Intravenous naftidrofuryl for critical limb ischaemia.

BACKGROUND: Peripheral arterial disease affects five per cent of men and women by late middle age. Approximately 25% of those affected will develop critical limb ischaemia (rest pain, ulceration and gangrene) within five years. Naftidrofuryl is a vasoactive drug which may be beneficial in the treatment of critical limb ischaemia. OBJECTIVES: To determine whether naftidrofuryl, when administered intravenously, is effective in alleviating symptoms and reducing progression of disease in patients with critical limb ischaemia. SEARCH METHODS: The Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator searched the Specialised Register (last searched May 2012) and CENTRAL (2012, Issue 4). We searched the reference lists of articles. We also contacted pharmaceutical companies for any unpublished trials. SELECTION CRITERIA: All randomised controlled trials of critical limb ischaemia in which participants were randomly allocated to intravenous naftidrofuryl or control (either pharmacological, inert placebo or conservative therapy) were included. People with intermittent claudication were not included. DATA COLLECTION AND ANALYSIS: Sixteen trials were identified, but eight were excluded because of poor methodology. The eight included trials involved a total of 269 participants from five different countries. The following outcomes were reported: pain reduction, rest pain/necrosis, progression of disease in terms of incidence of surgical reconstruction/amputation, mortality and side effects. On extraction of the data, odds ratios and mean differences were estimated where appropriate. MAIN RESULTS: Treatment with naftidrofuryl tended to show reduction of pain evaluated by both analogue score and analgesic consumption, but the effect was statistically non-significant (mean difference (MD): 0.42; 95% confidence interval (CI)1.19 to 0.35). Similarly, improvement in rest pain or skin necrosis occurred, but these effects were also non-significant. The effect on mean ankle systolic pressure was inconclusive. AUTHORS' CONCLUSIONS: Based on the results of these trials, it cannot be confirmed that intravenous naftidrofuryl is effective in the treatment of people with critical limb ischaemia. However, these results were based on trials of generally low methodological quality which had only a small number of participants, the duration of treatment was extremely short, and the methods varied between the trials. The wide range of endpoints effectively precluded any meaningful pooling of the results. Intravenous naftidrofuryl was withdrawn as a treatment for severe peripheral arterial disease in 1995 because of reported side effects.

Cardiovascular diseases and decline in cognitive function in an elderly community population: the Edinburgh Artery Study.

OBJECTIVE: To investigate cognitive performance and 4-year change in cognitive function in relation to different clinical manifestations of atherosclerotic disease in an elderly community population. METHODS: The Edinburgh Artery Study is a population cohort study of men and women who were recruited to a baseline survey in 1987 and 1988. From the time of study entry, the participants have been invited to two follow-up clinical examinations and continuously monitored for major fatal and nonfatal vascular events. All alive and eligible subjects were invited for cognitive testing in two study years when the mean age of the sample was 73.1 (standard deviation = 5.0) years. A follow-up cognitive assessment was performed in 2002 and 2003 on 452 survivors. RESULTS: In multivariate analyses controlling for demographic characteristics, depression, and major atherosclerotic risk factors, stroke was associated with a significantly worse performance on tests of verbal memory (p = .02) and letter fluency (p = .002). In addition, stroke was related to a significantly steeper 4-year decline in verbal memory performance (p = .04). Among the subjects who had not had an overt stroke, those with symptomatic peripheral arterial disease experienced a significantly greater 4-year decline in verbal memory functioning (p = .04). CONCLUSIONS: In older people, stroke is associated with both worse performance on cognitive tests and progressive verbal memory decline. Elderly individuals with vascular diseases other than stroke may also be vulnerable to a greater decline in verbal memory function. A relationship between vascular diseases and verbal memory decline may exist independently of depressed mood and major atherosclerotic risk factors.

Cognitive decline and markers of inflammation and hemostasis: the Edinburgh Artery Study.

