Pathogenesis and Prevention of Vascular Access Failure

Rebecca Hudson, David Johnson and Andrea Viecelli

#### Abstract

Dialysis vascular access failure is common, is rated as a critical priority by both patients and health professionals, and is associated with excess morbidity, mortality and healthcare costs. This chapter will discuss the mechanisms underpinning vascular access failure as well as strategies for preventing this adverse outcome, including systemic medical therapies (such as antiplatelet agents, fish oils, statins, inhibitors of the renin-angiotensin-aldosterone system, and calcium channel blockers), and local therapeutic interventions including innovative surgical techniques, minimally invasive AVF creation, far infra-red therapy, perivascular application of recombinant elastase, endothelial loaded gel foam wrap (Vascugel), and antiproliferative agents such as sirolimus (Coll-R) and paclitaxel-coated balloon angioplasty.

Keywords: arteriovenous fistula, arteriovenous graft, arteriovenous shunt, aspirin, cardiovascular agents/therapeutic use, clinical research, endovascular procedures, end-stage kidney disease, fish oils, graft occlusion, hemodialysis, maturation, risk factors, statins, thrombosis, treatment outcome, vascular access, vascular patency

#### 1. Introduction

The prevalence of end-stage kidney disease (ESKD) is increasing in the presence of a growing diabetic and aging population [1, 2]. Hemodialysis remains the most common form of kidney replacement therapy [3–5], with over 2 million people on hemodialysis worldwide [6]. To maintain successful hemodialysis, functional vascular access is required [7]. Hemodialysis vascular access consists of three forms: the arteriovenous fistula (AVF), the arteriovenous graft (AVG), and the central venous catheter (CVC). The AVF is a connection between a native artery and vein that is created via an end-to-side vein-to-artery anastomosis [8]. AVGs are created by interposing a prosthetic graft (classically with polytetrafluorethylene [PTFE]) between an artery and a vein [8]. The key requirements of such access are sufficient blood flow rate, low flow resistance, a low rate of complications and, for AVF and AVG, ease of cannulation.

A mature native AVF is considered superior to a synthetic AVG or CVC due to better long-term outcomes, including reduced rates of thrombosis, infection and interventions to maintain patency [9–11]. Balanced against these benefits, as a result of early thrombosis, neointimal hyperplasia formation and inadequate vasodilation (outward remodeling), between 20 and 60% of AVFs fail to mature to an adequate caliber to allow repeat cannulation and provide sufficient blood flow for

hemodialysis and thereby prevent timely usability of the AVF for hemodialysis [9]. AVGs can be used within days of access creation but long-term, they are at higher risk of developing venous stenosis, thrombosis and infection compared to a functioning AVF [12]. More than 50% of AVGs thrombose within 12 months of creation and they require significantly more interventions to maintain patency compared to a functioning AVF [12–14]. CVCs can be used immediately after insertion, but their long-term use is discouraged in light of the significantly higher risks of thrombosis, catheter-associated bacteremia and inadequate solute clearance [15–17].

peripheral arterial disease, cardiovascular disease and diabetes mellitus. Peripheral arterial disease interferes with the remodeling process required to achieve a functioning fistula, involving the development of neointimal hyperplasia and calcification, causing increased arterial stiffness and decreased elasticity [30]. Woods et al. [31] conducted a study involving 784 incident hemodialysis patients and found a 24% increased risk of AVF failure in those with peripheral arterial disease. This failure is attributable to the fact that for vascular access to be a success, it is essential that the artery used in the creation of the fistula is able to adequately increase diameter allowing for the increased blood flow required to supply the fistula and

In relation to cardiac disease, its adverse impact on fistula maturation is due to poor cardiac output and associated poor blood flow to the fistula, resulting in worse

Diabetes mellitus is associated with increased risks of intimal hyperplasia [35], and peripheral arterial disease [36], with these risks exaggerated further in the chronic kidney disease population leading to an appreciable rate of AVF failure in

Advancing age has been cited as a risk factor for failure of AVF maturation and survival, although this proves difficult to quantify with age also being a surrogate marker for increasing burden of comorbidities. Studies have indicated an increased failure rate of AVFs in 'older patients' with the definition of those greater than or equal to 65 years of age [39–41], contrasting with other literature which were unable to identify significant differences in functional access outcomes for older

Race and ethnicity have also been identified as risk factors for failure of AVF maturation, though again this has not been consistently replicated in the literature [43]. Studies however have identified AVF failure rate being more common in those of African racial background in comparison to Caucasians; along with Hispanics

A pertinent factor affecting the anastomosis and therefore the outcomes of AVFs includes both the experience of the surgeon in creating the fistula, as well as the technical issues associated with utilizing and managing the fistula. The formation of AVFs is difficult, with numerous studies indicating that there is a higher incidence of successful AVFs if the surgery is performed by an experienced vascular surgeon [45–49], with the emphasis being placed on the number of AVFs created over the

Outflow dynamics are influenced by several factors, one of which is obesity. Obesity is described as a risk factor for failure of vascular access separate to the increased incidence of diabetes in this group. It was observed that obese patients experienced poor secondary patency in a study by Kats et al. [51], with the underlying theory that this was due to the increased soft tissue mass leading to venous compression and outflow tract obstruction [52]. Diabetes has also been shown to be a negative predictor of venous remodeling [53], directly impacting the outflow from

Following arteriovenous access creation, ongoing access surveillance, care and cannulation by well trained staff/patient are paramount for preventing access fail-

The pathogenesis of vascular access failure is complex with the common final

pathway being the combination of insufficient vessel vasodilation, negative

3. Pathophysiology of arteriovenous access dysfunction

distal tissues [32, 33].

this group [27, 37, 38].

patients [26, 42].

an AVF.

81

ure [54–59].

when compared with non-Hispanics [40, 41, 44].

Pathogenesis and Prevention of Vascular Access Failure DOI: http://dx.doi.org/10.5772/intechopen.83525

total years of training [48, 50].

outcomes [34].

