Abstract

Background.

Renal failure is a major cause of morbidity in western Europe, with rising prevalence. Vascular access complications are the leading cause of morbidity among patients on haemodialysis. Considering the health care burden of vascular access failure, there is limited research dedicated to the topic.

Methods.

Randomised control trials of medications aimed at improving vascular access patency were identified using a medline search between January 1950 and January 2011.

Results.

Thirteen randomised trials were identified, investigating antiplatelets, anticoagulants and fish oil in preserving vascular access patency. Outcomes are presented and reviewed in conjunction with the underlying pathophysiological mechanisms of failure of vascular access.

Discussion.

Vascular access failure is a complex process. Most clinical trials so far have involved medications primarily aimed at preventing thrombosis. Other contributing pathways such as neointimal hyperplasia have not been investigated clinically. Improved outcomes may be seen by linking future therapies to these pathways.

Introduction

Renal failure is a major cause of morbidity in western Europe, with 117.1 per million population requiring haemodialysis and the prevalence predicted to rise in the next decade [ 1 ]. Complications of vascular access are the leading cause of morbidity among patients on haemodialysis, accounting for 30% of all hospital admissions per annum [ 2 ]. The annual cost to the UK's National Health Service in percutaneous interventions alone to maintain patency of vascular access is £84.1 million [ 3 ].

Creation of an autologous arteriovenous fistula (AVF) is the intervention of choice to create a vascular access point for haemodialysis [ 4 ]. Vascular access can be obtained by creation of an autologous AVF, insertion of a prosthetic interposition graft between artery and vein (AVG) or insertion of a prosthetic central dialysis line (Permacath). Prosthetic AVGs for peripheral dialysis access have the advantage of being useable almost immediately for dialysis, but they are limited by infective complications and poor patency rates when compared with autologous AVF. The primary patency of AVGs is estimated at 50% at 1 year, with a 6-fold intervention rate required to achieve similar patency to autologous grafts [ 5 ]. Permacath use is limited by frequent infective complications, central venous stenosis and is mainly used as a temporary measure, while other routes of vascular access are established. Autologous AVF have an annual primary patency of 85% if they mature adequately for use [ 6 ]; however, successful maturation has been reported to be as low as 50% [ 7 ]. The autologous AVF is therefore the access method of choice, with a national target that 67% of patients requiring haemodialysis have a working AVF [ 8 ]. For the rest of this article, autologous AVF will be referred to as AVF and prosthetic AVGs as AVG.

This article will review the pathophysiological mechanisms responsible for failure of AVF and AVG, followed by the outcomes of trials aimed at improving vascular access patency using both established and novel agents and how these relate to the underlying pathophysiology of vascular access failure.

Failure of vascular access

For vascular access to be successful, a conduit is required that has the properties of easy cannulation, flow rates of ∼400 mL/min and low resistance. Autologous arteriovenous fistula failure and prosthetic AVG failure occurs due to different pathophysiological processes and should therefore be considered separately. Furthermore, autologous AVF failure can be sub-categorized into lack of maturation, which is rapidly evident following AVF creation or failure of a mature AVF. Lack of maturation occurs in up to 50% of AVF and failure of a mature AVF occurs in ∼15% by 1 year. Prosthetic AVG failure occurs primarily due to stenosis at the graft-venous anastamosis segment, afflicting 50% of AVGs by 1 year.

Autologous AVF failure

Failure of maturation

The mechanisms behind failure of AVF to mature are complex. Successful maturation depends upon increased shear stress in the venous segment and subsequent compensation. Shear stress is a function of blood flow, blood viscosity and vessel radius. To maintain constant shear stress levels, the vein must dilate to increase the radius, as the other parameters are relatively fixed. High shear stress prompts vascular remodelling with endothelial cell alignment in the direction of flow, nitric oxide (NO) secretion and vasodilation [ 9 ]. Vasodilation alone, however, is not enough to normalize shear stress [ 10 ], and fragmentation of the elastic lamina is required to permit further dilatation. This has been shown to be influenced by matrix metalloproteinase release [ 11 ]. In addition, vascular smooth muscle cell (VSMC) hypertrophy occurs, with an increase in the vein wall cross-sectional area [ 12 ]. If compensatory mechanisms do not occur and shear stress is not high enough, a low flow state occurs with local release of prothrombotic and vasoconstrictive mediators [ 13 ]. Ultimately, this leads to failure of AVF maturation.

Multiple factors can therefore influence failure of AVF maturation by potentially limiting flow rates such as vein diameter [ 14 ], presence of a central stenosis and distal location. The role of surgical expertise is not well studied, though one study has shown that AVF created in low throughput units have poorer outcomes when compared with those with high volume [ 15 ]. In addition, identifying a pharmacological target to enhance AVF maturation is also difficult. Prevention of thrombosis within the graft may enhance the patency over a short period of time but may not lead to more useable AVF. Enhancing endothelial function and NO production may be a useful therapeutic target, though in the case of lack of maturation, technical factors such as vein calibre may be overwhelming.

Failure of mature AVF

The commonest cause of failure of a mature AVF is stenosis of the venous segment, with 20–40% occurring within the first few centimetres of vein distal to the anastamosis [ 16 ]. The underlying cause of stenosis is neointimal hyperplasia formation [ 5 ]. Neointimal hyperplasia is an inflammatory process in response to injury, with intimal layer thickening, VSMC proliferation and matrix deposition [ 17 ]. As neointimal hyperplasia formation progresses, the AVF becomes stenosed causing haemodynamic disturbance and limitation of flow, with eventual thrombosis and AVF failure.

The process of neointimal hyperplasia is initiated by endothelial damage, with subsequent endothelial cell dysfunction causing an inflammatory response, which drives the recruitment of leucocytes, proliferation, migration and differentiation of VSMCs and extracellular matrix deposition from fibroblasts and myofibroblasts (commonly differentiated VSMC). Endothelial damage can be induced by inevitable endothelial disruption by surgical trauma and haemodyamic changes to flow within the vein as it becomes arterialized. This hypothesis of AVF failure is largely extrapolated from studies of peripheral bypass grafts. Small animal studies have confirmed that haemodynamic changes associated with AVF formation promote similar pathobiological changes, in particular VSMC proliferation, migration and differentiation [ 18 , 19 ].

Figure 1 illustrates the underlying pathways of neointimal hyperplasia in AVF.

Fig. 1.

Pathophysiological pathways underlying stenosis and neointimal hyperplasia formation in matured AVF. Endothelial dysfunction occurs and the normal, protective effect of NO is lost. Exposure of the sub-endothelial matrix stimulates platelet activation and thrombus for formation at the site. Activated platelets release thrombin, Thromboxane A2, platelet derived growth factor (PDGF) and P-selectin. Thromboxane A2 and PDGF stimulate VSMC proliferation and migration from the tunica media to neointimal. P-selectin is a chemoattractant for leucocytes, which also migrate to the lesion. Once activated at the site, they secrete insulin-like growth factor (ILGF) and matrix metalloproteinases (MMP). Again, these stimulate proliferation and migration of VSMCs. Under the influence of these growth factors, VSMCs change from a quiescent to proliferative phenotype to form the abundant cellular element of the lesion. When proliferative, they also produce significant extracellular matrix: collagen and elastin. As the lesion of neointimal hyperplasia advances, it intrudes the lumen, limiting flow and causes AVF failure.

Fig. 1.

Pathophysiological pathways underlying stenosis and neointimal hyperplasia formation in matured AVF. Endothelial dysfunction occurs and the normal, protective effect of NO is lost. Exposure of the sub-endothelial matrix stimulates platelet activation and thrombus for formation at the site. Activated platelets release thrombin, Thromboxane A2, platelet derived growth factor (PDGF) and P-selectin. Thromboxane A2 and PDGF stimulate VSMC proliferation and migration from the tunica media to neointimal. P-selectin is a chemoattractant for leucocytes, which also migrate to the lesion. Once activated at the site, they secrete insulin-like growth factor (ILGF) and matrix metalloproteinases (MMP). Again, these stimulate proliferation and migration of VSMCs. Under the influence of these growth factors, VSMCs change from a quiescent to proliferative phenotype to form the abundant cellular element of the lesion. When proliferative, they also produce significant extracellular matrix: collagen and elastin. As the lesion of neointimal hyperplasia advances, it intrudes the lumen, limiting flow and causes AVF failure.