OBJECTIVES: To determine whether circulating markers of activated inflammation and hemostasis are associated with cognitive decline in older people. DESIGN: Prospective cohort study (Edinburgh Artery Study). SETTING: Eleven general practices in Edinburgh, Scotland. PARTICIPANTS: A sample of 452 men and women followed for 16 years. MEASUREMENTS: Biomarker data were collected in 1987/88, and cognitive assessment was first conducted in 1998/99, when the mean age of the sample +/- standard deviation was 73.1+/-5.0), and subsequently in 2002/03. Information was obtained on verbal declarative memory (Wechsler Logical Memory Test (LMT)), nonverbal reasoning (Raven's Standard Progressive Matrices), verbal fluency (Verbal Fluency Test), information processing speed (Wechsler Digit Symbol Test), and a general cognitive factor representing the variance common to the individual test scores. RESULTS: In age-adjusted analyses, plasma fibrinogen, interleukin-6 (IL-6), and intercellular adhesion molecule 1 (ICAM-1) were negatively associated with performance on all cognitive measures in 2002/03 except the LMT (correlation coefficients from -0.10 to -0.24). In multivariate analyses controlling for demographic characteristics, depression, and cardiovascular morbidity and risk factors, fibrinogen independently predicted 4-year decline in nonverbal reasoning (P<.05). Also, when cognitive change was estimated from peak prior level, IL-6 turned out to be inversely related to decline in information processing speed (P<.05). Similarly, ICAM-1 was associated with a greater decline in general cognitive ability (P<.05) and nonverbal ability (P<.05). CONCLUSION: Systemic markers of inflammation and hemostasis are associated with a progressive decline in general and specific cognitive abilities in older people, independent of major vascular comorbidity.

Low ankle-brachial pressure index predicts increased risk of cardiovascular disease independent of the metabolic syndrome and conventional cardiovascular risk factors in the Edinburgh Artery Study.

OBJECTIVE: To investigate whether a low ankle-brachial pressure index (ABI) predicts increased risk of cardiovascular disease (CVD) independent of the metabolic syndrome and conventional cardiovascular risk factors. RESEARCH DESIGN AND METHODS: The Edinburgh Artery Study is a population-based cohort study in which subjects were followed up until their death or for approximately 15 years. Low ABI at baseline was defined as <0.9; subjects with ABI >1.4 (n = 13) were excluded from the analyses. We used a modified version of the definition of the metabolic syndrome published in the Third Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults, replacing waist circumference criteria with BMI criteria. Data on relevant parameters were available for 1,467 men and women ages 55-74 years at baseline. Cox proportional hazards models were used to study cardiovascular morbidity and mortality before and after adjusting for potential confounding factors. RESULTS: We determined that 25% of the study population had the metabolic syndrome and that a low ABI was more prevalent among people with than without the metabolic syndrome (24 vs. 15%; P < 0.001). During the follow-up period, there were 226 deaths from CVD and 462 nonfatal cardiovascular events. The hazard ratio (95% CI) for low ABI after adjusting for age, sex, baseline CVD, diabetes, smoking status, LDL cholesterol, and metabolic syndrome was 1.5 (1.1-2.1) for CVD mortality and 1.5 (1.2-1.8) for all CVD outcomes. CONCLUSIONS: Low ABI is associated with increased risk of CVD independent of the metabolic syndrome and other major CVD risk factors.

Reduced lung function in patients with abdominal aortic aneurysm is associated with activation of inflammation and hemostasis, not smoking or cardiovascular disease.