Vascular access dysfunction is a major cause of morbidity, mortality and excess healthcare costs [9, 18–20]. Indeed, healthcare professionals, patients and caregivers consider vascular access function a top priority of research in hemodialysis and clinical practice [21]. There have been recent advances in the understanding of the biology of vascular access and its dysfunction, with neointimal hyperplasia leading to venous stenosis and inadequate outward remodeling being identified as the two major causes of dialysis vascular access dysfunction [7, 22]. This knowledge has led to the identification of potential therapeutic targets and the development of novel interventions to improve and maintain vascular patency [17].

This chapter will discuss the risk factors for, and pathogenesis of arteriovenous access failure. The advances in the understanding of arteriovenous access failure have led to the development of therapeutic targets and novel therapeutic interventions including systemic medical therapies with pleiotropic effects (such as antiplatelet agents, fish oils, statins, inhibitors of the renin-angiotensin-aldosterone system [RAAS], and calcium channel blockers), and local therapeutic interventions including innovative surgical techniques, minimally invasive AVF creation, far infra-red therapy, perivascular application of recombinant elastase, endothelial loaded gel foam wrap (Vascugel), and antiproliferative agents such as sirolimus (Coll-R) and paclitaxel-coated balloon angioplasty.

#### 2. Clinical predictors of arteriovenous access failure

Key contributors to successful AVF maturation and long-term function include adequate inflow properties determined by the size and quality of the feeding artery, cardiac output and blood pressure; anastomotic properties concerning the patent anastomosis between the artery and vein/interposition graft; and adequate outflow properties, which in turn are determined by the size and quality of the vein and presence or absence of collateral or accessory veins. The significance of these three factors in determining vascular access success highlight the importance of vascular mapping and planning prior to fistula creation.

Inflow properties are influenced by the location of the AVF, with patency increasing as the size of the feeding artery is increased (distal to proximal) [23]. Despite this, the distal radio cephalic AVF on the non-dominant side of the patient is the preferred initial site of AVF for vascular access [23], partly due to patient comfort along with the preservation of additional vascular access sites for future use. Female gender has been identified as a risk factor for failure of fistula maturation and survival, with investigations discovering significantly poorer outcomes of AVFs in females in comparison to males, though the reasons underpinning this are unclear [24–27]. It has been proposed that females have smaller vessels with associated decreased luminal diameters in comparison to males; however, this has not been consistently found to be a factor in unsuccessful AVFs [28, 29].

Key determinants of both inflow properties and anastomosis patency are the comorbidities of the patient undergoing AVF creation, influencing outcome via unfavorable effects on hemodynamics, with the most adverse effects seen from

#### Pathogenesis and Prevention of Vascular Access Failure DOI: http://dx.doi.org/10.5772/intechopen.83525

hemodialysis and thereby prevent timely usability of the AVF for hemodialysis [9]. AVGs can be used within days of access creation but long-term, they are at higher risk of developing venous stenosis, thrombosis and infection compared to a functioning AVF [12]. More than 50% of AVGs thrombose within 12 months of creation and they require significantly more interventions to maintain patency compared to a functioning AVF [12–14]. CVCs can be used immediately after insertion, but their long-term use is discouraged in light of the significantly higher risks of thrombosis,

Vascular access dysfunction is a major cause of morbidity, mortality and excess healthcare costs [9, 18–20]. Indeed, healthcare professionals, patients and caregivers consider vascular access function a top priority of research in hemodialysis and clinical practice [21]. There have been recent advances in the understanding of the biology of vascular access and its dysfunction, with neointimal hyperplasia leading to venous stenosis and inadequate outward remodeling being identified as the two major causes of dialysis vascular access dysfunction [7, 22]. This knowledge has led to the identification of potential therapeutic targets and the development of

This chapter will discuss the risk factors for, and pathogenesis of arteriovenous access failure. The advances in the understanding of arteriovenous access failure have led to the development of therapeutic targets and novel therapeutic interven-

antiplatelet agents, fish oils, statins, inhibitors of the renin-angiotensin-aldosterone system [RAAS], and calcium channel blockers), and local therapeutic interventions including innovative surgical techniques, minimally invasive AVF creation, far infra-red therapy, perivascular application of recombinant elastase, endothelial loaded gel foam wrap (Vascugel), and antiproliferative agents such as sirolimus

Key contributors to successful AVF maturation and long-term function include adequate inflow properties determined by the size and quality of the feeding artery, cardiac output and blood pressure; anastomotic properties concerning the patent anastomosis between the artery and vein/interposition graft; and adequate outflow properties, which in turn are determined by the size and quality of the vein and presence or absence of collateral or accessory veins. The significance of these three factors in determining vascular access success highlight the importance of vascular

Inflow properties are influenced by the location of the AVF, with patency increasing as the size of the feeding artery is increased (distal to proximal) [23]. Despite this, the distal radio cephalic AVF on the non-dominant side of the patient is the preferred initial site of AVF for vascular access [23], partly due to patient comfort along with the preservation of additional vascular access sites for future use. Female gender has been identified as a risk factor for failure of fistula maturation and survival, with investigations discovering significantly poorer outcomes of AVFs in females in comparison to males, though the reasons underpinning this are unclear [24–27]. It has been proposed that females have smaller vessels with associated decreased luminal diameters in comparison to males; however, this has not

Key determinants of both inflow properties and anastomosis patency are the comorbidities of the patient undergoing AVF creation, influencing outcome via unfavorable effects on hemodynamics, with the most adverse effects seen from

been consistently found to be a factor in unsuccessful AVFs [28, 29].

catheter-associated bacteremia and inadequate solute clearance [15–17].

Vascular Access Surgery - Tips and Tricks

novel interventions to improve and maintain vascular patency [17].

(Coll-R) and paclitaxel-coated balloon angioplasty.

mapping and planning prior to fistula creation.

80

2. Clinical predictors of arteriovenous access failure

tions including systemic medical therapies with pleiotropic effects (such as

peripheral arterial disease, cardiovascular disease and diabetes mellitus. Peripheral arterial disease interferes with the remodeling process required to achieve a functioning fistula, involving the development of neointimal hyperplasia and calcification, causing increased arterial stiffness and decreased elasticity [30]. Woods et al. [31] conducted a study involving 784 incident hemodialysis patients and found a 24% increased risk of AVF failure in those with peripheral arterial disease. This failure is attributable to the fact that for vascular access to be a success, it is essential that the artery used in the creation of the fistula is able to adequately increase diameter allowing for the increased blood flow required to supply the fistula and distal tissues [32, 33].