Prosthetic AVG failure

Stenosis in prosthetic AVGs occurs most commonly at the graft-venous anastamosis segment. Histological analysis of stenoses demonstrates a pathophysiological process similar to neointimal hyperplasia formation in AVF [ 20 ]. However, in the prosthetic graft segment, the most abundant cellular element is macrophages [ 20 ], a pathophysiologically distinct process characterized by the additional feature of an inflammatory foreign body reaction which, by virtue of the inflammatory mediators produced is likely to accelerate the process. Evolution of neointimal hyperplasia creates a flow limiting stenosis with eventual thrombosis and AVG failure.

A therapeutic approach to improving patency of established AVF and AVG would be either to prevent thrombus formation, prevent evolution of the underlying stenosis or a combination of these treatments. Obvious targets to prevent stenosis evolution are the inhibition of VSMC proliferation and maintenance of endothelial integrity. Most established approaches' primary aim is to prevent thrombosis in either the AVF or AVG. Potential ‘downstream’ effects on stenosis formation do exist with these approaches as will be discussed. More novel therapeutic strategies aimed at preventing stenosis evolution will also be reviewed.

Only thirteen randomized control trials were identified investigating outcomes in AVF and AVG. Table 1 summarizes the primary outcomes, secondary outcomes and adverse events of these trials by drug class. Table 2 lists confounding variables by baseline patient characteristics of each study. Table 3 by reported blood parameters and Table 4 by published relevant technical data. The trials will be summarized by drug class and results linked to underlying pathophysiological mechanisms.

Table 1.

Main outcomes of identified trials a

Trial Intervention Control Graft type n Duration Outcome 1 Outcome 2 Reported patency rates Adverse events 
Aspirin          
    Andrassy et al. [ 21 ]  Aspirin 1 g (alternate days) Placebo AVF 92 28 days Thrombosis: 4% aspirin versus 23% control, OR 0.15   Nil 
    Harter et al. [ 22 ]  Aspirin 160 mg od Placebo AVG 49 5 months Thrombosis: 72% placebo versus 32% aspirin   Nil: patients with history of GI bleed excluded from study 
    Diypridiamole          
    Sreedhara [ 23 ] 1994  Dipyridamole 75 mg tds or aspirin 325 mg od or dipyridamole and aspirin. Placebo AVG 107 (84 Type I, 23 Type II) 18 months Graft thrombosis: 21% dipyridamole alone, 80% aspirin alone, 25% dipyridamole + aspirin, 40% placebo. Relative risk of thrombosis, 0.35 dipyridamole and 1.99 aspirin. As outcome 1 Nil 
    DAC Study Group et al. [ 24 ]  Diypridamole 200 mg bd and aspirin 25 mg. Placebo AVG 649 1 year Loss of primary graft patency: 17% RRR in favour treatment. Median graft survival: 22.1 months, prolonged 6 weeks by treatment. 23% versus 25% at 1 year. 15% died/lost to follow-up primary outcome, 30% for secondary outcome, 40% did not get monthly flow monitoring 
    Thienopyridines          
    DAC Study Group [ 25 ]  Clopidogrel (300 mg loading→75 mg maint) Placebo AVF 877 6 weeks Fistula thrombosis 6 weeks: RRR 0.63 in favour treatment (12.2 versus 19.5%). Fistula useable for dialysis: 61.8 versus 59.5%, not significant. In 6 weeks, 61.8 versus 59.5% matured suitably to be considered for dialysis. No increase bleeding risk 
    Trimarchi 2006 [ 26 ]  Clopidogrel 75 mg Placebo AVG 24 3 years Time to thrombosis: 380 versus 90 days in favour treatment, OR 0.01. Mortality: 100% in control versus 16.7% treatment  100% mortality control versus 16.7% treatment. No increase bleeding risk. 
    Kaufman et al. [ 27 ]  Clopidogrel 75 mg and aspirin 325 mg Placebo AVG 200 Stopped 7 months Time to first episode thrombosis: non-significant benefit treatment (hazard ratio 0.81) Significant increase major bleeding events: every case of graft failure prevented, 1.21 major bleeding episodes occurred. Incomplete 44 significant bleeding events treatment versus 23 control 
    Grontoft et al. [ 28 ]  Ticolpidine 250 mg bd initiated 7/7 pre-operatively Placebo AVF and AVG 258 4 weeks Thrombosis at 4 weeks assessed by USA: 12 versus 19% in favour of control, not significant. NR 84% at 4 weeks. 5.8% patients died before completing study. 
    Grontoft et al. [ 29 ]  Ticlopidine 250 mg bd Placebo AVF 42 4 weeks Fistula function at 4 weeks: 47% not functioning in placebo versus 10.5% treatment arm.  Overall, 72% patency at 4 weeks. 15% patients did not complete study. No increased bleeding risk. 
    Fiskerstrand et al. [ 30 ]  Ticlopidine 250 mg bd Placebo AVF 18 4 weeks Fistula failure: 33.3% ticlopidine versus 55.5% placebo   11% patients did not complete study. 
    Kobayashi et al. [ 31 ]  Ticlopidine 200 mg bd Placebo Established AVF and AVG 107 3 months Patients requiring thrombectomy: reduction 1.18×/patient/4 weeks in favour treatment. NR n/a: established grafts 29% enrolled patients did not complete 12 weeks follow-up 
Warfarin          
    Crowther et al. [ 32 ]  Warfarin: target INR 1.4–1.9 Placebo AVG 107 24 months Graft loss: 73% warfarin versus 61% control Average time to graft failure: 199 days warfarin versus 83 days control (ns) 27 versus 39% at 24 months. 9.3% of grafts did not function suitably for access (n.s. difference between groups). Major haemorrhage: significant increase warfarin, 6 versus 0 major bleeding episodes. 
Fish oil          
    Schmitz et al. [ 33 ]  Fish oil 4000 mg Placebo AVG 12 12 months Primary patency: 75.6% fish oil versus 1.49% control Graft thrombosis: 75% control versus 16.6% fish oil 75.6% fish oil versus 14.9% control Nil 
Trial Intervention Control Graft type n Duration Outcome 1 Outcome 2 Reported patency rates Adverse events 
Aspirin          
    Andrassy et al. [ 21 ]  Aspirin 1 g (alternate days) Placebo AVF 92 28 days Thrombosis: 4% aspirin versus 23% control, OR 0.15   Nil 
    Harter et al. [ 22 ]  Aspirin 160 mg od Placebo AVG 49 5 months Thrombosis: 72% placebo versus 32% aspirin   Nil: patients with history of GI bleed excluded from study 
    Diypridiamole          
    Sreedhara [ 23 ] 1994  Dipyridamole 75 mg tds or aspirin 325 mg od or dipyridamole and aspirin. Placebo AVG 107 (84 Type I, 23 Type II) 18 months Graft thrombosis: 21% dipyridamole alone, 80% aspirin alone, 25% dipyridamole + aspirin, 40% placebo. Relative risk of thrombosis, 0.35 dipyridamole and 1.99 aspirin. As outcome 1 Nil 
    DAC Study Group et al. [ 24 ]  Diypridamole 200 mg bd and aspirin 25 mg. Placebo AVG 649 1 year Loss of primary graft patency: 17% RRR in favour treatment. Median graft survival: 22.1 months, prolonged 6 weeks by treatment. 23% versus 25% at 1 year. 15% died/lost to follow-up primary outcome, 30% for secondary outcome, 40% did not get monthly flow monitoring 
    Thienopyridines          
    DAC Study Group [ 25 ]  Clopidogrel (300 mg loading→75 mg maint) Placebo AVF 877 6 weeks Fistula thrombosis 6 weeks: RRR 0.63 in favour treatment (12.2 versus 19.5%). Fistula useable for dialysis: 61.8 versus 59.5%, not significant. In 6 weeks, 61.8 versus 59.5% matured suitably to be considered for dialysis. No increase bleeding risk 
    Trimarchi 2006 [ 26 ]  Clopidogrel 75 mg Placebo AVG 24 3 years Time to thrombosis: 380 versus 90 days in favour treatment, OR 0.01. Mortality: 100% in control versus 16.7% treatment  100% mortality control versus 16.7% treatment. No increase bleeding risk. 
    Kaufman et al. [ 27 ]  Clopidogrel 75 mg and aspirin 325 mg Placebo AVG 200 Stopped 7 months Time to first episode thrombosis: non-significant benefit treatment (hazard ratio 0.81) Significant increase major bleeding events: every case of graft failure prevented, 1.21 major bleeding episodes occurred. Incomplete 44 significant bleeding events treatment versus 23 control 
    Grontoft et al. [ 28 ]  Ticolpidine 250 mg bd initiated 7/7 pre-operatively Placebo AVF and AVG 258 4 weeks Thrombosis at 4 weeks assessed by USA: 12 versus 19% in favour of control, not significant. NR 84% at 4 weeks. 5.8% patients died before completing study. 
    Grontoft et al. [ 29 ]  Ticlopidine 250 mg bd Placebo AVF 42 4 weeks Fistula function at 4 weeks: 47% not functioning in placebo versus 10.5% treatment arm.  Overall, 72% patency at 4 weeks. 15% patients did not complete study. No increased bleeding risk. 
    Fiskerstrand et al. [ 30 ]  Ticlopidine 250 mg bd Placebo AVF 18 4 weeks Fistula failure: 33.3% ticlopidine versus 55.5% placebo   11% patients did not complete study. 
    Kobayashi et al. [ 31 ]  Ticlopidine 200 mg bd Placebo Established AVF and AVG 107 3 months Patients requiring thrombectomy: reduction 1.18×/patient/4 weeks in favour treatment. NR n/a: established grafts 29% enrolled patients did not complete 12 weeks follow-up 
Warfarin          
    Crowther et al. [ 32 ]  Warfarin: target INR 1.4–1.9 Placebo AVG 107 24 months Graft loss: 73% warfarin versus 61% control Average time to graft failure: 199 days warfarin versus 83 days control (ns) 27 versus 39% at 24 months. 9.3% of grafts did not function suitably for access (n.s. difference between groups). Major haemorrhage: significant increase warfarin, 6 versus 0 major bleeding episodes. 
Fish oil          
    Schmitz et al. [ 33 ]  Fish oil 4000 mg Placebo AVG 12 12 months Primary patency: 75.6% fish oil versus 1.49% control Graft thrombosis: 75% control versus 16.6% fish oil 75.6% fish oil versus 14.9% control Nil 
a

