Internationally, the arteriovenous fistula (AVF)

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1 IN THE LITERATURE More Than Reducing Early Fistula Thrombosis Is Required: Lessons From the Dialysis Access Consortium Clopidogrel Fistula Study Commentary on Dember LM, Beck GJ, Allon M, et al: Effect of clopidogrel on early failure of arteriovenous fistulas for hemodialysis: a randomized controlled trial. JAMA 299: , Internationally, the arteriovenous fistula (AVF) is the hemodialysis (HD) vascular access of choice. The US Centers for Medicare and Medicaid Services (CMS) advocate AVF use in the Fistula First initiative, targeting an increase in AVF use from 40% to 65%. 1 Despite these efforts, there has been a decline in AVF use among both incident and prevalent patients in several countries, 2,3 in part due to the characteristics of an increasingly elderly HD population. 2,4 These factors make the selection of patients eligible for an AVF, surgical creation of the AVF, and equally important, the maturation or suitability of the AVF for dialysis true challenges. 5,6 An AVF may not be suitable for use for several reasons, including primary failure or failure to mature; for simplicity, these entities will be referred to as suitability failure. Several decades ago, AVFs had a suitability failure rate of approximately 10% and a 1-year primary patency of 70% to 80%. Now suitability failure rates range between 30% and 70% 7 and primary patency rates are only 40% to 70%. Early suitability failure, occurring within the first few weeks after creation, is thought to be from surgical technical failure, thrombosis or stenosis, or development of accessory veins. The prior data that examine strategies to promote successful creation and maturation of AVFs are limited. Recently, a large-scale study was conducted to examine the effects of clopidogrel on AVF thrombosis and suitability for dialysis use. This study was undertaken by the Dialysis Address correspondence to Charmaine E. Lok, MD, Department of Medicine, Division of Nephrology, The Toronto General Hospital, 8NU-844, 200 Elizabeth St, Toronto, Ontario M5G 2C4, Canada. charmaine.lok@uhn. on.ca 2008 by the National Kidney Foundation, Inc /08/ $34.00/0 doi: /j.ajkd Access Consortium (DAC) and recently reported in JAMA. 8 WHAT DOES THIS IMPORTANT STUDY SHOW? The DAC clopidogrel study was a well-designed, multicenter, randomized double-blind placebo-controlled trial. Participants who underwent AVF creation were randomly assigned to receive clopidogrel (300-mg loading dose followed by 75 mg daily for 6 weeks) or placebo. Patients were included if they were eligible for an upper-extremity AVF and were expected to start HD within 6 months, and excluded if they had bleeding disorders or were unable to stop antiplatelet therapy during the 7-week intervention period. This eliminated patients who had a myocardial infarction or stroke within the previous year. Decisions regarding eligibility for AVF creation, timing of initiation of use, and procedures to enhance AVF maturation (ie, angioplasty) were determined by the individual centers. The primary outcome was unassisted AVF patency 6 weeks after AVF creation as determined by physical exam and defined by a bruit that was detectable along the vein at least 8 cm proximal to the anastamosis throughout systole and diastole. Importantly, both patients and examiners were blinded to study assignment. The secondary outcome was AVF dialysis suitability defined as the ability to use the AVF with 2 needles at a blood flow rate of 300 ml/min or greater for 8 sessions during a 30-day ascertainment period that began at least 120 days after AVF creation. If the AVF was not used during the ascertainment period, it was deemed a suitability failure. The proposed sample size of 1,284 patients was based on an assumed 25% AVF thrombosis rate in the placebo group and projected to provide 85% power to detect a 30% reduction in thrombosis rate. It also provided 80% power to 834 American Journal of Kidney Diseases, Vol 52, No 5 (November), 2008: pp