In relation to cardiac disease, its adverse impact on fistula maturation is due to poor cardiac output and associated poor blood flow to the fistula, resulting in worse outcomes [34].

Diabetes mellitus is associated with increased risks of intimal hyperplasia [35], and peripheral arterial disease [36], with these risks exaggerated further in the chronic kidney disease population leading to an appreciable rate of AVF failure in this group [27, 37, 38].

Advancing age has been cited as a risk factor for failure of AVF maturation and survival, although this proves difficult to quantify with age also being a surrogate marker for increasing burden of comorbidities. Studies have indicated an increased failure rate of AVFs in 'older patients' with the definition of those greater than or equal to 65 years of age [39–41], contrasting with other literature which were unable to identify significant differences in functional access outcomes for older patients [26, 42].

Race and ethnicity have also been identified as risk factors for failure of AVF maturation, though again this has not been consistently replicated in the literature [43]. Studies however have identified AVF failure rate being more common in those of African racial background in comparison to Caucasians; along with Hispanics when compared with non-Hispanics [40, 41, 44].

A pertinent factor affecting the anastomosis and therefore the outcomes of AVFs includes both the experience of the surgeon in creating the fistula, as well as the technical issues associated with utilizing and managing the fistula. The formation of AVFs is difficult, with numerous studies indicating that there is a higher incidence of successful AVFs if the surgery is performed by an experienced vascular surgeon [45–49], with the emphasis being placed on the number of AVFs created over the total years of training [48, 50].

Outflow dynamics are influenced by several factors, one of which is obesity. Obesity is described as a risk factor for failure of vascular access separate to the increased incidence of diabetes in this group. It was observed that obese patients experienced poor secondary patency in a study by Kats et al. [51], with the underlying theory that this was due to the increased soft tissue mass leading to venous compression and outflow tract obstruction [52]. Diabetes has also been shown to be a negative predictor of venous remodeling [53], directly impacting the outflow from an AVF.

Following arteriovenous access creation, ongoing access surveillance, care and cannulation by well trained staff/patient are paramount for preventing access failure [54–59].

#### 3. Pathophysiology of arteriovenous access dysfunction

The pathogenesis of vascular access failure is complex with the common final pathway being the combination of insufficient vessel vasodilation, negative

(inward) vascular remodeling and neointimal hyperplasia resulting in luminal narrowing and often associated thrombosis formation. The Achilles heel of this process is the graft-vein anastomosis in AVG and the perianastomotic region in AVF, respectively [1, 13]. The pathophysiologic cascade of events that lead to AVF and AVG failure [16, 17] have been categorized into upstream events, characterized by factors that lead to injury of endothelial—and smooth muscle cells and downstream events describing the cellular and cytokine responses that leads to neointimal hyperplasia and inward remodeling [16] (Figure 1).

There are multiple factors that contribute to the upstream events of vascular access dysfunction: (1) the proinflammatory uremic milieu that promotes endothelial dysfunction [16, 60], (2) hemodynamic stressors at the anastomosis site due to a combination of small and non-compliant vessels, low shear stress and turbulence [16, 61, 62], (3) vascular injury at the time of fistula or graft formation due to vessel manipulation through surgical technique or angioplasty [16, 61, 62], (4) a localized inflammatory response involving cytokine release and macrophage migration caused by the synthetic graft material used in the formation of the AVG [16], (5) possible genetic predisposition to neointimal hyperplasia and vasoconstriction [11, 16] (6) and repeat cannulation injury [16, 54].

formation and negative (inward) remodeling. In comparison to outward

4. Therapeutic interventions to prevent VA dysfunction

stenosis and resultant thrombosis [17, 63].

Pathogenesis and Prevention of Vascular Access Failure DOI: http://dx.doi.org/10.5772/intechopen.83525

outward and inward vascular remodeling.

negative (inward) vascular remodeling.

4.1 Systemic medical therapies

4.1.1 Antiplatelet agents

properties.

83

Figure 2.

4.1.1.1 Aspirin

remodeling, inward remodeling results in small lumen diameter and an increased risk of access failure [17]. As such, neointimal hyperplasia if combined with compensatory outward remodeling may not result in flow limiting stenosis due to preservation of the luminal caliber, whereas neointimal hyperplasia combined with impaired outward remodeling can result in hemodynamically significant vascular

Vascular remodeling response post fistula creation: comparison of the effects of neointimal hyperplasia with

The following section will discuss systemic medical and local interventions developed to minimize luminal narrowing caused by neointimal hyperplasia and

Antiplatelet agents including aspirin, dipyridamole, clopidogrel and ticlopidine

Aspirin irreversibly inhibits platelet cyclooxygenase-1 and -2 enzymes via acetylation, resulting in decreased formation of prostaglandin precursors and prostaglandin derivative thromboxane A2 [13]. Randomized controlled trials (RCT) on the efficacy of aspirin in preventing arteriovenous access failure have shown inconsistent results, with two small studies favoring aspirin [67, 68] and two studies showing no significant treatment benefit for the prevention of arteriovenous access thrombosis and failure (Table 1) [5, 69]. In a small RCT of 44 patients, AVG thrombosis was significantly reduced with 160 mg of aspirin daily compared to

are thought to prevent arteriovenous access failure primarily through their antithrombotic effect. Clinical trial results will be discussed separately for each agent given the differences in action of individual agents upon platelet aggregation, function and vascular biology including anti-inflammatory and antiproliferative

After formation of an AVF, rapid increase in blood flow through the feeding artery and draining vein causes vascular distension [63] leading to nitric oxide (NO) synthesis by endothelial cells which results in vascular smooth muscle relaxation and vasodilatation [64]. This response leads to structured vascular remodeling with the driving forces of wall shear stress and tension [63] leading to an increase in arterial and venous lumen size [65] and moderate thickening of the venous wall assisting in maturation [66] and positive (outward) remodeling, which overall results in a larger lumen and greater vascular success (Figure 2). In comparison, the smooth muscle and endothelial injury sustained from the upstream events described previously, trigger a cascade of downstream responses mediated through proinflammatory leukotrienes, chemokines, cytokines, vasoactive molecules, metalloproteinase and adhesion molecules that promote neointimal hyperplasia

#### Figure 1.

Pathogenesis of vascular access failure. This figure illustrates the different pathogenic mechanisms that result in vascular access failure. Image re-used from Viecelli et al. [13] with permission from Wiley.

