Search

Although the use of oral anticoagulants (vitamin K antagonists) has been abandoned in primary cardiovascular prevention due to lack of a favorable benefit-to-risk ratio, the indications for aspirin use in this setting continue to be a source of major debate, with major international guidelines providing conflicting recommendations. Here, we review the evidence in favor and against aspirin therapy in primary prevention based on the evidence accumulated so far, including recent data linking aspirin with cancer protection. While awaiting the results of several ongoing studies, we argue for a pragmatic approach to using low-dose aspirin in primary cardiovascular prevention and suggest its use in patients at high cardiovascular risk, defined as ≥2 major cardiovascular events (death, myocardial infarction, or stroke) projected per 100 person-years, who are not at increased risk of bleeding., (Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

The indications for the use of aspirin in primary cardiovascular prevention continue to be a source of intense debate, with major international guidelines providing conflicting advices. This document, written by delegates of the main Italian scientific societies dealing with cardiovascular prevention and modeled on a similar document by the European Society of Cardiology Working Group on Thrombosis, reviews the evidence in favor and against the use of aspirin therapy in primary prevention based on data cumulated so far, including recent data linking aspirin with cancer protection. While awaiting the results of several ongoing studies, this document argues for a pragmatic approach to the use of low-dose aspirin in primary cardiovascular prevention, and suggests its use in patients at high cardiovascular risk, defined as ≥2 major cardiovascular events (death, myocardial infarction, or stroke) projected per 100 person-years, who are not at increased risk of bleeding.

Arteries, veins and capillaries share the feature of hosting the "endothelial organ", an ubiquitous structure lining the surface of the entire circulatory tree. Endothelial cells and their supporting elements as the basement membrane, the intracellular matrix, and the surface covering glycocalyx, although displaying significant regional differences, maintain a common response to injury and to pharmacological stimuli. Sulodexide (SDX), a highly purified extractive glycosaminoglycan (GAG), shows many biological actions indicating effectiveness in arterial disorders and diseases. In fact, SDX besides inhibiting experimental arterial thrombogenesis displays, especially by the oral route, a number of vascular protective actions that are largely independent of those affecting blood coagulation. Among the activities relevant to arterial disorders, the agent provides restoration of damaged glycocalyx and of degraded intracellular matrix, as well as antiproliferative, antinflammatory, antioxidant, anti-proteolytic and anti-ischemic activities. Among the latter properties, the inhibiting effect on the enzyme family of matrix metalloproteinases (MMPs), and especially on the expression of MMP9 and its precursor, seems of crucial importance given the role of these matrix degrading enzymes in the pathogenesis and progression of atherothrombosis in coronary, carotid and peripheral arteries. These important biological data, many of them very recent, supply clues for the interpretation of a number of previous clinical trials in arterial diseases. Studies published in the years 1990-2005, showing significant reduction of cardiovascular events after a myocardial infarction, as well as a marked improvement in the walking ability in patients with peripheral arterial disease, deserve today an active re-appraisal likely conducive to new clinical research protocols in the field of primary and secondary prevention of cardiovascular disease of atherothrombotic nature.

Background: Anticoagulant treatment for intermittent claudication might improve functional capacity and prevent acute cardiovascular complications caused by peripheral obstructive arterial disease. This is an update of the review first published in 2001., Objectives: To assess the effects of anticoagulant drugs (heparin, low molecular weight heparin (LMWH) and oral anticoagulants) in patients with intermittent claudication (Fontaine stage II) in terms of improving walking capacity (pain-free walking distance or absolute walking distance), mortality, cardiovascular events, ankle/brachial pressure index, progression to surgery, amputation-free survival and side effects of these drugs., Search Methods: For this update the Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator searched the Specialised Register (last searched May 2013) and CENTRAL (2013, Issue 4)., Selection Criteria: All randomised trials of anticoagulants used to treat patients with intermittent claudication., Data Collection and Analysis: Seven studies were included. Only three studies (two evaluating oral anticoagulants, one evaluating heparin) met the high quality methodological inclusion criteria and were included in the primary analysis. Four other studies were included in the sensitivity analysis. The authors extracted the data independently., Main Results: No new studies were included for this update. Seven studies with a combined total of 802 participants were included in this review. No significant difference was observed between heparin treatment and control groups for pain-free walking distance or maximum walking distance at the end of treatment. There were no data to indicate that LMWHs benefit walking distance. Revascularisation or amputation-free survival rates were reported in one study only with a five year follow-up. No study reported a significant effect on overall mortality or cardiovascular events and the pooled odds ratios were not significant for these outcomes either. Major and minor bleeding events were significantly more frequent in the group treated with oral anticoagulants compared to control, with a non-significant increase in fatal bleeding events. No major bleeding events were reported in the study evaluating heparin, while a non-significant increase in minor bleeding events was reported., Authors' Conclusions: The benefit of heparin, LMWHs and oral anticoagulants for treatment of intermittent claudication has not been established while an increased risk of major bleeding events has been observed, especially with oral anticoagulants. There is no clear evidence to support the use of anticoagulants for intermittent claudication at this stage.

Sulodexide (SDX), a sulfated polysaccharide complex extracted from porcine intestinal mucosa, is a blend of two glycosaminoglycan (GAG) entities, namely a fast-moving heparin (HP) fraction and a dermatan sulfate (DS; 20%) component. The compound is unique among HP-like substances in that it is biologically active by both the parenteral and oral routes. A main feature of the agent is to undergo extensive absorption by the vascular endothelium. For this reason, in preclinical studies, SDX administered parenterally displays an antithrombotic action similar to that of HPs but associated with fewer alterations of the blood clotting mechanisms and tests, thus being much less conducive to bleeding risk than HPs. When given orally, SDX is associated with minimal changes in classic coagulation tests, but maintains a number of important effects on the structure and function of endothelial cells (EC), and the intercellular matrix. These activities include prevention or restoration of the integrity and permeability of EC, counteraction versus chemical, toxic or metabolic EC injury, regulation of EC-blood cell interactions, inhibition of microvascular inflammatory and proliferative changes, and other similar effects, thus allowing oral SDX to be considered as an endothelial-protecting agent. The best available clinical evidence of the efficacy of SDX administered orally with or without an initial parenteral phase is the following: alleviation of symptoms in chronic venous disease and especially acceleration of healing of venous leg ulcers; prevention of cardiovascular events in survivors after acute myocardial infarction; marked improvement of intermittent claudication in patients with peripheral occlusive arterial disease; and abatement of proteinuria in patients with diabetic nephropathy that may contribute to the amelioration or stabilization of kidney function. Although further clinical trials are warranted, SDX is presently widely accepted in many countries as an effective and safe long-term, endothelial-protecting drug.

Three new oral anticoagulant agents were tested versus warfarin in separate, large phase III randomized clinical trials for prevention of any stroke and systemic embolism in atrial fibrillation. Dabigatran, a direct thrombin inhibitor, is at 110 mg bid non-inferior and at 150 mg bid superior to warfarin; rivaroxaban, a factor X inhibitor, is also non-inferior, and apixaban, also a factor X inhibitor, is superior to warfarin on the same efficacy end point. Statistical analysis of subgroups does not suggest, for any of the tested drugs, major differences in relation to different risk levels and history of previous stroke/TIA. This re-appraisal of data was undertaken in search for possible additional information, by considering the absolute differences in efficacy and safety events versus warfarin and the corresponding efficiency and number needed to treat, also with regard to secondary versus primary prevention. By this approach, it appears that for all drugs, equivalence or advantage versus warfarin on the efficacy end point is largely driven by a reduction in hemorrhagic rather than ischemic strokes. Dabigatran shows a balanced effect on ischemic and hemorrhagic strokes, and apixaban is most effective in sparing intracranial bleeding versus warfarin. In secondary prevention, better efficiency is shown by dabigatran 150 and apixaban, versus rivaroxaban, despite the higher proportion of post-stroke/TIA patients (55 %) in the ROCKET AF trial of rivaroxaban seemed to favor better results of this drug in secondary prevention. These and other results of our approach should not be directly translated into clinical practice. They may supply useful suggestions to be subsequently tested in specific trials, although head-to-head comparative studies of the three drugs remain unlikely.

