4.1.1.2 Dipyridamole

Dipyridamole impairs platelet aggregation by inhibition of adenosine deaminase and phosphodiesterase, causing an increase of adenosine, adenine nucleotides and cyclic adenosine monophosphate (cAMP) levels [70]. As a phosphodiesterase inhibitor, it reduces vascular smooth muscle proliferation, and may prevent neointimal hyperplasia, stenosis and thrombosis of arteriovenous access [70, 71]. A randomized, double-blind, placebo-controlled parallel group study [69] of 107 patients with ESKD assessed the effect of dipyridamole (225 mg daily) and/or aspirin (325 mg daily) on the rate of AVG thrombosis over a treatment duration of 18 months (Table 1). The treatment groups were divided into two cohorts, type I which included patients with new AVGs (84 patients) vs type II which included patients with previously placed AVGs who had suffered graft thrombosis requiring thrombectomy or revision (23 patients). Dipyridamole reduced AVG thrombosis rates compared to placebo (RR 0.35, 95% CI 0.15–0.80, p = 0.02), used alone (17% vs 32%) or in combination with aspirin (23% vs 32%). A multicenter RCT involving 649 patients with new AVGs randomized individuals to dipyridamole (200 mg extended release twice daily) plus aspirin (25 mg twice daily) or placebo over 4.5 years with an additional 6-month follow-up [72]. At 12 months, the primary outcome of primary unassisted patency loss (patency without thrombosis or requirement of an intervention) occurred in 28% of patients treated with dipyridamole and aspirin compared to 23% receiving placebo (hazard ratio [HR] 0.82; 95% CI 0.68–0.98, p = 0.03) [72]. Pertaining to the evidence presented, dipyridamole alone or in combination with aspirin may be beneficial in preventing primary AVG failure.

### 4.1.1.3 Clopidogrel

Clopidogrel and ticlopidine are classed as thienopyridines. The active metabolite they produce irreversibly blocks the protein P2y12 component of the adenosine

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

diphosphate (ADP) receptors on the platelet surface, preventing activation of the GPIIb/IIa receptor complex and reducing platelet aggregation [13]. The effects of clopidogrel (300 mg load followed by 75 mg daily) on access failure were evaluated in an RCT involving 877 patients undergoing AVF formation (Table 1). The rate of early fistula thrombosis (within 6 weeks) was lower with treatment (53 of 436 patients, 12.2%) compared to placebo (84 of the 430, 19.5%; RR 0.63, 95% CI 0.46– 0.97, p = 0.18) [15], however, this benefit did not translate into an increase in the proportion of AVFs that became suitable for hemodialysis (61.8% vs 59.5%; RR 1.05, 95% CI 0.94–1.17, p = 0.4) [15]. A smaller RCT of 93 patients found that, compared with placebo, clopidogrel resulted in a lower risk of early fistula thrombosis (5.2% vs 21.6%; HR 0.72, 95% CI 0.41–1.01, p = 0.03) and a higher rate of first successful dialysis using the newly created AVF (92.3% vs 70.5%) [73]. In contrast, no benefit was identified from clopidogrel 75 mg and aspirin 325 mg vs placebo on graft thrombosis in an RCT involving 200 participants undergoing hemodialysis with newly formed AVGs (HR 0.81, 95% CI 0.47–1.40, p = 0.45) [74]. Considering the evidence to date, there remains uncertainty as to whether clopidogrel results in a clinically meaningful benefit beyond prevention of early thrombosis.

#### 4.1.1.4 Ticlopidine

placebo (32% vs 72%, odds ratio [OR] 0.18, 95% confidence interval [CI] 0.05–0.66, p < 0.01) after a mean follow-up of 5 months [67]. In contrary, a randomized, double-blind, placebo-controlled parallel group study [69] assessing the effect of dipyridamole and/or aspirin on AVG thrombosis showed a non-significant increase in thrombosis in 10 of 20 patients (50%) treated with 325 mg of aspirin daily compared to 6 of 19 (32%) patients on placebo (relative risk [RR] 1.99, 95% CI 0.88–4.48, p = 0.18) over a 18-month follow-up period. Inconsistent outcomes have also been described for aspirin used for prevention of AVF failure. In a study of 92 participants [68] randomized to 1000 mg of aspirin on alternate days over a 28 day period or placebo, the frequency of AVF thrombosis was reduced more than 4-fold by aspirin compared to placebo (2 of 45 [4.4%] vs 11 of 47 [23.4%], p < 0.05). However, the most recent and largest RCT showed no significant reduction in AVF failure at 12 months in 488 patients randomized to receive 100 mg of aspirin or placebo for 3 months following AVF creation. AVF failure was defined as a composite of AVF thrombosis, AVF abandonment and cannulation failure [5]. Neither the composite binary outcome (45% participants treated with aspirin vs 43% treated with placebo, RR 1.05, 95% CI 0.84–1.31, p = 0.68) nor the individual outcome components were reduced by low-dose aspirin: AVF thrombosis (20% vs 18%, RR 1.09, 95% CI 0.72–1.64, p = 0.70), AVF abandonment (24% vs 18%, RR 1.31, 95% CI 0.89–1.95, p = 0.17) and cannulation failure (40% vs 39%, RR 0.99, 95% CI 0.76–1.27, p = 0.92) [5]. Differences in treatment dose, duration, sample size and outcome definition makes comparison of treatment efficacy across trials difficult. Considering the cumulative evidence to date, there remains considerable

uncertainty as to whether aspirin reduces arteriovenous access failure.

