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NDT Advance Access first published online on January 31, 2007
This version published online on April 20, 2007
Nephrology Dialysis Transplantation, doi:10.1093/ndt/gfl821
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© The Author [2007]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Angiotensin converting enzyme inhibitors maintain polytetrafluroethylene graft patency

Atul Sajgure, MD1, Arindam Choudhury, MD2, Ziauddin Ahmed, MD3 and Devasmita Choudhury, MD

1Consultant Nephrologist, Sahyadri Specialty Hospital, Deccan Gymkhana, Pune, Maharashtra, India 411004, 2Assistant Professor Surgery, University of Virginia, Chief of Ambulatory Surgery, General/Vascular/Thoracic Surgery, Salem Veterans Affairs Medical Center, 1970 Roanoke Boulevard, Salem, VA 24153 USA and 3Associate Professor Medicine, Drexel University School of Medicine, Director of DCI Dialysis Unit, 245 North 15th Street, Philadelphia, PA 19129 USA

Correspondence and offprint requests to: Dr Devasmita Choudhury, Associate Professor Medicine, University of Texas Southwestern Medical School, Chief of Dialysis, Dallas Veterans Affairs Medical Center, 4500 South Lancaster Road, Dallas, TX 75216 USA Email: Devasmita.dev{at}med.va.gov



   Abstract
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 Abstract
Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Background. A patent vascular access is crucial for hemodialysis patients. Stenosis and thrombosis lead to access failure. Endothelial injury via angiotensin II may mediate a hyperplastic and prothrombotic response. Thus angiotensin II inhibition with angiotensin-converting enzyme inhibitors (ACEI) may prolong vascular access patency. This study determines the impact of ACEI use on access patency in both polytetrafluroethylene (PTFE) grafts and fistulas.

Methods. Demographics, access history and medication use were reviewed in 266 accesses from four dialysis centres. Primary patency, date of surgery to date of first access failure, was determined. Excluded accesses had incomplete history or <30 day patency. Groups divided into ACEI and non-ACEI based on patient use of ACEI during access patency. Statistical methods included: unpaired Student t to compare continuous variables, Chi-square and Fisher's Exact test to compare proportions and evaluate for risk estimation, univariate and multivariate Cox regression to investigate variables associated with duration of access patency. Cox-adjusted survival and Hazard curves were obtained for significant variables.

Results. Non-ACEI (PTFE) graft group included more males and older patients; however, when these covariates were adjusted during both univariate and multivariate regression, suggested, only ACEI use was associated with greater access patency duration, 671.7 days (ACEI) vs 460.0 days (non-ACEI), p = 0.012. ACEI group had fewer clotting events, 55% versus 71% (non-ACEI) group, p = 0.042. ACEI use had little effect on primary patency of the fistula however male gender increased time to fistula failure, p = 0.002.

Conclusions. Retrospective evaluation suggests ACEI use in patients with PTFE grafts may prolong and maintain patency. Fistula patency is affected by gender with longer patency noted in males. Further prospective studies are necessary to confirm the role of ACEI in maintaining vascular access patency.

Keywords: angiotensin converting enzyme inhibitors; dialysis; fistulas; grafts; patency; thrombosis



   Introduction
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 Abstract
 Introduction
Subjects and methods
 Results
 Discussion
 References
 
Arteriovenous access thrombosis is a significant cause of morbidity and cost for haemodialysis patients. Stenosis within the proximal 3 cm of the venous anastomosis is the primary reason for arteriovenous graft occlusion in 50–70% of cases [1]. Neointimal hyperplasia of the vein graft results in the stenotic lesion [2,3]. Vascular smooth muscle cell (VSMC) proliferation in the vein intima is seen as a response to injury [2,4]. Endothelial injury during graft placement, foreign body reaction, pulsatile shear stress, turbulence and repeated cannulation during dialysis may cause vein injury [4]. An important modulator of VSMC hyperplasia is angiotensin II [5]. Angiotensin II produced locally at the site of injury can induce autocrine growth factors including platelet-derived growth factor, basic fibroblast growth factor, and transforming growth factor-ß that stimulate VSMC proliferation [6]. Receptors for angiotensin-converting enzyme and angiotensin II are also present in the vessel wall [7]. Therefore inhibition of angiotensin II by angiotensin-converting enzyme inhibitors (ACEI) may block smooth muscle cell proliferation and be an important factor in the prevention of access stenosis in dialysis patients. Preventing access stenosis should then lead to lower numbers of access failures and increased access patency. In order to evaluate this hypothesis, we reviewed data of 266 dialysis accesses from patients using ACEI and those not using ACEI for initial event of access failure and primary (unassisted) patency. Our data suggests benefit in both the number of initial access failure events and primary patency for those patients on ACEI with polytetrafluroethylene (PTFE) grafts.