While the use of aspirin in the secondary prevention of cardiovascular atherothrombotic disease is well established, many aspects of primary prevention are still unclear. Uncertainties mostly depend on a doubtful risk-benefit ratio, because of the low atherothrombotic risk of populations involved on the one hand, and the non-negligible bleeding risk of treatment on the other. Areas of specific doubt are those of diabetes and asymptomatic peripheral arterial disease, where neither single trials nor meta-analyses allow issuing high-grade specific recommendations at the moment. The present review aims at giving an account on this topic, highlighting areas for further studies, but also attempting at providing a rationale for what to do practically now, while awaiting more conclusive evidence. Based on the results of a number of clinical trials and meta-analyses, and especially considering the absolute figures of the benefit (major cardiovascular events avoided) and of the harm (major bleeding events occurred related to aspirin), the authors recommend to limit primary cardiovascular prevention with aspirin (in apparently healthy subjects with no previous cardiovascular events) to subjects with an estimated global cardiovascular risk ≥2 major cardiovascular events per 100 patients-year, as assessed by the risk score assessments proposed in the Italian "Progetto Cuore" (www.progettocuore.it). This cut-off should also be adopted for primary prevention in patients with type 2 diabetes and/or asymptomatic peripheral arterial disease.

Although the efficacy of antiplatelet therapy is supported by numerous studies areas of uncertainty and doubt persist both in secondary and in primary prevention. In both settings it can be surmised that, with few exceptions, the relative risk reduction obtained, for instance, with aspirin, is rather uniform across the different clinical conditions and measures "efficacy" of the drug: while the absolute risk reduction varies according to the risk levels of the different conditions, and expresses the "efficiency" of the treatment. Especially in conditions at high risk as the acute coronary syndrome (ACS) the problem of "variability of response" or "resistance" to antiaggregating drugs is of remarkable importance. For aspirin resistance main factors are low compliance, interferences with other drugs, especially NSAIDS, diabetes and related glication phenomenon, and especially fast platelet turnover. Genetic polymorphism (C50T) of COX1 gene, has been described but its significance is debated. Regarding clopidogrel, drug interferences, diabetes mellitus, increased platelet turnover, and polymorphisms of the cytochrome P450 family are involved. A useful expression of antiplatelet resistance is "High on Treatment Platelet Reactivity" (HTPR). This entity has been found predictive of poor outcome in a number of studies of patients with ACS, but not in all. Similarly, genotyping patients for cytochrome P450 polymorphisms also shows predictivity, but not confirmed in all studies. Both genotyping and measuring HTPR can be useful for selection of high risk ACS patients and especially in clinical research. New antiplatelet drugs as prasugrel, ticagrelor, and the recent vorapaxar seem to overcome the problem of resistance. In primary prevention, even assuming a uniform efficacy of aspirin, the risk and hence the absolute number of events spared are much lower. Therefore, aspirin will be less efficient, and the net clinical benefit over the bleeding risk will be smaller. Inconclusive results have been found in healthy people as well as in people with diabetes but no prior cardiovascular event. However, in a recent meta-analysis including new trials bearing some factors of heterogeneity, a small but significant reduction in overall mortality suggests that, for aspirin in primary prevention, "the game is not over"., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Background: Terutroban is a selective prostaglandin endoperoxide (TP) receptor antagonist with antithrombotic, antivasoconstrictive and antiatherosclerotic properties and is currently in development for long-term cardiovascular secondary prevention., Objectives: TAIPAD is an international, double-blind, randomized controlled study comparing the effects of five dosages of oral terutroban vs. aspirin and placebo on platelet aggregation in peripheral arterial disease (PAD) patients., Patients/methods: After 10 day's placebo run-in, included patients (n = 435; ankle-brachial pressure index, 0.7 ± 0.1) were randomly allocated to aspirin 75 mg day(-1), terutroban 1, 2.5, 5, 10 or 30 mg day(-1) or placebo. On day 5, the placebo group was reallocated to one of the terutroban groups for the rest of the study (day 83). Ex vivo platelet aggregation induced by the thromboxane analog U46619 (7 μm) was measured 24 h after dosing, as well as platelet aggregation induced by arachidonic acid (AA), collagen and ADP., Results: Terutroban dose-dependently inhibited U46619-induced platelet aggregation at days 5 and 83. At day 5, the inhibition was significant vs. placebo for all terutroban dosages (P < 0.001). Terutroban (5, 10 and 30 mg day(-1)) was at least as effective as aspirin in inhibiting platelet aggregation induced by arachidonic acid (AA), collagen and adenosine diphosphate (ADP). Terutroban was well tolerated, with a safety profile similar to aspirin., Conclusions: In PAD patients, terutroban dose-dependently inhibited platelet aggregation 24 h after dosing, and was at least as effective as aspirin at 5, 10 and 30 mg day(-1). Terutroban was well tolerated., (© 2010 International Society on Thrombosis and Haemostasis.)

This review describes the current status of antiplatelet therapy in prevention of cardiovascular events of an atherothrombotic nature. The efficacy of aspirin clearly outweighs bleeding risk in secondary prevention, with the relevant exception of patients with peripheral arterial disease (PAD). In trials of primary prevention, aspirin has a limited advantage, which is challenged by the risk of major bleeding. A typical example is primary prevention in type 2 diabetes mellitus, in which a number of trials and a recent meta-analysis have confirmed these limitations. In various settings, clopidogrel has been shown to be marginally more effective than aspirin. Despite a non-negligible bleeding risk, the combination of aspirin-clopidogrel has provided satisfactory results in conditions at high thrombotic risk but rather disappointing results in the long-term treatment of chronic stable cardiovascular disease. The combination of aspirin-dipyridamole was shown to be superior to aspirin alone and equivalent to clopidogrel alone for secondary prevention in cerebrovascular patients. Limitations in the efficacy of antiplatelet agents are partly inherent in their mechanism of action and should not be considered simply as 'treatment failures'. Among other factors, individual variability of response to antiplatelet drugs also plays a meaningful role. Variability of response and 'resistance' may result from drug interactions, baseline and residual platelet hyperactivity, increased platelet turnover, pharmacogenetic factors and others. Poor biological response to aspirin and/or clopidogrel is also frequent in clinical settings such as diabetes, obesity and acute coronary syndromes. The correlation between biological resistance and impaired clinical efficacy of aspirin, and especially clopidogrel, is currently accepted, although with limitations due to the different methods used to assess platelet response. Indeed, the concept of individual 'tailoring' of antiplatelet regimens on the basis of previous laboratory or 'point of care' platelet function tests has been validated in a number of recent trials. The search for and validation of new antiplatelet agents with already known, or totally new, mechanisms of action have also been undertaken with increasing eagerness. Among new adenosine diphosphate receptor antagonists, prasugrel is already registered, and ticagrelor and cangrelor are being developed. New mechanisms being explored are blockade of thrombin-induced platelet aggregation (vorapaxar [SCH 530398]), and inhibition of collagen and ristocetin-mediated platelet functions (DZ-697b). Reappraisal of the neglected class of direct thromboxane A(2) antagonists was followed with less interest. Besides blocking the effects of thromboxane produced from platelets, drugs of this class (such as terutroban sodium and picotamide) may also protect cells from thromboxane produced by sources other than platelets, and some of them may preserve or enhance prostacyclin production. Terutroban is presently being tested in PAD and stroke prevention. Picotamide, marketed in Italy, was shown to reduce cardiovascular events and mortality in studies of PAD patients with diabetes. The results available with thromboxane inhibitors are particularly interesting because they are being obtained in conditions, such as type 2 diabetes and PAD, which are known to be refractory to aspirin.