Dipyridamole impairs platelet aggregation by inhibition of adenosine deaminase and phosphodiesterase, causing an increase of adenosine, adenine nucleotides and cyclic adenosine monophosphate (cAMP) levels [70]. As a phosphodiesterase inhibitor, it reduces vascular smooth muscle proliferation, and may prevent neointimal hyperplasia, stenosis and thrombosis of arteriovenous access [70, 71]. A randomized, double-blind, placebo-controlled parallel group study [69] of 107 patients with ESKD assessed the effect of dipyridamole (225 mg daily) and/or aspirin (325 mg daily) on the rate of AVG thrombosis over a treatment duration of 18 months (Table 1). The treatment groups were divided into two cohorts, type I which included patients with new AVGs (84 patients) vs type II which included patients with previously placed AVGs who had suffered graft thrombosis requiring thrombectomy or revision (23 patients). Dipyridamole reduced AVG thrombosis rates compared to placebo (RR 0.35, 95% CI 0.15–0.80, p = 0.02), used alone (17% vs 32%) or in combination with aspirin (23% vs 32%). A multicenter RCT involving 649 patients with new AVGs randomized individuals to dipyridamole (200 mg extended release twice daily) plus aspirin (25 mg twice daily) or placebo over 4.5 years with an additional 6-month follow-up [72]. At 12 months, the primary outcome of primary unassisted patency loss (patency without thrombosis or requirement of an intervention) occurred in 28% of patients treated with dipyridamole and aspirin compared to 23% receiving placebo (hazard ratio [HR] 0.82; 95% CI 0.68–0.98, p = 0.03) [72]. Pertaining to the evidence presented, dipyridamole alone or in combination with aspirin may be beneficial in

Clopidogrel and ticlopidine are classed as thienopyridines. The active metabolite they produce irreversibly blocks the protein P2y12 component of the adenosine

4.1.1.2 Dipyridamole

Vascular Access Surgery - Tips and Tricks

preventing primary AVG failure.

4.1.1.3 Clopidogrel

96

Three RCTs investigated the effects of ticlopidine on AVF thrombosis at 4 weeks (Table 1). Two small RCTs [75, 76] demonstrated that AVF thrombosis occurred in fewer patients receiving ticlopidine as compared with placebo. Grontoft et al. [75] studied 36 participants and showed that AVF thrombosis at 4 weeks was reduced in participants treated with 250 mg ticlopidine twice daily (11%) compared to placebo (47%, p < 0.05). In a pilot study of 18 participants [76], 250 mg ticlopidine given twice daily over 1 month resulted in half the thrombosis rates compared to placebo (25% vs 50% respectively). A multicenter RCT involving 250 participants [77] showed that ticlopidine did not significantly reduce AVF thrombosis compared to placebo at 4 weeks (12% vs 19%, OR 0.6, 95% CI 0.30–1.18, p = 0.1). A subsequent systematic review and meta-analysis of these trials [78] favored the use of ticlopidine in access thrombosis as a beneficial treatment (OR 0.45, 95% CI 0.25– 0.82, p = 0.009).

A meta-analysis of 21 RCTs using any type of antiplatelet drug to prevent arteriovenous access failure demonstrated a 51% reduction in patency loss of AVFs with antiplatelet therapy compared to placebo (6 trials, 1222 participants, RR 0.49, 95% CI 0.30–0.81), while clinical benefits in preventing AVG thrombosis remained uncertain (3 trials, 956 participants, RR 0.94, 95% CI 0.80–1.10) [79].

Based on the available evidence, there may be a short-term benefit of antiplatelet agents in reducing arteriovenous access thrombosis [15, 78–80], though clinically meaningful benefits, including improved long-term patency or access usability for dialysis, have not been found [15, 79]. Therapeutic approaches targeting vascular remodeling and neointimal hyperplasia may be more beneficial in the longer term [13].

#### 4.1.2 Omega-3 fatty acid supplementation (fish oil)

Omega-3 fatty acids (the active component of fish oil) are thought to reduce arteriovenous access thrombosis and improve maturation [81] through their antiproliferative [82], antiaggregatory [83], anti-inflammatory [84], antioxidant and vasodilatory effects [85–87].

Two RCTs have assessed the effect of fish oil on AVG patency (Table 1) [88, 89]. The largest study involved 196 patients with newly created AVGs treated with 4 g of fish oil or placebo for 12 months [89]. There was no statistically

significant difference in the proportion of participants experiencing graft patency loss (thrombosis or radiological or surgical interventions) at 12 months between fish oil (48%) and placebo (62%, RR 0.78, 95% CI 0.60–1.03, p = 0.06). However, participants treated with fish oil experienced lower rates of loss of graft patency (incident rate ratio [IRR] 0.58, 95% CI 0.44–0.75), radiological or surgical interventions (IRR 0.59, 95% CI 0.44–0.78) and thrombotic events (IRR0.5, 95% CI 0.35–0.72). Another RCT including 24 patients randomized to treatment with fish oil or placebo for 12 months found that fish oil treatment led to greater primary patency (thrombosis free) after 12 months of follow-up (75.6% vs 14.9% respectively, p = 0.03) [88]. An RCT by Bowden et al. [90] was unable to replicate these findings in 29 participants, with no difference in the mean time to primary patency loss (thrombosis or venous outflow stenosis >50% requiring angioplasty) in the treatment group (254 52 days, standard error of the mean [SEM] 51.8) compared to the placebo group (254 35 days, SEM 34.6) over the 8-month follow-up period. The heterogeneity in outcome definitions (primary patency loss vs thrombosis) makes comparison across trials difficult. Although a risk reduction in graft thrombosis was described in a meta-analysis of data from four trials, this analysis incorporated events other than graft thrombosis including infection [86] and interventions [90]. When only including the trials that assessed the frequency of graft thrombosis [78], fish oil was no longer associated with a significant treatment benefit compared to placebo (OR 0.24; 95% CI, 0.03–1.95).

access) in 2353 participants (94% AVF, 6% AVG) (Table 1) [94]. Simvastatin plus ezetimibe resulted in a 13% reduction in vascular occlusive events compared with placebo (RR 0.87, 95% CI 0.75–1.00, p = 0.05). Results were broadly similar for the individual components of the composite outcomes. However, the same group was unable to replicate this result in a post hoc analysis of the AURORA (A Study to Evaluate the Use of Rosuvastatin in Subjects on Regular Hemodialysis: An Assessment of Survival and Cardiovascular Events) trial cohort [94]. Specifically, occlusive vascular events were comparable between the rosuvastatin and placebo groups (28.9% vs 27.6%, respectively, RR 1.06, 95% CI 0.91–1.23, p = 0.44). When the SHARP and AURORA results were pooled, low density lipoprotein cholesterol (LDL-C) lowering therapy did not significantly reduce vascular occlusive events. These results were limited by the post hoc analysis of exploratory trial outcomes and the failure to include other large studies of cholesterol-lowering therapy (such as the Der Deutsche Diabetes Dialyze [4D] study [95]), such that results should be

Retrospective observational cohort analyses by Saran et al. [96] and Pisoni et al. [97] found statins were not beneficial in improving cumulative fistula survival. Specifically, statin therapy did not improve access maturation [97] or primary access patency [96]. Similarly, a retrospective review of 265 patients, of which 90% were on either simvastatin or atorvastatin, found that statin therapy did not affect the number of stenotic lesions in AVFs or time to primary angioplasty [91].

