High-intensity Atorvastatin for Arteriovenous Fistula Failure (HAFF): A Feasibility Pilot Study

Primary failure is the most common complication of newly created arteriovenous fistulas (AVFs) and an important contributor to end stage renal disease (ESRD) patients' morbidity and mortality. Recently, the investigators have found that high intensity atorvastatin (40 mg/day) reduces AVF primary failure significantly when compared to other statins or no statin treatment in three separate prospective and retrospective studies done in collaboration with the University of Miami. Based on these findings and considering the necessity for a therapy to improve AVF maturation rates, the investigators propose the realization of a feasibility pilot double blinded randomized controlled trial (RCT). In this study, a total of 50 patients will be randomly allocated to receive high intensity atorvastatin (40 mg daily) or placebo starting at two weeks before surgery and until the end of the observational period (6 weeks after surgery). Present trial will reveal crucial feasibility information such as the appropriateness of the eligibility criteria, patient recruitment and retention rates, compliance, adverse events, efficacy of patient follow-ups, and readiness of the facilities and involved personnel; while having as a secondary endpoint the predictive measurements of diameter and AVF blood flow 6 weeks after fistula creation useful for the estimation of the probable effect of proposed intervention. Here, the investigators aim to pave the way for a future multicenter Phase II RCT seeking to prove the efficacy of atorvastatin therapy as a perioperative intervention to reduce AVF primary failure.

STUDY BACKGROUND AND PURPOSE. Approximately, 30-50% of newly created arteriovenous fistulas (AVF) never mature independently to support hemodialysis, leading to salvage interventions or abandonment of the fistula and creation of a new dialysis access. Failed AVFs are thus associated with increased morbidity, mortality and health care expenditures.

Only two published studies have assessed the effect of statins on AVF primary failure, with contrasting results. Pisoni et al. concluded that statins did not improve AVF maturation, using a retrospective analysis of 317 patients and pooling all statins together as a drug class. Unfortunately, this approach overlooks the potential pleiotropic effects of distinct drugs on AVF remodeling. Overcoming the limitations of Pisoni et al.'s study, the investigators recently published a manuscript evaluating the benefits of three different statins (atorvastatin, rosuvastatin and simvastatin) on AVF outcomes using a retrospective analysis of 535 patients. In this work done in collaboration with the University of Miami, the investigators found a highly statistical significant risk reduction (76%, odds ratio \[OR\] 0.18, p=0.005) of AVF primary failure by atorvastatin. No other statins significantly improved AVF maturation in this cohort. Interestingly, this study showed that atorvastatin is particularly beneficial for one-stage AVF (96% risk reduction, OR 0.03, p=0.005) and, that higher doses of the drug are associated with lower rates of primary failure in one-stage fistulas. Two more studies done by the same group, a prospective and another retrospective, also support this finding indicating that the use of statins prior to fistula creation is beneficial for the unassisted survival of the AVF.

Compared to other statins, atorvastatin has a distinctive physicochemical and pharmacokinetic profile. These characteristics could explain the differential pleiotropic action of atorvastatin in investigators' study, and why it is superior to its counterparts in improving vascular remodeling after AVF creation.

Based on above findings, the investigators propose a pilot clinical trial to evaluate the feasibility of a study involving ESRD patients undergoing AVF surgery at AMC. Indeed, the investigators long-term goal is the realization of a large multicenter Phase II Randomized Controlled Trial (RCT) to test the efficacy of atorvastatin as a safe and inexpensive therapeutic intervention for the reduction of AVF primary failure.

The present proposal will be implemented as presented in the following specific aim (SA): Evaluate the feasibility of performing a RCT with patients taking atorvastatin and undergoing AVF surgery at Albany Medical College.