od, once daily; bd, twice dailty; tds, three times daily.

Table 2.

Patient characteristics

Trial Age Male Race BMI Diabetes Smoking BP/HTN Other Compliance Follow-up 
Aspirin           
    Andrassy et al. [ 21 ]  NR NR NR NR NR NR Six HTN placebo versus one aspirin Reduction arterial flow six placebo versus one aspirin NR Complete 
    Harter et al. [ 22 ]  49 45% NR NR NR NR NR All variables stated to be ‘well matched’ Four non-compliance 29.5% did not complete study 
Dipyridamole           
    Sreedhara 1994 [ 23 ]  54 42% 30% black 24 NR NR NR NR NR 88% 
    DAC Study Group et al. [ 24 ]  60 39% 71% black 30 19.4% 5% 144/74 NR 83% 15% lost primary, 30% secondary 
Thienopyridine           
    DAC Study Group [ 25 ]  53 62% 48% black 30 48% 19% 140/78  87% 8% did not complete 
    Trimarchi 2006 [ 26 ]  71 NR NR NR 25% NR NR  NR NR 
    Kaufman et al. [ 27 ]  62 99% 70% black NR 47% NR NR Hx PUD 17% 33% had study medication discontinued prior to termination Terminated early 
    Grontoft et al. [ 28 ]  58 63% NR 24 NR NR NR NR Not reported 15% did not complete study 
    Grontoft et al. [ 29 ]  44 66% NR NR 52% NR NR  NR 85% completed study 
    Fiskerstrand et al. [ 30 ]  NR NR NR NR NR NR NR NR  16.6% did not complete study 
    Kobayashi et al. [ 31 ]  NR 37% NR NR NR NR NR NR 71% completed study 29% did not complete study 
Warfarin           
    Crowther et al. [ 32 ]  65 77% NR 80 versus 74 kg 43% 31% NR NR INR above 1.45 9.1%, within 47% and below 43.1% 100% 
Fish oil           
    Schmitz et al. [ 33 ]  53 45% 79% black N/a: 79 kg (weight) 58%  160 mmHg: reduction by 30 versus 15 mmHg in treatment arm. No concurrent anti-platelet use 100% 96% 
Trial Age Male Race BMI Diabetes Smoking BP/HTN Other Compliance Follow-up 
Aspirin           
    Andrassy et al. [ 21 ]  NR NR NR NR NR NR Six HTN placebo versus one aspirin Reduction arterial flow six placebo versus one aspirin NR Complete 
    Harter et al. [ 22 ]  49 45% NR NR NR NR NR All variables stated to be ‘well matched’ Four non-compliance 29.5% did not complete study 
Dipyridamole           
    Sreedhara 1994 [ 23 ]  54 42% 30% black 24 NR NR NR NR NR 88% 
    DAC Study Group et al. [ 24 ]  60 39% 71% black 30 19.4% 5% 144/74 NR 83% 15% lost primary, 30% secondary 
Thienopyridine           
    DAC Study Group [ 25 ]  53 62% 48% black 30 48% 19% 140/78  87% 8% did not complete 
    Trimarchi 2006 [ 26 ]  71 NR NR NR 25% NR NR  NR NR 
    Kaufman et al. [ 27 ]  62 99% 70% black NR 47% NR NR Hx PUD 17% 33% had study medication discontinued prior to termination Terminated early 
    Grontoft et al. [ 28 ]  58 63% NR 24 NR NR NR NR Not reported 15% did not complete study 
    Grontoft et al. [ 29 ]  44 66% NR NR 52% NR NR  NR 85% completed study 
    Fiskerstrand et al. [ 30 ]  NR NR NR NR NR NR NR NR  16.6% did not complete study 
    Kobayashi et al. [ 31 ]  NR 37% NR NR NR NR NR NR 71% completed study 29% did not complete study 
Warfarin           
    Crowther et al. [ 32 ]  65 77% NR 80 versus 74 kg 43% 31% NR NR INR above 1.45 9.1%, within 47% and below 43.1% 100% 
Fish oil           
    Schmitz et al. [ 33 ]  53 45% 79% black N/a: 79 kg (weight) 58%  160 mmHg: reduction by 30 versus 15 mmHg in treatment arm. No concurrent anti-platelet use 100% 96% 
Table 3.

Blood parameters a

Trial Urea (mmol/L) Cholesterol (g/dL) Hb (g/dL) Haematocrit (l/L) Albumin (g/dL)  Platelets (×10 9 /L)  Other 
Aspirin        
    Andrassy et al. [ 21 ]  NR NR NR NR NR NR  
    Harter et al. [ 22 ]  NR NR NR NR NR NR  
Dipyridamole        
    Sreedhara 1994 [ 23 ]         
    DAC Study Group et al. [ 24 ]  NR NR 11.8 NR 37 NR  
Thienopyridine        
    DAC Study Group et al. [ 25 ]  NR NR 11.6 NR 37 NR  
    Trimarchi 2006 [ 26 ]  NR NR NR 33 NR NR  
    Kaufman et al. [ 27 ]  Urea reduction ratio: 69 164 mg/dL 11.3 NR 36 NR  
    Grontoft et al. [ 28 ]  29.5 6.05 9.13 NR NR NR  
    Grontoft et al. [ 29 ]  NR NR NR NR NR NR  
    Fiskerstrand et al. [ 30 ]  NR NR NR NR NR 250  
    Kobayashi et al. [ 31 ]  NR NR NR NR NR NR  
Warfarin        
    Crowther et al. [ 32 ]  NR NR 10.5 NR 35 216 Average INR 1.45 Rx group, 43.1% below therapeutic range. 
Fish oil        
    Schmitz et al. [ 33 ]  NR 180 mg/dL NR 32 NR NR  
Trial Urea (mmol/L) Cholesterol (g/dL) Hb (g/dL) Haematocrit (l/L) Albumin (g/dL)  Platelets (×10 9 /L)  Other 
Aspirin        
    Andrassy et al. [ 21 ]  NR NR NR NR NR NR  
    Harter et al. [ 22 ]  NR NR NR NR NR NR  
Dipyridamole        
    Sreedhara 1994 [ 23 ]         
    DAC Study Group et al. [ 24 ]  NR NR 11.8 NR 37 NR  
Thienopyridine        
    DAC Study Group et al. [ 25 ]  NR NR 11.6 NR 37 NR  
    Trimarchi 2006 [ 26 ]  NR NR NR 33 NR NR  
    Kaufman et al. [ 27 ]  Urea reduction ratio: 69 164 mg/dL 11.3 NR 36 NR  
    Grontoft et al. [ 28 ]  29.5 6.05 9.13 NR NR NR  
    Grontoft et al. [ 29 ]  NR NR NR NR NR NR  
    Fiskerstrand et al. [ 30 ]  NR NR NR NR NR 250  
    Kobayashi et al. [ 31 ]  NR NR NR NR NR NR  
Warfarin        
    Crowther et al. [ 32 ]  NR NR 10.5 NR 35 216 Average INR 1.45 Rx group, 43.1% below therapeutic range. 
Fish oil        
    Schmitz et al. [ 33 ]  NR 180 mg/dL NR 32 NR NR  
a

Av, average.