Whereas a case-control study of 60 dialysis patients receiving either folic acid and/ or statin discovered improved primary patency in 35 patients with AVFs [34].

4.1.4 Renin-angiotensin-aldosterone system blockers (angiotensin-converting enzyme

The renin-angiotensin-aldosterone system (RAAS) is an important modulator of the vascular smooth muscle cell proliferation that occurs in the intimal layer of the vein in response to injury [98]. Additionally, angiotensin II produced locally at the site of injury can induce growth factors that further promote vascular smooth muscle proliferation and a prothrombotic environment [98]. Blocking these pathways in animal models with the use of angiotensin-converting enzyme inhibition (ACEI) has been shown to prevent smooth muscle cell proliferation and migration [99, 100], inhibit intimal hyperplasia and extracellular matrix deposition [100– 102], promote venous dilation [103] and prevent platelet activation [104, 105]. In the clinical setting, the effects of ACEI and/or angiotensin II type 1 receptor blockers (ARB) on primary and secondary arteriovenous access outcomes has been confined to retrospective observational cohort studies with conflicting findings (Table 1) [98, 99, 106–108]. A multi-center observational study by Sajgure et al. [98] compared the use of ACEI vs placebo on primary patency duration in AVGs (179 participants) and AVFs (87 participants) over a 24 month period. A longer primary patency duration was observed in the treatment AVG group compared with placebo (HR 0.48, 95% CI 0.31–0.73, p = 0.01), though no benefit was observed with the use of ACEI in AVFs (p = 0.45). Chen et al. [108] performed a retrospective analysis of the efficacy of ACEI and/or ARB therapy on primary patency loss of AVGs and AVFs in 42,244 patients over a 96-month period

inhibitors and angiotensin II type I receptor blockers)

In summary, the evidence for benefits of statin use in the prevention of vascular access complications in hemodialysis patients is based on observational trial data and post hoc analysis of RCTs. To date, no RCT has been developed to determine the effect of statin therapy on primary patency rates in newly formed vascular access. There is currently insufficient evidence to support the routine use of statin

considered hypothesis-generating only.

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

therapy for preserving vascular access.

99

A large multicenter trial (Omega-3 fatty acids (fish oils) and aspirin in vascular access outcomes in renal disease [FAVORED]) [5] is the only RCT to date to examine the effect of fish oil on AVF failure. This trial included 567 patients with newly created AVF randomized to 4 g of fish oil daily or matching placebo for 3 months post AVF creation. At 12-month follow-up, no significant differences between the fish oil and placebo groups were identified for the primary composite outcome of AVF failure (47% identified in both groups, RR 1.03, 95% CI 0.86–1.23, p = 0.78) or for the individual components of the composite including AVF thrombosis (22% vs 23%, RR 0.98, 95% CI 0.72–1.34, p = 0.9), fistula abandonment (19% vs 22%, RR 0.87, 95% CI 0.62–1.2, p = 0.43) or cannulation failure (40% vs 39%, RR 1.03, 95% CI 0.83–1.26, p = 0.81) [5].

A recent meta-analysis of all RCTs (5 trials, 833 participants) evaluated the effect of fish oil supplementation in preventing arteriovenous access failure using standardized outcome definitions [81]. Key findings included that fish oil supplementation prevented primary patency loss with moderate certainty (RR 0.81, 95% CI 0.68–0.98), and that low quality evidence suggested that fish oil may have little effect on dialysis suitability failure (RR 0.95, 95% CI 0.73–1.23), access abandonment (RR 0.78, 95% CI 0.59–1.03), need for interventions (RR 0.82, 95% CI 0.64– 1.04) or all-cause mortality (RR 0.99, 95% CI 0.51–1.92).

#### 4.1.3 Statin therapy

Statins have been shown to reduce inflammation in the ESKD population, while also improving endothelial function beyond the effect of cholesterol lowering [91]. There is experimental evidence that statins reduce neointimal hyperplasia and vascular remodeling, which appears to be mediated by the reduction of vascular endothelial growth factor-A and matrix metalloproteinase (MMP) [92], and promotion of vasodilatation (via endothelial derived NO) [93].

An ancillary analysis of the Study of Heart and Renal Protection (SHARP) RCT comparing the effects of simvastatin/ezetimibe 20 mg/10 mg vs placebo on vascular access occlusive events (defined as any access revision procedure, access thrombosis, removal of an old dialysis access, or formation of new permanent dialysis

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

significant difference in the proportion of participants experiencing graft patency loss (thrombosis or radiological or surgical interventions) at 12 months between fish oil (48%) and placebo (62%, RR 0.78, 95% CI 0.60–1.03, p = 0.06). However, participants treated with fish oil experienced lower rates of loss of graft patency (incident rate ratio [IRR] 0.58, 95% CI 0.44–0.75), radiological or surgical interventions (IRR 0.59, 95% CI 0.44–0.78) and thrombotic events (IRR0.5, 95% CI 0.35–0.72). Another RCT including 24 patients randomized to treatment with fish oil or placebo for 12 months found that fish oil treatment led to greater primary patency (thrombosis free) after 12 months of follow-up (75.6% vs 14.9% respectively, p = 0.03) [88]. An RCT by Bowden et al. [90] was unable to replicate these findings in 29 participants, with no difference in the mean time to primary patency loss (thrombosis or venous outflow stenosis >50% requiring angioplasty) in the treatment group (254 52 days, standard error of the mean [SEM] 51.8) compared to the placebo group (254 35 days, SEM 34.6) over the 8-month follow-up period. The heterogeneity in outcome definitions (primary patency loss vs thrombosis) makes comparison across trials difficult. Although a risk reduction in graft thrombosis was described in a meta-analysis of data from four trials, this analysis incor-

porated events other than graft thrombosis including infection [86] and

benefit compared to placebo (OR 0.24; 95% CI, 0.03–1.95).

1.04) or all-cause mortality (RR 0.99, 95% CI 0.51–1.92).

motion of vasodilatation (via endothelial derived NO) [93].

1.03, 95% CI 0.83–1.26, p = 0.81) [5].