Goal of this study was to investigate whether appropriately applied spa therapy in several indications could be associated with a subsequent fall in the need for costly health services and missed working days due to sick-leave. The Naiade project was a multicenter observational, longitudinal, questionnaire-based study comparing an "entry" inquiry addressed to patients before an entry thermal cycle, and a "return" inquiry after 1 year. Routine statistical methods were used for comparisons. The study was carried out in 297 of the 340 certified Italian spa centers. Inquiries were managed by the spa doctor(s), with the collaboration of family doctors, and when necessary, hospitals, other health services, labour offices and employers. After exclusion of regular customers and of patients with acute disease phases or severe health conditions, 39,943 patients divided into eight diseases subgroups (rheumatic, respiratory, dermatologic, gynaecologic, otorhynologic, urinary, vascular and gastroenteric) underwent entry inquiry and appropriate spa treatment. Patients who returned for treatment after 1 year ("index year") were 23,680 (59.2%) and received return inquiry. Outcomes considered were: frequency and duration of hospitalisation periods; missed working days; regular use of disease-specific drugs; and resort to "non-spa" rehabilitation therapies. The data collected at return inquiry were compared with those of entry inquiry. All the considered outcomes appeared to be significantly reduced in the index year in seven of the eight disease subgroups in comparison with the previous year. In conclusion, disease-appropriate spa treatments were followed by a reduction in the need of subsequent health interventions in most disease subgroups. The health promoting value of spa treatments should therefore undergo more rigorous assessment with randomised controlled studies.

Diabetes mellitus affects about 8% of the adult population. The estimated number of patients with diabetes, presently about 170 million people, is expected to increase by 50-70% within the next 25 years. Diabetes is an important component of the complex of 'common' cardiovascular risk factors, and is responsible for acceleration and worsening of atherothrombosis. Major cardiovascular events cause about 80% of the total mortality in diabetic patients. Diabetes also induces peculiar microangiopathic changes leading to diabetic nephropathy conducive to end-stage renal failure, and to diabetic retinopathy that may progress to vision loss and blindness. In terms of major cardiovascular events, coronary heart disease and ischaemic stroke are the main causes of morbidity and mortality in diabetic patients. Peripheral arterial disease frequently occurs, and is more likely to be conducive to critical limb ischaemia and amputation than in the absence of diabetes. Although there are a number of differences in the pathogenesis and clinical features of diabetic macroangiopathy and microangiopathy, these two entities often coexist and induce mutually worsening effects. Endothelial injury, dysfunction and damage are common starting points for both conditions. Causes of endothelial injury can be distinguished into those 'common' to nondiabetic atherothrombosis, such as hypertension, dyslipidaemia, smoking, hypercoagulability and platelet activation; and those more specific and in some cases 'unique' to diabetes and directly related to the metabolic derangement of the disease, such as (i) desulfation of glycosaminoglycans (GAGs) of the vascular matrix; (ii) formation of advanced glycation end-products (AGE) and their endothelial receptors (RAGE); (iii) oxidative and reductive stress; (iv) decline in nitric oxide production; (v) activation of the renin-angiotensin aldosterone system (RAAS); and (vi) endothelial inflammation caused by glucose, insulin, insulin precursors and AGE/RAGE. Prevention of major cardiovascular events with the antithrombotic agent aspirin (acetylsalicylic acid) is widely recommended, but reportedly underutilised in patients with diabetes. However, some data suggest that aspirin may be less effective than expected in preventing cardiovascular events and especially mortality in patients with diabetes, as well as in slowing progression of retinopathy. In contrast, a recent study found picotamide, a direct thromboxane inhibitor, to be superior to aspirin in diabetic patients. Clopidogrel was either equivalent or less active in diabetic versus nondiabetic patients, depending upon different clinical settings.Recent studies have shown that some GAG compounds are able to reduce micro- and macroalbuminuria in diabetic nephropathy, and hard exudates in diabetic retinopathy, but it is as yet unknown whether these agents also influence the natural history of microvascular complications of diabetes. Lifestyle changes and physical exercise are also essential in preventing cardiovascular events in diabetic patients. Available data on the control of the metabolic state and the main risk factors show that careful adjustment of blood sugar and glycated haemoglobin is more effective in counteracting microvascular damage than in preventing major cardiovascular events. The latter objective requires a more comprehensive approach to the whole constellation of risk factors both specific for diabetes and common to atherothrombosis. This approach includes lifestyle modifications, such as dietary changes and smoking cessation and the use of HMG-CoA reductase inhibitors (statins), which are able to correct the lipid status and to prevent major cardiovascular events independently of the baseline lipidaemic or cardiovascular status. Tight control of hypertension is essential to reduce not only major cardiovascular events but also microvascular complications. Among antihypertensive measures, blockade of the RAAS by means of ACE inhibitors or angiotensin II receptor antagonists recently emerged as a potentially polyvalent approach, not only for treating hypertension and reducing cardiovascular events, but also to prevent or reduce albuminuria, counteract diabetic nephropathy and lower the occurrence of new type 2 diabetes in individuals at risk.

Aim: To evaluate the efficacy of water supplementation treatment in patients with functional dyspepsia or irritable bowel syndrome (IBS) accompanying predominant constipation., Methods: A total of 3872 patients with functional dyspepsia and 3609 patients with irritable bowel syndrome were enrolled in the study by 18 Italina thermal centres. Patients underwent a first cycle of thermal therapy for 21 d. A year later patients were re-evaluated at the same centre and received another cycle of thermal therapy. A questionnaire to collect personal data on social and occupational status, family and pathological case history, life style, clinical records, utilisation of welfare and health structure and devices was administered to each patient at basal time and one year after each thermal treatment. Sixty patients with functional dyspepsia and 20 with IBS and 80 healthy controls received an evaluation of gastric output and oro-cecal transit time by breath test analysis. Breath test was performed at basal time and after water supplementation therapies. Gastrointestinal symptoms were evaluated at the same time points. Breath samples were analyzed with a mass spectometer and a gascromatograph. Results were expressed as T(1/2) and T-lag for octanoic acid breath test and as oro-cecal transit time for lactulose breath test., Results: A significant reduction of prevalence of symptoms was observed at the end of the first and second cycles of thermal therapy in dyspeptic and IBS patients. The analysis of variance showed a real and persistant improvement of symptoms in all patients. After water supplementation for 3 wk a reduction of gastric output was observed in 49 (87.5%) of 56 dyspeptic patients. Both T(1/2) and T-lag were significantly reduced after the therapy compared to basal values [91 +/- 12 T(1/2) and 53 +/- 11 (T-lag), Tables 1 and 2] with results of octanoic acid breath test similar to healthy subjects. After water supplementation for 3 wk oro-cecal transit time was shorter than that at the beginning of the study., Conclusion: Mineral water supplementation treatment for functional dyspepsia or constipation accompanying IBS can improve gastric acid output and intestinal transit time.