#### Figure 2.

(inward) vascular remodeling and neointimal hyperplasia resulting in luminal narrowing and often associated thrombosis formation. The Achilles heel of this process is the graft-vein anastomosis in AVG and the perianastomotic region in AVF, respectively [1, 13]. The pathophysiologic cascade of events that lead to AVF and AVG failure [16, 17] have been categorized into upstream events, characterized by factors that lead to injury of endothelial—and smooth muscle cells and down-

stream events describing the cellular and cytokine responses that leads to

There are multiple factors that contribute to the upstream events of vascular access dysfunction: (1) the proinflammatory uremic milieu that promotes endothelial dysfunction [16, 60], (2) hemodynamic stressors at the anastomosis site due to a combination of small and non-compliant vessels, low shear stress and turbulence [16, 61, 62], (3) vascular injury at the time of fistula or graft formation due to vessel manipulation through surgical technique or angioplasty [16, 61, 62], (4) a localized inflammatory response involving cytokine release and macrophage migration caused by the synthetic graft material used in the formation of the AVG [16], (5) possible genetic predisposition to neointimal hyperplasia and vasoconstriction

After formation of an AVF, rapid increase in blood flow through the feeding artery and draining vein causes vascular distension [63] leading to nitric oxide (NO) synthesis by endothelial cells which results in vascular smooth muscle relaxation and vasodilatation [64]. This response leads to structured vascular remodeling with the driving forces of wall shear stress and tension [63] leading to an increase in arterial and venous lumen size [65] and moderate thickening of the venous wall assisting in maturation [66] and positive (outward) remodeling, which overall results in a larger lumen and greater vascular success (Figure 2). In comparison, the smooth muscle and endothelial injury sustained from the upstream events described

Pathogenesis of vascular access failure. This figure illustrates the different pathogenic mechanisms that result in

vascular access failure. Image re-used from Viecelli et al. [13] with permission from Wiley.

previously, trigger a cascade of downstream responses mediated through proinflammatory leukotrienes, chemokines, cytokines, vasoactive molecules, metalloproteinase and adhesion molecules that promote neointimal hyperplasia

neointimal hyperplasia and inward remodeling [16] (Figure 1).

[11, 16] (6) and repeat cannulation injury [16, 54].

Vascular Access Surgery - Tips and Tricks

Figure 1.

82

Vascular remodeling response post fistula creation: comparison of the effects of neointimal hyperplasia with outward and inward vascular remodeling.

formation and negative (inward) remodeling. In comparison to outward remodeling, inward remodeling results in small lumen diameter and an increased risk of access failure [17]. As such, neointimal hyperplasia if combined with compensatory outward remodeling may not result in flow limiting stenosis due to preservation of the luminal caliber, whereas neointimal hyperplasia combined with impaired outward remodeling can result in hemodynamically significant vascular stenosis and resultant thrombosis [17, 63].

### 4. Therapeutic interventions to prevent VA dysfunction

The following section will discuss systemic medical and local interventions developed to minimize luminal narrowing caused by neointimal hyperplasia and negative (inward) vascular remodeling.

#### 4.1 Systemic medical therapies

#### 4.1.1 Antiplatelet agents

Antiplatelet agents including aspirin, dipyridamole, clopidogrel and ticlopidine are thought to prevent arteriovenous access failure primarily through their antithrombotic effect. Clinical trial results will be discussed separately for each agent given the differences in action of individual agents upon platelet aggregation, function and vascular biology including anti-inflammatory and antiproliferative properties.

#### 4.1.1.1 Aspirin

Aspirin irreversibly inhibits platelet cyclooxygenase-1 and -2 enzymes via acetylation, resulting in decreased formation of prostaglandin precursors and prostaglandin derivative thromboxane A2 [13]. Randomized controlled trials (RCT) on the efficacy of aspirin in preventing arteriovenous access failure have shown inconsistent results, with two small studies favoring aspirin [67, 68] and two studies showing no significant treatment benefit for the prevention of arteriovenous access thrombosis and failure (Table 1) [5, 69]. In a small RCT of 44 patients, AVG thrombosis was significantly reduced with 160 mg of aspirin daily compared to


type II

85

325 mg daily or

32%, type II 50% vs 80%

0.88–4.48, p = 0.18

Dipyridamole

95% CI 0.15–0.80,

p = 0.02

 0.35,

Aspirin +

—type I 23% vs 32%,

type II 100% vs 80%

Dipyridamole—type

17% vs 32%, type II 83%

vs 80%

 I

Dipyridamole

Dipyridamole

 225 mg

daily

[thrombosed

AVG requiring

new AVG])

Clopidogrel

Trial Ghorbani

RCT

93

DM (26.9%)

AVF

 Clopidogrel

 75 mg daily Placebo

 1.5

 Primary AVF failure at

8 weeks 5.2% vs 21.6%; HR 0.72,

95% CI 0.41–1.01,

92% vs 71%, p = 0.008

> p = 0.03

et al. [73]

Dember

RCT

877

 Smoking history

AVF

 Clopidogrel loading dose followed

by 75 mg daily

 300 mg

Placebo

 1.5

 Thrombosis

post fistula creation

12% vs 20%, RR 0.63,

95% CI 0.46–0.97,

p = 0.018

 at 6 weeks

Failure to attain suitability for dialysis 62% vs 60%, RR 1.05,

95% CI 0.94–1.17,

p = 0.40

(62%), DM (48%), CAD (28%), CVD

(6%), PVD (3%)

et al. [15] Clopidogrel

Trial Kaufman

RCT

200

DM (47%)