Vascular Access Surgery - Tips and Tricks

4.1.3 Statin therapy

98

interventions [90]. When only including the trials that assessed the frequency of graft thrombosis [78], fish oil was no longer associated with a significant treatment

access outcomes in renal disease [FAVORED]) [5] is the only RCT to date to examine the effect of fish oil on AVF failure. This trial included 567 patients with newly created AVF randomized to 4 g of fish oil daily or matching placebo for 3 months post AVF creation. At 12-month follow-up, no significant differences between the fish oil and placebo groups were identified for the primary composite outcome of AVF failure (47% identified in both groups, RR 1.03, 95% CI 0.86–1.23, p = 0.78) or for the individual components of the composite including AVF thrombosis (22% vs 23%, RR 0.98, 95% CI 0.72–1.34, p = 0.9), fistula abandonment (19% vs 22%, RR 0.87, 95% CI 0.62–1.2, p = 0.43) or cannulation failure (40% vs 39%, RR

A recent meta-analysis of all RCTs (5 trials, 833 participants) evaluated the effect of fish oil supplementation in preventing arteriovenous access failure using standardized outcome definitions [81]. Key findings included that fish oil supplementation prevented primary patency loss with moderate certainty (RR 0.81, 95% CI 0.68–0.98), and that low quality evidence suggested that fish oil may have little effect on dialysis suitability failure (RR 0.95, 95% CI 0.73–1.23), access abandonment (RR 0.78, 95% CI 0.59–1.03), need for interventions (RR 0.82, 95% CI 0.64–

Statins have been shown to reduce inflammation in the ESKD population, while also improving endothelial function beyond the effect of cholesterol lowering [91]. There is experimental evidence that statins reduce neointimal hyperplasia and vascular remodeling, which appears to be mediated by the reduction of vascular endothelial growth factor-A and matrix metalloproteinase (MMP) [92], and pro-

An ancillary analysis of the Study of Heart and Renal Protection (SHARP) RCT comparing the effects of simvastatin/ezetimibe 20 mg/10 mg vs placebo on vascular access occlusive events (defined as any access revision procedure, access thrombosis, removal of an old dialysis access, or formation of new permanent dialysis

A large multicenter trial (Omega-3 fatty acids (fish oils) and aspirin in vascular

access) in 2353 participants (94% AVF, 6% AVG) (Table 1) [94]. Simvastatin plus ezetimibe resulted in a 13% reduction in vascular occlusive events compared with placebo (RR 0.87, 95% CI 0.75–1.00, p = 0.05). Results were broadly similar for the individual components of the composite outcomes. However, the same group was unable to replicate this result in a post hoc analysis of the AURORA (A Study to Evaluate the Use of Rosuvastatin in Subjects on Regular Hemodialysis: An Assessment of Survival and Cardiovascular Events) trial cohort [94]. Specifically, occlusive vascular events were comparable between the rosuvastatin and placebo groups (28.9% vs 27.6%, respectively, RR 1.06, 95% CI 0.91–1.23, p = 0.44). When the SHARP and AURORA results were pooled, low density lipoprotein cholesterol (LDL-C) lowering therapy did not significantly reduce vascular occlusive events. These results were limited by the post hoc analysis of exploratory trial outcomes and the failure to include other large studies of cholesterol-lowering therapy (such as the Der Deutsche Diabetes Dialyze [4D] study [95]), such that results should be considered hypothesis-generating only.

Retrospective observational cohort analyses by Saran et al. [96] and Pisoni et al. [97] found statins were not beneficial in improving cumulative fistula survival. Specifically, statin therapy did not improve access maturation [97] or primary access patency [96]. Similarly, a retrospective review of 265 patients, of which 90% were on either simvastatin or atorvastatin, found that statin therapy did not affect the number of stenotic lesions in AVFs or time to primary angioplasty [91]. Whereas a case-control study of 60 dialysis patients receiving either folic acid and/ or statin discovered improved primary patency in 35 patients with AVFs [34].

In summary, the evidence for benefits of statin use in the prevention of vascular access complications in hemodialysis patients is based on observational trial data and post hoc analysis of RCTs. To date, no RCT has been developed to determine the effect of statin therapy on primary patency rates in newly formed vascular access. There is currently insufficient evidence to support the routine use of statin therapy for preserving vascular access.

#### 4.1.4 Renin-angiotensin-aldosterone system blockers (angiotensin-converting enzyme inhibitors and angiotensin II type I receptor blockers)

The renin-angiotensin-aldosterone system (RAAS) is an important modulator of the vascular smooth muscle cell proliferation that occurs in the intimal layer of the vein in response to injury [98]. Additionally, angiotensin II produced locally at the site of injury can induce growth factors that further promote vascular smooth muscle proliferation and a prothrombotic environment [98]. Blocking these pathways in animal models with the use of angiotensin-converting enzyme inhibition (ACEI) has been shown to prevent smooth muscle cell proliferation and migration [99, 100], inhibit intimal hyperplasia and extracellular matrix deposition [100– 102], promote venous dilation [103] and prevent platelet activation [104, 105].

In the clinical setting, the effects of ACEI and/or angiotensin II type 1 receptor blockers (ARB) on primary and secondary arteriovenous access outcomes has been confined to retrospective observational cohort studies with conflicting findings (Table 1) [98, 99, 106–108]. A multi-center observational study by Sajgure et al. [98] compared the use of ACEI vs placebo on primary patency duration in AVGs (179 participants) and AVFs (87 participants) over a 24 month period. A longer primary patency duration was observed in the treatment AVG group compared with placebo (HR 0.48, 95% CI 0.31–0.73, p = 0.01), though no benefit was observed with the use of ACEI in AVFs (p = 0.45). Chen et al. [108] performed a retrospective analysis of the efficacy of ACEI and/or ARB therapy on primary patency loss of AVGs and AVFs in 42,244 patients over a 96-month period