We studied circulating levels of endothelin-1, catecholamines and nitric oxide after a mental arithmetic test in 14 patients with early ischemic lesions of the extremities due to systemic sclerosis and slightly impaired peripheral vascular flow. The test induced an increase (P<0.01) in blood pressure, heart rate, endothelin-1 and catecholamine levels, whereas it did not change the low basal levels of nitric oxide. In healthy subjects (n=20) the test significantly (P<0.01) decreased endothelin-1 without affecting nitric oxide. The low basal levels of nitric oxide and the high plasma concentration of endothelin-1 after psychological stress cannot be explained by an impaired release from the limited ischemic lesions alone. This suggests a diffuse microvascular derangement that aggravates the course of peripheral microvascular ischemic lesions.

Thrombophilia is the term now used to describe predisposition to increased risk of venous and occasionally arterial thromboembolism due to hematological abnormalities. It can be a multifactorial disorder where congenital defects of anticoagulant or procoagulant factors may be combined with acquired hematological abnormalities. It should be considered in patients with a documented unexplained thrombotic episode or a positive family history. The aim of this document is to provide guidelines for investigation and management of patients with thrombophilia in the presence or absence of venous thromboembolism (VTE).

Aims: Patients with diabetes are at excessive risk of mortality and cardiovascular morbidity. Previous studies suggest that aspirin may be less effective in diabetic patients. In this multi-centre, randomized, double blind trial picotamide, a dual inhibitor of thromboxane A2 synthase and receptor, was compared with aspirin for the prevention of mortality and major cardiovascular events in diabetics with peripheral arterial disease (PAD)., Methods and Results: A total of 1209 adults aged 40-75 years with type 2 diabetes and PAD were randomized to receive picotamide (600 mg bid) or aspirin (320 mg od) for 24 months. The cumulative incidence of the 2 years overall mortality was significantly lower amongst patients who received picotamide (3.0%) than in those who received aspirin (5.5%) with a relative risk ratio for picotamide versus aspirin of 0.55 (95% CI: 0.31-0.98%). Events were reported in 43 patients (7.1%) on picotamide and 53 (8.7%) on aspirin. The combined endpoint of mortality and morbidity had a slightly lower incidence in the picotamide group but this difference did not reach statistical significance., Conclusion: Picotamide is significantly more effective than aspirin in reducing overall mortality in type 2 diabetic patients with associated PAD.

Aim: In the present study the effect of defibrotide, an antithrombotic and profibrinolytic agent, was investigated in patients with chronic venous insufficiency (CVI) due to deep vein obstruction and/or reflux (chronic deep vein insufficiency, CDVI)., Methods: The study was a multicenter, randomized, double blind placebo controlled trial in which only patients with CDVI confirmed by ultrasound were enrolled. All patients were treated with adequate elastic compression and randomized to receive either oral defibrotide (800 mg/die) or matching placebo for 1 year. Patients with active or previous leg ulcer were excluded., Results: A total of 288 patients were randomized and 159 completed the study. At baseline ultrasound investigation, obstructive changes were found in 2/3 of all patients thus ascertaining a post-thrombotic syndrome (PTS). The primary endpoint, ankle circumference, was significantly reduced under defibrotide from day 120 throughout 360. Scores for pain and edema were improved. The number of episodes of superficial thrombophlebitis and deep vein thrombosis was significantly lower under defibrotide (n=2) than under placebo (n=10). The majority of these events occurred in the subset of patients with documented PTS., Conclusion: Treatment with defibrotide in addition to elastic compression in patients with objectively assessed CDVI, mostly due to PTS, resulted in clinical benefits and prevented thrombotic complications harmful to the limb conditions.

Twelve patients with chronic critical limb ischemia in whom a spinal cord stimulation (SCS) system had been implanted for at least one year had increased microvascular flow and achieved healing of trophic acral lesions. After switching off the system, the clinical improvement persisted for 10 days and the neurohormonal pattern showed high plasma values of beta-endorphin and Met-enkephalin, normal dynorphin B, endothelin-1 and catecholamines, and low nitric oxide. Met-enkephalin levels were further increased (P < 0.01) immediately after switching on the electrical stimulation again. The persistence of high plasma opioid levels after switching off the spinal cord stimulation explains the absence of subjective complaints and suggests an involvement of opioids in the regulation and improvement of the microcirculation., (Copyright 2004 Elsevier Inc.)

Carotid plaques with different degrees of carotid stenosis are a common condition in the aged population (10% or more after age 75). If the definition of "symptomatic"carotid stenosis (SCS) indicates association with homolateral neurologic hemispheric lesions and/or retinal deficits even in absence of ischemic changes at CT scan, the overwhelming majority of carotid stenoses can be defined asymptomatic (ACS). Considering the low absolute risk of ipsilateral stroke,the additional risk of myocardial infarction, and the perioperative risk, surgery although beneficial in relative terms, should not be applied indiscriminately but rather in selected cases. There is therefore ample space for medical treatments as reduction of risk factors (especially hypertension), antiplatelet drugs, and statins, both in alternative with, as well as before and after surgery.

Background: We have shown that normal D-dimer levels obtained after the discontinuation of oral anticoagulant treatment (OAT) has a high negative predictive value for recurrent venous thromboembolism (VTE). The aim of the present study was to assess the predictive value of D-dimer for recurrent VTE in subjects with a previous unprovoked event who are either carriers of inherited thrombophilia or not., Methods and Results: We prospectively evaluated 599 patients (301 males) with a previous VTE episode. They were repeatedly examined for D-dimer levels after OAT withdrawal and were screened for inherited thrombophilic alterations. Alterations were detected in 130 patients (21.7%), factor V Leiden (70 patients; 2 of whom were homozygotes) and prothrombin mutation (38 patients) were the most prevalent ones. Recurrent events were recorded in 58 subjects (9.7%) during a follow-up of 870.7 patient-years. Altered D-dimer levels at 1 month after OAT withdrawal were associated with a higher rate of subsequent recurrence in all subjects investigated, especially in those with an unprovoked qualifying VTE event (hazard ratio, 2.43; 95% confidence interval, 1.18 to 4.61) and in those with thrombophilia (hazard ratio, 8.34; 95% confidence interval, 2.72 to 17.43). The higher relative risk for recurrence of altered D-dimer was confirmed by multivariate analysis after adjustment for other risk factors. The negative predictive value of D-dimer was 92.9% and 95.8% in subjects with an unprovoked qualifying event or with thrombophilia, respectively., Conclusions: D-dimer levels measured 1 month after OAT withdrawal have a high negative predictive value for recurrence in subjects with unprovoked VTE who are either carriers or not carriers of congenital thrombophilia.

Background: Unrecognized thrombophilic defects increase the risk of venous thromboembolism (VTE) in women during oral contraception (OC). We evaluated the sensitivity and specificity of a family history of VTE to identify thrombophilia in women before OC and after venous thrombotic complications during OC., Methods: Thrombophilia screening was performed after obtaining a family history by means of a standardized questionnaire in (1) thrombosis-free women before OC and (2) women after an episode of VTE during OC., Results: We evaluated 479 thrombosis-free women before OC (age range, 15-49 years); family history was positive in 49 (10.2%). Thrombophilic defects were identified in 36 participants (7.5%; 95% confidence interval [CI], 5%-10%), 3 of whom had a positive family history (8.3%). The sensitivity and positive predictive value of family history of thrombophilic defects were 8.3% (95% CI, 2%-22%) and 6.1% (95% CI, 1%-17%), respectively. We also evaluated 189 women after VTE complications during OC (age range, 15-49 years); family history was positive in 48 (25.4%; 95% CI, 19%-32%), 22 of whom had a thrombophilic defect (45.8%; 95% CI, 31%-61%). Thrombophilic defects were identified in 81 women (42.8%; 95% CI, 36%-50%). The sensitivity and positive predictive value of family history of thrombophilic defects were 27.2% (95% CI, 18%-38%) and 45.8% (95% CI, 31%-61%), respectively., Conclusion: Family history of VTE has low sensitivity and positive predictive value for identifying women with thrombophilia who are more susceptible to VTE complications during OC.