AVG

 Aspirin 325 mg daily +

Placebo

 NR

 Cumulative

 incidence of

Cumulative

of first graft thrombosis for patients

with grafts without

previous thrombosis

(n = 111) HR 0.52, 95% CI 0.22–

1.26, p = 0.14

 incidence

thrombosis

HR 0.81, 95% CI 0.47–

1.40, p = 0.45

Clopidogrel

 75 mg daily

et al. [74]

Study

 Number of

Co-morbidities

 Access type

Intervention

 Control

 Treatment

Primary outcome

Secondary outcome

(antiplatelet

 agents vs

placebo)

(antiplatelet

 agents vs

placebo)

duration

(months)

participants

 and aspirin

Study

 Number of

Co-morbidities

 Access type

Intervention

 Control

 Treatment

Primary outcome

Secondary outcome

(clopidogrel

placebo)

Successful HD within

6 months of AVF

creation

 vs

Pathogenesis and Prevention of Vascular Access Failure DOI: http://dx.doi.org/10.5772/intechopen.83525

(clopidogrel

placebo)

 vs

duration

(months)


#### Pathogenesis and Prevention of Vascular Access Failure DOI: http://dx.doi.org/10.5772/intechopen.83525

Aspirin

84

Trial Irish et al.

RCT

388

HTN (94%),

AVF

 Aspirin 100 mg daily Placebo

> smoking history

(54%), DM (49%),

CAD (11%), PVD

(4%), CHD (4%),

CVD (3%)

[5].

Study

 Number of

Co-morbidities

 Access type

Intervention

 Control

 Treatment

Primary outcome

Secondary outcome

(aspirin vs placebo)

duration

(aspirin vs placebo)

(months)

 3

 Proportion of subjects

AVF thrombosis at

12 months

with AVF failure

(thrombosis,

20% vs 18%, RR 1.09,

Vascular Access Surgery - Tips and Tricks

95% CI 0.72–1.64,

p = 0.70

> AVF

12 months 24% vs 18%, RR 1.31,

95% CI 0.89–1.95.

p = 0.17

Cannulation

12 months 40% vs 39%, RR 0.99,

95% CI 0.76–1.27,

p = 0.92

> Harter et al.

RCT

44

NR

AVG

 Aspirin 160 mg daily Placebo

 4

 Thrombosis

 at study end

Number of thrombotic

events per patient

month

0.16 vs 0.46, p < 0.05

(mean 5 months) 32% vs 72%, OR o.18,

95% CI 0.05–0.66,

p < 0.01

[67]

Andrassy

RCT

92

NR

AVF

Aspirin 1000 mg

Placebo

 1

 Thrombosis 4% vs 23%, p < 0.05

 at 28 days

NR

alternate days

et al. [68] Dipyridamole

Trial Sreedhara

RCT

107

NR

AVG

 Aspirin 325 mg daily, or

Placebo

 18

Thrombosis

18 months

Aspirin

—type I 50% vs

 at

RR of thrombosis with

new AVG Aspirin 1.99, 95% CI

Dipyridamole

225 mg + Aspirin

(84 type I [new

AVG] and 23

et al. [69]

Study

 Number of

Co-morbidities

 Access type

Intervention

 Control

 Treatment

Primary outcome

Secondary outcome

(antiplatelet

vs placebo)

 agent(s)

(antiplatelet

vs placebo)

 agent(s)

duration

(months)

participants

 and/or aspirin

 failure at

abandonment

 at

abandonment

cannulation

 failure) at

12 months 45% vs 47%, RR 1.05,

95% CI 0.84–1.31,

p = 0.68

 or


(53%), CAD (33%),

87

experiencing

patency loss (thrombosis

or radiological

surgical 12 months 48% vs 62%, RR 0.78,

95% CI 0.60–1.03,

p = 0.06

interventions)

 at

 or

Radiological

 or surgical

intervention

maintain patency IRR 0.59, 95% CI 0.44–

0.78

Thrombotic

IRR 0.5, 95% CI 0.35–

0.72

Pathogenesis and Prevention of Vascular Access Failure DOI: http://dx.doi.org/10.5772/intechopen.83525

NR

 events

 to

 graft

IRR 0.58, 95% CI 0.44–

0.75

CHD (20%), PVD

(15%), CVD (14%)

Bowden

RCT

29

 DM (69%), smoking

AVG

 6 g of fish oil daily

 Placebo

 8

 Primary patency loss

(thrombosis

outflow stenosis >50% requiring angioplasty)

254

vs 254

 35 days, SEM

34.6, NS

 52 days, SEM 51.8

 or venous

history (3%)

et al. [90]

Schmitz

RCT

24

DM (58%)

AVG

 4 g of fish oil daily

 Placebo

 12

 Primary patency

NR

(thrombosis

12 months 75.6% vs 14.9%, p = 0.03

 free) at

et al. [88] Statin therapy

Trial Herrington

Post hoc

2353

 DM (22%), smoking

AVF (94%), AVG

Simvastatin

 (20 mg)

Placebo

 5

 Vascular access occlusive

Access revision 18.6% vs 21.4% RR 0.85, CI 0.67–1.08

Access thrombosis

9.3% vs 10.3% RR 0.90, CI 0.64–1.27

Removal of old or formation of new

vascular access

event (access requiring

any revision procedure,

access thrombosis, removal of an old dialysis access, or

formation of new

permanent dialysis

access)

(6%)

plus Ezetimibe (10 mg)

daily

history (15%)

analysis of

RCT

et al. [94]

Study

 Number of

Co-morbidities

 Access type

Intervention

 Control

 Treatment

Primary outcome

Secondary outcome

(statin vs placebo)

follow-up

(statin vs placebo)

(years)


#### Pathogenesis and Prevention of Vascular Access Failure DOI: http://dx.doi.org/10.5772/intechopen.83525

Ticlopidine

86

Trial Grontoft

RCT

250

DM (27%)

AVF

 Ticlopidine 250 mg

Placebo

 1

 Thrombosis 12% vs 19%, OR 0.6, 95%

CI 0.30–1.18, p = 0.1

 at 4 weeks

> twice daily

et al. [77] Grontoft

RCT

36

DM (61%)

AVF

 Ticlopidine 250 mg

Placebo

 1

 Thrombosis 11% vs 47%, p < 0.05

 at 4 weeks

NR

Vascular Access Surgery - Tips and Tricks

twice daily

et al. [75] Fickerstrand

RCT

18

NR

AVF

 Ticlopidine 250 mg

Placebo

 1

 Thrombosis

 at 4 weeks

NR

25% vs 50%

twice daily

et al. [76]

Omega-3 fatty acid

Trial Irish et al.

