Randomized Controlled Trial to Evaluate the AVERT System in PCI Procedures for the

Reduction of Contrast Volume Use and Contrast-Induced Acute Kidney Injury

RESULTS FROM THE AVERT TRIAL

Roxana Mehran, MDProfessor of Medicine (Cardiology) and Population Health Evidence and Policy

Director of Interventional Cardiovascular Research and Clinical TrialsThe Icahn School of Medicine at Mount Sinai, New York, NY

on behalf of AVERT Investigators

Conflict of Interest

• Grant/Research Support (Institutional)

• Advisory Board

• Consulting Fees/Honoraria

• The Medicines Co., BMS, Astra Zeneca, Lilly/Daiichi Sankyo, Bayer

• Janssen (J+J), Abbott Vascular

• Medscape

Within the past 12 months, I or my spouse/partner have had a financial interest/arrangement or affiliation with the organization(s) listed below. These relationships may lead to bias in my presentation.

Affiliation/Financial Relationship Company

• Contrast-induced acute kidney injury (CI-AKI) can occur in up to 20-30% of patients with prior renal impairment and is associated with increased morbidity and mortality

• Risk factors for CI-AKI can be categorized as non-modifiable (i.e. patient co-morbidities) and modifiable (i.e. procedure related) factors1

• Contrast volume is a critical modifiable risk factor that the interventional cardiologist can potentially control during the procedure

1. Mehran R, et al. J Am Coll Cardiol 2004; 44(7): 1393-1399.

Background: Contrast-Induced Acute Kidney Injury

Minimizing Contrast UsageInsights from NCDR Cath-PCI Registry1

4

• Iodinated contrast hypothesized to cause AKI/CIN

• Increasing contrast volume increases risk of AKI/CIN

• Data suggest minimizing contrast dose

1Tsai, et al. JACC, Jan 2014, 1-9.

AVERT System• Consists of a Contrast Modulator and Modulation Reservoir

• Contrast Modulator applies adjustable resistance along the Reservoir line. Once the operator injects the media, part of the contrast is administered to the patient, while the balance (excess contrast) is diverted to the Modulation Reservoir.

• The amount of contrast diverted can be adjusted per physician preference by moving the pin on the Contrast Modulator to alter the resistance along the diversion line.

AVERT Pilot Study

6

OFF

ON

• 21 patients at a single investigational center

• Key findings:

Image quality comparable with AVERT ON vs OFF

Safe – no device-related serious adverse events

Effective – 40% reduction of contrast injected with AVERT ON vs OFF (comparison shots)

Independent, blinded analysis verified reflux reduction in comparison shots.

Source: Kaye et al., Catheter Cardiovasc Interv. 2013 Dec 10. [Epub ahead of print]

AVERT – Study ObjectivesPrimary

Efficacy:

Reduction of contrast volume used in AVERT + hydration compared to hydration only

Reduction in incidence of CI-AKI [defined as a serum creatinine (SCr) increase >0.3 mg/dl from baseline]

Safety: Evaluation of device safety

Secondary Evaluation of image quality Rate of protocol defined severe adverse events through 30 days of

follow-up Change in kidney function

AVERT – Statistical Assumptions• Rejection of the null hypothesis will indicate a statistically

significant difference in the mean volume of contrast used; the device will be considered superior if the device group mean is lower and the above test is statistically significant. This objective will be assessed with a two sample t-test of means. at the one-sided 0.025 alpha level.

Power Calculation • one-sided 0.025 alpha level. The control group population CIN

proportion was assumed to be 22.5% and the treatment group rate of CIN was assumed to be 13.05%, a 42% relative reduction. Based on these assumptions, a total sample size of 548 evaluable subjects will provide 80% power for the primary efficacy endpoint

• This sample size will provide 90% power for objective 1.