Table 4.

Technical data

Trial No. Centre Graft type Graft location Anastamosis type Vessel quality graded? Graft monitoring Previous CVC Previous access 
Aspirin         
    Andrassy et al. [ 21 ]  AVF NR End-to-end: 41 32: ‘poor’; 60: ‘good’ Clinical NR NR 
End-to-side: 4 
Side-Side: 47 
    Harter et al. [ 22 ]  Single surgeon AVG All wrist or forearm radio-cephalic. NR No Clinical NR NR 
    Dipyridmaole         
    Sreedhara 1994; [ 23 ] DAC Study Group et al. [ 24 ][ 25 ]  79% primary grafts, 21% revision or post-thrombectomy  NR No Clinical assessment NR NR 
 13 94% PTFE, 5% other prosthetic material, 1% autologous interposition 49% forearm, 44% upper arm, 6% leg, 1% chest NR No US indicator dilution technique + dialysis flow rates. 65% 51% 
Thienopyridine         
    DAC Study Group et al. [ 25 ]  9: 71 surgeons at 27 hospitals 99.5% AVF, 0.5% prosthetic excluded from trial. 54% forearm, 46% upper arm of which 69% brachiocephalic and 25% basilic transposition. NR No Clinical assessment NR 80% 
    Trimarchi 2006 [ 26 ]  75% radiocephalic, 25% brachiocephalic  NR NR Clinical/venous outlet monitoring NR NR 
    Kaufman et al. [ 27 ]  multicentre PTFE Forearm: 64% NR No Clinical 70% 53% 
    Grontoft et al. [ 28 ]  AVF: 90%, prosthetic: 6.2%, autologous interposition: 3.4% 75% wrist 75% end-to-side Good 73%, poor 17% US NR 17% 
    Grontoft et al. [ 29 ]  AVF ‘Most’ radiocephalic ‘Most’ end-to-side anastamosis No NR NR ‘A few’ 
    Fiskerstrand et al. [ 30 ]  AVF Brescia-Cimino NR No Clinical NR  
    Kobayashi et al. [ 31 ]  NR AV shunt: 64.4%, AV graft: 31.7%, AVF: 3.7% NR NR No Clinical NR NR 
Warfarin         
    Crowther et al. [ 32 ]  PTFE Forearm loop: 81% NR No Clinical NR 6.5% 
Fish oil         
    Schmitz et al. [ 33 ]  PTFE 7 mm Upper arm straight: 29%, forearm loop: 42%, forearm straight: 34% NR No Dialysis venous outflow pressure/clinical NR 37% 
Trial No. Centre Graft type Graft location Anastamosis type Vessel quality graded? Graft monitoring Previous CVC Previous access 
Aspirin         
    Andrassy et al. [ 21 ]  AVF NR End-to-end: 41 32: ‘poor’; 60: ‘good’ Clinical NR NR 
End-to-side: 4 
Side-Side: 47 
    Harter et al. [ 22 ]  Single surgeon AVG All wrist or forearm radio-cephalic. NR No Clinical NR NR 
    Dipyridmaole         
    Sreedhara 1994; [ 23 ] DAC Study Group et al. [ 24 ][ 25 ]  79% primary grafts, 21% revision or post-thrombectomy  NR No Clinical assessment NR NR 
 13 94% PTFE, 5% other prosthetic material, 1% autologous interposition 49% forearm, 44% upper arm, 6% leg, 1% chest NR No US indicator dilution technique + dialysis flow rates. 65% 51% 
Thienopyridine         
    DAC Study Group et al. [ 25 ]  9: 71 surgeons at 27 hospitals 99.5% AVF, 0.5% prosthetic excluded from trial. 54% forearm, 46% upper arm of which 69% brachiocephalic and 25% basilic transposition. NR No Clinical assessment NR 80% 
    Trimarchi 2006 [ 26 ]  75% radiocephalic, 25% brachiocephalic  NR NR Clinical/venous outlet monitoring NR NR 
    Kaufman et al. [ 27 ]  multicentre PTFE Forearm: 64% NR No Clinical 70% 53% 
    Grontoft et al. [ 28 ]  AVF: 90%, prosthetic: 6.2%, autologous interposition: 3.4% 75% wrist 75% end-to-side Good 73%, poor 17% US NR 17% 
    Grontoft et al. [ 29 ]  AVF ‘Most’ radiocephalic ‘Most’ end-to-side anastamosis No NR NR ‘A few’ 
    Fiskerstrand et al. [ 30 ]  AVF Brescia-Cimino NR No Clinical NR  
    Kobayashi et al. [ 31 ]  NR AV shunt: 64.4%, AV graft: 31.7%, AVF: 3.7% NR NR No Clinical NR NR 
Warfarin         
    Crowther et al. [ 32 ]  PTFE Forearm loop: 81% NR No Clinical NR 6.5% 
Fish oil         
    Schmitz et al. [ 33 ]  PTFE 7 mm Upper arm straight: 29%, forearm loop: 42%, forearm straight: 34% NR No Dialysis venous outflow pressure/clinical NR 37% 

Anti-platelet agents

Anti-platelets are well established in the treatment of patients with end-stage renal failure where use significantly reduces the risk of cardiovascular events [ 34 ]. Aspirin, dipyridamole and thienopyridines have all been investigated. The majority of randomized control trials have investigated anti-platelet use with thrombosis as an end point of graft survival. Aspirin inhibits platelets through irreversible inhibition of the prostaglandin H-synthase C (COX) enzyme [ 35 ], part of the arachidonic acid pathway that forms thromboxane A 2 . Dipyridamole inhibits cyclic adenosine monophosphate (cAMP) phosphodiasterase, affecting the NO/cyclic guanosine monophosphate signalling pathway [ 36 ], part of the platelet activation pathway. Ticlopidine and clopidogrel both irreversibly inhibit adenosine diphosphate (ADP)-dependent pathways of platelet aggregation mainly via P2 Y12 G-protein-coupled receptor, which initiates platelet aggregation and amplifies the response to thromboxane A 2 and thrombin [ 37 ].

Aside from direct anti-platelets effects, administration of aspirin and dipyridamole at physiologically relevant doses has been shown to reduce neointimal hyperplasia in a primate bypass graft model [ 38 ]. Dipyridamole alone has been shown to inhibit VSMC proliferation induced by platelet-derived growth factor (PDGF) and fibroblast growth factor [ 39 , 40 ]. Subsequent research, however, has demonstrated no effect of aspirin on VSMC proliferation and an inhibition using dipyridamole at concentrations in excess of physiological relevance if taken systemically [ 41 ], so the ‘pleiotropic’ effects of anti-platelets agents have yet to be fully established. There is little evidence that Ticlopidine or clopidogrel have direct effects upon VSMC. While direct effects of anti-platelet agents on cellular pathways of neointimal hyperplasia are contentious, inhibition of platelet activation may have down-stream effects on such pathways. Platelet activation results in release of over a dozen chemokines, growth factors and small molecules [ 42 ]. PDGF is mitogenic to VSMCs [ 43 ], as is Thromboxane A2 [ 44 ]. P-selectin binds to P-selectin glycoprotein ligand 1 on leucocytes [ 45 ]. This further contributes to pathways of intimal hyperplasia with activated leucocytes releasing matrix metalloproteinase 9 and insulin-like growth factor 1 [ 46 ]. Figure 2 summarizes potential downstream effects of platelet activation that may inhibit pathways of AVF and AVG stenosis.

Fig. 2.

The potential downstream effects of platelet activation. Activated platelets secrete PDGF, which is directly mitogenic to VSMC, the key cellular element of AVF stenosis. P-selectin attracts circulating leucocytes, which in AVG eventually forms the largest cellular element of the stenosis and contribute to AVF stenosis by secretion of insulin-like growth factor. Thromboxane A2 is also purported to enhance VSMC proliferation, as is the presence of thrombin.

