgical procedure. Critical ischemia is an indication for arterial revascularization as soon as possible (grade A recommendation); this may be performed either by open surgery or by an endovascular procedure of one of the types that are now undergoing rapid development, or one of the crural treatment options. There is inadequate evidence concerning the optimal drug regimen after revascularization procedures. CONCLUSION: The diagnostic assessment of PAOD is based on physical examination, measurement of the ankle-brachial index (ABI), and duplex ultrasonography. Acetylsalicylic acid and statins are indicated for patients with symptomatic PAOD. Endovascular procedures should be used if indicated. Randomized studies are needed to provide better evidence on many open questions in the treatment of PAOD.

Prevalence of deep vein thrombosis in acutely admitted ambulatory non-surgical intensive care unit patients.

BACKGROUND: Data on prevalence rates of venous thromboembolism (VTE) in different patient populations are scarce. Most studies on this topic focus on older patients or patients with malignancies, immobilization or thrombophilia. Less is known about the VTE risk profile of non-surgical patients presenting with a variety of medical diseases of differing severity. Aim of the present study was to investigate VTE prevalence in a pospective cohort study of ambulatory medical intensive care unit patients within 24 h after acute admission. METHODS: Prospective cohort study of 102 consecutive patients after acute admission to medical intensive care unit. Ultrasound compression sonography, APACHE-II-Scoring and laboratory examination was performed within 24 hours after admission.Possible determinants of a high risk of VTE were examined. In all patients with a confirmed diagnosis of DVT or suspicion of PE thoracic computer tomography (CT) was performed. RESULTS: VTE was found in 7.8% out of 102 of patients, mean APACHE-II-Score was 14 (mortality risk of about 15%). Thrombus location was femoropopliteal in 5 patients, iliacal in 2 and peroneal in 1 patient. Five VTE patients had concomitant PE (62.5% of VTE, 4.9% of all patients). No predictors of prevalent VTE were identified from univariable regression analysis although relative risk was high in patients with a history of smoking (RR 3.40), immobility (RR 2.50), and elevated D-Dimer levels (RR 3.49). CONCLUSIONS: Prevalent VTE and concomitant PE were frequent in acutely admitted ICU patients.

The diagnosis, treatment and follow-up of extracranial carotid stenosis.

BACKGROUND: Extracranial atherosclerotic lesions of the carotid bifurcation cause 10% to 20% of all cases of cerebral ischemia. Until now, there have been no comprehensive evidence- and consensus-based recommendations for the management of patients with extracranial carotid stenosis in Germany and Austria. METHODS: The literature was systematically searched for pertinent publications (1990-2011). On the basis of 182 randomized clinical trials (RCTs) and 308 systematic reviews, 30 key questions were answered and evidence-based recommendations were issued. RESULTS: The prevalence of extracranial carotid stenosis is more than 5% from age 65 onward. Men are affected twice as frequently as women. The most important diagnostic technique is Doppler- and color-coded duplex ultrasonography. RCTs have shown that the treatment of high-grade asymptomatic carotid stenosis with carotid endarterectomy (CEA) can lower the 5-year risk of stroke from 11% to 5%. Intensive conservative treatment may lower the stroke risk still further. Moreover, RCTs have shown that CEA for symptomatic 50% to 99% carotid stenosis lowers the 5-year stroke risk by 5% to 16%. Meta-analyses of the 13 available RCTs comparing carotid artery stenting (CAS) with CEA have shown that CAS is associated with a 2% to 2.5% higher risk of periprocedural stroke or death and with a 0.5% to 1% lower risk of periprocedural myocardial infarction. If no particular surgical risk factors are present, CEA is the standard treatment for high-grade carotid stenosis. CAS may be considered as an alternative to CEA if the rate of procedure-related stroke or death can be kept below 3% or 6% for asymptomatic and symptomatic stenosis, respectively. CONCLUSION: Further studies are needed so that better selection criteria can be developed for individually tailored treatment.