9

PT HIGHLY LIKELY TO HAVE PCIw/ baseline eGFR 20-30 - OR –>30 to <60 w/ 2 comorbidities

Central lab

Mobile blood draw

Blood draw kits

Pt transport

TRIAL

n = 578 | 45 sites

CINwithin 5 days post-procedure

TREATMENT CONTROLRandomized 1:1

BLOOD DRAWS

Discharge, 48, 72 (96 & 120 if needed)

PHONE VISIT

30 day

- Exclusions -*LV functional assess using contrast

media

*Unable to undergo protocol-specified

peri-procedural hydration

*Acute renal failure/unstable renal

function

*Acute STEMI within 72 hrs of

currently having STEMI

Major Inclusion Criteria

• Planned definite PCI, planned staged PCI, or coronary diagnostic procedure anticipated to become PCI

• At risk for developing CI-AKI• eGFR (ml/min) > 20 and < 30 or

• eGFR (ml/min) > 30 and < 60 with at least two co-morbidities

o NYHA III/IV

o Diabetes: type I or II requiring insulin or type II on oral medications

o Albuminuria (+2)

o Anemia (<12 mg/ml female; <13 mg/ml male)

o Medically treated hypertension

o > 75 years of age

Hydration Regimen

Peri-Procedural Hydration• Required for all patients

• Isotonic NaCl or NaHCO3 1.0-1.5 ml/kg/hr (could be adjusted for subjects unable to tolerate higher volumes)

