High-density lipoprotein-cholesterol and not HbA1c was directly related to cardiovascular outcome in PROactive.

AIM: In PROactive, pioglitazone reduced the incidence of death, myocardial infarction and stroke, and significantly improved HbA1c, systolic blood pressure (SBP), triglycerides and high-density lipoprotein (HDL)-cholesterol relative to placebo. As these glycaemic and lipid parameters are major cardiovascular (CV) risk factors, we assessed their separate contribution to the reduced incidence of CV outcomes. METHODS: Patients (n = 5238) with type 2 diabetes and macrovascular disease were randomized to 45 mg pioglitazone or placebo. Relationships among treatment, outcome (time to first event of all-cause mortality, myocardial infarction and stroke) and 10 laboratory measurements and vital signs were investigated using log-linear models. Continuous variable measurements (percent changes from baseline to average of all postbaseline values prior to censoring) were made discrete by categorizing into tertiles. Log-linear models were fitted to multiway tables of discrete data and analysis of deviance used to summarize sources of variation in the data. RESULTS: Although pioglitazone treatment was associated with a decrease in HbA1c and an increase in HDL-cholesterol (HDL-C), only the change from baseline HDL-C predicted the outcome (χ(2) = 28.89, p < 0.0001). No other variables, including HbA1c, triglycerides and systolic blood pressure, showed significant direct associations with outcome. When the analysis was extended to include baseline statin use, this was associated with an improved outcome independently of HDL-C changes. CONCLUSIONS: This post hoc analysis suggests that HDL-C, but probably not HbA1c, is a driver of pioglitazone's favourable influence on CV outcome.

Reprinted article "The fate of the claudicant--a prospective study of 1969 claudicants".

A prospective study of 1969 patients with intermittent claudication receiving placebo medication for a minimum of 1 year is reported. Patients were carefully monitored and only four patients were lost to follow-up. Annual mortality was 4.3%. Thirty-six patients developed a definite myocardial infarction, 27 a major stroke, 32 required a major amputation and 111 required surgical or radiological intervention for deteriorating ischaemia of the leg. The entry characteristics of the patients were analysed as a predictor of serious cardiovascular events. The most sensitive predictors of total mortality were age, history of coronary heart disease and an ankle/arm pressure ratio below 0.5. Of the laboratory measurements performed only the initial white cell count was a significant predictor of myocardial infarction, stroke and vascular deaths.

The next 10 years in the management of peripheral artery disease: perspectives from the 'PAD 2009' Conference.

OBJECTIVES: To briefly inform on the conclusions from a conference on the next 10 years in the management of peripheral artery disease (PAD). DESIGN OF THE CONFERENCE: International participation, invited presentations and open discussion were based on the following issues: Why is PAD under-recognised? Health economic impact of PAD; funding of PAD research; changes of treatment options? Aspects on clinical trials and regulatory views; and the role of guidelines. RESULTS AND CONCLUSIONS: A relative lack of knowledge about cardiovascular risk and optimal management of PAD patients exists not only among the public, but also in parts of the health-care system. Specialists are required to act for improved information. More specific PAD research is needed for risk management and to apply the best possible evaluation of evidence for treatment strategies. Better strategies for funding are required based on, for example, public/private initiatives. The proportion of endovascular treatments is steadily increasing, more frequently based on observational studies than on randomised controlled trials. The role of guidelines is therefore important to guide the profession in the assessment of most relevant treatment.

Arteriogenic gene therapy in patients with unreconstructable critical limb ischemia: a randomized, placebo-controlled clinical trial of adenovirus 5-delivered fibroblast growth factor-4.

The objectives of this study were to assess the safety and potential clinical efficacy of adenovirus-delivered fibroblast growth factor-4 (Ad5FGF-4) by intramuscular injection into patients with critical limb ischemia (CLI). This study was a double-blind, randomized, placebo-controlled study with escalating dose groups of 2.87 x 10(8) to 2.87 x 10(10) viral particles. Thirteen patients with CLI were randomized to receive active drug (n = 10) or placebo (n = 3). Safety evaluations and efficacy parameters (ankle-brachial index, digital subtraction angiograms, magnetic resonance imaging, and scintigraphy) were performed at baseline and for 12 weeks after treatment. Injections of Ad5FGF-4 were generally well tolerated and considered safe. Transfection efficacy at these concentrations may have been limited or local. The small sample size did not allow any firm conclusions regarding clinical efficacy but a trend toward more and slightly larger blood vessels was observed in the angiograms. It is concluded that intramuscular injection of Ad5FGF-4 into CLI patients seemed safe, but transfection efficacy was limited at the assessed doses. Conclusions regarding clinical efficacy are impossible to draw from this small patient cohort.