OBJECTIVE: Abdominal aortic aneurysms often coexist with reduced lung function and chronic obstructive pulmonary disease (COPD). These conditions are each associated with cigarette smoking, cardiovascular disease, and evidence of increased inflammatory and hemostatic activity. The aim of this study was to determine if these factors accounted for the link between aneurysms and pulmonary disease. METHODS: The design was a case-control study comparing patients with an asymptomatic abdominal aortic aneurysm with population-based controls without an aneurysm. Aneurysms were diagnosed by ultrasound scan, and pulmonary function was measured by respiratory questionnaire and spirometry. Activation of inflammation and hemostasis was measured by assay of plasma interleukin-6 (IL-6), fibrinogen, von Willebrand factor (vWF), tissue plasminogen activator (tPA) antigen, fibrin D-dimer, and plasmin antiplasmin complexes. RESULTS: Cases with an abdominal aortic aneurysm (n = 89) had more COPD and worse expiratory lung function as measured by forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) than controls (n = 98) (FEV1, 1.9 vs 2.2 L, P < .01; FEV1/FVC, 0.67 vs 0.75, P < .001) and did not differ in restrictive function (FVC, 2.9 vs 3.0 L, P = .33). Cases also had higher levels of lifetime cigarette smoking (30 vs 24 pack-years, P < 0.01), cardiovascular disease (35% vs 18%, P = .01), plasma fibrinogen (3.5 vs 3.1 g/L, P = .02), IL-6 (2.8 vs 1.8, pg/mL, P < .001), plasmin antiplasmin complexes (596 vs 384 microg/L, P = .01), and D-dimer (442 vs 93 ng/mL, P < .001). On multiple logistic regression analysis of lung function and COPD on the risk of aneurysm, both cigarette smoking and cardiovascular disease had little effect on the relationships. For the markers of activated inflammation and hemostasis, plasmin antiplasmin complexes and D-dimer had the most important confounding effect on the odds ratios. All markers combined had a substantial effect: odds ratio of aneurysm for a one standard deviation decrease in FEV1 fell from 2.3 (95% confidence interval [CI], 1.5 to 3.5) (P < .01) to 1.3 (95% CI, 0.55 to 2.4) (P > or = .05). CONCLUSION: The association between reduced respiratory function and abdominal aortic aneurysm was not accounted for by cigarette smoking or cardiovascular disease. We hypothesize that activation of inflammation and hemostasis in response to injury may be an important explanation of the association between aneurysm formation and reduced respiratory function. Further studies are required to test this hypothesis.

Hemostatic factors, inflammatory markers, and progressive peripheral atherosclerosis: the Edinburgh Artery Study.

The interplay between inflammatory and hemostatic mechanisms may play a crucial role in the development and progression of atherosclerosis. The authors evaluated the separate and joint associations of hemostatic and inflammatory variables on peripheral atherosclerotic progression in the Edinburgh Artery Study, a population cohort study of 1,592 men and women aged 55-74 years that started in 1987. Levels of fibrinogen, fibrin D-dimer, von Willebrand factor, tissue plasminogen activator antigen, factor VII, prothrombin fragment 1 + 2, urinary fibrinopeptide A, C-reactive protein, and interleukin-6 were measured at baseline. Arm and ankle blood pressures were measured, and atherosclerotic progression was assessed by computing ankle brachial index (ABI) at baseline (1,582 participants) and after 12 years of follow-up (813 participants). Fibrinogen (p = 0.05) and D-dimer (p < or = 0.05) were significantly associated with ABI change independently of baseline ABI and cardiovascular disease risk factors. However, these associations were no longer significant when analyses were adjusted for either C-reactive protein or interleukin-6. Moreover, subjects with higher levels of both D-dimer and interleukin-6 at baseline had the greatest ABI decline. In conclusion, fibrinogen and D-dimer, but not other hemostatic factors, were associated with progressive peripheral atherosclerosis. Since D-dimer and fibrinogen are acute phase reactants, these data support the hypothesis that inflammation is more related to atherosclerosis than is hypercoagulation.

The health-related quality of life of people with peripheral arterial disease in the community: the Edinburgh Artery Study.