Fig. 2.

The potential downstream effects of platelet activation. Activated platelets secrete PDGF, which is directly mitogenic to VSMC, the key cellular element of AVF stenosis. P-selectin attracts circulating leucocytes, which in AVG eventually forms the largest cellular element of the stenosis and contribute to AVF stenosis by secretion of insulin-like growth factor. Thromboxane A2 is also purported to enhance VSMC proliferation, as is the presence of thrombin.

With regard to facilitating maturation of AVF, anti-platelet agents may prevent thrombus formation in a low-flow graft, potentially ‘buying time’ for maturation to occur. In addition, aspirin has been shown to induce NO release from the endothelium experimentally, an effect that may encourage AVF maturation [ 47 ].

Outcome of clinical trials

Three trials were identified examining the use of aspirin. There was a consistent trend for aspirin to reduce graft thrombosis with reductions measured in AVF and AVG >1–6 months when compared to placebo. Thrombosis rates of 4 versus 23% (Andrassy [ 21 ]) and 32 versus 72% (Harter [ 22 ]) were reported with minimal side effects of use. These trials, however, are old and have small numbers, with little reporting of patient and graft confounding variables.

Dipyridamole has potential pleiotropic effects on pathways of neointimal hyperplasia formation such as VSMC proliferation. The most recent trial [ 24 ] demonstrated primary AVF patency of 23 versus 25% at 1 year in 649 patients taking dipyridamole and aspirin. AVF survival time was shown to be prolonged by 6 weeks with dipyridamole treatment compared to control. Confounding variables were well reported with minimal side effects. Unfortunately, primary patency rates in this trial were lower than expected, potentially leading to an effect of treatment being lost.

Thienopyridines have been investigated in seven trials as summarized in Table 1 . Ticlopidine has been investigated in four trials [ 28–31 ], with an overall consistent trend to improve thrombosis over a short period in both AVF and AVG. These trials were limited by small numbers, short follow-up periods and lack of reporting of confounding variables.

Clopidogrel has been the focus of three trials. The most recent trial [ 25 ] investigated 877 patients undergoing AVF creation and demonstrated a reduction in AVF occlusion at 6 weeks (relative risk reduction 0.63). The secondary outcome was the number of AVF useable for dialysis. There was no significant difference in either group at 6 weeks.

The Kaufman [ 27 ] trial raised an issue over the safety of clopidogrel in patients undergoing haemodialysis in a trial of 200 patients that was halted early due to a significant increase in bleeding risk.

Taking the trials using anti-platelet treatment together, it appears that treatment does appear to reduce thrombosis within both AVF and AVG. What is unclear is if this translates into any clinical benefit. The largest long-term trial using dipyridamole demonstrated a prolongation of AVG survival by 6 weeks. This may be of critical benefit to haemodialysis patients, allowing time for ‘rescue’ endovascular procedures for example. However, it indicates that treatment goes little beyond preventing graft thrombosis and may have little effect on pathways of neointimal hyperplasia formation. Similarly, clopidogrel use also appears to prevent graft thrombosis in the short term, but by 6 weeks, there does not appear to be a difference in the number of AVF that have matured suitably for use. Again, this indicates that there is no positive effect on the underlying mechanisms that result in AVF maturation. Anti-platelet use may have a critical role in maintenance of AVF and AVG, but it is likely that supplemental agents, specifically targeting pathways of neointimal hyperplasia formation and AVF maturation will be required to yield more significant clinical benefits.

Warfarin

Warfarin prevents coagulation within the AVF or AVG, potentially prolonging the duration of patency. No effects upon pathways of neointimal hyperplasia have been reported. One trial has been performed investigating the use of warfarin in maintaining the patency of prosthetic AVGs [ 32 ]. Warfarin therapy (INR target of 1.4–1.9) was compared to placebo in 107 patients followed-up for 2 years. Overall, graft loss was 73% in the warfarin group compared with 61% in the control group. There was a significant increase in major haemorrhage in those treated with warfarin (six cases versus zero). Less than half of the patients enrolled achieved the target INR, which may explain the lack of efficacy seen. Similar to anti-platelet treatment, anticoagulants may delay AVG occlusion but do not attenuate the underlying pathophysiological pathways, therefore adjunctive agents are required.

Fish oil

Fish oils have been demonstrated to have anti-platelet effects, prolong bleeding times and reduce intimal hyperplasia in autogenous grafts [ 48 ]. In addition, reductions in neointimal hyperplasia formation following balloon injury in primates [ 47 ] and enhanced endothelial function [ 50 ] have been reported. Such effects may improve AVF and AVG patency by addressing the problem of both thrombosis and stenosis and enhanced endothelial function may also contribute to improved AVF maturation.

Schmitz et al. [ 33 ] examined the effect of 4000 mg of fish oil daily versus placebo in a trial of 24 patients undergoing AVG. Patients were followed-up for 1 year with primary patency reported as 75.6% in the fish oil group compared with 14.9% in the control group. The trial was performed at a single centre and confounding variables well reported, with even matching between the two groups. While results were encouraging the failure rate in the placebo arm was high and numbers enrolled were small. This trial has formed the basis of a larger randomized control trial into the effect of fish oil on haemodialysis grafts [ 51 ].

Potential future therapies

Clinical research so far has concentrated mainly on the use of anti-platelet or anticoagulant agents to preserve the lifespan of haemodialysis access grafts. Thrombosis is the final result of the underlying pathophysiological mechanism of vascular access failure: either an evolving stenosis caused by neointimal hyperplasia or a low flow state caused by failure of maturation. Thus, agents that treat secondary consequences (anti-platelets and anticoagulants) may ‘buy time’ for grafts but do not address the primary fundamental underlying stenosis. It is unsurprising that there appears to be a lack of clear clinical efficacy. Key therapeutic targets to improve vascular access outcomes would be to:

  • (1) Reduce endothelial dysfunction. This may improve AVF maturation and reduce neointimal hyperplasia formation in AVF and AVG.

  • (2) Inhibit VSMC proliferation and migration, the most abundant cellular element in neointimal hyperplasia.

Potential benefits of existing pharmacological strategies upon these targets will be discussed followed by more novel therapeutic strategies. Table 5 summarizes these more novel therapeutic strategies.

Table 5.

Novel therapies to reduce neointimal hyperplasia

Agent Potential therapeutic benefit(s) Clinical outcomes reported 
Cilostazol Anti-platelet effect Improved patency of angioplasty in haemodialysis patients with 100 mg Cilostazol. 
Inhibition of VSMC proliferation Reduced restenosis following coronary angioplasty. 
Inhibition of neointimal hyperplasia  
Statins Anti-platelet effect Improved AVF patency in retrospective analysis (71.5 versus 39.1%). 
Inhibition of VSMC proliferation Improved infrainguinal bypass graft patency in 2× retrospective analyses. 
Enhanced endothelial function  
Allogenic endothelial cell implants Enhanced endothelial function Safety of technique demonstrated. No clinical outcomes as yet. 
NO Enhance endothelial function Minimal benefit on restenosis following coronary angioplasty, with high incidence side effects. 
MAP kinase inhibitors Inhibit VSMC proliferation Experimental models only. 
Agent Potential therapeutic benefit(s) Clinical outcomes reported 
Cilostazol Anti-platelet effect Improved patency of angioplasty in haemodialysis patients with 100 mg Cilostazol. 
Inhibition of VSMC proliferation Reduced restenosis following coronary angioplasty. 
Inhibition of neointimal hyperplasia  
Statins Anti-platelet effect Improved AVF patency in retrospective analysis (71.5 versus 39.1%). 
Inhibition of VSMC proliferation Improved infrainguinal bypass graft patency in 2× retrospective analyses. 
Enhanced endothelial function  
Allogenic endothelial cell implants Enhanced endothelial function Safety of technique demonstrated. No clinical outcomes as yet. 
NO Enhance endothelial function Minimal benefit on restenosis following coronary angioplasty, with high incidence side effects. 
MAP kinase inhibitors Inhibit VSMC proliferation Experimental models only. 