2 In the Literature 835 Table 1. Studies of Antiplatelet Agents for Prevention of Fistula Thrombosis Thrombosis (%) Year Reference N Intervention Intervention Duration Intervention Control Andrassy et al 92 Aspirin (500 mg/d) 4 wk Michie et al 12 Sulfinpyrazone (200 mg, 4x/d) 3 mo Albert Aspirin (500 mg, 3x/d) v 6 wk 6 (Aspirin) 0 (Sulfinpyrazone) sulfinpyrazone (200 mg, 3x/d) 12 Grontoft et al 36 Ticlopidine (250 mg, 2x/d) 4 wk Fiskerstrand et al 15 Ticlopidine (250 mg, 2x/d) 1 mo Janicki et al 26 Sulfinpyrazone (200 mg, 3x/d) 3 wk Janicki et al 26 Ticlopidine (250 mg, 2x/d) 3 wk Grontoft et al 260 Ticlopidine (250 mg, 2x/d) 4 wk Dember et al 877 Clopidegrel (300 mg load, 75 mg 1x/d) 6 wk Adapted from Dember et al. detect a 20% reduction in AVF suitability, assuming a 40% suitability failure rate in the placebo group. However, after enrollment of 877 participants, the data and safety monitoring board recommended early stopping of the study after the 4th interim analysis, based on a prespecified stopping rule for efficacy of the intervention on the primary endpoint. Further calculations indicated that continuing the trial would not have shown a statistically significant benefit of clopidogrel on the suitability outcome. Patients who received clopidogrel had a 37% lower risk of thrombosis compared to those on placebo (ie, relative risk [RR], 0.63; 95% confidence interval [CI], 0.46 to 0.97; P 0.018); this effect was primarily seen in forearm AVFs (RR, 0.53 [95% CI, 0.36 to 0.77]) compared to upper arm AVFs (RR, 0.89 [95% CI, 0.52 to 1.53]). There was no interaction between AVF location and treatment assignment (P 0.15). Despite the reduced proportion of thrombosis in the treatment group, there was a surprisingly high suitability failure in both groups: 61.8% in the clopidogrel group and 59.5% in the placebo group (RR, 1.05 [95% CI, 0.94 to 1.17]; P 0.40). Fistulas were abandoned with no expectation of future use in 32.8% of patients, 13.7% did not use the AVFs despite treatment with dialysis, and 14.1% had a fistula in use during the ascertainment period but failed to meet suitability criteria. The side effect profile was similar in both groups. HOW DOES THIS STUDY COMPARE WITH PRIOR STUDIES? This DAC clopidogrel study is by far the largest multicenter randomized controlled trial (RCT) of antiplatelet therapy on fistula outcomes, with previous trials summarized in Table 1. A metaanalysis of these non-dac studies suggested a beneficial effect of antiplatelet treatment as an adjuvant to increase AVF and graft patency, in contrast to the results of the DAC clopidogrel study. Ongoing prospective studies include an Australian-led multicenter study of fish oil and aspirin to assess 3-month AVF patency. 18 Observational data from the Dialysis Outcomes and Practice Patterns Study (DOPPS) evaluating 2,815 incident HD patients demonstrated that consistent aspirin use was related to a significantly lower risk of final AVF failure (adjusted hazard ratio, 0.63 [95% CI, 0.42 to 0.95]). 19 However, this study only included patients whose AVFs were already used for dialysis, clearly representing a different scenario than the DAC clopidogrel study. When comparing studies, not only should the specific intervention be considered, but also the specific population and outcomes. Population In the DAC clopidogrel study, 61% of AVFs were not suitable for dialysis, even though the patient risk profile was relatively low: the average age, less than that of the US HD population, 4 there were fewer women included, and those with significant vascular disease were often excluded. This failure rate is significantly higher than that reported in other studies 7 and highlights the importance of both patient and access selection. Patient criteria for an AVF were not defined in this study and remain undefined in national guidelines and in the wider literature. Preopera-