   Subjects and methods
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 Abstract
 Introduction
 Subjects and methods
Results
 Discussion
 References
 
Two hundred twenty-three patient charts were reviewed from four different centres with hospital-based chronic dialysis units from 1 December 1999 to 31 December 2001. Two of the centres were Veterans Hospitals with academic affiliations, and the other two centres were inner-city university-based teaching hospitals. All patients with forearm or upper arm PTFE grafts, and forearm or upper arm fistulas were included for review.

Two hundred sixty-six haemodialysis accesses were identified from 196 patient charts with complete data for review. Charts were reviewed for demographics including age, gender, race, medications including the use of ACEI, statins, presence or absence of diabetes mellitus, presence or absence of hypotension or hypertension, type and location of access including fistula or PTFE graft and primary (unassisted) patency of the access. The number of patients on routine daily aspirin and standard anti-platelet agents were negligible during the time period of chart review. Primary patency was defined as the number of days the access was patent from the date of insertion to the date of first access failure or date of review. Access failure was defined as access thrombosis, access angioplasty or thrombectomy or need for access revision because of poor function.

If a patient received ACEI or angiotensin receptor blocker (ARB) at any time during the patency period of the access being evaluated, the access was placed in the ACEI group for data analysis. If the patient never received any ACEI or ARB for the duration of the access patency, the access being evaluated was placed in the non-ACEI group for data analysis. No distinction was made on the type or dosage of ACEI.

Access thrombosis within 30 days of access placement, access thrombosis from known hypotension or those accesses without complete data pertaining to the vascular access were excluded. Each access was considered a unit of observation.

Student's unpaired t-test was used to compare the data with continuous variables in two series. The data with continuous variables are given as mean values ±SD. Chi-square and Fisher's exact tests were used to compare the proportions and to evaluate for risk estimation. Univariate and multivariate Cox regression analysis was used to investigate variables associated with duration of access patency. The level of significance was defined as {alpha} = 0.05. For multivariate analysis, the variables entered the model by ‘Enter’ method and the model fit was confirmed. Cox adjusted survival and hazard curves were obtained for the significant variables. All statistical analysis was performed with SPSS 11.0 (Graduate Pack) for Windows.



   Results
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 Abstract
 Introduction
 Subjects and methods
 Results
Discussion
 References
 
One hundred ninety-six patients (139 men, 57 women) had 266 accesses. Each access was treated as a separate data point for analysis. One hundred forty-three patients had a single access placed, 40 patients had two access placements, 10 had three accesses, two had four accesses and one had five accesses placed. Mean patient age was 55.9 ± 13.6 years.

Demographic and clinical access data in the ACEI and non-ACEI group are presented in Table 1. Mean patient age and number of males were noted to be greater in the non-ACEI group. A greater number of Hispanic patients were found in the ACEI group. Access patency in days was greater in the ACEI group, but did not reach statistical significance (P = 0.096). Univariate Cox regression to evaluate the effect of each covariate, including age, gender, race, hypertension, diabetes, site of access placement (lower vs upper arm), type of access (graft vs fistula), use of ACEI, and use of statins on the duration of access patency was perfomed. Univariate Cox regression suggested that gender, access type and ACEI use are important in increasing access patency duration (Table 2). Subsequent multivariate Cox regression (‘Enter’ method) confirmed the independent importance of these factors (adjusted for other factors) in maintaining access patency (Table 3). Survival curves show that ACEI use and having a fistula improves the number of access survival days and increases time to failure, while female gender predisposes to earlier access failure (Figure 1).