• PCI – 2 hrs pre-procedure / 4-12 hrs post-procedure

• Diagnostic – 2 hrs pre-procedure / institutional SOC post-procedure

N-acetylcysteine• Allowed per investigator’s discretion

Study OrganizationPrincipal Investigator, Roxana Mehran, MD

• Mt Sinai Icahn School of Medicine

Steering Committee

• Gregg Stone, MD, Chair – Cardiovascular Research Foundation

• Somjot Brar, MD – Kaiser Permanente, Los Angeles, CA

• Hitinder Gurm, MD – University of Michigan, Ann Arbor, MI

• Anand Prasad, MD – University of Texas, San Antonio, TX

• James Tumlin, MD – University of Tennessee, Chattanooga, TN

Statistics

• NAMSA, Minneapolis, MN

Adverse Event Adjudication

• Cardiovascular Research Foundation

Sponsor/Project & Data Management/Monitoring

• Osprey Medical, Minneapolis MN

Enrolling Sites - 39

SitePrincipal

Investigator Total #

Enrolled

North Mississippi Medical Center Barry Bertolet 83

North Carolina Heart & Vascular Institute Lee Jobe 71

Gateway Cardiovascular Research Center Bassam Al-Joundi 31

Kaiser Permanente LA Medical Center Somjot Brar 29

Mount Sinai Hospital, New York George Dangas 27

Tallahassee Memorial Hospital Wayne Batchelor 24

University of Florida College of Medicine Dominick Angiolillo 23

The Moses H. Cone Memorial Hospital Michael Cooper 19

Mayo Clinic Hospital Patricia Best 18

University of Chicago Medical Center Atman Shah 18

Jewish Hospital Naresh Solankhi 17

VA North Texas Health Care System Subhash Banerjee 17

St. Vincent's Medical Center Peter Kuhlman 16

U Texas Health Science Center Anand Prasad 15

South Carolina Heart Hospital Bashir Lone 14

Heart Center Alfred Hospital, Australia Stephen Duffy 14

St. Luke's Hospital Anthony Hart 12

Baptist Memorial Hospital David Wolford 11

Harbor UCLA Medical Center Joseph Thomas 10

Emory University Hospital Midtown Gautam Kumar 10

SitePrincipal

InvestigatorTotal #

Enrolled

Stanford Hospital and Clinics David Lee 9

Sentara CV Research Inst./Norfolk General Paul Mahoney 9

Heart and Vascular Institute of FLA Patrick Cambier 9

UCSD Medical Center Ehtisham Mahmud 8

Ochsner Clinic Foundation Rajan Patel 8

VA Long Beach Medical Center Arnold Seto 8

York Hospital Paul Tolerico 7

Houston Methodist Research Foundation Alpesh Shah 7

Cardiovascular Associates of East Texas Jeffery Carr 6

University of Illinois at Chicago Amer Ardati 5

Oklahoma Heart Hospital Thomas McGarry 4

Abbott Northwestern Hospital M. Nicholas Burke 3

Allegheny General David Lasorda 3

Auckland City Hospital, New Zealand Peter Ruygrok 3

St. Joseph's Hospital of Atlanta George Chang 2

Baylor St. Luke's Medical Center Guilherme Silva 2

Norton Audubon Hospital Divyesh Bhatka 2

Coliseum Medical Center Maria Bartlett 2

The Heart Hospital Baylor Plano David Brown 2

Patient Flow

No Procedure (N=2)

N=620 Consented and Screened

N=578 Randomized

N=286 Control N=292 AVERT

N=284 Procedure CompletedEvaluated for Contrast Reduction

N=283 Procedure CompletedEvaluated for Contrast Reduction

N=282* Evaluated for CI-AKI N=281 Evaluated for CI-AKI

N=280 Completed 30 Day Visit N=269 Completed 30 Day Visit

* 2 control group patients completed 30 day study follow-up but are missing SCr and CI-AKI status

No Procedure (N=9)

Withdrew Post-Procedure (N=2) Withdrew

Pre-30 Day FU (N=12)

Withdrew Pre-30 Day FU (N=4)

Key Baseline Characteristics by Treatment Group

Control

(N=286)

AVERT

(N=292)P-value

Age (years) 72.3 ± 9.4 71.0 ± 9.3 0.11

Age > 75, n (%) 135 (47.2) 119 (40.8)

Female Gender, n (%) 113 (39.5) 114 (39.0) 0.93

BMI (kg/m2) 30.9 ± 7.0 31.1 ± 6.8 0.69

eGFR (mL/min/1.73m2) 45.6 ± 10.7 45.6 ± 10.7 0.96

Previous MI, n (%) 104 (36.4) 105 (36.0) 0.93

Previous CABG, n (%) 92 (32.2) 90(30.8) 0.78

Previous PCI, n (%) 132 (46.2) 154 (52.7) 0.11

Hypertension, n (%) 283 (99.0) 288 (98.6) 1.00

CHF, n (%) 88 (30.8) 99 (33.9) 0.42

Diabetes, n (%) 182 (63.6) 193 (66.1) 0.54

Anemia, n (%) 112 (39.2) 118 (40.4) 0.79

P-values based on t-test, Wilcoxon or Fisher’s exact test

1) Primary Endpoint – Contrast Volume Results

Control

(N=284)

AVERT

(N=283)

Relative

Reduction

(AVERT vs.

Control)

P-value

based on

t-test

P-value based

on Wilcoxon

P-value based

on log

transformation

Contrast

(ml)

101.3 + 71. 1

78 (13, 400)

85.6 + 50.5

1 (16, 276)15.5% 0.002 0.035 0.022

Based on one-sided tests using Fisher’s combination method and a 0.025 alpha level

Left shift towards lower contrast volume with AVERT

dia

gn

os t i

c an

gio

PC

I

1 les io

n

2 les io

ns

3 les io

ns

rad

ial

fem

ora

l

-2 0 0

-1 5 0

-1 0 0

-5 0

5 0

0

{p=0.002

Subgroup analysis – Contrast Volume

Dia

gno

stic

PC

I

1 le

sio

n

2 le

sio

ns

≥3 le

sio

ns

50

-50

-100

-150

-200

0

p=0.51

Ch

ange

in C

on

tras

t (

mls

)

Rad

ial

Fem

ora

l

p<.0001

Change in contrast and 95% CI’s are based Hodges-Lehmann location shiftP-values based on interaction term from regression model with a 0.15 alpha level