RCT

536

HTN (94%),

AVF

 4 g of fish oil daily

 Placebo

 3

AVF failure

AVF thrombosis at

12 months

(thrombosis,

abandonment

cannulation

 failure) at

12 months 47% both groups, RR 1.03,

95% CI 0.86–1.23,

p = 0.78

 or

22% vs 23%, RR 0.98,

95% CI 0.72–1.34,

p = 0.9

> AVF

12 months 19% vs 22%, RR 0.87,

95% CI 0.62–1.2,

p = 0.43

Cannulation

12 months 40% vs 39%, RR 1.03,

95% CI 0.83–1.26,

p = 0.81

> Lok et al.

RCT

196

 HTN (86%), smoking

AVG

 4 g of fish oil daily

 Placebo

 12

Proportion of

Rate of loss of graft

patency

participants

history (55%), DM

[89]

 failure at

abandonment

 at

smoking history (54%), DM (49%),

CAD (11%), PVD

(4%), CHD (4%),

CVD (3%)

[5]

Study

 Number of

Co-morbidities

 Access type

Intervention

 Control

 Treatment

Primary outcome (fish

Secondary outcome

(fish oil vs placebo)

duration

oil vs placebo)

(months)

participants

supplementation

 (fish oil)

Study

 Number of

Co-morbidities

 Access type

Intervention

 Control

 Treatment

Primary outcome

Secondary outcome

(ticlopidine

placebo)

NR

 vs

(ticlopidine

placebo)

 vs

duration

(months)


Saran et al.

89

Retrospective

2462

 HTN (87.8%), DM

AVF 900 (8.3%

Statin therapy of

NR

 4

 Primary access patency

NR

(unassisted access

patency)

AVG RR 0.97, p = 0.805

AVF RR 0.93, p = 0.762

Secondary access

patency (assisted access

survival)

AVG RR 1.01, p = 0.920

AVF RR 1.03, p = 0.903

varying doses

(Simvastatin,

Atorvastatin,

Pravastatin,

Lovastatin)

Fluvastatin)

on statin), AVG

1944 (9.6% on

statin)

(49.7%), Obesity

(35.9%)

observational

cohort

analysis

Renin-angiotensin-aldosterone

Trial Chen et al.

Retrospective

42,244

 HTN (81%), DM

AVF 89.4%

ACEI/ARB therapy of

Nonuse

8

 Primary patency loss

NR

AVF

ACEI-HR 0.59, 95% CI

0.56–0.62, p < 0.05

ARB-HR 0.53, 95% CI

0.51–0.56, p < 0.05

AVG

ACEI-HR 0.56, 95% CI

0.48–0.64, p < 0.05

ARB-HR 0.54, 95% CI

0.47–0.61, p < 0.05

varying doses

ACEI Enalapril, Lisinopril, Quinapril, Captopril, Fosinopril, Ramipril,

Cilazapril)

(Benazepril,

(32.3% on an

(51%), CAD (24%),

Dyslipidemia

CVD (6%), PVD

(3%)

 (17%),

ACEI, 15% on an

ARB)

AVG 10.6% (6.2% on an

ACEI, 7.1% on an

ARB)

ARB Losartan, Irbesartan, Valsartan, Olmesartan)

> Jackson et al.

Retrospective

332

 DM (75%), HTN

AVF (64%) AVG

ARB therapy of varying

Nonuse

4

 Primary patency loss

NR

AVF

HR 0.35, 95% CI 0.16–

0.76, p = 0.008

AVG

HR 0.41, 95% CI 0.18–

0.95, p = 0.04

(36%)

doses (Irbesartan,

Losartan, Valsartan)

(62%), smoking

history (36%)

cohort

analysis

[99]

(Candesartan,

analysis

[108]

Study

 Number of participants

 system blockers

(angiotensin-converting

Co-morbidities

 Access type

Intervention

 Control

 Treatment

Primary outcome

Secondary outcome

Pathogenesis and Prevention of Vascular Access Failure DOI: http://dx.doi.org/10.5772/intechopen.83525

(ACEI/ARB

placebo)

 vs

follow-up

(years)

 enzyme inhibitors and angiotensin

 II type I receptor blockers) therapy

[96]


Pathogenesis and Prevention of Vascular Access Failure DOI: http://dx.doi.org/10.5772/intechopen.83525

29.7 vs 33.5%

15% vs 16.2% RR 0.93, CI 0.75–1.00

RR 0.87, 95% CI 0.75–

1.00, p = 0.05

Herrington

88

Post-hoc

2439

 DM (27%), smoking

AVF (89%), AVG

Rosuvastatin

 10 mg

Placebo

 4.5

 Vascular access occlusive

event

NR

28.9% vs 27.6% RR 1.06, 95% CI 0.91–

1.23, p = 0.44

Vascular Access Surgery - Tips and Tricks

daily

(11%)

history (14%)

analysis of

RCT

et al. [94] Birch et al.

Retrospective

265

 HTN (93%), DM

AVF

Statin therapy of

No

1.8

 Interval of time to

Primary AVF patency (time from creation to

first HR 1.17, 95% CI 0.747–

1.834, p = 0.49

intervention)

angioplasty to maintain

AVF function Mean time 8.9 vs

7.3 months, p = 0.25

Number of stenotic

lesions

98 vs 99 stenoses, p = 0.28

statin

therapy

variable doses

(Simvastatin,

Atorvastatin,

Pravastatin,

Lovastatin)

(53%)

analysis

[91]

Pisoni et al.