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  		Table 1. Demographic and clinical parameters of all study accesses (combined PTFE and fistulas)

 

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  		Table 2. Univariate cox regression analysis for duration of patency in days in all accesses

 

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  		Table 3. Multivariate cox model for duration of access patency in days

 

Figure 1
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  		Fig. 1. Survival and hazard curves showing duration of access patency in all accesses in relation to (A) gender, (B) type of access and (C) ACEI.

 
PTFE grafts—descriptive and analytic characteristics between ACEI vs non-ACEI groups (Table 4)
Of 179 PTFE grafts, 80 were in the ACEI group and 99 in non-ACEI group. Mean patient age in the non-ACEI group was older compared with the ACEI group, 59.2 and 54.5 years, respectively; P = 0.015. Other group differences were noted in gender, Hispanic race, presence of diabetes, number of access thrombosis and days of patency. The graft patency duration in days was significantly longer 671.7 ± 6.7.7 (mean ± SEM) in the ACEI group, compared with 459.8 ± 47.9 in the non-ACEI group (P = 0.012). The number of clotting events were fewer in those grafts in the ACEI group, 55% in comparison with 71% in non-ACEI group; P = 0.042. Univariate Cox regression for age, gender, race, access site, hypertension, diabetes, statin use and ACEI use suggested that ACEI use was important in improving PTFE graft survival (Table 5). Multivariate Cox model (Enter method) using the same variables confirmed this finding (Table 6). In this model, when adjusted for all the other factors, ACEI use was the only independent factor influencing the PTFE graft survival. Figure 2 illustrates the cumulative hazard and survival function for PTFE grafts in the ACEI vs non-ACEI groups.


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  		Table 4. PTFE grafts—comparison of parameters between ACEI and non-ACEI groups

 

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  		Table 5. Univariate cox regression analysis for duration of patency in days for PTFE grafts

 

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  		Table 6. Multivariate cox regression analysis for duration of patency in days for PTFE grafts

 

Figure 2
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  		Fig. 2. Use of ACEI increases the time to PTFE graft failure.

 
Fistulas—descriptive and analytic characteristics of ACEI and non-ACEI groups (Table 7)
Characteristics of both ACEI and non-ACEI groups were similar except for gender and race. Male gender was more predominant in the non-ACEI group and Hispanic race more predominant in the ACEI group. Univariate Cox regression for gender, race, age, site of access, access type, diabetes, hypertension, statin use and ACEI use in relation to duration of access patency suggested male gender to be important in determining access patency (Table 8). Multivariate (Enter method) Cox regression confirmed the importance of male gender as an independent factor (after adjusting for all the other factors) in maintaining access patency (Table 9). Figure 3 demonstrates cumulative hazard and survival in fistulas in relation to gender.


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  		Table 7. Fistulas-comparison of parameters between ACEI and non-ACEI groups

 

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  		Table 8. Univariate Cox regression for duration of patency (days) in fistulas

 

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  		Table 9. Multivariate Cox Regression analysis for duration of patency in days for fistulas

 

Figure 3
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  		Fig. 3. Male gender increases the time to failure of fistula accesses.

 


   Discussion
Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
References
 
Both patient morbidity and high cost associated with haemodialysis access thrombosis [8] necessitates investigation for preventive medical intervention. Mechanical obstruction from neointimal hyperplasia at the anastomotic sites of the draining vein [3], in addition to a prothrombotic environment are factors likely predisposing to access thrombosis. Given a role for angiotensin II in both stimulating vascular smooth muscle hyperplasia and promoting a prothrombotic environment, use of angiotensin II inhibitors may be beneficial in preventing thrombosis. This study then evaluates the primary patency of haemodialysis fistulas and grafts of patients taking ACEI for various reasons including hypertension, diabetes or cardiac-related issues. Findings are notable for increased number of days of PTFE graft patency and decreased events of thrombosis in PTFE grafts in those haemodialysis patients taking ACEI.