We investigated the role of frequent fibrinogen polymorphisms in venous thromboembolic disease in conjunction with inherited thrombophilia. Two hundred unrelated subjects, all carriers of the factor V R506Q mutation (FV Leiden), were genotyped at the fibrinogen gene cluster. Among these subjects, 100 had experienced previous venous thromboembolism (VTE) and 100 were still asymptomatic for VTE. Significant differences were observed between the groups for the BclI polymorphism (P = 0.004). Scanning, by sequencing the DNA regions flanking the BclI marker, revealed new polymorphisms, a C to T transition and a G to T transversion at 1520 and 3369 base pairs 3' to the beta gene stop codon respectively. These markers showed less association with the clinical phenotype than BclI itself. A combined genotype including 10 markers was more frequent among the asymptomatic subjects (17%) than among patients (3%), and was associated with a reduction in fibrinogen antigen level (2.42 +/- 0.35 vs 2.69 +/- 0.41 g/l, P = 0.028) among the asymptomatic subjects. Our data suggest that, in the presence of inherited thrombophilia, frequent fibrinogen polymorphisms may interact to modulate the risk of venous thromboembolism.

Introduction: The aim of the study was to evaluate the mechanism of the anticoagulant action of sulodexide, a mixture of glycosaminoglycans (GAGs) composed of dermatan sulfate (DS) and fast moving heparin (FMH), in vitro., Materials and Methods: Thrombin clotting time (TCT) was measured in human platelet poor plasma (PPP). A chromogenic substrate assay was used to determine the pseudo-first order constant kinetic of thrombin inhibition (k'=k(obs)/min) either in defibrinated PPP or antithrombin (AT) or heparin cofactor II (HCII) depleted defibrinated PPP in the absence and presence of sulodexide or its components, alone and in combination. The interaction between DS and FMH was analysed by both the algebraic fractional and isobole graphical methods., Results: Sulodexide, DS and FMH produced a dose-dependent prolongation of TCT with unclottable TCT at sulodexide above 4 microg/ml and at DS or FMH above 5 microg/ml. Sulodexide and its components alone and in combination produced a dose-dependent linear increase in the rate of thrombin inhibition in defibrinated PPP. The algebraic fractional and the isobole graphical methods indicated an additive effect between DS and FMH. In AT depleted PPP, the dose-dependent increase in k' produced by sulodexide was significantly lower than in PPP, while the dose-dependent increase in k' produced by DS was similar to the increase produced in PPP. In HCII depleted PPP, the dose-dependent increase in k' produced by sulodexide was significantly lower than in PPP, while the dose-dependent increase in k' produced by FMH was similar to the increase produced in PPP., Conclusions: Thrombin inhibition produced by sulodexide is due to the additive effect of its components, namely, HCII catalysis by DS and AT catalysis by FMH.

Background: Purpose of this study was to assess the effects of thermal hydrotherapy (balneokinesis) with a sulphurous water on clinical symptoms, quality of life and some functional parameters in patients with varicose veins., Patients and Methods: 70 patients with primary or secondary symptomatic varicosis were enrolled and submitted to elastic compression therapy. Patients were then randomized to receive (50 pts, group A) or not receive (20 pts, group B) balneokinetic treatment for 12 days "on top" of elastic compression. Clinical symptoms, quality of life and functional parameters obtained with light reflex plethysmography (PPG) and laser Doppler fluxmetry (LDF) were assessed after 3 and 6 months., Results: Scores for subjective symptoms as pain, edema, and venous claudication were decreased after 6 months in both groups, but more evidently in group A submitted to balneokinesis. Some parameters related to quality of life evaluation as "bodily pain" and "emotional role" were improved only in patients undergoing balneokinesis. Regarding functional parameters, with PPG venous refilling time after foot exercise moderately increased in both groups. With LDF a significant improvement in the veno-arteriolar reflex was seen in the group treated with balneokinesis., Conclusions: These results show additional benefits of balneokinetic treatment in patients with symptomatic varices submitted to elastic compression. In fact, clinical and quality of life improvements were observed. The associated amelioration in the veno-arteriolar reflex may support these subjective benefits.

The G20210A prothrombin mutation, associated with elevated prothrombin levels, is a risk factor for venous thromboembolism (VTE) and displays a strong interaction with oral contraceptives (OC). No data are available on VTE risk of OC use in women with high prothrombin levels, either associated or not with the mutation. The aim of this study was to evaluate the risk of VTE in OC users with high prothrombin levels, either including or excluding carriers of the prothrombin mutation. Prothrombin levels were measured by a chromogenic assay in 152 women who suffered from VTE in reproductive age and in 296 healthy women. Subjects carrying thrombophilic alterations other than the G20210A prothrombin mutation were excluded. Prothrombin levels were stratified into quartiles. The OR of subjects in the upper quartile were 3.10 [95% confidence interval (CI) 1.73-5.55] and 2.07 (95% CI 1.11-3.85) in all women and in those not carrying the prothrombin mutation, respectively. Among the 152 patients, 88 had experienced VTE during OC; in the control group we considered as OC users the women who had used OC for at least 6 months in the 2 years before presentation but had stopped the treatment at least 3 months before the time of blood sampling (n = 127). For the interaction between OC and prothrombin levels only the two extreme strata of prothrombin were considered. Women with the lowest prothrombin levels and who did not use OC were used as reference category. The VTE risk of using OC in subjects with prothrombin levels in the upper quartile was increased 5.4-fold (95% CI 2.38-12.3) and 3.5-fold (95% CI 1.48-8.22) in all women and in those not carrying the prothrombin mutation, respectively. We conclude that elevated prothrombin levels, even in women without the G20210A prothrombin mutation, are associated with an increased risk for venous thromboembolism and that oral contraceptive use potentiates such association.

Carotid atherosclerosis is one of the main risk factors for ischemic stroke. The annual risk of ipsilateral stroke for asymptomatic, albeit severe stenoses is as low as 1 to 2%, but increases to 13% in patients with recent ischemic symptoms. However the risk decreases after the first 2-3 years from the symptomatic episode, dropping to 3%. Echo-color Doppler ultrasonography is the screening method of choice, being highly accurate, noninvasive and low-cost. Carotid angiography still represents the gold standard, however, less invasive techniques as RM angiography and Angio-CT are becoming increasingly common. Based on NASCET, ECST and ACAS results, carotid endarterectomy (CE) is strongly recommended for severe symptomatic stenoses, while for the moderate symptomatic and the severe asymptomatic ones the benefit in terms of stroke risk reduction is modest and surgery should be restricted to selected cases in surgical centers of high experience. For severe asymptomatic stenoses NNT is too high to recommend indiscriminate surgery; we are waiting for the results of ACSRS trial, designed to identify a subset of patients at risk of ipsilateral stroke greater than 4%/y, that may be considered for CE, while patients at low risk will be spared from unnecessary operation. Apart from surgery, in all patients with carotid atherosclerosis correction of cardiovascular risk factors is mandatory. Antiplatelet therapy (ASA alone or with dypiridamole, ticlopidine) is effective in secondary prophylaxis of athero-thrombotic stroke; its use in asymptomatic carotid stenoses can be recommended, even if more because of a plausible rationale than of clinical trial-based evidences.

