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

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.

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.