(37,771 with AVFs [32.3% on an ACEI, 15% on an ARB], 4473 with AVGs [6.2% on an ACEI, 7.1% on an ARB]). ACEI use was associated with prolonged primary patency in both AVFs (HR 0.59, 95% CI 0.56–0.62, p < 0.05) and AVGs (HR 0.56, 95% CI 0.48–0.64, p < 0.05). Similarly, ARB use was shown to be beneficial in AVFs (HR 0.53, 95% CI 0.51–0.56, p < 0.05), and AVGs (HR0.54, 95% CI 0.47– 0.61, p < 0.05) [108]. Furthermore, Jackson et al. [99] reported that ARB use prolonged 1- and 2-year primary patency in both, AVFs (55.2% at 1 year, 49.1% at 2 years; HR 0.35, 95% CI 0.16–0.76, p = 0.008) and AVGs (50.2% at 1 year, 29.7% at 2 years; HR0.41, 95% CI 0.18–0.95, p = 0.039). An international, prospective, observational study by Saran et al. [96] elucidated a clinically significant relationship between ACEI use and reduction in secondary AVF failure (RR 0.56, p = 0.01) and a trend toward improving primary AVF patency failure, while there was no significant treatment benefit in AVGs (primary RR 1.02, p = 0.846, secondary RR 1.16, p = 0.133). The same study found no significant benefit associated with the use of ARB in preventing primary or secondary patency failure in AVFs or AVGs. Available evidence is limited by substantial heterogeneity of treatment agents, dose, outcome definitions and study populations and unadjusted confounding associated with the observational study design. Randomized-controlled trials to confirm potential benefits of RAAS inhibitors are required.

at changing the anatomical configuration is a potential strategy to minimize this injury [17]. Baharat et al. [126] compared the use of the piggybacking Straight-Line Onlay Technique (pSLOT) to the traditional end-to-side (ETS) and side-to-side Straight-Line Onlay Techniques (SLOT), in a study of 125 patients (Table 1). They found a significant reduction in juxta-anastomotic stenosis using the novel pSLOT (3.7%) compared to traditional methods of ETS (14%) and SLOT (8.3%) (p = 0.04). This was accompanied by a significant reduction in overall fistula failure (pSLOT 16.7%, ETS 40.3%, SLOT 33.3%, p = 0.01) over the median 19-month follow-up. The Optiflow Vascular Anastomotic device is a sutureless device that is able to provide reproducible anastomosis at a controlled geometry of 60° between the artery and vein, resulting in reduced surgical time, and optimized flow patterns and shear stress [13, 113], with a likely capability of shielding the perianastomotic region and preventing stenosis with its prosthetic material [13, 113]. This device is thought to clinically improve both vascular access maturation and patency [13]. Manson et al. [113] demonstrated safety and technical practicality in a human pilot study involving 10 patients. Subsequently, a prospective study of 41 patients performed at two centers by Chemla et al. [127] evaluated the maturation, patency, and safety of AVF using the Optiflow device. Unassisted maturation (defined as an outflow vein >/= 5 mm in diameter and flow >/= 500 ml/min not requiring intervention to maintain or promote maturation) was achieved in 72% of AVFs at 42 days and 68% at 90 days, unassisted patency in 88% of AVFs at 42 days and 78% at 90 days, and no serious device-related adverse events were reported [127]. In summary, the Optiflow device has shown promise in very small sample sizes and requires further

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

evaluation in an RCT that is powered to confirm these clinical benefits.

pseudoaneurysm) occurred in 8% of participants. These results suggest that endovascular AVF creation may be a viable, minimally invasive alternative for creating vascular access. However, long-term outcomes are currently lacking and comparison to open surgical techniques in a randomized controlled fashion may be

Infrared radiation is an invisible electromagnetic wave, with wavelengths ranging from 5.6 to 1000 μm [17]. This energy is perceived as heat by the thermoreceptors in the surrounding skin [116]. Far infrared therapy (FIT) has been shown to

difficult due to the unique location and type of vessels used for AVF.

The creation of an AVF with an endovascular approach using a radiofrequency magnetic catheter-based system is suggested to cause less vessel trauma, resulting in a reduced stimulus for the formation of neointimal hyperplasia [13, 128]. Clinically this has the potential to translate into improved vascular access maturation and patency [13]. A prospective, single-arm, multicenter study (Novel Endovascular Access Trial [NEAT]) enrolled 80 patients (57% pre-dialysis and 43% on dialysis) who underwent endovascular arteriovenous anastomosis creation (Table 1) [114]. The AVF was successfully created in 98% of participants (95% CI 91–100%). Physiologically suitable AVF dialysis, defined as a brachial artery flow ≥500 mL/min and vein diameter ≥ 4 mm within 3 months, was achieved in 87% of participants (95% CI 75–94%) and 64% (95% CI 48–78%) were able to receive prescribed hemodialysis through the AVF using two-needle cannulation. Primary patency at 12 months was 69% (95% CI 54–79%) and cumulative patency 84% (95% CI 71–91%), and 24 secondary AVF interventions were required in 19 participants (0.46/patient-year). Serious procedure-related adverse events (access-site management, hemostasis and

4.2.2 Endovascular AVF creation

4.2.3 Far infrared therapy

101

#### 4.1.5 Calcium channel blockers

Based on animal and human studies, calcium channel blockers (CCB) may inhibit neointimal hyperplasia [109, 110] and thereby reduce maturation failure [111] and restenosis post angioplasty [112]. In a prospective, observational study of 2313 participants (of which 970 were on CCB) [96], CCB use was associated with prolonged primary patency of AVGs (RR 0.86, p = 0.034), while no association with CCB was found for secondary AVG patency (RR 0.88, p = 0.153) as well as primary (RR 1.14, p = 0.3) and secondary AVF patency (RR 1.16, p = 0.374) (Table 1). A retrospective study by Chen et al. [108] including 42,244 patients (37,771 with AVFs [32.3% on a CCB], 4473 with AVGs [20.6% on a CCB]), described a significant relationship between CCB use and prolonged primary patency in both AVF (HR 0.485, CI 0.470–0.501) and AVG (HR 0.482, CI 0.442– 0.526) groups. While there has currently been minimal investigation into the use of CCB in prevention of vascular access failure, further research may be warranted given the wide use of this antihypertensive agent in the hemodialysis population.

#### 4.2 Local interventions

Targeted interventions to reduce upstream injury include new surgical techniques [113] and endovascular access creation [114], interventions to mitigate downstream responses include far infra-red therapy [115, 116], perivascular application of recombinant elastase [117, 118] and endothelial loaded gel foam wrap (Vascugel) [119–121], whereas antiproliferative agents including sirolimus [122] and paclitaxel [123, 124] have been developed to prevent neointimal hyperplasia and promote outward remodeling and vasodilatation [1, 13].