Screening for thrombophilia in women candidate to the pill is still a matter of debate. Oral contraceptives may trigger venous thromboembolic events in carriers of common inherited thrombophilic defects. General screening is not cost-effective from an epidemiological point of view if the objective is to prevent death due to venous thromboembolism during oral contraception (OC). However, clinicians deal with single patients and personal and/or family history for venous thromboembolism have limited value for identifying those women at risk of VTE complications during OC. A pharmacogenetics approach in prescribing OC on the basis of each woman's genetic make-up could increase drug safety. A proper evaluation of the cost-effectiveness, the medical, psychosocial and legal consequences is needed before general screening with genetic testing for inherited thrombophilia can be recommended before OC.

Background and Objectives: To investigate the effects of age, sex and vitamin status on total plasma homocysteine (tHCy), both after fasting (FtHCy) and two hours post-methionine load (PML-tHCy). The secondary aim was to determine the reference values for FtHCy and PML-tHCy., Design and Methods: A cohort of apparently healthy volunteers underwent blood sampling for FtHCy, PML-tHCy, creatinine, serum folate, vitamin B12 and vitamin B6 (pyridoxal-5-phosphate, PLP)., Results: In 147 subjects (M/F= 82/65, age range: 14-94 years), FtHCy was significantly higher in men than in women. In men, age and folate levels explained 20.5% and 19.0% of FtHCy variance, respectively. In women, age and vitamin B12 accounted for 22.6% and 17.8% of FtHCy variance, respectively. PML-tHCy was similar in men and women. PML-tHCy was negatively correlated with folate in both sexes, and with vitamin B12 and age in women only. Folate accounted for 20% of the variance of PML-tHCy in men, while in women vitamin B12 and PLP explained 40% and 20% of variance of PML-tHCy, respectively. The reference values of FtHCy and PML-tHCy were: 19.63 and 40.18 mol/L, respectively, for men under 45 years, 14.26 and 28.31 mol/L, respectively, for women under 45 years, 28.38 and 36.48 mol/L for men above 45 years, and 22.49 and 44.06 mol/L for women above 45 years., Interpretation and Conclusions: Age, gender and vitamin status influence both FtHCy and PML-tHCy in normal subjects. Reference values should be calculated according to age and sex.

Aims: Patients with peripheral arterial obstructive disease require treatment to prevent major cardiovascular events and to relieve intermittent claudication. The walking performance of peripheral arterial obstructive disease patients was used to evaluate the usefulness of sulodexide, a glycosaminoglycan containing fast moving heparin and dermatan sulphate., Methods and Results: A randomized, multicentre, double-blind, placebo-controlled study was performed in 286 patients with Leriche-Fontaine stage II peripheral arterial obstructive disease. Patients received placebo (n=143) or sulodexide (n=143) for 27 weeks. The primary end-point was the doubling of the pain-free walking distance at the end of treatment, and this was achieved by 23.8% of patients treated with sulodexide and 9.1% of those on placebo (P=0.001). The pain-free walking distance increased on average (+/-SE) by 83.2+/-8.6 m (+64.7% from baseline) with sulodexide and 36.7+/-6.2 m (+29.9% from baseline) with placebo (P=0.001). The maximum walking distance increased by 142.3+/-15.8 m (+76.0% from baseline) and 54.5+/-8.4 m (+27.9% from baseline) (P<0.001), respectively. Results for patients with type II diabetes were similar to those for non-diabetic patients. Plasma fibrinogen decreased with sulodexide, but increased with placebo., Conclusion: Sulodexide improved the walking ability of peripheral arterial obstructive disease patients to a significantly greater extent than placebo, with a concurrent significant decrease in fibrinogen. The treatment was well tolerated., (Copyright 2001 The European Society of Cardiology. Published by Elsevier Science Ltd. All rights reserved.)

Genetic and nutritional factors are determinants of total plasma homocysteine (tHCy) whose increased levels play a pathogenic role in atherothrombosis and cardiovascular disease. This study investigated the influence of sex, age, creatinine, serum folate, vitamin B12 and vitamin B6 (pyridoxal- 5-phosphate, PLP) on fasting (FtHCy) and two hour postmethionine loading levels of tHCy in 147 apparently healthy subjects (M/F= 82/65, age range: 14-94 y). FtHCy was higher in men than women (9.89 vs 8.00 μmol/L, p< 0.01). In males, the main determinants of FtHCy were age and folate levels, respectively explaining 20.5% and 19.0% of FtHCy variance. In women, besides age (22.6%), vitamin B12 (17.8%) rather than folate was a major determinant of FtHCy. Two hour postload tHCy, expressed both as absolute value (PML) and as the difference between 2 hour postload tHCy and FtHCy (delta tHCy) was negatively correlated with folate in both sexes, and with vitamin B12 and age in women only. In males folate was the main determinant, explaining 20% of the variance of postload values, while in females vitamin B12 and PLP were predominant, explaining respectively 40% and 20% of that variance. Age was not among the main determinants of postload values in either sex. These results demonstrate that age and vitamin status differently influence both the fasting and the postmethionine plasma homocysteine levels in normal subjects.

Aims: The interaction between the R506Q mutation of factor V and the G20210A mutation of prothrombin with oral contraceptives on venous thromboembolism was evaluated., Methods and Results: Three hundred and one women of reproductive age who had venous thromboembolism (140 while using oral contraceptives) and 650 healthy women (173 on oral contraceptives at presentation) were examined. Of the patients, 19.3% were carriers of R506Q (two homozygotes) and 9.6% were heterozygous carriers of G20210A; eight patients (2.7%) were heterozygous for both mutations. Among controls, 2.9% were carriers of R506Q, 3.1% of G20210A, while one case was a heterozygous carrier of both mutations. The relative risk (odds ratio) associated with carriership of R506Q or G20210A mutations was 10.3 and 4.7, respectively; it was 45.6 in carriers of both mutations. The odds ratio of using oral contraceptives in the absence of both mutations was 2.4. The odds ratios according to oral contraceptives use and the presence of R506Q or G20210A or both mutations were 41.0, 58.6 and 86.5, respectively. While the odds ratio for R506Q remains elevated (8.9) in non-oral contraceptive users, the odds ratio for G20210A was 2.0 and did not reach statistical significance., Conclusions: Our data showed a strong interaction between oral contraceptive use and the presence of either R506Q or G20210A mutations. In non-oral contraceptive users the risk of venous thromboembolism was significantly increased in carriers of R506Q but not in those with the G20210A mutation., (Copyright 2002 The European Society of Cardiology.)

Sulodexide, a highly purified glycosaminoglycan, was investigated for treatment of venous leg ulcers. Patients (n = 235) undergoing local treatment including wound care and compression bandaging, were randomised to receive either sulodexide or matching placebo for three months. Primary study endpoint was complete ulcer healing after 2 months; secondary endpoints were ulcer healing at 3 months and the time-course changes of ulcer areas. The proportion of patients with complete ulcer healing was higher with sulodexide at 2 months (p = 0.018) and 3 months. The "number needed to treat" to obtain one additional patient healed with sulodexide was 7 at 2 months and 5 at 3 months. The changes in ulcer surface area with time were significant for sulodexide only (p = 0.004). Fibrinogen significantly decreased in sulodexide patients (p = 0.006). In conclusion, sulodexide associated with local treatment proved to be effective and well tolerated in the management of venous leg ulcers.