Favo

rsA

vert

Favo

rs

Co

ntr

ol { {

Kidney Function Through 72 hours

SCr increase Control

N= 282

AVERT

N= 281% Change

Odds Ratio -

(95% CI)P-value2

≥ 0.5mg/dL 22/282 (7.8%) 28/281 (10.0%) 27.7% 1.308 (0.729, 2.347) 0.85

≥ 25% 47/282 (16.7%) 41/281 (14.6%) -12.5% 0.854 (0.541, 1.347) 0.29

0.5mg/dL or ≥ 25% 47/282 (16.7%) 43/281 (15.3%) -8.2% 0.903 (0.575, 1.418) 0.37

Control AVERT P-value1

Subject with CI-AKI 74/282 (26.2%) 76/281 (27.0%) 0.72

CI-AKI Reduction (n=563)

2) Renal Function Results

2P-value based on one-sided Fisher’s exact test; alpha level of 0.025

1P-value based on one-sided Fisher’s exact test; alpha level of 0.025 and Fisher’s combination method

Risk of CI-AKI by subgroups

OR 1.03 [0.62-1.69] p=0.94

OR 1.06 [0.60-1.86]

OR 0.79 [0.48-1.29] p=0.82

OR 1.55 [0.87-2.76]

OR 1.07 [0.68-1.70]

OR 0.78 [0.41-1.48]

OR 0.94 [0.27-3.29] p=0.20

OR 0.76 [0.45-1.26]

OR 1.61 [0.84-3.11]

Diagnostic angiography

PCI

Age ˂75 years

Age ≥75 years

Diabetes

CHF

Favors AVERT Favors Control

OR 1.04 [0.72-1.51] p=0.72All patients

eGFR >60 ml/min

eGFR >40 to ≤60 ml/min

eGFR ≥20 to ≤40 ml/min

P-values based on interaction term from logistic regression model with a 0.15 alpha level

0 .0 1 0 .1 1 0 1 0 01

G ro u p 1

No Diabetes

No CHF

OR 1.06 [0.45-2.51] p=0.81

OR 1.21 [0.76-1.91] p=0.28

Image Quality/System Turned Off AVERT

N=283Number of Subjects w/ AVERT System turned OFF during procedure 14/283 (4.9%)

Image Quality (related to AVERT System) 2 (0.7%)

Adverse Event 2 (0.7%)

Device Deficiency 1 (0.4%)

Image Quality (not related to AVERT System) 1 (0.4%)

User Error 1 (0.4%)

Other 7 (2.5%)

Adjudicated Adverse EventsAVERT

N= 292

Number of Events

Number of Subjects with Event (%)

Confidence Limits

Device Related Events 1 1 (0.3%)

0.1%, 1.9%

Secondary Endpoint - Results

Adjudicated Adverse Events through 30 daysControl N= 286 AVERT N= 292

Event Type Number of

Events

Number of Subjects

with Event (%)

Confidence Limits

Number

of

Events

Number of Subjects

with Event (%)

Confidence Limits P-value

Myocardial Infarction 7 7 (2.4%)

1.2%, 5.0%

4 4 (1.4%)

0.5%, 3.5%

0.37

Spontaneous 4 4 (1.4%)

0.5%, 3.5%

4 4 (1.4%)

0.5%, 3.5%

1.00

Related to PCI 3 3 (1%)

0.4%, 3.0%

0 0 (0%)

0.0%, 1.3%

0.12

Dialysis dependent CI-AKI 1 1 (0.3%)

0.1%, 2.0%

3 3 (1%)

0.4%, 3.0%

0.62

Unplanned re-hospitalization 29 23 (8%)

5.4%, 11.8%

28 26 (8.9%)

6.1%, 12.7%

0.77

Major bleeding (not CABG related) 5 4 (1.4%)

0.5%, 3.5%

6 6 (2.1%)