The suggestion that ACEI use can improve new graft survival was noted by Diskin and colleagues [9] in their observational evaluation of the effect of various medications on graft survival. Our multi-centre evaluation supports this hypothesis in showing that PTFE graft survival is increased almost 6 months (671.7 ± 67.6 days in ACEI group vs 459.8 ± 47.9 days in non-ACEI group (P = 0.009), with a lower event rate for graft clotting in those patients using ACEI during their graft life vs those not on ACEI therapy. This further confirms findings by Gradiziki et al. [10] who noted a 53% risk reduction of PTFE thrombosis in their small single-centre study.

A recent small prospective randomized study of 24 total patients suggested benefit in PTFE graft patency in those taking {omega}-3-enriched fish oil capsules 2 weeks after PTFE engraftment compared with placebo, 75.6 vs 14.9% 1-year access survival [11]. Our retrospective study also shows similar improvements in PTFE graft patency with ACEI use. Whether there may be added benefit to using both ACEI and {omega}-3-enriched fish oil to maintain graft patency will be important to investigate.

Native fistulas have prolonged survival compared with PTFE grafts, and this was evident in our study, where no difference was detected in primary (unassisted) patency between accesses in the ACEI group vs those in the non-ACEI group (87 fistulas). Male gender, however, is significantly associated with increased fistula patency and was previously noted by others [12]. Differences in vessel calibre do not necessarily explain the lower patency rates in women [12]. It is possible that studying a greater number of fistula accesses may have confirmed observations made by Sone and colleagues. In their prospective case, control analysis of 912 fistulas of which 212 were noted to be on ACEI or ARB therapy, they calculated a thrombosis prevention odds ratio of 1.79 for those on ACEI or ARB thearpy [13]. However in another study, a retrospective analysis of 900 fistulas in the DOPPS (Dialysis Outcomes and Practice Patterns Study) database, of which 168 were associated with ACEI use, no difference in primary fistula patency between use of ACEI and non-use of ACEI was noted; however, significant differences in secondary (assisted) fistula patency amongst the two groups was noted [14]. A recent study evaluating the effect of haemoglobin on vascular access survival also noted a decrease in relative risk of vascular access failure in those patients on ACEI or ARB therapy [15].

While this study suggests associated benefit in using ACEI to maintain primary PTFE access patency and is in agreement with several other studies, it is in contrast to the data from the DOPPS (US) database study which showed no benefit with ACEI use for either primary or secondary PTFE graft patency [14]. Our study did not evaluate secondary patency. The differences in outcome may be due to the retrospective nature of the studies, including our own, that suffer from indication bias for the study medication being investigated. In addition, covariates other than age, gender, and diabetes, such as intact PTH or haemoglobin <10 gm/dl, may play a role in maintaining access [15]. Neither this study nor the DOPPS adjusted for PTH or haemoglobin, and may be factors explaining the differences in outcome. A previous randomized trial using dipyridamole found improved patency in newly placed PTFE grafts while aspirin was found to increase thrombosis [16]. As very few patients were on routine use of anti-platelet medication, including aspirin, during the time of this study, our analysis did not adjust for these medications which may bias our favourable study results. In addition, associations with improved primary patency have been suggested with the use of calcium channel blockers [9,14]. This was not evaluated in our study and may also impact outcomes. Given the retrospective nature of both our study and the DOPPS study, medication compliance and/or the average number of days on ACEI could not be determined—factors that can affect average patency duration. As medication dosage may be varied based on clinical indication and individual tolerance, this factor was not evaluated in this or other studies. This underscores the need for further randomized prospectively controlled claian trials using ACEI in the prevention of vascular access patency.

In summary, our multi-centre retrospective study suggests that use of ACEI in patients with PTFE grafts may maintain primary patency. These results added to current literature prompts prospective evaluation of ACEI in the prevention of vascular access thrombosis before routine ACEI use for this indication can be recommended.

Conflict of interest statement. A small part of this study has been published in abstract form in J Am Soc Nephr 2000; 11: 182A.



   Notes
 
This version contains a change to the authors.