Health related quality of life in patients with critical limb ischemia.

Critical limb ischemia (CLI) is the terminal stage of peripheral artery disease. Research in recent years has been largely focussed on treatment options such as bypass surgery / endovascular treatment, surgery / primary amputation and additional benefits of supportive pharmacotherapy. Despite this plethora of treatment options, however, patients continue to have a reduced health related quality of life (HRQoL). Aim of the present work was to review the available evidence of improvement of HRQoL with regard to different treatment options. We found that a number of clinical studies have been conducted using HRQoL measures mostly as secondary outcomes in patients with CLI and other less severe forms of peripheral arterial disease. The studies demonstrate a consistent improvement of HRQoL over baseline within the first few months after the intervention. Prostaglandins, but no other pharmacotherapies, appear to be effective in patients without an option for revascularization. Due to a largely differing patient population under investigation and the different degrees of disease progression it appears difficult however to compare different treatment options with respect to their impact on HRQoL. HRQoL improvement as a predefined endpoint of novel therapeutic approach studies should be considered more consequently.

Treatment of peripheral arterial disease using stem and progenitor cell therapy.

Peripheral arterial disease (PAD) is a highly prevalent atherosclerotic syndrome associated with significant morbidity and mortality. PAD is most commonly caused by atherosclerosis obliterans (ASO) and thromboangiitis obliterans (TAO), and can lead to claudication and critical limb ischemia (CLI), often resulting in a need for major amputation and subsequent death. Standard treatment for such severe cases of PAD is surgical or endovascular revascularization. However, up to 30% of patients are not candidates for such interventions, due to high operative risk or unfavorable vascular involvement. Therefore, new strategies are needed to offer these patients a viable therapeutic option. Bone-marrow derived stem and progenitor cells have been identified as a potential new therapeutic option to induce angiogenesis. These findings prompted clinical researchers to explore the feasibility of cell therapies in patients with peripheral and coronary artery disease in several small trials. Clinical benefits were reported from these trials including improvement of ankle-brachial index (ABI), transcutaneous partial pressure of oxygen (TcO(2)), reduction of pain, and decreased need for amputation. Nonetheless, large randomized, placebo-controlled, double-blind studies are necessary and currently ongoing to provide stronger safety and efficacy data on cell therapy. Current literature is supportive of intramuscular bone marrow cell administration as a relatively safe, feasible, and possibly effective therapy for patients with PAD who are not subjects for conventional revascularization.

Stem cell and progenitor cell therapy in peripheral artery disease. A critical appraisal.

Atherosclerotic peripheral artery disease (PAD) is a common manifestation of atherosclerosis. The occlusion of large limb arteries leads to ischaemia with claudication which can progress to critical limb ischaemia (CLI) with pain at rest, and to tissue loss. At present, common therapy for CLI is either surgical or endovascular revascularisation aimed at improving blood flow to the affected extremity. However, major amputation and death are still frequent complications. Exploring new strategies for revascularisation of ischaemic limbs is thus of major importance. Bone marrow (BM)-derived stem and progenitor cells have been identified as a potential new therapeutic option to induce therapeutic angiogenesis. Encouraging results of preclinical studies have rapidly led to several small clinical trials, in which BM-derived mononuclear cells were administered to patients with limb ischaemia. Clinical benefits were reported from these trials including improvement of ankle-brachial index (ABI), transcutaneous partial pressure of oxygen (TcPO2), reduction of pain, and decreased need for amputation. Nonetheless, large randomised, placebo-controlled, double-blind studies are necessary and currently ongoing (BONMOT-CLI, JUVENTUS and NCT00498069). Further research relates to the optimal cell type and dosage, the isolation method, the role of colony-stimulating factors, administration route, and the supportive stimulation of cells with reduced functioning due to advanced PAD. Autologous stem cell therapy for ischaemic peripheral disease seems to be a promising new tool for the treatment of severe limb ischaemia. Preliminary evidence has established its safety, feasibility and effectiveness on several important endpoints. Several large endpoints studies are underway to further consolidate this evidence.

