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.

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.

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.

Impact of peripheral arterial disease in patients with diabetes--results from PROactive (PROactive 11).

We compared cardiovascular disease outcomes according to the presence of peripheral arterial disease (PAD) at baseline in a post hoc analysis from the PROactive study. Of the 5238 patients in PROactive (a study of pioglitazone versus placebo in patients with type 2 diabetes and macrovascular disease; mean follow-up=34.5 months), 1274 had PAD at baseline (619=pioglitazone; 655=placebo). Patients with PAD at baseline showed significantly higher rates of the primary endpoint, main secondary endpoint, all-cause mortality (all P<0.0001), and stroke (P=0.0175) than those with no PAD at baseline. The risk of PAD alone was similar to that of myocardial infarction alone. In patients with no PAD at baseline, the event rates of the primary endpoint (P=0.0160), main secondary endpoint (P=0.0453), and acute coronary syndrome (P=0.0287) were significantly lower with pioglitazone than with placebo. This beneficial effect of pioglitazone was not seen in patients with PAD at baseline. In the total population, there was a higher frequency of leg revascularizations with pioglitazone than placebo-this was wholly due to first events that occurred within the initial 12 months of treatment. The presence of PAD increased the risk of all major cardiovascular events. Those without PAD at baseline seemed to benefit more from pioglitazone treatment than the overall PROactive population.

PROactive 06: cost-effectiveness of pioglitazone in Type 2 diabetes in the UK.

AIMS: To determine the cost-effectiveness of adding pioglitazone to existing treatment regimens in patients with Type 2 diabetes with a history of macrovascular disease who are at high risk of further cardiovascular events. METHODS: We conducted two analyses. A within-trial cost-effectiveness analysis (CEA) based on data from the PROspective pioglitAzone Clinical Trial In macroVascular Events (PROactive) Study was performed to estimate the impact of additional pioglitazone treatment on life expectancy, quality-adjusted life expectancy (QALE) and macrovascular events. PROactive data was then used as a basis for a lifetime modelling analysis using a modified version of the validated CORE diabetes model that simulated the same outcomes over a 35-year time horizon. We accounted for direct medical costs from a health-care payer perspective and related these to the clinical outcomes from the study. Costs and benefits were discounted at 3.5% per annum and extensive sensitivity analyses were performed to account for uncertainty in input parameters. RESULTS: (i) Within-trial CEA: compared with placebo, pioglitazone was associated with improved life expectancy (undiscounted 0.0109 years), increased QALE [0.0190 quality-adjusted life years (QALYs)] and slightly higher costs ( pounds 102 per patient). After a mean treatment period of 3 years, the incremental cost-effectiveness ratio (ICER) of pioglitazone vs. placebo was pounds 5396 per QALY gained. The ICERs were relatively insensitive to cost and utility values and were most sensitive to event rates in the pioglitazone arm. (ii) Long-term CEA: pioglitazone was associated with improvements in clinical outcomes based on model projections beyond the PROactive Study. Patients treated with pioglitazone could expect improved life expectancy (undiscounted 0.406 years), increased QALE (0.152 QALYs) and higher costs of care ( pounds 619 per patient) compared with those on existing treatment alone. The base case analysis indicated that the ICER of pioglitazone vs. placebo was pounds 4060 per QALY gained. The cost-effectiveness acceptability curve showed there was an 84.3% likelihood that pioglitazone would be considered cost-effective in the UK using a willingness-to-pay threshold of pounds 30 000 per QALY gained. These long-term results were most sensitive to variation in the time horizon, the duration of cardiovascular benefit of pioglitazone, and changes in mortality rates. CONCLUSIONS: The addition of pioglitazone to existing therapy in patients with Type 2 diabetes at high risk of further cardiovascular events is cost-effective and represents good value for money by currently accepted standards in the UK.

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.

Study of temporal and perfusion physiology of skin capillaries in the dorsum of the foot.

The aim of this study was twofold: firstly, to study the nature of any temporal variation in capillary numbers, and secondly to determine the proportion of perfused to total nutritional capillaries in normal skin. Using in vivo microscopy, the temporal behaviour of the number of visible capillaries in the skin of the dorsum of foot was observed over periods of time varying from 5 min to 55 days in 15 healthy subjects. Capillary perfusion was then studied by comparing capillary numbers before and after intravenous injection of sodium fluorescein. The mean percent difference in the number of visible capillaries over a mean period of 25.3 days was 5.5%. The percentage ratio of perfused to total capillaries was 54.2%. This study shows that there is little quantitative change in capillary numbers over periods of up to 50 days, and that under physiological conditions, about half of the nutritional capillaries of skin are not perfused.