Retrospective

601

 HTN (92%), DM

AVF (53%), AVG

Statin therapy not

No

6

 Primary access failure

NR

(access never useable for

dialysis) AVF 37% vs

38%, OR 0.97, 95% CI

0.59–1.58, p = 0.9

AVG 20% vs 14%, OR

1.52, 95% CI 0.76–3.09,

p = 0.23

access survival AVF HR 1.26, 95% CI

0.76–2.16, p = 0.35

AVG HR 0.88, 95% CI

0.59–1.32, p = 0.54

> Righetti et al.

Case-control

60

 HTN, dyslipidemia

 AVF

 Atorvastatin

or Simvastatin

20 mg daily and/or folic

acid 5 mg daily

 10–

statin or

folic

acid

therapy

 10–20 mg

No

3

 Primary access patency

NR

71.5% vs 39.1% after

2 years, p < 0.05

study

[34]

Cumulative

statin

therapy

specified

(47%)

(52%), CAD (29%),

PVD (18%), CVD

(10%)

observational

cohort

analysis

[97]


cohort

91

1944 (40.8% on

Felodipine, Mibefradil,

AVF RR 1.14, p = 0.3

Secondary access

patency

AVG RR 0.88, p = 0.153

AVF RR 1.16, p = 0.374

Nifedipine, Verapamil,

Diltiazem, Isradipine,

Nicardipine,

Nisoldipine)

CCB)

analysis

Chen et al.

Retrospective

42,244

 HTN (81%), DM

AVF 89.4%

CCB therapy of varying

Nonuse

8

 Primary patency loss

NR

AVF HR 0.485, CI

0.470–0.501

AVG HR 0.482, CI

0.442–0.526

Pathogenesis and Prevention of Vascular Access Failure DOI: http://dx.doi.org/10.5772/intechopen.83525

doses

(Amlodipine,

Felodipine, Nifedipine,

Verapamil, Diltiazem,

Isradipine,

Nicardipine)

(32.3% on CCB),

AVG 10.6% (20.6% on CCB)

(51%), CAD (24%),

Dyslipidemia

CVD (6%), PVD

(3%)

 (17%),

analysis

[108]

New surgical techniques

Trial Chemla et al.

Prospective

41

NR

AVF

Optiflow device

 NR

 3

 Unassisted maturation

NR

(outflow vein >/= 5 mm

in diameter and flow >/=

500 ml/min not requiring intervention

maintain or promote

maturation)

72% at 42 days & 68% at

90 days Unassisted patency

88% at 42 days & 78% at

90 days

> Bharat et al.

Comparative

125

 HTN (43%), DM

AVF

 pSLOT vs SLOT vs ETS

 NR

 19

 Formation of juxta-

NR

anastomotic

pSLOT (3.7%, p = 0.04)

vs SLOT (8.3%, p = NS)

vs ETS (14%, p = NS)

Fistula failure

 stenosis

(41%)

study

[126]

 to

study

[127]

Study

 Number of

Co-morbidities

 Access type

Intervention

 Control

 Treatment

Primary outcome

 Secondary outcome

follow-up

(months)

participants

 to optimize flow dynamics


#### Pathogenesis and Prevention of Vascular Access Failure DOI: http://dx.doi.org/10.5772/intechopen.83525

Saran et al.

90

Retrospective

2462

 HTN (87.8%), DM

AVF 900 (18.7%

ACEI/ARB therapy of

Nonuse

4

AVF

NR

Unassisted primary

access patency ACEI-RR 0.77, p = 0.09

ARB-RR 1.45, p = 0.06

Secondary access

patency

ACEI-RR 0.56, p = 0.01

Vascular Access Surgery - Tips and Tricks

ARB-RR 1.33, p = 0.31

AVG

Primary access patency ACEI-RR 1.02, p = 0.85

ARB-RR 1.09, p = 0.63

Secondary access

patency

ACEI-RR 1.16, p = 0.13

ARB-RR 1.3, p = 0.17

> Sajgure et al.

Multicentre

266

 HTN (95%), DM

AVF (33%) AVG

ACEI of varying doses Placebo

 2

 Primary patency

duration (mean in days

AVG

672

HR 0.48, 95% CI 0.31–

0.73, p = 0.01

AVF

530

 80 vs 501

p = 0.45

 76,

 68 vs 460

 48,

 SEM)

NR

(57%)

(67%)

observational

study

Calcium channel blocker therapy

Trial

Saran et al.

Retrospective

2462

 HTN (87.8%), DM

AVF 900 (44.1%

CCB therapy of varying

Nonuse

4

 Unassisted primary

NR

access patency AVG RR

0.86, p = 0.034

doses

(Amlodipine,

on CCB), AVG

(49.7%), Obesity

(35.9%)

observational

[96]

Study

 Number of

Co-morbidities

 Access type

Intervention

 Control

 Treatment

Primary outcome

 Secondary outcome

follow-up

(months)

participants

[98]

varying doses

ACEI Enalapril, Lisinopril, Quinapril, Captopril, Fosinopril, Moexipril,

Ramipril)

ARB Losartan, Irbesartan,

Valsartan)

(Candesartan,

(Benazepril,

on ACEI, 4.1% on

(49.7%), Obesity

(35.9%)

ARB), AVG 1944

(17% on ACEI,

3.8% on ARB)

analysis

[96]


Perivascular

93

Trial Dwivedi

RCT

89

 DM (44%), HTN

AVG

 Single dose escalation

Placebo

 12

 Safety (adverse events)

Percentage change in

intraoperative

vein diameter Low 13%, p = 0.01;

medium 15% p = 0.070;

Pathogenesis and Prevention of Vascular Access Failure DOI: http://dx.doi.org/10.5772/intechopen.83525

> high 12%, p < 0.001; vs

5% placebo Percentage change in

intraoperative

flow volume Low 19%, p = 0.34;

medium 36%, p = 0.09,

high 46%, p = 0.02; vs

15% placebo Secondary patency at

12 months

10 mcg vs placebo; HR

0.79, 95% CI 0.33–1.92,

p = 0.61 30 mcg vs

placebo; HR 0.76, 95%

CI 0.31–1.89, p = 0.55

Unassisted maturation

at 3 months 10 mcg 67%, 30 mcg 70% vs placebo 54%, NS

Luminal stenosis (hemodynamically

significant)

3 months 10 mcg 41%, 30 mcg 35%

vs placebo 40%, NS

 at

Hye et al.