Pharmacological strategies to reduce neointimal hyperplasia

Established agents

Cilostazol

Cilostazol is a phosphodiasterase III inhibitor. It has multiple effects including accumulation of intracellular cAMP, which has anti-platelet and vasodilatory effects [ 52 ]. Direct inhibition of VSMC proliferation by cilostazol has been reported, with a putative mechanism being via down-regulation of E2F [ 53 ]. Cilostazol inhibits VSMC proliferation in response to PDGF in a concentration-dependent manner [ 54 ]. Taken together, cilostazol theoretically could have benefits on AVF and AVG stenosis evolution, AVF maturation and thrombosis. The CREST trial demonstrated significant reductions in restenosis in patients undergoing coronary angioplasty in those taking cilostazol [ 55 ]. In patients on haemodialysis undergoing angioplasty for peripheral vascular disease, 5-year patency of the target vessels in patients receiving 100 mg cilostazol twice daily was 58.4% compared to 34.7% in the control group [ 56 ].

It is encouraging that efficacy of cilostazol has been seen in a group of patients with end-stage renal failure on a pathophysiological process similar to neointimal hyperplasia in AVF failure. Experimentally, cilostazol appears to have effects that could impact upon AVF stenosis by reducing pathways of intimal hyperplasia.

Statins

In addition to cardiovascular benefits [ 57 ], statins have been demonstrated to have pleiotropic effects [ 58 ]. Effects reported include inhibition of VSMC proliferation and migration [ 59 ], enhanced endothelial NO release [ 60 ] and reduced cytokine secretion [ 61 ]. These pleiotropic effects occur as a down-stream effect of mevalonate inhibition on isoprenoid intermediates [ 62 ].

One retrospective analysis of 60 patients with autologous AVF demonstrated improved fistula patency (71.5 versus 39.1%) at 2 years in those taking folic acid and statin compared to those on no statin therapy [ 63 ]. Two large retrospective studies [ 64 , 65 ] of patients with infrainguinal bypass grafts demonstrated significant prolongation of graft survival in patients on statin therapy. The positive effect of statins in retrospective analyses, in combination with theoretical benefits upon pathways of neointimal hyperplasia formation suggest that statins could potentially play a role in improving the patency of vascular access grafts, both by inhibiting pathways of neointimal hyperplasia formation and potentially enhancing endothelial function and assist AVF maturation.

Novel therapeutic strategies to reduce neointimal hyperplasia

Allogenic endothelial cell implants

Integrity of the vascular endothelium is critical to vascular tone and health. Endothelial function and adaptation appears critical to AVF maturation, and endothelial injury is central to the theory of neointimal hyperplasia formation and subsequent AVF stenosis. Novel work by Conte et al. [ 16 ] has investigated perivascular placement of implants containing allogenic aortic endothelial cells to restore vascular endothelial integrity following AVF creation. Reductions in thrombosis, inflammation and stenosis were demonstrated in a porcine model, and Phase I/II trials have been completed demonstrating safety in 57 patients undergoing autologous AVF creation and prosthetic AVG placement. No significant difference in patency was seen; however, the trial was powered to assess safety, not efficacy. A larger randomized trial is expected.

Nitric oxide: exogenous administration and enhancing endogenous production

NO production is important to vascular integrity. It has also been shown to have a key role in vascular remodelling that allows for successful AV fistula maturation and is important in preventing neointimal hyperplasia formation. Enhancement of local NO production either by systemic administration or local application may improve outcomes in vascular access surgery. Systemic therapy with NO donor compounds and NO precursor compounds has successfully reduced neointimal hyperplasia formation in arterial animal models [ 66 , 67 ]. Results in small trials in humans have been disappointing, however, with conflicting results reported and a high incidence of side effects reported [ 68 , 69 ]. Local application of NO donor compounds to areas of endothelial injury may circumvent problems with systemic side effects and promising results have been demonstrated in animal studies [ 70 ].

Mitogen Activated Protein (MAP) kinase inhibitors

MAP kinases are an intracellular signalling mechanism belonging to the family of serine–threonine protein kinases. Extracellularsignal-regulated kinase 1/2 (ERK 1/2) MAP kinase has been shown to be integral to the signalling pathway for VSMC proliferation, and p38 and ERK1/2 signalling is responsible for VSMC migration in response to PDGF [ 71 , 72 ].

Systemic administration of both ERK1/2 [ 72 ] and p38 [ 73 ] inhibitors has been shown to reduce intimal hyperplasia in small animal models. Systemic use in humans is unrealistic as the ubiquity of MAP kinases is such that side effects would be unpredictable. Topical application or pre-incubation of transplanted vein circumvents this and success has been achieved in animal models where anti-proliferative and anti-inflammatory effects have been recorded in the VSMCs of vein grafts [ 74 ].

Conclusion

Over 150 years ago, Virchow proposed a triad of factors that cause thrombosis: interruption of blood flow, abnormal vessel wall and blood coagulant constituents. Clinical trials aimed at improving patency of autologous AVF and prosthetic AVGs have mainly focused upon preventing blood coagulation, with minimal benefits demonstrated. There is a paucity of laboratory and clinical research into vascular access failure; however, developments in molecular medicine may demonstrate benefit by addressing the other limbs of the triad. Therapeutic agents aimed at reducing neointimal hyperplasia via VSMC inhibition and restoration of endothelial integrity have potential to improve outcomes in vascular access surgery. Prospective randomized trials of agents in routine clinical use are required, along with greater volume of laboratory-based research to enhance our understanding of the problem.

References

1.
Stengel
B
Billon
S
Van Dijk
PCW
, et al.  . 
Trends in the incidence of renal replacement therapy for end-stage renal disease in Europe, 1990–1999
Nephrol Dial Transplant
 , 
2003
, vol. 
18
 (pg. 
1824
-
1833
)
2.
Arora
P
Kausz
AT
Obrador
GT
Hospital utilization among chronic dialysis patients
J Am Soc Nephrol
 , 
2000
, vol. 
11
 (pg. 
740
-
746
)
3.
Sandhu
S
Salvaging and maintaining non-maturing Brescia-Cimino haemodialysis fistulae by percutaneous intervention
Clin Radiol
 , 
2006
, vol. 
61
 (pg. 
402
-
403
)
4.
Huber
TS
Carter
JW
Carter
RL
, et al.  . 
Patency of autogenous and polytetrafluoroethylene upper extremity arteriovenous hemodialysis access: a systematic review
J Vasc Surg
 , 
2003
, vol. 
38
 (pg. 
1005
-
1011
)
5.
Roy-Chaudhury
P
Haemodialysis vascular access dysfunction: a cellular and molecular viewpoint
J Am Soc Nephrol
 , 
2006
, vol. 
17
 (pg. 
1112
-
1127
)
6.
Schwab
SJ
Harrington
JT
Singh
A
, et al.  . 
Vascular access for haemodialysis
Kidney Int
 , 
1999
, vol. 
55
 (pg. 
2078
-
2090
)
7.
Miller
PE
Towlani
A
Luscy
CP
, et al.  . 
Predictors of adequacy of arteriovenous fistulas in hemodialysis patients
Kidney Int
 , 
1999
, vol. 
56
 (pg. 
275
-
280
)
8.
The UK National Kidney Federation. Executive Summary of the Kidney Alliance Report ‘End Stage Renal Failure—A Framework for Planning and Service Delivery’
 , 
2009
 
