Holger Lawall

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.

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.

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.

Effect of nebivolol vs. hydrochlorothiazide on the walking capacity in hypertensive patients with intermittent claudication.

Aims Whereas product labels of beta blockers list peripheral arterial disease (PAD) as a contraindication, current PAD guidelines state otherwise. We aimed to evaluate the clinical efficacy and safety of the ß1 selective blocker nebivolol in hypertensive patients with PAD. Methods and results This multicentre, prospective, double-blind, active controlled, parallel-group study compared once-daily treatment with nebivolol (Neb) 5 mg vs. hydrochlorothiazide (HCTZ) 25 mg, in hypertensive patients with Fontaine stage II (intermittent claudication). The primary endpoint was the initial claudication distance (ICD) during treadmill exercise after 24-week treatment in the per protocol population, using a noninferiority statistical approach. A total of 177 patients (mean age was 66.3 ± 9.2 years, 76.7% men) were randomized to study treatment and 127 completed the study; the intent-to-treat (ITT) analysis was performed on 163 patients, the per protocol analysis on 127 patients. Both drugs lowered blood pressure significantly. After 24-week treatment, ICD increased in the Neb group in the ITT population by 28.3% (95% CI 15.6–41.0) vs. in the HCTZ group by 26.5% (14.4–38.5), and in the per protocol population in the Neb group by 26.4% (13.4–39.4) vs. in the HCTZ group by 32.1% (18.4–45.7). Thus, noninferiority of Neb could neither be confirmed nor rejected. An increase of absolute claudication distance (ACD, mean percentage increase after 24 weeks on Neb 15.8 ± 33.2 vs. on HCTZ 20.2 ± 46.6) was observed without statistical differences between groups. Ankle-brachial index (ABI) increased slightly in both groups. Generally, both treatments were well tolerated. Conclusion The increases in ICD, ACD and ABI with nebivolol suggest that this medication does not have negative effects on hypertensive patients with symptomatic PAD, and can be used for treatment of hypertension in these patients at high cardiovascular risk without reducing the walking ability.

Intermittent intravenous urokinase for critical limb ischemia in diabetic foot ulceration

Patients with diabetic foot ulceration and critical limb ischemia have a high risk of major amputation, especially if limbs can not be revascularized. Urokinase is effective in improving microcirculation in critical limb ischemia and might improve outcomes. There are no data on the efficacy and safety of urokinase treatment (survival free of major amputation, ulcer healing and the rate of minor and major bleeding). Therefore, we aimed to investigate the effect of urokinase treatment in a phase II clinical trial. We performed an open, prospective, non-controlled, multicenter phase II cohort study in 77 type-2 diabetic patients with critical limb ischemia and diabetic foot ulceration. Patients had no surgical or endovascular treatment option based on interdisciplinary consensus. Urokinase (1 Mio IU if plasma fibrinogen >or=2.5 g/l, 0.5 Mio IU if fibrinogen <2.5 g/l) was administered for 21 days as an intravenous infusion over 30 minutes. Each patient was followed up for 12 months. Treatment for a median of 21 days resulted in 33% of patients being alive, having no major amputation and completely healed ulcers after 12 months. Total survival rate was 84.6%, amputation-free survival 69.2% and rate of major amputation 21.1%. Eighty-two percent of patients experienced at least once a complete ulcer healing within the course of study. Three serious adverse events were urokinase-related. Urokinase treatment in diabetic patients with critical limb ischemia appears to be effective, feasible and safe. Although this calls for a larger, randomized and controlled trial, the results are highly relevant for clinical practice to prevent these patients from receiving major amputation due to diabetic foot syndrome.

Long-term outcomes after medical and interventional therapy of critical limb ischemia.

BACKGROUND Recommendations of clinical guidelines for the treatment of critical limb ischemia (CLI) are based on randomized controlled trials. Recent data from clinical practice are however lacking. Therefore a prospective observational study in patients with critical limb ischemia (CLI) in 3 hospitals with a specialized vascular medicine department was conducted to document the clinical course and outcome of patients with critical limb ischemia (CLI) in clinical practice. METHODS 155 patients were stratified: 56 received endovascular intervention, 82 prostanoids and 17 antibiotic treatment. Patients with surgical revascularisation and primary amputation were excluded. All patients received structured wound treatment, analgesia and vascular risk factor treatment during hospital stay. RESULTS Age 72.0+/-12.7 years, hospitalisation 23.2+/-20.3 days. 56.1% had Diabetes, 9.7% multiresistant staphylococcus aureus infection. 40% patients had rest pain, 60% ischemic tissue loss. At discharge 40.0% had no ulcers, 48.4% ongoing trophic alterations, 10.3% received major amputation and 4.5% had stable necrosis. After 18 month rate of major amputation was 6.3% (prostanoids), 14.5% (endovascular treatment; p=n.s. vs. prostanoids) and 26.7% (antibiotics; p=0.0323 vs. prostanoids). Major amputations were not different in logistic regression analyses adjusting for baseline characteristics. Wound healing and mortality rate was not different between groups (26.8, 25.0 and 23.5%). CONCLUSION Structured therapy at specialized vascular centres in combination with interventional or conservative treatment is beneficial in patients with critical limb ischemia. Survival without amputation is higher than expected over 18 months.

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.

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.

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

BackgroundData 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.MethodsProspective 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.ResultsVTE 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).ConclusionsPrevalent VTE and concomitant PE were frequent in acutely admitted ICU patients.

Screening bei peripherer arterieller Verschlusskrankheit

ZusammenfassungBeinarterienstenosen sind oft hinweisend auf eine generalisierte Atherosklerose im arteriellen System. Sie können leicht und verlässlich durch Hausärzte oder ärztliches Hilfspersonal diagnostiziert werden mit Doppler-Ultraschallmessungen und der Berechnung des Knöchel-Arm-Index („ankle-brachial index“, ABI). Ein erniedrigter Wert (<0,9) ist nicht nur ein Zeichen für das Vorliegen einer peripheren arteriellen Verschlusskrankheit, sondern ist auch assoziiert mit einer Verdopplung des Risikos für koronare bzw. zerebrovaskuläre Ereignisse. Patienten mit niedrigem ABI sollten, auch wenn noch keine Symptome bestehen, intensive Präventionsmaßnahmen erhalten, die in Art und Intensität denen für Patienten mit koronarer Herzerkrankung entsprechen.AbstractLeg artery stenoses often indicate generalized atherosclerosis of the arterial circulation and can be easily and reliably diagnosed by the family physician or nursing staff with Doppler ultrasound measurement and calculation of the ankle-brachial index (ABI). A decreased value (<0.9) is not only a sign of peripheral arterial disease but is also associated with a doubled risk of future coronary or cerebrovascular events. Patients with a low ABI, even if still asymptomatic, should receive intensive preventive measures in the same manner and intensity as patients with coronary disease.