BACKGROUND: Previous studies investigating the health-related quality of life of those with peripheral arterial disease have focused on patients recruited from hospital clinics. The health-related quality of life of people with peripheral arterial disease in the general population is unknown. AIMS: We aimed to determine the health-related quality of life of people with intermittent claudication and asymptomatic peripheral arterial disease in the general population and to compare it with those with angina and those with no peripheral arterial disease or angina. DESIGN OF STUDY: Analysis of cross-sectional data from the 12-year follow-up of a population-based cohort. SETTING: Edinburgh, Scotland. METHOD: Data from the Edinburgh Artery Study cohort's 12-year follow-up was analysed. Participants' peripheral arterial disease status was measured using the World Health Organisation intermittent claudication questionnaire and the ankle brachial pressure index. Self-assessed health-related quality of life data was collected using the SF-36 generic questionnaire. Health-related quality of life scores were calculated and their associations with peripheral arterial disease status groups were tested. RESULTS: Subjects with intermittent claudication had significantly worse median health-related quality of life scores than patients without claudication in all domains except social functioning and mental health. Patients with claudication had a significantly lower physical component summary score than those without claudication (P

Changes in ankle brachial index in symptomatic and asymptomatic subjects in the general population.

OBJECTIVE: To determine changes over time in the ankle brachial index (ABI) among subjects with and without intermittent claudication in the general population. DESIGN OF STUDY: Population cohort study. SETTING: General population in Edinburgh, Scotland. SUBJECTS: A total of 1592 men and women aged 55 to 74 years selected at random from age-sex registers of 11 general practices and followed up over 12 years. Main outcome measures Changes in ABI for each leg recorded at baseline in 1988 and at subsequent 5-year and 12-year clinical examinations. RESULTS: Overall, 695 subjects (348 men and 347 women) had valid ABI measurements on both legs at all three examinations. At baseline, the ABI was on average.03 higher in the right leg than the left (P < or =.001). Men had a mean ABI that was.07 higher than women (P < or =.001). Mean ABI in the worse leg showed little change over 12 years in both men and women. However, in the whole population, the ABI in the better leg showed a significant drop, 1.15 to 1.08 (P < or =.001). A total of 179 cases of intermittent claudication were identified during the 12-year follow-up. At baseline, ABI in the worse leg of the claudicants was significantly lower than in healthy subjects (.99 vs 1.08; P < or =.01). In claudicants, mean ABI in the worse leg fell by.04 over 5 years (P < or =.05) and in the better leg showed a highly significant drop of.09 (P < or =.001) to levels similar to those of the worse leg. CONCLUSIONS: The mean ABI in the worse leg of study subjects showed little progression over 12 years. Individuals with intermittent claudication experienced a greater decline in both legs compared with those without claudication. Deterioration occurred more rapidly in the limb with a higher ABI at baseline, which possibly indicates a systemic tendency to atherosclerosis.

Relationship of the platelet glycoprotein PlA and fibrinogen T/G+1689 polymorphisms with peripheral arterial disease and ischaemic heart disease.

INTRODUCTION: Genetic variation in plasma fibrinogen and the platelet receptor GP IIIa locus has been independently associated with increased risks of ischaemic heart disease, but there have been few reports on the relationship with peripheral arterial disease. This study determined the risk of peripheral arterial disease and ischaemic heart disease associated with polymorphisms of fibrinogen T/G(+1689) and platelet glycoprotein Pl(A) genes and the effects of cigarette smoking and fibrinogen. MATERIALS AND METHODS: In the 5-year follow-up phase of the Edinburgh Artery Study, 939 subjects (60-79 years) had DNA extracted from a venous blood sample. One hundred sixteen subjects were identified as having angina, 87 a myocardial infarction, 104 had intermittent claudication and 663 subjects comprised a healthy group. RESULTS: Distribution of the fibrinogen genotype was similar across the disease and healthy groups. Logistic regression analyses found no significant association between fibrinogen genotype and ischaemic heart disease and peripheral arterial disease. A lower percentage of claudicants had the Pl(A2) allele (8.3% vs. 15.2%, p=0.025). After adjustment for age and sex, the risk of IC associated with the Pl(A2) was half that of the homozygous Pl(A1) genotype (OR 0.49, 95% CI 0.25, 0.88; p<==0.05). Adjustment for lifetime smoking and fibrinogen levels increased the odds slightly to nonsignificance. CONCLUSIONS: The Pl(A2) genotype was associated with a decreased risk of developing IC. There was no significant relationship between fibrinogen T/G(+1689) genotype and ischaemic and peripheral heart disease in this older population.