3 836 tive vascular mapping was performed in approximately 75% of patients, yet did not appear to contribute to improved AVF suitability. This confirmation of previous studies that demonstrate limited yield of preoperative vascular mapping 20,21 is disconcerting, especially as it is unclear if preoperative mapping was a standard approach in most centers or if patients with poor vessels on physical exam were sent for mapping. Preoperative mapping typically provides data on vessel size and presence of peripheral and central lesions that are presumably corrected prior to AVF creation. Clearly more than just vessel size is required for eligibility, otherwise preoperative vessel mapping and corrective intervention would have facilitated greater fistula suitability overall. Outcomes The DAC investigators carefully considered and clearly struggled with the selection of outcomes. 17 They chose AVF primary patency as the primary outcome since the biological effect of clopidogrel would be more closely related to thrombosis rather than dialysis suitability, which is more influenced by variations in clinical practice. However, the investigators also recognized that improving fistula patency is of little value if it does not translate into improved suitability The investigators indicated that the completeness and reliability of the ascertainment of this outcome will be a major focus during the conduct of this trial. 17 However, while the definition and ascertainment of the outcome was reliable, was it really valid? Only 2% of patients in each group had surgical or percutaneous intervention to restore patency or promote maturation before 6 weeks. The investigators themselves recognized that a procedure to restore function of arteriovenous access is required in close to 50% of patients within 1 year of access placement. 17 While this may not specifically relate to early failures, previous studies have demonstrated that approximately one-third (24% to 42%) of all AVFs will require intervention to facilitate maturation. In a recent study of the natural history of AVFs, 25 only 9% of AVFs matured without need for intervention. Given the low intervention rate, was it really suitability failure that was found or failure of clinicians to intervene early on fistulas that were failing to mature? Lok and Moist While the definition and ascertainment of the suitability outcome was well implemented, careful consideration of aspects that may contribute to fistula dialysis suitability other than preventing early thrombosis, such as stricter protocols for fistula eligibility and facilitative preoperative and postoperative intervention, may have provided a more accurate assessment of the AVF suitability failure outcome. A comparison of outcomes with other studies is difficult due to the lack of standardized definitions for fistula primary failure, failure to mature, and now dialysis suitability. Such standardized definitions are needed. WHAT SHOULD CLINICIANS AND RESEARCHERS DO? Although a landmark study, the DAC clopidogrel study is essentially a negative trial that leaves clinicians, researchers, and administrators several important points for careful consideration. Considerations for Clinicians Clopidogrel cannot be recommended for use to reduce early AVF thrombosis and improve AVF dialysis suitability. Instead, clinicians and surgeons should agree upon and test eligibility criteria for AVF creation to tailor access choice and reduce the high failure rate. A recent, easy-toadminister, 4-variable prediction score has been developed and validated to estimate a patient s risk of fistula failure to mature 7 that can be used in conjunction with other eligibility criteria. Given the results of this well designed RCT, a reevaluation of the Fistula First one-size-fits-all approach may reduce suitability failure. A functioning fistula is the agreed-upon ultimate goal, but placing it first may not always be the correct approach for all patients. For example, if a patient is deemed to be at high risk using eligibility criteria or the prediction score, placing a synthetic graft to mature (dilate and toughen) vessels in preparation for future AVF creation when the graft fails has been demonstrated to be a successful strategy 26 and suggested by the National Kidney Foundation Kidney Disease Outcomes Quality Initiative (KDOQI) clinical practice guidelines. 27 This study demonstrates that achieving a suitable AVF is not an easy task. The