The primary outcome in this study will be our ability to recruit the patients and follow them up after surgery for 6 weeks through the standard clinical and laboratory tests for ESRD patients undergoing this procedure. This pilot study will help evaluate important feasibility aspects such as the appropriateness of the eligibility criteria, patient recruitment and retention rates, compliance, competency of personnel and site (which include availability and readiness of facilities and study coordinators, pharmacists, nurses, and others) and also to document any adverse event.

The secondary endpoints will be the ultrasonographic (US) measurements of diameter and AVF blood flow 6 weeks after fistula creation. Diameter and blood flow at 6-week have been shown to be of value as predictors of AVF maturation, and having this information is useful to better assess the sample size for future main trials after obtaining the variance estimation of proposed intervention. This information will help to cut study time and expenses in the future.

STUDY DESIGN Enrollment. Patients scheduled to undergo AVF creation will be evaluated by participating surgeons at Albany Medical College approximately one month prior to surgery. Pre-operative vascular assessment will be performed by Doppler ultrasound and the patient's chart will be reviewed for additional relevant information pertinent to the surgery or the proposed intervention. Potential candidates will be approached by the PI and/or vascular surgeons, and clinical research coordinator (CRC) to enroll in this study. If subject agrees the informed consent is obtained, blood will be collected for a baseline Liver test function (LFT), C-reactive protein (CRP), creatine phosphokinase (CPK), and lipid profile, and the patient's clinical information will be entered into Qualtrics (clinical research management software). If the results of the baseline blood panel do not warrant an exclusion, and eligibility criteria are met, patients will be contacted and they will receive the study medication and date they should start the therapy (2 weeks prior to surgery). The patient's primary doctor will be notified and a note will be entered into the patient's electronic record to inform of his/her participation in the study. The day prior to treatment initiation, patients will be called as a reminder. Investigators' goal is to enroll fifty patients, who will be randomized to receive either atorvastatin (40mg, once daily) or placebo. The active drug and matching placebo will be compounded by Pfizer Inc. (New York, NY), the original producer and owner of Lipitor. To ensure that results will not be biased, neither the participants nor the researchers will know which patient belong to the placebo group, nor the statin group. Each patient will participate in the study for eight weeks. This study will be completed in no more than 2 years.

INFORMED CONSENT (ICF). The investigators will follow the AMC Institutional Review Board and U.S. Department of Health \& Office for Human Research protection guidelines. Subjects will be recruited for this study from the hemodialysis and chronic kidney disease populations at Albany Medical College. All patients will receive the same standard of care independently of their enrollment, compliance or retention in the study. Subjects will be free to withdraw from the study at will.

SAMPLE SIZE and STATISTICAL considerations. This feasibility pilot trial is focused at site and investigator level and it is not required to provide power calculation. However, this study must be seen in the context of the future Phase II trial that should result from it, as pilot trial size can impact the overall sample size across both the main and pilot trials combined. The trial sample size of 25 patients per arm (50 patients in total) was selected according Whitehead et al., and it could give investigators the additional advantage of calculating the standardized variance of our secondary endpoints if a medium experimental effect size is observed.

FOLLOW-UP. Follow-up of patients will be performed by the PI as well as the CRC. The day of the AVF surgery, patients will be interviewed to assess compliance and adverse events. If a patient reports significant side effects, she/he will be asked to discontinue the therapy and the final blood panel will be ordered (LFT, CRP, CPK, and lipids). Otherwise, patients will be reminded to continue with the treatment until their next follow-up appointment with the vascular surgeon 2-3 weeks after operation (5-6 weeks after treatment initiation); when a LFT will be done following the American College of Cardiologists/American Heart Association (ACC/AHA) guidelines for monitoring patients who have begun statin therapy. If any surgical complications arise prior to the final evaluation, these will be recorded and treated accordingly, and the study treatment will be discontinued. The day of the final evaluation (8 weeks after intervention initiation), compliance will be evaluated as well as the AVF status will be assessed by Doppler ultrasound and auscultation; the secondary endpoints will be recorded (AVF diameter and blood flow) and a final lab panel will be drawn as done at baseline. Additional outcomes will include changes in lipid profiles, LFTs, and CRP from baseline; frequency of adverse effects; as well as patient compliance and retention rates in each arm of the study.