Transatlantic Conference on Clinical Trial Guidelines in Peripheral Arterial Disease: clinical trial methodology. Basel PAD Clinical Trial Methodology Group.

Guidelines for the clinical development of drugs in peripheral arterial disease (PAD) have been issued by the Food and Drug Administration for the United States and by the regulatory agency of the European Union for Europe. With increasing globalization, transatlantic cooperation in drug research and development is essential for the future and would be substantially facilitated by the existence of transatlantic guidelines. A conference was held in Basel, Switzerland, in November 1997 to discuss the scientific background of the existing guidelines on the basis of published evidence and the extensive knowledge of clinical investigators and experienced regulators. The meeting was attended by 52 invited experts from the United States and Europe, as well as by representatives from the 2 regulatory authorities. The main conclusions from the meeting are presented and may serve as a reference for the future development of transatlantic guidelines for the evaluation of pharmacotherapy in PAD.

International study of ketanserin in Raynaud's phenomenon.

PURPOSE: The effects of ketanserin on primary or secondary Raynaud's phenomenon due to connective tissue disease were studied in a large, international group of patients. PATIENTS AND METHODS: The study population consisted of 222 patients from 10 countries. After a run-in period of one month of placebo therapy, patients were randomly assigned in a double-blind manner to receive ketanserin 40 mg three times daily (n = 113) or placebo (n = 109) for three months. Total finger blood flow was measured in 41 patients in a warm and cool room before and during treatment. Vasospastic episodes were assessed by diaries and global evaluations. RESULTS: A significant reduction of 34% in frequency of episodes occurred with ketanserin, compared to 18% with placebo (p = 0.011). There was a 1% reduction in duration of episodes with ketanserin therapy, compared to a 2% increase with placebo therapy, but this finding was not statistically significant (p = 0.29). No difference was observed in severity of attacks. Global evaluations by investigators (p = 0.03) and patients (p less than 0.01) showed an overall benefit with ketanserin compared to that seen with placebo. Patients with primary or secondary Raynaud's phenomenon responded similarly to treatment. No changes in total finger blood flow were found. CONCLUSION: Ketanserin significantly improves the subjective symptoms of patients with primary or secondary Raynaud's phenomenon and is an appropriate agent to use in this disease when conservative measures fail.

The effect of normovolaemic haemodilution on the early patency rate of small calibre vascular prostheses studied in a new animal model.

A new animal model has been developed to study early thrombosis in small calibre vascular prostheses. It consists of an ePTFE graft 2 cm long and of 3mm internal diameter inserted into a rabbit abdominal aorta in which the distal run-off is reduced by narrowing both common iliac arteries using clips with a standard gap. Scanning electron microscopy and in vivo gamma imaging of the graft using labelled autologous platelets showed that, as in the human, platelets played a primary role in the model graft thrombosis. This model was used to study the effect of haemodilution on early graft patency. Moderate normovolaemic haemodilution dramatically improved the early patency rate.

Serotonin and haemorrheology.

One of the crucial determinants of tissue perfusion is the flow behaviour, that is the rheology, of the blood itself. In the microcirculation the most important factor is the ability of the cellular components of blood to deform as they pass through the narrower capillary passages. Until recently, it was thought that the deformability of the red cells was more important than that of the white cells, because of their numerical superiority. Recently, the flow behaviour of white cells is thought to be at least equally important. There is now extensive epidemiological, experimental and clinical evidence linking the microrheological properties of blood to tissue ischaemia. The possible role of serotonin in altering haemorrheology is inferred from studies using specific serotonin antagonists. Ketanserin, given orally has been shown to improve blood filterability in patients with myocardial infarction and intermittent claudication. There was also a specific effect on white cells. It is postulated on the basis of these and other experiments that in situations of tissue ischaemia, when there is a local increase in plasma serotonin levels, the deleterious effect of serotonin on blood cell rheology may have an important role in perpetuating the ischaemia.

Platelet-induced granulocyte aggregation in vitro.