9.
Asif
A
Roy-Chaudhury
P
Beathard
GA
Early arteriovenous fistula failure: a logical proposal for when and how to intervene
Clin J Am Soc Nephrol
 , 
2006
, vol. 
1
 (pg. 
332
-
339
)
10.
Dixon
BS
Why don't fistulas mature?
Kidney Int
 , 
2006
, vol. 
70
 (pg. 
1413
-
1422
)
11.
Tronc
F
Mallat
Z
Lehoux
S
Role of matrix metalloproteinases in blood flow-induced arterial enlargement: interaction with NO
Vasc Biol
 , 
2000
, vol. 
20
 (pg. 
E120
-
E126
)
12.
Corpataux
JM
Haesler
E
Silacci
P
Low-pressure environment and remodelling of the forearm vein in Brescia-Cimino haemodialysis access
Nephrol Dial Transplant
 , 
2002
, vol. 
17
 (pg. 
1057
-
1062
)
13.
Paszkowiak
JJ
Dardik
A
Arterial wall shear stress: Observations from the bench to the bedside
Vasc Endovasc Surg
 , 
2003
, vol. 
37
 (pg. 
47
-
57
)
14.
Lauvao
LS
Ihnat
DM
Goshima
KR
, et al.  . 
Vein diameter is the major predictor of fistula maturation
J Vasc Surg
 , 
2009
, vol. 
49
 (pg. 
1499
-
1504
)
15.
Ernandez
T
Saudan
P
Berney
T
, et al.  . 
Risk factors for early failure of native arteriovenous fistulas
Nephron Clin Pract
 , 
2005
, vol. 
101
 (pg. 
c39
-
c44
)
16.
Conte
MS
Nugent
HM
Gaccione
P
, et al.  . 
Multicenter phase I/II trial of the safety of allogenic endothelial cell implants after the creation of arteriovenous access for hemodialysis use: the V-HEALTH study
J Vasc Surg
 , 
2009
, vol. 
50
 (pg. 
1359
-
1368
)
17.
Varty
K
Porter
K
Bell
PR
, et al.  . 
Vein morphology and bypass graft stenosis
Br J Surg
 , 
1996
, vol. 
83
 (pg. 
1375
-
1379
)
18.
Schachner
T
Laufer
G
Bonatti
J
In vivo (animal) models of vein graft disease
Eur J Cardiothorac Surg
 , 
2006
, vol. 
30
 (pg. 
451
-
463
)
19.
Van Tricht
I
De Wachter
D
Tordoir
J
, et al.  . 
Hemodynamics and complications encountered with arteriovenous fistulas and grafts as vascular access for hemodialysis: a review
Ann Biomed Eng
 , 
2005
, vol. 
33
 (pg. 
1142
-
1157
)
20.
Roy-Chaudhury
P
Wang
Y
Krishnamoorthy
M
, et al.  . 
Cellular phenotypes in human stenotic lesions from haemodialysis vascular access
Nephrol Dial Transplant
 , 
2009
, vol. 
24
 pg. 
2786
 
21.
Andrassy
K
Malluche
H
Bornefeld
H
Prevention of p.o. clotting of av. cimino fistula with acetylsalicylic acid. Results of a prospective double blind study
Klin Wochenschr
 , 
1974
, vol. 
52
 (pg. 
348
-
349
)
22.
Harter
H
Burch
J
Majerus
P
, et al.  . 
Prevention of thrombosis in patients on hemodialysis by low-dose aspirin
N Engl J Med
 , 
1979
, vol. 
301
 (pg. 
577
-
579
)
23.
Sreedhara
R
Himmelfarb
J
Lazarus
JM
, et al.  . 
Anti-platelet therapy in graft thrombosis: results of a prospective, randomized, double-blind study
Kidney Int
 , 
1994
, vol. 
45
 (pg. 
1477
-
1483
)
24.
DAC Study Group, Dixon BSea
Effect of dipyridamole plus aspirin on hemodialysis graft patency
N Eng J Med
 , 
2009
, vol. 
360
 (pg. 
2191
-
2201
)
25.
DAC Study Group
Dember
LM
, et al.  . 
Effect of clopidogrel on early failure of arteriovenous fistulas for hemodialysis: A randomized controlled trial
JAMA
 , 
2008
, vol. 
299
 (pg. 
2164
-
2171
)
26.
Trimarchi
H
Young
P
Forrester
M
, et al.  . 
Clopidogrel diminishes hemodialysis access graft thrombosis
Nephron Clin Pract
 , 
2006
, vol. 
102
 (pg. 
c128
-
132
)
27.
Kaufman
JS
O'connor
TZ
Zhang
JH
, et al.  . 
Randomized controlled trial of clopidogrel plus aspirin to prevent hemodialysis access graft thrombosis
J Am Soc Nephrol
 , 
2003
, vol. 
14
 (pg. 
2313
-
2321
)
28.
Grontoft
KC
Larsson
R
Mulec
H
, et al.  . 
Effects of ticlopidine in AV-fistula surgery in uremia. Fistula Study Group
Scand J Urol Nephrol
 , 
1998
, vol. 
32
 (pg. 
276
-
283
)
29.
Grontoft
KC
Mulec
H
Gutierrez
A
, et al.  . 
Thromboprophylactic effect of ticlopidine in arteriovenous fistulas for haemodialysis
Scand J Urol Nephrol
 , 
1985
, vol. 
19
 (pg. 
55
-
57
)
30.
Fiskerstrand
CE
Thompson
IW
Burnet
ME
, et al.  . 
Double-blind randomized trial of the effect of ticlopidine in arteriovenous fistulas for hemodialysis
Artif Organs
 , 
1985
, vol. 
9
 (pg. 
61
-
63
)
31.
Kobayashi
K
Maeda
K
Koshikawa
S
, et al.  . 
Antithrombotic therapy with ticlopidine in chronic renal failure patients on maintenance hemodialysis—a multicenter collaborative double blind study
Thromb Res
 , 
1980
, vol. 
20
 (pg. 
255
-
261
)
32.
Crowther
MA
Clase
CM
Margetts
PJ
, et al.  . 
Low-intensity warfarin is ineffective for the prevention of PTFE graft failure in patients on hemodialysis: a randomized controlled trial
J Am Soc Nephrol
 , 
2002
, vol. 
13
 (pg. 
2331
-
2337
)
33.
Schmitz
PG
McCloud
LK
Reikes
ST
, et al.  . 
Prophylaxis of hemodialysis graft thrombosis with fish oil: double-blind, randomized, prospective trial
J Am Soc Nephrol
 , 
2002
, vol. 
13
 pg. 
184
 
34.
Final report on the aspirin component of the ongoing Physicians’ Health Study
Steering Committee of the Physicians’ Health Study Research Group
N Engl J Med
 , 
1980
, vol. 
321
 (pg. 
129
-
135
)
35.
Meadows
TA
Bhatt
DL
Clinical aspects of platelet inhibitors thrombus formation
Circ Res
 , 
2007
, vol. 
100
 (pg. 
1261
-
1275
)
36.
Aktas
B
Utz
A
Hoenig-Liedl
P
, et al.  . 
Dipyridamole enhances NO/cGMP-mediated vasodilator-stimulated phosphoprotein phosphorylation and signaling in human platelets: in vitro and in vivo/ex vivo studies
Stroke
 , 
2003
, vol. 
34
 (pg. 
764
-
769
)
37.
Storey
RF
Sanderson
HM
White
AE
, et al.  . 
The central role of the P(2T) receptor in amplification of human platelet activation, aggregation, secretion and procoagulant activity
Br J Haematol
 , 
2000
, vol. 
110
 (pg. 
925
-
934
)
38.
McCann
RL
Hagen
PO
Fuchs
JC
Aspirin and dipyridamole decrease intimal hyperplasia in experimental vein grafts
Ann Surg
 , 
1980
, vol. 
191
 (pg. 
238
-
243
)
39.
Himmelfarb
J
Couper
L
Dipyridamole inhibits PDGF- and bFGFinduced vascular smooth muscle cell proliferation
Kidney Int
 , 
1997
, vol. 
52
 (pg. 
1671
-
1677
)
40.
Zhu
W
Masaki
T
Cheung
AK
, et al.  . 
Cellular pharmacokinetics and pharmacodynamics of dipyridamole in vascular smooth muscle cells
Biochem Pharmacol
 , 
2006
, vol. 
72
 (pg. 
956
-
964
)
41.
Masaki
T
Kamerath
CD
Kim
A
, et al.  . 
In vitro pharmacological in-hibition of human vascular smooth muscle cell proliferation for the prevention of hemodialysis vascular access stenosis
Blood Purif
 , 
2004
, vol. 
22
 (pg. 
307
-
312
)
42.
Shi
G
Morrell
CN
Platelets as initiators and mediators of inflammation at the vessel wall
Thromb Res
 , 
2011
, vol. 
127
 (pg. 
387
-
390
)
43.
Huang
B
Dreyer
T
Heidt
M
, et al.  . 
Insulin and local growth factor PDGF induce intimal hyperplasia in bypass graft culture models of saphenous vein and internal mammary artery
Eur J Cardiothorac Surg
 , 
2002
, vol. 
21
 (pg. 
1002
-
1008
)
44.
Sachinidis
A
Flesch
M
Ko
Y
, et al.  . 
Thromboxane A2 and vascular smooth muscle cell proliferation
Hypertension
 , 
1995
, vol. 
26
 (pg. 
771
-
780
)
45.
Handa
K
Nudelman
ED
Stroud
MR
, et al.  . 
Selectin GMP-140 (CD62; PADGEM) binds to sialosyl-Le(a) and sialosyl-Le(x), and sulfated glycans modulate this binding
Biochem Biophys Res Commun
 , 
1991
, vol. 
181
 (pg. 
1223
-
1230
)
46.
Porter
KE
Thompson
MM
Loftus
IM
, et al.  . 
Production and inhibition of the gelatinolytic matrix metalloproteinases in a human model of vein graft stenosis
Eur J Vasc Endovasc Surg
 , 
1999
, vol. 
17
 (pg. 
404
-
412
)
47.
Taubert
D
Berkels
R
Schroder
H
, et al.  . 
Aspirin induces nitric oxide release from vascular endothelium: a novel mechanism of action
Br J Pharmacol
 , vol. 
143
 (pg. 
159
-
165
)
48.
Sarris
GE
Fann
JI
Sokoloff
MH
, et al.  . 
Mechanisms responsible for inhibition of vein-graft arteriosclerosis by fish oil
Circulation
 , 
1989
, vol. 
80
 (pg. 
I109
-
I123
)
49.
Harker
LA
Kelley
AB
Hanson
SR
, et al.  . 
Interruption of vascular thrombus formation and vascular lesion formation by dietary n-3 fatty acids in nonhuman primates
Circulation
 , 
1993
, vol. 
87
 (pg. 
1017
-
1029
)
50.
Cartwright
IJ
Pockley
AG
Galloway
JH
, et al.  . 
The effects of dietary x-3 polyunsaturated fatty acids on erythrocyte membrane phospholi-pids, erythrocyte deformability and blood viscosity in healthy volun- teers
Atherosclerosis
 , 
1985
, vol. 
55
 (pg. 
267
-
281
)
51.
Irish
A
Gursharan
D
Mori
T
, et al.  . 
Preventing AVF thrombosis: the rationale and design of the Omega-3 fatty acids (Fish Oils) and Aspirin in Vascular access OUtcomes in REnal Disease (FAVOURED) study
BMC Nephrol
 , 
2009
, vol. 
10
 pg. 
1
 