   References
Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 

  1. Schwab SJ, Harrington JT, Singh A, et al. (1999) Vascular access for haemodialysis. Kidney Int 55:2078–2090.[CrossRef][Web of Science][Medline]
  2. Swedberg SH, Brown BG, Sigley R, Wight TN, Gordon D, Nicholls SC. (1989) Intimal fibromuscular hyperplasia at the venous anastomosis of PTFE grafts in haemodialysis patients. Clinical, immunocytochemical, light and electron microscopic assessment. Circulation 80:1726–1736.[Abstract/Free Full Text]
  3. Roy-Chaudhury P, Kelly BS, Miller MA, et al. (2001) Venous neointimal hyperplasia in polytetrafluoroethylene dialysis grafts. Kidney Int 59:2325–2334.[Web of Science][Medline]
  4. Hehrlein C. (1995) How do AV fistulae lose function? The roles of haemodynamics, vascular remodelling, and intimal hyperplasia. Nephrol Dial Transplant 10:1287–1290.[Free Full Text]
  5. Gibbons GH, Pratt RE, Dzau VJ. (1992) Vascular smooth muscle cell hypertrophy vs. hyperplasia. Autocrine transforming growth factor-beta 1 expression determines growth response to angiotensin II. J Clin Invest 90:456–461.[Web of Science][Medline]
  6. Gibbons GH and Dzau VJ. (1994) The emerging concept of vascular remodeling. N Engl J Med 330:1431–1438.[Free Full Text]
  7. Nakamura Y, Nakamura K, Matsukura T, Nakamura K. (1988) Vascular angiotensin converting enzyme activity in spontaneously hypertensive rats and its inhibition with cilazapril. J Hypertens 6:105–110.[Web of Science][Medline]
  8. Executive summary. (1999) United States Renal Data System 1999 Annual Data Report. Am J Kidney Dis 34:S9–S19.[Medline]
  9. Diskin CJ, Stokes TJ, Thomas SG, et al. (1998) An analysis of the effect of routine medications on haemodialysis vascular access survival. Nephron 78:365–368.[CrossRef][Web of Science][Medline]
  10. Gradzki R, Dhingra RK, Port FK, Roys E, Weitzel WF, Messana JM. (2001) Use of ACE inhibitors is associated with prolonged survival of arteriovenous grafts. Am J Kidney Dis 38:1240–1244.[Web of Science][Medline]
  11. Schmitz PG, McCloud LK, Reikes ST, Leonard CL, Gellens ME. (2002) Prophylaxis of haemodialysis graft thrombosis with fish oil: double-blind, randomized, prospective trial. J Am Soc Nephrol 13:184–190.[Abstract/Free Full Text]
  12. Miller CD, Robbin ML, Allon M. (2003) Gender differences in outcomes of arteriovenous fistulas in haemodialysis patients. Kidney Int 63:346–352.[CrossRef][Web of Science][Medline]
  13. Sone M, Moriyama T, Mifune N, Shirota S, Omae K, Nishida E, Ogawa T, Nihei H. (2000) Angiotensin II inhibition prevents the occlusion of arteriovenous fistula in hemodialysis patients: A prospective case control study. J Am Soc Nephrol 11:197A.[CrossRef]
  14. Saran R, Dykstra DM, Wolfe RA, Gillespie B, Held PJ, Young EW. (2003) Association between vascular access failure and the use of specific drugs: the Dialysis Outcomes and Practice Patterns Study (DOPPS). Am J Kidney Dis 40:1255–1263.[CrossRef][Web of Science]
  15. Garrancho JM, Kirchgessner J, Arranz M, et al. (2005) Haemoglobin level and vascular access survival in haemodialysis patients. Nephrol Dial Transplant 20:2453–2457.[Abstract/Free Full Text]
  16. Sreedhara R, Himmelfarb J, Lazarus JM, Hakim RM. (1994) Anti-platelet therapy in graft thrombosis: results of a prospective, randomized, double-blind study. Kidney Int 45:1477–1483.[Web of Science][Medline]
Received for publication: 12.10.06
Accepted in revised form: 19.12.06


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