#### 4.2.1 New surgical techniques to alter wall shear stress

Turbulent low-flow with low shear stress at the anastomosis leads to endothelial dysfunction, increased oxidative stress and an inflammatory and prothrombotic state, promoting AVF/AVG inward remodeling and neointimal hyperplasia [16, 125]. Optimization of flow dynamics through novel surgical techniques aimed

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

(37,771 with AVFs [32.3% on an ACEI, 15% on an ARB], 4473 with AVGs [6.2% on an ACEI, 7.1% on an ARB]). ACEI use was associated with prolonged primary patency in both AVFs (HR 0.59, 95% CI 0.56–0.62, p < 0.05) and AVGs (HR 0.56, 95% CI 0.48–0.64, p < 0.05). Similarly, ARB use was shown to be beneficial in AVFs (HR 0.53, 95% CI 0.51–0.56, p < 0.05), and AVGs (HR0.54, 95% CI 0.47– 0.61, p < 0.05) [108]. Furthermore, Jackson et al. [99] reported that ARB use prolonged 1- and 2-year primary patency in both, AVFs (55.2% at 1 year, 49.1% at 2 years; HR 0.35, 95% CI 0.16–0.76, p = 0.008) and AVGs (50.2% at 1 year, 29.7% at 2 years; HR0.41, 95% CI 0.18–0.95, p = 0.039). An international, prospective, observational study by Saran et al. [96] elucidated a clinically significant relationship between ACEI use and reduction in secondary AVF failure (RR 0.56, p = 0.01) and a trend toward improving primary AVF patency failure, while there was no significant treatment benefit in AVGs (primary RR 1.02, p = 0.846, secondary RR 1.16, p = 0.133). The same study found no significant benefit associated with the use of ARB in preventing primary or secondary patency failure in AVFs or AVGs. Available evidence is limited by substantial heterogeneity of treatment agents, dose, outcome definitions and study populations and unadjusted confounding associated with the observational study design. Randomized-controlled trials to confirm

Based on animal and human studies, calcium channel blockers (CCB) may inhibit neointimal hyperplasia [109, 110] and thereby reduce maturation failure [111] and restenosis post angioplasty [112]. In a prospective, observational study of 2313 participants (of which 970 were on CCB) [96], CCB use was associated with prolonged primary patency of AVGs (RR 0.86, p = 0.034), while no association with CCB was found for secondary AVG patency (RR 0.88, p = 0.153) as well as primary (RR 1.14, p = 0.3) and secondary AVF patency (RR 1.16, p = 0.374) (Table 1). A retrospective study by Chen et al. [108] including 42,244 patients (37,771 with AVFs [32.3% on a CCB], 4473 with AVGs [20.6% on a CCB]), described a significant relationship between CCB use and prolonged primary patency in both AVF (HR 0.485, CI 0.470–0.501) and AVG (HR 0.482, CI 0.442– 0.526) groups. While there has currently been minimal investigation into the use of CCB in prevention of vascular access failure, further research may be warranted given the wide use of this antihypertensive agent in the hemodialysis population.

Targeted interventions to reduce upstream injury include new surgical techniques [113] and endovascular access creation [114], interventions to mitigate downstream responses include far infra-red therapy [115, 116], perivascular application of recombinant elastase [117, 118] and endothelial loaded gel foam wrap (Vascugel) [119–121], whereas antiproliferative agents including sirolimus [122] and paclitaxel [123, 124] have been developed to prevent neointimal hyperplasia

Turbulent low-flow with low shear stress at the anastomosis leads to endothelial dysfunction, increased oxidative stress and an inflammatory and prothrombotic state, promoting AVF/AVG inward remodeling and neointimal hyperplasia [16, 125]. Optimization of flow dynamics through novel surgical techniques aimed

and promote outward remodeling and vasodilatation [1, 13].

4.2.1 New surgical techniques to alter wall shear stress

potential benefits of RAAS inhibitors are required.

4.1.5 Calcium channel blockers

Vascular Access Surgery - Tips and Tricks

4.2 Local interventions

100

at changing the anatomical configuration is a potential strategy to minimize this injury [17]. Baharat et al. [126] compared the use of the piggybacking Straight-Line Onlay Technique (pSLOT) to the traditional end-to-side (ETS) and side-to-side Straight-Line Onlay Techniques (SLOT), in a study of 125 patients (Table 1). They found a significant reduction in juxta-anastomotic stenosis using the novel pSLOT (3.7%) compared to traditional methods of ETS (14%) and SLOT (8.3%) (p = 0.04). This was accompanied by a significant reduction in overall fistula failure (pSLOT 16.7%, ETS 40.3%, SLOT 33.3%, p = 0.01) over the median 19-month follow-up.

The Optiflow Vascular Anastomotic device is a sutureless device that is able to provide reproducible anastomosis at a controlled geometry of 60° between the artery and vein, resulting in reduced surgical time, and optimized flow patterns and shear stress [13, 113], with a likely capability of shielding the perianastomotic region and preventing stenosis with its prosthetic material [13, 113]. This device is thought to clinically improve both vascular access maturation and patency [13]. Manson et al. [113] demonstrated safety and technical practicality in a human pilot study involving 10 patients. Subsequently, a prospective study of 41 patients performed at two centers by Chemla et al. [127] evaluated the maturation, patency, and safety of AVF using the Optiflow device. Unassisted maturation (defined as an outflow vein >/= 5 mm in diameter and flow >/= 500 ml/min not requiring intervention to maintain or promote maturation) was achieved in 72% of AVFs at 42 days and 68% at 90 days, unassisted patency in 88% of AVFs at 42 days and 78% at 90 days, and no serious device-related adverse events were reported [127]. In summary, the Optiflow device has shown promise in very small sample sizes and requires further evaluation in an RCT that is powered to confirm these clinical benefits.

#### 4.2.2 Endovascular AVF creation

The creation of an AVF with an endovascular approach using a radiofrequency magnetic catheter-based system is suggested to cause less vessel trauma, resulting in a reduced stimulus for the formation of neointimal hyperplasia [13, 128]. Clinically this has the potential to translate into improved vascular access maturation and patency [13]. A prospective, single-arm, multicenter study (Novel Endovascular Access Trial [NEAT]) enrolled 80 patients (57% pre-dialysis and 43% on dialysis) who underwent endovascular arteriovenous anastomosis creation (Table 1) [114]. The AVF was successfully created in 98% of participants (95% CI 91–100%). Physiologically suitable AVF dialysis, defined as a brachial artery flow ≥500 mL/min and vein diameter ≥ 4 mm within 3 months, was achieved in 87% of participants (95% CI 75–94%) and 64% (95% CI 48–78%) were able to receive prescribed hemodialysis through the AVF using two-needle cannulation. Primary patency at 12 months was 69% (95% CI 54–79%) and cumulative patency 84% (95% CI 71–91%), and 24 secondary AVF interventions were required in 19 participants (0.46/patient-year). Serious procedure-related adverse events (access-site management, hemostasis and pseudoaneurysm) occurred in 8% of participants. These results suggest that endovascular AVF creation may be a viable, minimally invasive alternative for creating vascular access. However, long-term outcomes are currently lacking and comparison to open surgical techniques in a randomized controlled fashion may be difficult due to the unique location and type of vessels used for AVF.