Background: Chronic venous disorders carry lifelong medical and social burdens. Within conservative approaches, spa hydrotherapy is popular among patients with venous disorders in Europe, but whether the practice is associated with health or social benefits remains controversial., Methods: The present work is a substudy of the nation-wide Italian Naiade Project, a large multicenter observational exercise on spa treatments in different disease groups. The "Chronic Phlebopathies" substudy included 2504 patients with primary or secondary varicosis or non-varicose venous insufficiency. After a first visit and administration of a detailed questionnaire, patients underwent a "thermal cycle" of 15-20 days consisting of underwater active and passive physical therapy with mineral waters. The same procedures were repeated after 1 year on the 1352 patients (54%) who spontaneously returned to the same spa. Primary endpoints of the study were some indicators of the use of health resources related to the year after the first thermal cycle, compared with the same indicators recorded at first visit using appropriate statistical methods., Results: The occurrence of acute venous episodes, working days missed, number and duration of hospital admissions, consumption of drugs and physical therapies were all significantly reduced in the year after thermal therapy, thus indicating lesser use of health resources., Conclusions: The study suggests that thermal hydrotherapy in patients with chronic venous disorders is associated with health and social benefits.

Background and Objectives: We evaluated a new test, based on prothrombin activation by Echis Carinatus snake venom in the absence/presence of unfractionated heparin, in patients with venous thromboembolism (VTE)., Design and Methods: The test (activated prothrombin heparin-inhibition test) was performed in 555 unselected, unrelated patients who had suffered from at least one objectively confirmed VTE and the results were compared with those obtained in 408 healthy controls., Results: In 71 (12.8%) of the 555 patients the results of the test, expressed as a normalized ratio, were below the cut-off. This compared with 19 (5% by definition) results below the cut-off in the control group. The crude OR for VTE in subjects with altered vs those with normal results was 3.00 (95% CI: 1.78-5.07). ORs did not significantly change after adjustment for age (2.86, 95% CI: 1.68-4.85) and age/sex (2.80, 95% CI: 1.64-4.77) by logistic regression. After adjustment for antithrombin III, fibrinogen and prothrombin levels the risk associated with altered results remained significantly high. The overall OR for VTE in females (3.22; 95% CI: 1.53-6.75) was higher than that in males (2.69; 95% CI: 1.27-5.69). However, for both sexes there was a sharp increase in the risk of VTE associated with altered results in patients aged less than 45 years (crude OR 9.61; 95% CI: 3.38-27.3)., Interpretation and Conclusions: Lower than expected thrombin inhibition by endogenous antithrombin action after full activation by heparin addition was found to be a common feature in patients who suffered from previous venous thrombotic events, and may reflect a hitherto unrecognized thrombophilic alteration.

In some patients with previous venous thromboembolism (VTE) D-dimer levels (D-Dimer) tend to increase after oral anticoagulant therapy (OAT) is stopped. The aim of our study was to evaluate the predictive value of D-Dimer for the risk of VTE recurrence after OAT withdrawal. After a first episode of deep vein thrombosis (DVT) of the lower limbs and/or pulmonary embolism (PE), 396 patients (median age 67 years, 198 males) were followed from the day of OAT discontinuation for 21 months. D-dimer was measured on the day of OAT withdrawal (T1), 3-4 weeks (T2) and 3 months (+/- 10 days, T3) thereafter. The main outcome events of the study were: objectively documented recurrent DVT and/or PE. D-dimer was found to be increased in 15.5%, 40.3% and 46.2% of the patients at T1, T2 and T3, respectively. In 199 (50.2%) patients, D-dimer levels were elevated in at least one measurement. During a follow-up of 628.4 years, 40 recurrences were recorded (10.1% of patients; 6.4% patient-years of follow-up). D-dimer was increased in at least one measurement in 28 of these cases, but remained normal in 11 subjects (three of whom had recurrent events triggered by circumstantial factors, three with malignancy-associated factors) (in one subject D-dimer was not measured). The negative predictive value (NPV) of D-dimer was 95.6% (95% CI 91.6-98.1) at T3 and was even higher (96.7%; 95% CI 92.9-98.8) after exclusion of the six recurrences due to circumstantial factors. Only five idiopathic recurrences occurred in the 186 patients with consistently normal D-dimer. In conclusion, D-dimer has a high NPV for VTE recurrence when performed after OAT discontinuation.

Objectives: to assess the effect of treatment with mesoglycan, a sulphated polysaccharide compound, on the healing of venous ulcers. Design randomised, placebo-controlled, double-blind, multicentre trial., Methods: non-diabetic outpatients with chronic venous insufficiency confirmed by duplex ultrasound, normal ankle/arm pressure index and presence of a leg ulcer were eligible. Patients were randomised to mesoglycan, 30 mg/day intramuscularly for 3 weeks followed by 100 mg/day orally, or matching placebo, as an adjunct to compression therapy and topical wound care. Treatment and observation were continued until complete ulcer healing or for 24+/-1 weeks. Time to ulcer healing and healing rates were estimated with the Kaplan-Meier method., Results: One hundred and eighty-three patients were randomised and included in the analysis (92 mesoglycan, 91 placebo). Median ulcer area upon inclusion was 3.6 cm(2)in the mesoglycan group and 3.9 cm(2)in the placebo group. The estimated time to heal 75% of the patients was 90 days on mesoglycan versus 136 days on placebo, while the cumulative rate of healing by the end of observation was 97% versus 82%, respectively. The difference in favour of mesoglycan was statistically significant (p < 0.05, centre-stratified Cox's model). The relative risk of ulcer healing with mesoglycan was 1.48. The rate of adverse events was 7/92 on mesoglycan and 6/91 on placebo., Conclusions: treatment with mesoglycan in addition to established venous ulcer therapy resulted in a significantly faster and more frequent ulcer healing, and did not raise any safety concerns., (Copyright 2001 Harcourt Publishers Limited.)

Background: Anticoagulant treatment for intermittent claudication might improve functional capacity, and prevent acute cardiovascular complications caused by peripheral obstructive arterial disease., Objectives: To assess the effects of anticoagulant drugs (heparin, low molecular weight heparin (LMWH) and oral anticoagulants) in patients with intermittent claudication (Fontaine stage II) in terms of improving walking capacity (pain-free walking distance or absolute walking distance), mortality, cardiovascular events, ankle/brachial pressure index, progression to surgery, amputation-free survival and side effects of these drugs., Search Strategy: Randomised trials of anticoagulants for intermittent claudication were sought using the search strategy described by the Cochrane Peripheral Vascular Diseases Review Group. Additional trials were sought through: reference lists resulting from this search; recent conference proceedings; contact with authors of published trials and pharmaceutical companies producing anticoagulants., Selection Criteria: All randomised trials of anticoagulants used to treat patients with intermittent claudication., Data Collection and Analysis: Thirteen trials were initially considered eligible for inclusion in the review. Two studies evaluated oral anticoagulants, five evaluated standard heparin, and six evaluated LMWHs. Only three studies (two evaluating oral anticoagulants, one evaluating heparin) met the high quality methodological inclusion criteria and were included in the primary analysis. Four other studies were included in the sensitivity analysis. The reviewers extracted the data independently., Main Results: No significant difference was observed between heparin treatment and control groups for pain-free walking distance or maximum walking distance at the end of treatment. There were no data to indicate that LMWHs benefit walking distance. Revascularisation or amputation-free survival rates were reported in one study only with a five year follow-up. No study reported a significant effect on overall mortality or cardiovascular events and the pooled odds ratios were not significant for these outcomes either. Major and minor bleeding events were significantly more frequent in the group treated with oral anticoagulants compared to control, with a non-significant increase in fatal bleeding events. No major bleeding events were reported in the study evaluating heparin, while a non-significant increase in minor bleeding events was reported., Reviewer's Conclusions: No benefit of heparin, LMWHs or oral anticoagulants has been established for intermittent claudication. An increased risk of major bleeding events has been observed especially with oral anticoagulants. The use of anticoagulants for intermittent claudication cannot be recommended at this stage.