52.
Morishita
R
A scientific rationale for the CREST trial results: evidence for the mechanism of action of cilostazol in restenosis
Atheroscler Supp
 , 
2006
, vol. 
6
 (pg. 
41
-
46
)
53.
Kim
M
Park
K
Lee
K
, et al.  . 
Cilostazol inhibits vascular smooth muscle cell growth by downregulation of the transcription factor E2F
Hypertension
 , 
2005
, vol. 
45
 (pg. 
552
-
556
)
54.
Hayashi
S
Morishita
R
Matsushita
H
Cyclic AMP inhibited proliferation of human aortic smooth muscle cells, accompanied by induction of p53 and p21
Hypertension
 , 
2000
, vol. 
35
 (pg. 
237
-
243
)
55.
Douglas
JS
Jr
Holmes
DR
Jr
Kereiakes
DJ
, et al.  . 
Coronary stent restenosis in patients treated with cilostazol
Circulation
 , 
2005
, vol. 
112
 (pg. 
2826
-
2832
)
56.
Tsuchikane
E
Fukuhara
A
Kobayashi
T
, et al.  . 
Impact of cilostazol on restenosis after percutaneous coronary balloon angioplasty
Circulation
 , vol. 
100
 (pg. 
21
-
26
)
57.
Influence of pravastatin and plasma lipids on clinical events in the West of Scotland Coronary Prevention Study (WOSCOPS)
Circulation
 , 
1998
, vol. 
97
 (pg. 
1440
-
1445
)
58.
Kleemann
R
Princen
HM
Emeis
JJ
, et al.  . 
Rosuvastatin reduces atherosclerosis development beyond and independent of its plasma cholesterol-lowering effect in APOE*3-Leiden transgenic mice: evidence for antiinflammatory effects of rosuvastatin
Circulation
 , 
2003
, vol. 
108
 (pg. 
1368
-
1374
)
59.
Porter
KE
Naik
J
Turner
NA
, et al.  . 
Simvastatin inhibits human saphenous vein neointima formation via inhibition of smooth muscle cell proliferation and migration
J Vasc Surg
 , 
2002
, vol. 
36
 (pg. 
150
-
157
)
60.
Kaesemeyer
WH
Caldwell
RB
Huang
J
, et al.  . 
Pravastatin sodium activates endothelial nitric oxide synthase independent of its cholesterol-lowering actions
J Am Coll Cardiol
 , 
1999
, vol. 
33
 (pg. 
234
-
241
)
61.
Ferro
D
Basili
S
Alessandri
C
, et al.  . 
Inhibition of tissue-factor-mediatedthrombin generation by simvastatin
Atherosclerosis
 , 
2000
, vol. 
149
 (pg. 
111
-
116
)
62.
Mason
JC
Statins and their role in vascular protection
Clin Sci (Lond)
 , 
2003
, vol. 
105
 (pg. 
251
-
266
)
63.
Righetti
M
Ferrario
G
Serbelloni
P
, et al.  . 
Some old drugs improve late primary patency of native arteriovenous fistulas in hemodialysispatients
Ann Vasc Surg
 , 
2009
, vol. 
23
 (pg. 
491
-
497
)
64.
Abbruzzese
TA
Havens
J
Belkin
M
, et al.  . 
Statin therapy is associated with improved patency of autogenous infrainguinal bypass grafts
J Vasc Surg
 , 
2004
, vol. 
39
 (pg. 
1178
-
1185
)
65.
Henke
PK
Blackburn
S
Proctor
MC
, et al.  . 
Patients undergoing infrainguinal bypass to treat atherosclerotic vascular disease are underprescribed cardioprotective medications: effect on graft patency, limb salvage, and mortality
J Vasc Surg
 , 
2004
, vol. 
39
 (pg. 
357
-
365
)
66.
Chen
C
Mattar
SG
Lumsden
AB
Oral administration of L-arginine reduces intimal hyperplasia in balloon-injured rat carotid arteries
J Surg Res
 , 
1999
, vol. 
82
 (pg. 
17
-
23
)
67.
Groves
PH
Banning
AP
Penny
WJ
, et al.  . 
The effects of exogenous nitric oxide on smooth muscle cell proliferation following porcine carotid angioplasty
Cardiovasc Res
 , 
1995
, vol. 
30
 (pg. 
87
-
96
)
68.
Wohrle
J
Hoher
M
Nusser
T
, et al.  . 
No effect of highly dosed nitric oxide donor molsidomine on the angiographic restenosis rate afterpercutaneous coronary angioplasty: a randomized, placebo controlled, double-blind trial
Can J Cardiol
 , 
2003
, vol. 
19
 (pg. 
495
-
500
)
69.
Lablanche
JM
Grollier
G
Lusson
JR
, et al.  . 
Effect of the direct nitricoxide donors linsidomine and molsidomine on angiographic restenosis after coronary balloon angioplasty. The ACCORD Study. Angioplastic Coronaire Corvasal Diltiazem
Circulation
 , 
1997
, vol. 
95
 (pg. 
83
-
89
)
70.
Rolland
PH
Mekkaoui
C
Palassi
M
, et al.  . 
Efficacy of local molsidomine delivery from a hydrogel-coated angioplasty balloon catheter in the atherosclerotic porcine model
Cardiovasc Interven Radiol
 , 
2003
, vol. 
26
 (pg. 
65
-
72
)
71.
Zhan
Y
Kim
S
Izumi
Y
, et al.  . 
Role of JNK, p38, and ERK in plateletderived growth factor-induced vascular proliferation, migration, and gene expression
Arterioscler Thromb Vasc Biol
 , 
2003
, vol. 
23
 (pg. 
795
-
801
)
72.
Gennaro
G
Menard
C
Michaud
SE
, et al.  . 
Inhibition of vascular smooth muscle cell proliferation and neointimal formation in injured arteries by a novel, oral mitogen-activated protein kinase/extracellular signal-regulated kinase inhibitor
Circulation
 , 
2004
, vol. 
110
 (pg. 
3367
-
3371
)
73.
Ohashi
N
Matsumori
A
Furukawa
Y
, et al.  . 
Role of p38 mitogenactivatedprotein kinase in neointimal hyperplasia after vascular injury
Arterioscler Thromb Vasc Biol
 , 
2000
, vol. 
20
 (pg. 
2521
-
2526
)
74.
Pintucci
G
Saunders
PC
Gulkarov
I
, et al.  . 
Anti-proliferative and antiinflammatory effects of topical MAPK inhibition in arterialized veingrafts
FASEB J
 , 
2006
, vol. 
20
 (pg. 
398
-
400
)

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