Recent studies have shown that the response of granulocytes to stimulation is increased by the presence of platelets. Using an assay based on counting aggregates with a Coulter Counter, we found that heparinized or citrated platelet-rich plasma directly caused aggregation of isolated granulocytes. Platelets themselves were frequently present within the granulocyte aggregates. The degree of aggregation depended on the platelet:granulocyte ratio, and increased over a 2--5 min period of mixing, with a slower increase thereafter. Aggregation was calcium-dependent, increased by stimulation of the platelets with ADP or collagen but not serotonin, and only slightly reduced by a thrombin inhibitor (hirudin, at concentrations up to 0.9 U/ml). A similar adhesive interaction in vivo might be relevant to thrombotic and ischaemic pathology.

Influence of blood cells and blood flow on venous endothelium.

The principal emphasis in the past has been on the physical characteristics of the vein wall and to some extent the flow characteristics of the blood it contains. The interaction between the blood cells and the venous endothelium has been largely neglected until recently. This brief review summarises the secretion by the endothelium of such important substances as fibrinolytic agents, antiplatelet agents and venodilators. Many of these secretory activities are modulated by the wall shear stress which in turn is related to the rheological properties of the blood. The rheological properties of bulk venous blood have been shown to be significantly abnormal in patients with venous hypertension. Such haemodynamic and haemorheological alterations also play an important role in the interaction between the formed elements of blood and the vessel wall. Most recently this has assumed the importance in relation to the margination and adhesion of white cells to the endothelium and the subsequent activation of the white cells. Interaction between the circulatory blood and the venous endothelium probably plays an important role in the pathophysiology of both simple varicose veins and the more serious complications of venous disease such as thrombosis.

A meta-analysis of randomized placebo control trials in Fontaine stages III and IV peripheral occlusive arterial disease.

In patients with Fontaine Stage III and IV POAD unsuitable for arterial reconstruction, Iloprost, a prostacyclin analogue, has been shown in six RCTs to have a significant (p < 0.05) beneficial effect with regards to the probability of being alive with both legs at six months follow-up. Iloprost has significant (p < 0.05) beneficial effects over placebo on ulcer healing and pain relief, but these were relatively soft endpoints to study when side effects may have unblinded many observers and patients. Further studies are indicated to investigate the possible benefit of repeated courses of treatment with Iloprost in patients with non-reconstructable Fontaine Stage III and IV POAD as well as studies looking at patients who may be suitable only for relatively high risk reconstructions. Meta-analysis of all other RCTs of pharmacotherapeutic agents in patients with Fontaine Stage III and IV POAD showed no significant benefit over placebo for any of the endpoints reported.

Venous claudication. A report of 15 cases and a review of the literature.

The symptom of intermittent claudication is not invariably due to arterial disease. Exercise-related pain resulting from venous insufficiency is poorly defined, but has been described by a number of authors in the past. Fifteen patients with symptoms suggestive of venous claudication are reported. The history and clinical findings are described. The further investigation of these patients is outlined, starting with the non-invasive methods of Doppler ultrasonography and strain gauge plethysmography. Ascending phlebography was performed on all affected limbs (n. 19) and descending phlebography was performed on those shown to have a patent deep venous system. These investigations demonstrated deep venous abnormalities associated with the distinct symptom complex. Venous claudication is defined and the literature reviewed. It is hoped that a clearer understanding of the condition will result in more frequent and accurate diagnosis with subsequent benefit to the patient.

Chronic venous disorders of the leg: epidemiology, outcomes, diagnosis and management. Summary of an evidence-based report of the VEINES task force. Venous Insufficiency Epidemiologic and Economic Studies.

BACKGROUND: To critically review the classification, epidemiology, outcomes, diagnosis and treatment of chronic venous disorders of the leg (CVDL), to issue evidence-based recommendations, and to identify areas requiring further research. METHODS: Articles identified by an extensive literature search were scored by members of an international task force. Only those articles with a moderate or strong rating for internal validity were retained. RESULTS: A scoring system weighing CVDL severity according to the probability of ulcer occurrence is proposed. Epidemiological data on the frequency of CVDL and its risk factors are reviewed. The following items are evaluated: costs associated with treatment; clinical outcomes related to CVDL and its treatment; available generic and disease-specific measures of quality of life; diagnostic procedures used to detect venous reflux; and efficacy of available treatments. CONCLUSIONS: CVDL is an important public health problem, based on its prevalence, cost and impact on quality of life. High-priority areas for research on CVDL are identified.

Pathophysiology of venous leg ulceration--an update.