SUBJECT POPULATION. Investigators will enroll fifty subjects aged over 18 years old with stage 4 or 5 CKD scheduled to undergo AVF creation from the clinic at Albany Medical College. AMC has a long history of providing medical care to underrepresented minorities. In investigators' previous studies women composed 45% of the study population, 30% were black, 10% were Hispanic, and 5% other minority races (Asian, Native American, etc.). Investigators anticipate similar rates of inclusion of women and minorities in the current proposal. It has been reported an increased AVF maturation rate failure in women, therefore, they could potentially benefit more from the proposed intervention. Overall, investigators are not aiming at recruiting patients from specific ethnic or racial group in this study.

DATA ANALYSIS. Analyses will be performed after all patients have completed the study by the participating biostatistician, the PI or other study researchers under their supervision. In addition to the baseline and follow-up laboratory tests, relevant clinical information will be collected from patients including age, gender, ethnicity, prior vascular access and surgical history, concurrent medications, and comorbidities. With the exception of numerical variables such as laboratory values and age, all other clinical variables will be annotated as binary. At the conclusion of the study, the patient characteristics of both treatment arms will be compared to assure their equivalency. The study data will be analyzed following the recommended intention-to-treat protocol, in which all enrolled patients are accounted for at the end of the observational period. If differences in baseline characteristics are not statistically significant (p\<0.05), a Fisher's exact test will be used to compare AVF blood flow and diameter between study arms. On the other hand, if significant differences are detected in one or more relevant baseline variables, logistic regression analyses will be used to adjust for the effect of baseline covariables on the secondary endpoints. An evaluation of compliance, retention rates and adverse effects will be also performed for all the patients and the distinct subpopulations. If compliance is found to be an issue, the analysis of endpoints using a per-protocol approach will be considered. The SAS statistical software package, version 9.2 (Cary, NC), will be used for all statistical analyses.

RISKS. Atorvastatin has a well-established safety and adverse reactions profiles and is already used in the hemodialysis population for different indications. Chronic Kidney Disease participants enrolled in this trial have elevated risks of cardiovascular events, and although only statin-naïve patients or statin-free in the last 6 months prior to enrollment will be eligible to participate, it is likely that many of these patients already have an indication for statin treatment. In order to minimize the occurrence of potential adverse effects, the investigators will carefully evaluate the potential candidates for the study prior to the enrollment and will follow the 2013 ACC/AHA blood cholesterol guidelines recommendations. The investigators will do fasting lipid panel, hepatic transaminase levels, CRP and CPK at baseline, at 5-6 weeks after therapy initiation, and at the final follow up at 8 weeks of therapy. There are no additional risks associated with the procedures that are going to be performed in this study other than phlebotomy and surgery-related complications.

BENEFITS. The great potential benefit of Atorvastatin in this study is to reduce primary AVF failure in the treated group. Knowledge obtained from this pilot study will be of paramount importance and may lead to a phase II trial that will pave the way toward an effective treatment of AVF primary failure with a widely available medication.

Eligibility Criteria:
Inclusion Criteria:

* age\>18 years of age;
* stage 4 or 5 CKD;
* one-stage AVF surgery is planned (radiocephalic or brachiocephalic);
* and statin-naïve or at least 6 months from last statin use.

Exclusion Criteria:

* revision of an existing AVF instead of a de novo access;
* known intolerance or hypersensitivity to statins;
* active liver disease;
* elevation in AST, ALT or CPK of more than 3 times the upper limit of normal;
* baseline LDL\<40 mg/dL;
* coadministration of strong interacting drugs;
* any condition in which statins are contraindicated;
* involvement in another trial where the intervention may confound the outcome of this trial.