The optimal long-term treatment of acute venous thromboembolism (VTE) in patients with malignancy remains undefined. In particular, based on current evidence, it is uncertain whether secondary prophylaxis using standard intensity oral anticoagulant therapy is associated with higher risks of bleeding and recurrent thrombosis in patients with cancer than in those without cancer. This study compared the outcome of anticoagulation courses in 95 patients with malignancy with those of 733 patients without malignancy. All patients were participants in a large, nation-wide population study and were prospectively followed from the initiation of their oral anticoagulant therapy. Based on 744 patient-years of treatment and follow-up, the rates of major (5.4% vs 0.9%), minor (16.2% vs 3.6%) and total (21.6% vs 4.5%) bleeding were statistically significantly higher in cancer patients compared with patients without cancer. Bleeding was also a more frequent cause of early anticoagulation withdrawal in patients with malignancy (4.2% vs. 0.7%; p <0.01; RR 6.2 (95% CI 1.95-19.4). There was a trend towards a higher rate of thrombotic complications in cancer patients (6.8% vs. 2.5%; p = 0.058; RR 2.5 [CI 0.96-6.5]) but this did not achieve statistical significance. In the group of patients with cancer, the bleeding rate was high across the different INR categories and was independent of the temporally associated International Normalized Ratio (INR). In contrast, the bleeding rate was increased only with INR values greater than 4.5 in the group of patients without cancer. The rate of thrombotic events was significantly higher in both cohorts when the INR was less than 2.0. In conclusion, patients with malignancy treated with oral anticoagulants have a higher rate of bleeding and possibly an increased risk of recurrent thrombosis compared with patients without malignancy. Safer and more effective anticoagulant therapy is needed for this challenging group of patients.

Very low factor IX (FIX) levels in patients during oral anticoagulant (OA) treatment, due to mutations in the FIX gene, with prolonged activated partial thromboplastin time (aPTT) and associated with bleeding complications have recently been described. We measured aPTT in 595 OA patients while being within therapeutic ranges. Patients were divided into increasing international normalized ratio (INR) classes, and FIX determined in those belonging to the first and fifth quintiles of the aPTT distribution in each INR class. Results obtained in patients of all the first aPTT quintiles were compared with those of all the fifth quintiles. While INR was not different (2.79 versus 2.77 INR), aPTT was longer (1.65 versus 1.21 ratio; P < 0.0001) and FIX lower (0.29 versus 0.44 IU/ml; P < 0.0001) in patients of the fifth quintiles. Only one patient had a markedly reduced FIX (0.03 IU/ml). Bleeding rate was 4.8 and 6.2% patient-years (not significant) in patients of the first and fifth quintiles, respectively. We therefore found that FIX levels vary greatly in spite of similar achieved anticoagulation intensity; very low FIX is, however, a rare condition. In conclusion, screening for the recently identified mutations in FIX gene does not seem justified, and identifying patients with disproportionately prolonged aPTT, to detect those with particularly low FIX levels, is difficult because of the effect of the achieved anticoagulation intensity. Therefore, aPTT measurement is indicated only in patients with increased bleeding during OA.

Defibrotide is an antithrombotic drug which enhances prostacyclin production and activates fibrinolytic system. The aim of this study was to investigate the improvement of walking distance in patients with intermittent claudication treated with defibrotide. DICLIS was a double blind, placebo-controlled study which included patients with walking distance autonomy at a standardized treadmill test < or =350 > or =100 meters. A total of 310 patients were randomly allocated to placebo (n = 101), defibrotide 800 mg/day (n = 104) or defibrotide 1200 mg/day (n = 105). During a one year follow-up, the Absolute Walking Distance (AWD) was measured six times (0, 30, 60, 90, 180, 360 days). Similar improvement in walking distance was found in the three groups until the 90th day; thereafter placebo group showed no further increase, while AWD continued to increase in the defibrotide groups. Between the 180th and 360th day visits, AWD was significantly higher (P <0.01) in patients given defibrotide than in patients given placebo. No difference in efficacy was observed between the two dosages of defibrotide. No differences in side effects were observed among the three groups. The results of the present trial suggest that long-term administration of defibrotide improves walking distance in patients with intermittent claudication.

Background: Hyperhomocysteinemia is a common finding in heart transplant recipients and may represent a risk factor for graft failure. However, the time-course, determinants and effects of medical therapy on total homocysteine plasma levels after heart transplantation remain undetermined. The aim of this study was to prospectively analyze 1) the time-course of total homocysteine in heart transplant recipients; 2) the effects of folate supplements and cyclosporine A on total homocysteine; 3) the relation among renal function, serum vitamin levels, and total homocysteine., Methods: Fifty-two heart transplant recipients consecutively evaluated for routine follow-up during 1998 were included in the study (mean age 54 +/- 12 years; 28% female). Among the 52 patients, 10 patients were treated with folate for the entire period of the study (Group F), while 26 patients never received folate (Group NF). The remaining 16 patients who did not take folate on a regular basis were excluded from subgroup analysis. Total homocysteine and creatinine plasma levels were assayed at entry into the study (time 0) and at the end of the study, 12 months later (time 12)., Results: Homocysteinemia increased significantly from time 0 to time 12 (p < 0.001), regardless of creatinine plasma levels (p = 0.03) and folate intake (p < 0.01). However, total homocysteine levels were lower in Group F compared to Group NF at time 0 and time 12 (p < 0.02). On multivariate analysis, time of follow-up, serum creatinine and lack of folate intake were positive independent predictors of total homocysteine., Conclusions: Homocysteinemia increased over time in heart transplant recipients, regardless of renal function and folate administration. Lower total homocysteine levels were associated with folate intake, suggesting that folate supplements may play a role in the prevention of vascular allograft disease.

Background: Whether elderly patients are at increased risk of complications during oral anticoagulant treatment (OAT) is still a matter of debate., Method: Bleeding and thrombotic events occurring during OAT in 461 patients, aged 75 years or older when they started OAT, and in 461 patients younger than 70 years, matched for sex, OAT indication, and treating center, were examined in a prospective, multicenter, inception-cohort study., Results: Bleeding rate was 9.9% and 6.6% patient-years in elderly and young patients, respectively (P = .07), and 2.1% and 1.1% for major bleeding (P = .19); 6 and 1 events, respectively, were fatal (all intracranial, relative risk, 6.4; P = .05). In the elderly, bleeding rate was lower (4.5%) for international normalized ratios (INRs) between 2.0 and 2.9; it was higher during the first 90 treatment days (P = .05) and when arterial vascular disease was the indication for OAT (P = .03). Thrombosis rate was 4.2% and 2.5% patient-years in elderly and young patients, respectively (P = .10); however, 13 and 5 events were fatal (relative risk, 2.8; P = .04). Thrombosis rate was lower (1.5%) for INRs between 2.0 and 2.9; it was higher during the first 90 treatment days (P<.001) and 6 of 7 venous events occurred at lower than 2.0 INRs., Conclusions: A nonsignificant trend was noted toward a higher rate of both bleeding and thrombotic complications in elderly vs matched younger patients. Intracranial bleeding and fatal thrombotic events were significantly more frequent in the elderly. Our results also indicate that lower than 2.0 INRs do not preclude bleeding in the elderly nor offer adequate protection from thrombotic events. Moderate anticoagulation (2.0-3.0 INRs) in elderly patients seems the safest and most effective.