The microcirculatory component of the pathophysiology of venous ulceration is now attracting considerable research interests, but is still far from fully elucidated. Currently, the central role is filled by the inappropriately activated white cell and its interaction with the endothelium. Interstitial oedema, pericapillary fibrin cuff and capillary microthromboses could all fit in with this hypothesis. However, there are other demonstrated changes, for instance in lymphatic drainage, intrinsic fibrinolysis and hemorheological changes which also need to be taken into account. The interaction between the microcirculatory changes is an obvious target for the systemic pharmacotherapy of venous ulceration.

Effects of buflomedil on erythrocyte deformability.

This brief communication outlines recent experiments on the effects of buflomedil, a new vasoactive agent, on red cell deformability in patients with leg ischemia. In this randomized, double-blind-cross-over study, 10 patients received 200 mg buflomedil and matching placebo intravenously. Red cell filterabiltiy in these patients was significantly improved after buflomedil administration versus baseline values with no significant change in filterability versus baseline after placebo administration.

Clinical relevance of blood viscosity and red cell deformability including newer therapeutic aspects.

Peripheral ischemia is mostly due to narrowing of the vessels, although blood supply is also influenced by the hemorheologic properties of the blood. Recent research has revealed that abnormally high blood viscosity can be a contributing cause in ischemia. Therapeutically decreasing the blood viscosity improves the ischemia by increasing flow through the narrowed vessels and may as such offer a valuable alternative to surgery. Different possible therapeutic approaches for decreasing blood viscosity and the related clinical evidence are discussed.

Initial filtration rate and initial clogging in the Hemorheometre.

The role of different factors contributing to red cell filterability in the Hemorheometre has been investigated. Although the original method uses a small volume of suspension to determine red cell filterability, the present experiments showed that the results obtained are still significantly affected by filter clogging. Consequently a change in filterability could be due to a change in filter clogging possibly by residual leucocytes. An adaptation of filter chamber and filling method is described, resulting in a simpler and faster measuring procedure. The inaccuracy in measuring low haematocrits contributes significantly to experimental errors. Therefore a definition of red cell filterability based on the red cell count (instead of haematocrit) of the suspension is suggested.

Management of the diabetic foot.

If the diabetic foot fails to respond adequately to a short period of basic primary treatment surgery must be considered. The main factor determining its nature and extent is the severity of large-vessel disease. If investigation shows this to be of minor significance local surgery is usually successful. In the presence of definite large-vessel disease, however, major amputation is usually necessary, though arterial reconstruction with local distal amputation may occasionally be feasible. The factors to be taken into consideration in the choice of treatment are discussed.

A review of alternative approaches in the management of iatrogenic femoral pseudoaneurysms.

The management of iatrogenic pseudoaneurysms (IPAs) demands close co-operation between radiologist, vascular surgeon and plastic surgeon. Ideally, each patient should be reviewed employing a team approach. Many IPAs require only observation; those with a volume greater than 6 cm3 will require treatment as spontaneous thrombosis is uncommon. Radiological treatment options include ultrasound guided compression repair (UGCR), embolisation, and covered stenting. Occasionally, these are unsuccessful or contra-indicated, and the vascular surgical approach is discussed in detail. Finally, the role of the plastic surgeon in dealing with skin ischaemia is detailed.

Therapeutic aspects of white blood cell rheology in severe ischaemia of the leg.

In order to investigate the involvement of white blood cells (WBC) in ischaemia, we have used micropore filtration techniques to measure the flow properties of cells from patients with severe leg ischaemia, before and after therapy (amputation or pharmacological). Compared to age-matched controls, WBC from patients had impaired ability to flow through 8 microns and 5 microns pore filters. This applied to fractionated granulocytes and mononuclear cells, as well as to unfractionated mixed WBC. WBC from blood drawn from the ischaemic leg had worse filterability than those from arm blood of the same patients. Judging from WBC morphology, the percentage of active WBC was higher in samples drawn from ischaemic patients compared to controls. After amputation of the ischaemic leg, significant improvement was observed, so that the WBC were no longer significantly different from controls. The flow abnormalities may reflect activation of WBC by factors released in the ischaemic tissue. A cycle of WBC trapping, activation, tissue damage and further activation and trapping could contribute to the worsening of tissue ischaemia. Pharmacological intervention in this degenerative cycle might be possible, and our preliminary data show that Trental infusion (600 mg over 6 hours) improves the filterability of granulocytes from severely ischaemic patients.