Biological and clinical effects of sulodexide in arterial disorders and diseases.

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.

Thromboxane Antagonism with terutroban in Peripheral Arterial Disease: the TAIPAD study.

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.

Has time come for a re-assessment of spa therapy? The NAIADE survey in Italy.

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.

Thrombophilia and venous thromboembolism. International consensus statement. Guidelines according to scientific evidence.

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).

Effects of defibrotide in patients with chronic deep insufficiency. The PROVEDIS study.

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.

Venous thromboembolism, oral contraceptives and high prothrombin levels.

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.

Clinical, functional and quality of life changes after balneokinesis with sulphurous water in patients with varicose veins.

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.

Sulodexide in the treatment of intermittent claudication. Results of a randomized, double-blind, multicentre, placebo-controlled study.

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.

Changes in the use of health resources by patients with chronic phlebopathies after thermal hydrotherapy. Report from the Naiade project, a nation-wide survey on thermal therapies in Italy.

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.

Venous thromboembolism in young women; role of thrombophilic mutations and oral contraceptive use.

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.

Thrombophilia in young women candidate to the pill: reasons for and against screening.

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.

Management of patients with carotid stenosis.

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.

Anticoagulants (heparin, low molecular weight heparin and oral anticoagulants) for intermittent claudication.

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.

A placebo-controlled, double-blind study of mesoglycan in the treatment of chronic venous ulcers.

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.

A comparison of the safety and efficacy of oral anticoagulation for the treatment of venous thromboembolic disease in patients with or without malignancy.

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.

Assessment of activated partial thromboplastin time and factor IX in subjects attending an anticoagulation clinic.

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.

Increasing plasma homocysteine during follow-up in heart transplant recipients: effects of folate and renal function.

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.