4 In the Literature 837 appropriate patient must be identified, with vessel selection, experienced surgical technique, follow up, and facilitative intervention as necessary. When these issues are optimized, one could reconsider a trial of antiplatelet therapy. Implications for Achieving Performance Measures The US CMS developed clinical performance measures (CPMs) based on KDOQI guidelines, 1,5 recommending a national goal of increasing AVF use to 65% with the stipulation that AVF use must be via 2 needles. The panel rationalized that given the estimation for fistula failure rates, AV fistulas may even need to be placed in up to 85% of patients starting hemodialysis in order to reach the target of 65% for prevalent patients. Given the results of this study, if 85% of patients received an AVF, only 34% of patients would have useable AVF via 2 needles. Implications for Researchers Choosing the most appropriate primary outcome is always challenging. While thrombosis is a readily quantifiable hard outcome, it is only one of many factors that determine AVF suitability, and as such can only be considered a surrogate endpoint. Clinicians need a clinically important outcome that can be interpreted into a meaningful change in practice and that can improve patient care at the bedside. Examining the literature on graft patency highlights this point. Although access flow monitoring with intervention can improve access flow and, in some cases, reduce thrombosis rates, few studies have shown benefit in overall graft survival. 28,29 The limitation of many clinical end points is the need for larger sample sizes, longer follow-up periods, and greater resources that may prohibit the study. While the authors criticize that their own criteria in ascertaining suitability failure were too stringent, they provide an excellent example to researchers on the use of sensitivity analysis and the use of conditional power calculations for the secondary outcome. While this study was terminated early for a perceived benefit in reducing thrombosis, it was executed following predetermined O Brien- Fleming stopping rules with 4 interim analyses. The stopping boundary allocated the majority of the total to the last interim analysis so that a very large treatment effect was required to meet the stopping rule. The careful use of a data and safety monitoring board during the design and interim analysis phases ensured that such termination would provide important information on the secondary clinical endpoint of AVF suitability failure. While the reduced sample size of 877 was 32% smaller than the target sample size for this outcome, the higher than expected failure rate of 61% (versus 40%) provided a 95% CI that suggested clopidogrel might have reduced the risk of suitability failure by a clinically unimportant 6%. The investigators success in designing and implementing the largest, multicenter double blind RCT of AVF patency to date is a great inspiration to researchers. Such a study could not have been possible without their careful methodological planning, execution, and collaboration In conclusion, while clopidogrel reduced early AVF thrombosis, its use cannot be recommended as it failed to improve AVF suitability for dialysis cannulation. The high AVF suitability failure rate of 61% has significant implications for clinicians, administrators, researchers, and importantly, our patients. One needs to consider a multipronged approach to improving fistula suitability rates. This may include the use of antiplatelet agents, aggressive monitoring with intervention, and specified selection of patients for fistulas and enhanced cannulation skills. Evaluation and validation of such approaches require standardized patient and outcome definitions and rigorous clinical trials testing as exemplified by the DAC. Charmaine E. Lok, MD Toronto General Hospital University of Toronto Toronto, Canada Louise Moist, MD London Health Sciences Center University of Western Ontario London, Canada ACKNOWLEDGEMENTS Financial Disclosure: None. REFERENCES 1. Clinical Performance Measures (CPM) Project: Phase III ESRD CPM Final. Available at:

5 838 CPM Final.pdf. Accessed June 1, Moist LM, Chang SH, Polkinghorne KR, McDonald SP: Trends in hemodialysis vascular access from the Australia and New Zealand Dialysis and Transplant Registry (ANZDATA) 2000 to Am J Kidney Dis 50: , Moist LM, Trpeski L, Na Y, Lok CE: Increased hemodialysis catheter use in Canada and associated mortality risk: data from the Canadian Organ Replacement Registry Clin J Am Soc Nephrol 2008 (in press) 4. US Renal Data System: USRDS 2006 Annual Data Report: Atlas of endstage renal disease in the United States. In Costs of CKD and ESRD: Vascular Access, Betheseda, MD, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Lok CE: Fistula first initiative: advantages and pitfalls. Clin J Am Soc Nephrol 2: , Lacson E Jr, Lazarus JM, Himmelfarb J, et al: Balancing Fistula First with Catheters Last. Am J Kidney Dis 50: , Lok CE, Allon M, Moist L, et al: Risk equation determining unsuccessful cannulation events and failure to maturation in arteriovenous fistulas (REDUCE FTM I). J Am Soc Nephrol 17: , Dember LM, Beck GJ, Allon M, et al: Effect of clopidogrel on early failure of arteriovenous fistulas for hemodialysis: a randomized controlled trial. JAMA 299: , Andrassy K, Malluche H, Bornefeld H, et al: Prevention of p.o. clotting of av. cimino fistulae with acetylsalicyl acid. Results of a prospective double blind study. Klin Wochenschr 52: , Michie D, Wombolt D: Use of sulfinpyrazone to prevent thrombus formation in arteriovenous fistulas and bovine grafts of patients on chronic hemodialysis. Curr Ther Res 22: , Albert E: Prevention of early thrombus formation in arteriovenous fistulae. Dial Transplant 10:167C-167D, Grontoft KC, Mulec H, Gutierrez A, Olander R: Thromboprophylactic effect of ticlopidine in arteriovenous fistulas for haemodialysis. Scand J Urol Nephrol 9:55-57, 13. Fiskerstrand CE, Thompson IW, Burnet ME, et al: Double-blind randomized trial of the effect of ticlopidine in arteriovenous fistulas for hemodialysis. Artif Organs 9:61-63, 14. Janicki K, Dmoszynska A, Janicka L, et al: Influence of antiplatelet drugs on occlusion of arteriovenous fistula in uraemic patients. Int Urol Nephrol 24:83-89, Janicki K, Janicka L, Dmoszynska A, Marczewski K, Smarz I: Effects of ticoplidine on platelet activity and Lok and Moist occlusion of arteriovenous fistulas in IPD patients. Dial Transplant 23: , Grontoft KC, Larsson R, Mulec H, et al: Effects of ticlopidine in AV-fistula surgery in uremia. Fistula Study Group. Scand J Urol Nephrol 32: , Dember LM, Kaufman JS, Beck GJ, et al: Design of the Dialysis Access Consortium (DAC) Clopidogrel Prevention of Early AV Fistula Thrombosis Trial. Clin Trials 2: , Ashley I: Personal communication, July FAVOURED Trial: Fish oil and aspirin in vascular access outcomes in renal disease 19. Hasegawa T, Elder SJ, Bragg-Gresham JL, et al: Consistent aspirin use associated with improved arteriovenous fistula survival among incident hemodialysis patients in the Dialysis Outcomes and Practice Patterns Study. Clin J Am Soc Nephrol 3: , Peterson WJ, Barker J, Allon M: Disparities in fistula maturation persist despite preoperative vascular mapping. Clin J Am Soc Nephrol 3: , Korten E, Toonder IM, Schrama YC, et al: Dialysis fistulae patency and preoperative diameter ultrasound measurements. Eur J Vasc Endovasc Surg 33: , Huber TS, Ozaki CK, Flynn TC, et al: Prospective validation of an algorithm to maximize native arteriovenous fistulae for chronic hemodialysis access. J Vasc Surg 36: , Falk A: Maintenance and salvage of arteriovenous fistulas. J Vasc Interv Radiol 17: , Rooijens PP, Burgmans JP, Yo TI, et al: Autogenous radial-cephalic or prosthetic brachial-antecubital forearm loop AVF in patients with compromised vessels? A randomized, multicenter study of the patency of primary hemodialysis access. J Vasc Surg 42: , Biuckians A, Scott EC, Meier GH, et al: The natural history of autologous fistulas as first-time dialysis access in the KDOQI era. J Vasc Surg 47: , Slayden GC, Spergel L, Jennings WC: Secondary arteriovenous fistulas; converting prosthetic AV grafts to autogenous dialysis access. Semin Dial 2008 (in press) 27. Vascular Access 2006 Work Group: Clinical practice guidelines for vascular access. Am J Kidney Dis 48:S176- S247, Polkinghorne KR, Lau KK, Saunder A, et al: Does monthly native arteriovenous fistula blood-flow surveillance detect significant stenosis a randomized controlled trial. Nephrol Dial Transplant 21: , Moist LM, Churchill DN, House AA, et al: Regular monitoring of access flow compared with monitoring of venous pressure fails to improve graft survival. J Am Soc Nephrol 14: , 2003

Pharmacological approaches to preventing vascular access failure GUIDELINES

NEPHROLOGY 2008; 13, S12 S16 doi:10.1111/j.1440-1797.2008.00993.x Pharmacological approaches to preventing vascular access failure Date written: December 2006 Final submission: March 2008 Author: Kevan