RCT

151

 CAD (55%), DM

AVF

 PRT-201 at 0.01 mg or

Placebo

 12

 Unassisted primary

patency at 12 months

10 mcg vs placebo; HR

0.69, 95% CI 0.39–1.22,

p = 0.19

30 mcg vs placebo; HR

0.67, 95% CI 0.38–1.19,

p = 0.17

0.03 mg applied once

to newly formed AVF

(45%), HTN (28%),

PVD (24%), CVD

(20%)

[117]

 blood

 outflow

13% vs 14%, NS

>/25% increase in outflow vein diameter

intraoperatively

33% vs 15%, high,

p = 0.052

of low (0.01, 0.03 mg),

medium (0.1, 0.3,

1.0 mg) and high (3.0,

6.0, 9.0 mg) PRT-201

immediately

 at AVG

placement

(40%)

et al. [118]

Study

 Number of

Co-morbidities

 Access type

Intervention

 Control

 Treatment

Primary outcome

Secondary outcomes

(PRT-201 vs placebo)

follow-up

(PRT-201 vs placebo)

(months)

participants

 application

 of

recombinant

 elastase

(pSLOT 16.7%, p = 0.01),


#### Pathogenesis and Prevention of Vascular Access Failure DOI: http://dx.doi.org/10.5772/intechopen.83525

(pSLOT 16.7%, p = 0.01),

SLOT (33.3%, p = NS),

ETS (40.3%, p = NS)

Endovascular

92

Trial Lok et al.

Prospective

80

 HTN (92%), DM

AVF

Endovascular

 AVF

NR

 12

Percentage of

Primary patency at

Vascular Access Surgery - Tips and Tricks

12 months 69%, 95% CI 54–79%

Cumulative

 patency at

12 months 84%, 95% CI 71–91%

endovascular

suitable for HD at

3 months

91%, 95% CI 81–97%

 AVF

creation

(65%), CAD (22%),

CVD (15%), CHD

(12%), PVD (5%)

study

[114]

Far infrared therapy

Trial

Lin et al.

RCT

122

 HTN (65%), DM

AVF

 40 min FIT, 3 times

Placebo

 12

 Rate of AVF malfunction

Cumulative

 primary

unassisted AVF

patency

within 12 months

(thrombosis,

intervention

12% vs 29%, p = 0.02

 required)

87% vs 70%, p = 0.01

Physiologic AVF

maturation

82% vs 60% p = 0.008

NR

weekly

(40%)

[115]

Lin et al.

RCT

145

 HTN (54%), DM

AVF

 40 min FIT, 3 times

Placebo

 12

 Effect of FIT on access

flow at 12 months

13.2

132.3 ml/min, p < 0.021

AVF malfunction 12.9% vs 30.1%, p < 0.01

AVF unassisted patency 85.9% vs 67.6%, p < 0.01

 114.7 vs 33.4

weekly

(33%)

[116]

Study

 Number of

Co-morbidities

 Access type

Intervention

 Control

 Treatment

Primary outcome (FIT

Secondary outcome

(FIT vs placebo)

duration

vs placebo)

(months)

participants

Study

 Number of

Co-morbidities

 Access type

Intervention

 Control

 Treatment

Primary outcome

 Secondary outcome

follow-up

(months)

participants

 AVF creation


Paclitaxel-coated

95

Trial

Kitrou et al.

RCT

40

NR

AVF

PCB treatment of

HPB

 12

Device success

Dialysis circuit primary

patency

PCB 270 days; HPB

161 days; HR 0.479; 95%

CI 0.237–0.968;

p = 0.04

Pathogenesis and Prevention of Vascular Access Failure DOI: http://dx.doi.org/10.5772/intechopen.83525

> Procedure related

complications

Nil

35% vs 100%, p < 0.001

Anatomic success

100% both groups

Clinical success 100% both groups

Target lesion

revascularization-free

survival

PCB 308 days; HPB

161 days; HR 0.478; 95%

CI 0.236–0.966,

Katsanos

RCT

40

 DM (20%), HTN

AVF (35%), AVG

PCB treatment of

HPB

 6

 Primary patency of

Dialysis circuit survival

95% vs 90%, p = 0.274;

HR 0.33, 95% CI 0.03 to

3.36, p = 0.349

treated lesion 70% vs 25% p < 0.001,

HR 0.30, 95% CI 0.12–

0.71, p = 0.006

Device success 45% vs 100%, p < 0.001

Procedural success

100% both groups

 straight-line

polytetrafluoroethylene;

 PCB,

 onlay technique; SLOT, side-to-side

paclitaxel-coated

 balloon angioplasty;

cerebrovascular

 disease; AVF,

failing access

(13%)

(65%)

et al. [124] RCT, randomized controlled trial; HTN, hypertension;

arteriovenous

mean; NS, not significant; HD, hemodialysis;

straight-line

HPB, high pressure balloon angioplasty.

Table 1. Summary of trial results of systemic medical therapies and local

interventions

 on vascular access outcomes in

hemodialysis

 patients.

 onlay technique; ETS, end-to-side; FIT, far infrared therapy; PRT-201, perivascular

 fistula; AVG arteriovenous

 graft; mg, milligrams; RR, relative risk; CI, confidence interval; NR, not reported; OR, odds ratio; HR, hazard ratio; IRR, incident rate ratio; SEM, standard error of the

 ACEI,

angiotensin-converting

 enzyme inhibition; ARB, angiotensin II typ. 1 receptor blockers; pSLOT, piggybacking

 application of recombinant

 elastase; PTFE,

 DM, diabetes mellitus; CAD, coronary artery disease; PVD, peripheral vascular disease; CHD, congestive heart disease; CVD,

 p = 0.03

failing AVF

[123]

Study

 Number of

Co-morbidities

 Access type

Intervention

 Control

 Treatment

Primary outcomes

Secondary outcomes

(PCB vs HPB)

(PCB vs HPB)

follow-up

(months)

participants

 balloon angioplasty


 high pressure angioplasty.

#### Table 1.

 Summary of trial results of systemic medical therapies and local interventions on vascular access outcomes in hemodialysis patients.