Thromboelastography.

The Thromboelastograph has now been in use for over 50 years and has been largely regarded as a research tool. Increasing automation and refinement of the TEG and standardisation of results has led to decreased speculation regarding its validity as an assay of haemostasis. There are increasing clinical applications including cardiothoracic surgery and liver transplantation. This review discusses the principles and limitations of the TEG. It also focuses on the current clinical applications and potential research interests.

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.

Sequential retroperitoneal venous hemorrhage and embolism of an angio-seal puncture closure device complicating iliac artery angioplasty.

PURPOSE: To present a case of iatrogenic puncture closure device embolization complicating surgery for retroperitoneal hemorrhage (RPH) secondary to angioplasty-induced common iliac vein trauma. METHODS AND RESULTS: A 78-year-old woman with rest pain underwent successful kissing balloon dilation of her aortoiliac bifurcation for a calcified ostial stenosis of the left common iliac artery. Hemostatic puncture closure devices (Angio-Seal) were used to secure both femoral punctures. A right-sided retroperitoneal hematoma developed, and during surgical exploration of the right groin, the Angio-Seal device was removed. The only bleeding site found was the external iliac artery puncture and it was repaired. She again became hypovolemic 18 hours later and was returned to surgery, where bilateral groin explorations and laparotomy by the vascular surgical team found a tear in the left common iliac vein. After repair, the patient was stable for 48 hours when the left leg became critically ischemic. Angiography detected a new high-grade stenosis in the left profunda femoris artery; embolectomy retrieved a footplate from the left puncture closure device. The patient died 11 days later from multiorgan failure. CONCLUSIONS: RPH should be considered early as an occult cause of hypovolemic shock developing soon after even technically straightforward iliac angioplasty. Interventionists should be aware that using the Angio-Seal device risks acute limb ischemia if footplate embolization occurs.

In vivo microscopic study of microcirculatory perfusion of the skin of the foot in peripheral vascular disease.

OBJECTIVES: the aim of this study was to determine the proportion of perfused capillaries in the skin of the foot in patients with peripheral vascular disease, and compare it with that in normal subjects. DESIGN: experimental study comparing capillary perfusion in nine patients with severe peripheral vascular disease (group 2) with seven age- and sex-matched control subjects (group 1). MATERIALS AND METHODS: using in vivo video microscopy, a method was developed to measure the ratio of perfused to total capillaries, by comparing the numbers of corresponding capillaries before and after intravenous injection of sodium fluorescein. RESULTS: the mean percentage ratio of perfused to total capillaries was 54.7% (range 41-87%, standard deviation 16.5) in group 1, and 86.0% (range 62-100%, standard deviation 13.2) in group 2 (p<0.001, t-test). CONCLUSION: a significantly higher proportion of capillaries is perfused in the skin of the foot of patients with severe peripheral vascular disease than in that of normal subjects. This is of important pathophysiological significance and may have clinical implications with regard to the role of pharmacological intervention in severe limb ischaemia.

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.

Quantitative study of capillary density in the skin of the foot in peripheral vascular disease.

BACKGROUND: The aim of this study was to investigate possible differences in capillary density of the skin of the foot between normal subjects and patients with peripheral vascular disease. METHODS: Using in vivo video microscopy, a method was developed to measure the average capillary density (ACD) of the skin of the foot and toes. In a cross-sectional observational study, 21 patients with intermittent claudication and 23 patients with rest pain or ischaemic ulceration were compared with 19 age- and sex-matched controls. RESULTS: Mean(s.e.m). values of ACD of the foot were 33.7(1.9) and 34.4(1.7) per mm2 in the right and left sides respectively for controls, 31.2(1.8) per mm2 (P not significant) and 31.9(2.6) per mm2 (P not significant) in the symptomatic and contralateral sides respectively for patients with claudication, and 22.0(1.8) per mm2 (P < 0.001) and 24.3(1.7) per mm2 (P < 0.001) in the symptomatic and contralateral sides respectively for patients with rest pain or ulceration. CONCLUSION: Capillary density of the skin of the foot is significantly reduced in patients with arterial ulceration compared with that in patients with claudication and healthy subjects.