Article Examining the Association between Hemodialysis Access Type and Mortality: The Role of Access Complications Pietro Ravani,* † Robert Quinn,* † Matthew Oliver, ‡ Bruce Robinson, § Ronald Pisoni, § Neesh Pannu, | Jennifer MacRae,* † Braden Manns,* † Brenda Hemmelgarn,* † Matthew James,* † Marcello Tonelli,* † and Brenda Gillespie ¶ Abstract Background and objectives People receiving hemodialysis to treat kidney failure need a vascular access (a fistula, a graft, or a central venous catheter) to connect to the blood purification machine. Higher rates of access complications are considered the mechanism responsible for the excess mortality observed among catheter or graft users versus fistula users. We tested this hypothesis using mediation analysis. Design, setting, participants, & measurements We studied incident patients who started hemodialysis therapy from North America, Europe, and Australasia (the Dialysis Outcomes and Practice Patterns Study; 1996–2011). We evaluated the association between access type and time to noninfectious (e.g., thrombosis) and infectious complications of the access (mediator model) and the relationship between access type and time-dependent access complications with 6-month mortality from the creation of the first permanent access (outcome model). In mediation analysis, we formally tested whether access complications explain the association between access type and mortality. Results Of the 6119 adults that we studied (mean age =64 [SD=15] years old; 58% men; 47% patients with diabetes), 50% had a permanent catheter for vascular access, 37% had a fistula, and 13% had a graft. During the 6-month study follow-up, 2084 participants (34%) developed a noninfectious complication of the access, 542 (8.9%) developed an infectious complication, and 526 (8.6%) died. Access type predicted the occurrence of access complications; both access type and complications predicted mortality. The associations between access type and mortality were nearly identical in models excluding and including access complications (hazard ratio, 2.00; 95% confidence interval, 1.55 to 2.58 versus hazard ratio, 2.01; 95% confidence interval, 1.56 to 2.59 for catheter versus fistula, respectively). In mediation analysis, higher mortality with catheters or grafts versus fistulas was not the result of increased rates of access complications. Conclusions Hemodialysis access complications do not seem to explain the association between access type and mortality. Clinical trials are needed to clarify whether these associations are causal or reflect confounding by underlying disease severity. Clin J Am Soc Nephrol 12: 955–964, 2017. doi: https://doi.org/10.2215/CJN.12181116 Introduction About 70% of people with end stage kidney failure (approximately 3 million people globally) are treated with hemodialysis (1,2). Although effective for sus- taining life, hemodialysis therapy is associated with poor outcomes (one in six people die each year), and it is extremely costly. People receiving hemodialysis make up ,1% of the Centers for Medicare and Medicaid Services (CMS) beneficiaries but account for 6%–7% of health care spending (3). A large fraction of this cost is related to establishing and maintaining a vascular access (a fistula, a graft, or a tunneled catheter) that allows access to the bloodstream for the delivery of hemodialysis therapy (4,5). Complications of this hemodialysis access (i.e., clotting or infection) are common and lead to access-related procedures or medical interventions, which are considered a key driver of morbidity and mortality in this patient population (4,6,7). Clinical practice guidelines (8–10) recommend the fistula as the best form of access, because many observational studies have shown that fistula users have fewer access complications (11) and better prognosis (12) than graft or catheter users. Recogniz- ing the potential to improve patient outcomes and lower the costs of providing care, the CMS developed a national initiative to increase the use of fistulas and reduce the use of catheters (13,14). The CMS also incorporated vascular access quality out- comes into Quality Incentive Program metrics and tied funding to the attainment of fistula utilization targets (15). Although these initiatives are well inten- tioned to improve outcomes, the quality of the evidence on which they are based is low when assessed against recommended standards (16). There has never been a randomized comparison of different access strategies with mortality or other hard end points as the outcome, and the observational literature Departments of *Medicine and † Community Health Sciences, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada; ‡ Department of Medicine, University of Toronto, Toronto, Ontario, Canada; § Arbor Research Collaborative for Health, Ann Arbor, Michigan; | Department of Medicine, Division of Nephrology, University of Alberta, Edmonton, Alberta, Canada; and ¶ Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, Michigan Correspondence: Dr. Pietro Ravani, Foothills Medical Centre, 1403 29th Street NW, Calgary, AB T2N 2T9, Canada. Email: pravani@ ucalgary.ca www.cjasn.org Vol 12 June, 2017 Copyright © 2017 by the American Society of Nephrology 955