[Angiology]. / Angiologie.

The management of vascular disease has become more and more important due to increasing evidence of the extent of peripheral arterial disease in the population and venous thromboembolism in nonsurgical patients. The treatment not only includes the therapy of the cardiovascular risk factors and the application of platelet inhibitors but also the use of new drugs and new endovascular devices. Up till now it is still unclear whether the interventional therapy of carotid stenoses and the endovascular application of stent grafts in abdominal aortic aneurysm are superior to surgery. If the indication is given, hemodynamic renal artery stenoses should be treated by interventional procedures. The effect of medical prophylaxis of venous thromboembolism in nonsurgical patients is evident and proven by large studies. New anticoagulants enlarge the therapy of prophylaxis and treatment of venous thromboembolism.

A modified calculation of ankle-brachial pressure index is far more sensitive in the detection of peripheral arterial disease.

BACKGROUND: Ankle-brachial pressure index (ABI) is a simple, inexpensive, and useful tool in the detection of peripheral arterial occlusive disease (PAD). The current guidelines published by the American Heart Association define ABI as the quotient of the higher of the systolic blood pressures (SBPs) 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 SBPs of the upper limbs. We hypothesized that considering the lower of the two ankle arterial SBPs of a side as the numerator and the higher of the brachial SBPs as the denominator would increase its diagnostic yield. METHODS: The former method of eliciting ABI was termed as high ankle pressure (HAP) and the latter low ankle pressure (LAP). ABI was assessed in 216 subjects and calculated according to the HAP and the LAP method. ABI findings were confirmed by arterial duplex ultrasonography. A significant arterial stenosis was assumed if ABI was <0.9. RESULTS: LAP had a sensitivity of 0.89 and a specificity of 0.93. The HAP method had a sensitivity of 0.68 and a specificity of 0.99. McNemar's test to compare the results of both methods demonstrated a two-tailed P < .0001, indicating a highly significant difference between both measurement methods. CONCLUSIONS: LAP is the superior method of calculating ABI to identify PAD. This result is of great interest for epidemiologic studies applying ABI measurements to detect PAD and assessing patients' cardiovascular risk.

[Antiplatelet therapy in patients with peripheral arterial disease (PAD)]. / Besondere Aspekte der antithrombozytären Therapie bei peripherer arterieller Verschlusskrankheit. Pathophysiologische Grundlagen und Konsequenzen für die Praxis.

Peripheral arterial disease (PAD) is not an uncommon but a commonly neglected condition by many medical practitioners. Its prevalence steadily increases with age. In Germany almost one fifth of the patients aged > 65 years suffer from it. With increasing life expectancy the prevalence of PAD seems to be on the increase. PAD is a manifestation of diffuse and severe atherosclerosis. 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 patients with PAD die of either heart attacks or strokes and they die of the former conditions far earlier than controls. Numerous authors have reported activation of the coagulatory system in PAD, possibly because of the diffuse pattern of the disease. Platelet hyperactivity in PAD may play a role in the process that leads to complications and disease progression. Thus, antiplatelet treatment in these patients may be essential to reduce their high mortality rate. Antiplatelet therapy for prevention of secondary vascular events is the cornerstone of pharmacological intervention in PAD. Based on current evidence, treating patients with PAD with antiplatelet drugs appears to be effective in reducing the risk of coronary and cerebrovascular events, in maintaining arterial and graft patency, and in slowing progression of disease. On the other hand, several studies indicated, that platelets in patients with PAD are relatively aspirin-resistant. The data from the CAPRIE Trial suggest a clinically and statistically significant better risk reduction with clopidogrel than with aspirin in patients with PAD. Aspirin alone should no longer be considered the optimal therapy for PAD.