#### 4.2.3 Far infrared therapy

Infrared radiation is an invisible electromagnetic wave, with wavelengths ranging from 5.6 to 1000 μm [17]. This energy is perceived as heat by the thermoreceptors in the surrounding skin [116]. Far infrared therapy (FIT) has been shown to

inhibit vascular smooth muscle cell proliferation and platelet aggregation [116], promote vasodilation [129], improve endothelial function [130] and reduce oxidative stress [13]. These pleiotropic effects upon vascular biology may be beneficial in improving maturation and vascular patency [13, 116]. An RCT by Lin et al. [116] involving 145 hemodialysis patients evaluated the effect of FIT on access blood flow and unassisted patency in native AVFs over a 12-month period (Table 1). Compared to placebo, FIT resulted in increased blood flow (13.2 114.7 vs 33.4 132.3 ml/min, p < 0.021) and unassisted patency (85.9% vs 67.6% respectively, p < 0.01) [116]. Additionally, Lin et al. [115] conducted an RCT involving 122 patients with advanced CKD pre-dialysis who underwent AVF creation. FIT applied for 40 min three times a week for 12 months, resulted in lower rates of AVF malfunction (thrombosis or requirement of intervention) compared with placebo (12% vs 29% respectively p = 0.02), higher maturation rates (82% vs 60% p = 0.008), and higher rates of cumulative unassisted AVF patency (87% vs 70% p = 0.01) at 12 months [115]. A subsequent meta-analysis of RCTs and quasi-RCTs by Wan et al. [131] included 21 studies and 1899 patients of whom 960 were treated with FIT. The result of this meta-analysis demonstrated that FIT improved primary AVF patency (pooled risk ratio [PRR] 1.24; 95% CI 1.12–1.37, p < 0.001), improved vascular access blood flow (mean difference [MD], 81.69 ml/min; 95% CI 46.17– 117.21, p < 0.001), superior vascular access diameter level compared to control (MD 0.36 mm; 95% CI, 0.22–0.51, p < 0.001) and reduced AVF occlusion rates (PRR 0.2; 95% CI 0.08–0.46, p < 0.001) [131]. The quality of evidence provided in this meta-analysis is limited by small-scale studies of short duration (maximum 12 months). Given the convenience of FIT application during dialysis sessions and its non-invasive nature, this treatment strategy warrants further study to confirm the proposed benefits in improving vascular access maturation and patency.

is a potential immediate effect of high dose PRT-201 on intraoperative vein outflow diameter and blood flow, clinically meaningful long-term outcomes have not yet

Vascugel is an endothelial-cell-loaded wrap comprising a gel foam with allogeneic aortic endothelial cells [1, 53, 121]. Vascugel mediates its effects through the local delivery of "functional" endothelial cells at the anastomosis to promote outward vascular remodeling and prevent neointimal hyperplasia [1]. Preclinical studies involving porcine models of AVF and AVG have reported that local application of Vascugel resulted in a reduction in thrombus formation and vessel wall inflammation, an increase in luminal diameter and outward remodeling accompanied by reductions in MMP-2 expression, neovascularization and adventitial fibrosis [119, 120]. A phase II trial by Conte et al. [121] suggested that the use of Vascugel was a safe approach for local response to injury control at anastomotic sites,

although it did not significantly affect primary and assisted patency rates in treated AVF and AVG compared with placebo (Table 1). A retrospective analysis of this trial showed an improved primary patency when Vascugel was used in AVGs of diabetic patients (p = 0.05), although the results of such a post hoc analysis should be interpreted with caution [53]. In summary, Vascugel has been identified as a safe intervention, though its clinical benefit on vascular access function has not been consistently demonstrated in human trials. Adequately powered RCTs investigating

4.2.6 Antiproliferative agents: COLL-R (drug-eluted combination product of collagen

Sirolimus (rapamycin) is an antiproliferative agent with immunosuppressive, anti-inflammatory and antiproliferative effects [139, 140], that has been shown to reduce vascular smooth muscle cell proliferation [13] and neointimal hyperplasia in vascular access [122]. When delivered locally, sirolimus reduces neointimal hyperplasia in coronary re-stenosis [1, 141–143]. COLL-R is a drug-eluted combination product of sirolimus and a collagen membrane, which can be implanted around the adventitial surface either at the arteriovenous anastomosis of the AVF or at the graftvein anastomosis of the AVG [1, 13, 122]. Sirolimus is then eluted from the COLL-R, inhibiting neointimal proliferation at the anastomosis [122], translating clinically to a potential improvement in vascular access maturation and patency [13]. A single-arm phase II study by Paulson et al. [122] containing a cohort of 12 hemodialysis patients undergoing AVG formation with intraoperative COLL-R placement demonstrated primary unassisted patency rates of 75% at 12 months and 38% at 24 months and a thrombosis rate of 0.37 episodes per patient year (Table 1) [122]. In a sub-group of 5 patients, whole blood sirolimus levels reached a mean peak of 4.8 ng/mL at 6 h and were less than 1 ng/mL at 1 week. Results from a phase III RCT evaluating AVF suitability for dialysis at 6 months with and without a perivascular Sirolimus-Eluting

Drug-eluting balloons can deliver antiproliferative agents (such as paclitaxel) at angioplasty sites and thereby reduce neointimal hyperplasia and restenosis following endothelial injury caused by the angioplasty [1, 144]. Paclitaxel-coated balloon (PCB) angioplasty has been successfully used to treat coronary stenosis [145] and

been addressed in adequately powered RCTs.

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

its clinical application are still needed.

membrane and sirolimus)

Collagen Implant are currently awaited (NCT02513303).

4.2.7 Paclitaxel-coated balloon angioplasty

103

4.2.5 Endothelial loaded gel foam wrap (Vascugel)

### 4.2.4 Perivascular application of recombinant elastase

Elastin is a protein that provides blood vessels with their elasticity enabling control of vessel diameter [132]. Recombinant human type-1 pancreatic elastase (PRT-201) preferentially cleaves the peptide bonds abundant in elastin [133, 134]. Fragmentation of elastin leads to vasodilation and inhibits migration of adventitial myofibroblasts into the intimal layer [13, 135]. The rationale behind the use of PRT-201 is the theoretical assumption that application after AVF creation should destroy the elastin in the arteries and veins thereby resulting in faster AVF dilatation and maturation [1, 13]. Due to difficulties with inactivation of the enzyme following systemic administration, PRT-201 needs to be applied locally during surgery to provide targeted antiprotease effect [136]. Animal studies reported an increase in vessel diameter, blood flow, and inhibition of intimal hyperplasia with use of PRT-201 [137, 138]. An RCT [118] of 89 patients comparing low (0.01, 0.03 mg), medium (0.1, 0.3, 1.0 mg) and high (3.0, 6.0, 9.0 mg) dose PRT-201 vs placebo applied during AVG creation reported a larger percentage increase in outflow vein diameter intraoperatively with PRT-201 (5% placebo vs 13% [p = 0.01], 15% [p = 0.070], 12% [p < 0.001] in the low, medium and high dose groups, respectively) (Table 1). In contrast, only high dose PRT-201 led to a significant increase in blood flow compared to placebo (15% placebo vs 19% [p = 0.34], 36% [p = 0.09], 46% [p = 0.02], low, medium and high doses respectively) [118]. Conversely, a double-blind, randomized, placebo-controlled trial of a single local application of PRT-201 in 151 patients with advanced kidney disease undergoing AVF creation found no significant difference in unassisted primary patency over 1 year with low dose PRT compared to placebo (HR 0.69, 95% CI 0.39–1.22, p = 0.19 for 10 μg PRT-201 and HR 0.67, 95% CI 0.38–1.19, p = 0.17 for 30 μg PRT-201) [117]. While there

inhibit vascular smooth muscle cell proliferation and platelet aggregation [116], promote vasodilation [129], improve endothelial function [130] and reduce oxidative stress [13]. These pleiotropic effects upon vascular biology may be beneficial in improving maturation and vascular patency [13, 116]. An RCT by Lin et al. [116] involving 145 hemodialysis patients evaluated the effect of FIT on access blood flow and unassisted patency in native AVFs over a 12-month period (Table 1). Compared to placebo, FIT resulted in increased blood flow (13.2 114.7 vs 33.4 132.3 ml/min, p < 0.021) and unassisted patency (85.9% vs 67.6% respectively, p < 0.01) [116]. Additionally, Lin et al. [115] conducted an RCT involving 122 patients with advanced CKD pre-dialysis who underwent AVF creation. FIT applied for 40 min three times a week for 12 months, resulted in lower rates of AVF malfunction (thrombosis or requirement of intervention) compared with placebo

Vascular Access Surgery - Tips and Tricks

(12% vs 29% respectively p = 0.02), higher maturation rates (82% vs 60% p = 0.008), and higher rates of cumulative unassisted AVF patency (87% vs 70% p = 0.01) at 12 months [115]. A subsequent meta-analysis of RCTs and quasi-RCTs by Wan et al. [131] included 21 studies and 1899 patients of whom 960 were treated with FIT. The result of this meta-analysis demonstrated that FIT improved primary AVF patency (pooled risk ratio [PRR] 1.24; 95% CI 1.12–1.37, p < 0.001), improved vascular access blood flow (mean difference [MD], 81.69 ml/min; 95% CI 46.17– 117.21, p < 0.001), superior vascular access diameter level compared to control (MD 0.36 mm; 95% CI, 0.22–0.51, p < 0.001) and reduced AVF occlusion rates (PRR 0.2; 95% CI 0.08–0.46, p < 0.001) [131]. The quality of evidence provided in this meta-analysis is limited by small-scale studies of short duration (maximum 12 months). Given the convenience of FIT application during dialysis sessions and its non-invasive nature, this treatment strategy warrants further study to confirm the proposed benefits in improving vascular access maturation and patency.

Elastin is a protein that provides blood vessels with their elasticity enabling control of vessel diameter [132]. Recombinant human type-1 pancreatic elastase (PRT-201) preferentially cleaves the peptide bonds abundant in elastin [133, 134]. Fragmentation of elastin leads to vasodilation and inhibits migration of adventitial myofibroblasts into the intimal layer [13, 135]. The rationale behind the use of PRT-201 is the theoretical assumption that application after AVF creation should destroy the elastin in the arteries and veins thereby resulting in faster AVF dilatation and maturation [1, 13]. Due to difficulties with inactivation of the enzyme following systemic administration, PRT-201 needs to be applied locally during surgery to provide targeted antiprotease effect [136]. Animal studies reported an increase in vessel diameter, blood flow, and inhibition of intimal hyperplasia with use of PRT-201 [137, 138]. An RCT [118] of 89 patients comparing low (0.01, 0.03 mg), medium (0.1, 0.3, 1.0 mg) and high (3.0, 6.0, 9.0 mg) dose PRT-201 vs placebo applied during AVG creation reported a larger percentage increase in outflow vein diameter intraoperatively with PRT-201 (5% placebo vs 13% [p = 0.01], 15% [p = 0.070], 12% [p < 0.001] in the low, medium and high dose groups, respectively) (Table 1). In contrast, only high dose PRT-201 led to a significant increase in blood flow compared to placebo (15% placebo vs 19% [p = 0.34], 36% [p = 0.09], 46% [p = 0.02], low, medium and high doses respectively) [118]. Conversely, a double-blind, randomized, placebo-controlled trial of a single local application of PRT-201 in 151 patients with advanced kidney disease undergoing AVF creation found no significant difference in unassisted primary patency over 1 year with low dose PRT compared to placebo (HR 0.69, 95% CI 0.39–1.22, p = 0.19 for 10 μg PRT-201 and HR 0.67, 95% CI 0.38–1.19, p = 0.17 for 30 μg PRT-201) [117]. While there

4.2.4 Perivascular application of recombinant elastase

102

is a potential immediate effect of high dose PRT-201 on intraoperative vein outflow diameter and blood flow, clinically meaningful long-term outcomes have not yet been addressed in adequately powered RCTs.