0.9%, 4.4%

0.75

Stroke 0 0 (0%)

0.0%, 1.3%

1 1 (0.3%)

0.1%, 1.9%

1.00

All-Cause Mortality 3 3 (1%)

0.4%, 3.0%

5 5 (1.7%)

0.7%, 3.9%

0.72

Cardiovascular 3 3 (1%)

0.4%, 3.0%

5 5 (1.7%)

0.7%, 3.9%

0.72

Non-Cardiovascular 0 0 (0%)

0.0%, 1.3%

0 0 (0%)

0.0%, 1.3%

--

Revascularization of target lesion 6 6 (2.1%)

1.0%, 4.5%

4 4 (1.4%)

0.5%, 3.5%

0.54

P-values based on Fisher’s exact test

1. Serum Creatinine increase of 0.5mg/dL or >25%

2. Per protocol analysis - excluded subjects where related protocol deviations occurred that may have affected kidney function:

• Baseline Serum Creatinine drawn > 72 hours prior to procedure

• Hydration started prior to baseline Serum Creatinine draw

• Hydration protocol not followed

• Contrast outside coronaries (>10 mL) during procedure or within 5 days

Per Protocol Post Hoc Analysis

Patient Flow - Per Protocol Post Hoc Analysis

No Procedure (N=2)

N=578Randomized

N=286 Control Group N=292 AVERT Group

N=284Procedure Completed Evaluated for

Contrast Reduction

N=283Procedure Completed Evaluated

for Contrast Reduction

N=282*Evaluated for CI-AKI Endpoint

Discharge to 5 Days

N=281Evaluated for CI-AKI Endpoint

Discharge to 5 Days

N=280Completed 30 Day Visit

N=269Completed 30 Day Visit

* 2 control group patients completed 30 day study follow-up but are missing SCr and CI-AKI Status

N=232Evaluated for Contrast Reduction

N=242Evaluated for Contrast Reduction

N=230Evaluated for CI-AKI Endpoint

N=240Evaluated for CI-AKI Endpoint

No Procedure (N=9)

Withdrew Post-Procedure (N=2)

Per protocol exclusions Per protocol exclusions

Withdrew Pre-30 Day FU (N=12)

Withdrew Pre-30 Day FU (N=4)

Control (N=232) AVERT (N=242)Relative Reduction

(AVERT vs. Control)P-value1

All Patients99.1 + 71.8

70.5 (13-382)

83.1 + 48.8

70.0 (16-276)16.2% 0.004

1Based on one-sided tests using Fisher’s combination method and a 0.025 alpha level

Contrast Results Per Protocol Post Hoc Analysis

Contrast Volume Reduction (N=474)

Left shift towards lower contrast volume with AVERT

CI-AKI Results - Per Protocol Post Hoc Analysis

Control AVERT

Relative Reduction

(AVERT vs. Control)

P-value

All Patients 41/230 (17.8%) 34/240 (14.2%) 20.5% 0.171

PCI (N=202) 19/96 (19.8%) 15/106 (14.2%) 28.5% 0.352

Diagnostics (N=268) 22/134 (16.4%) 19/134 (14.2%) 13.6% 0.732

Baseline eGFR

>40 to <60 (N=264)29/135 (21.5%) 14/129 (10.9%) 49.5% 0.022

CI-AKI Reduction (N=470)

1P-value based on one-sided Fisher’s exact test; alpha level of 0.0252P-value based on two-sided Fisher’s exact test

Conclusions The AVERT™ System is safe and reduces CMV injection

significantly during coronary angiography and PCI while

maintaining adequate image quality.

Use of this device did not result in a significant reduction of

CI-AKI

The benefit seen in pts with moderate CKD at baseline

warrants further investigation.

Next Generation: DyeVert™ System• Consists of a Pressure Compensating Valve (PCV) and Reservoir Chamber

• PCV automatically adjusts resistance in diversion line.

• Self-adjusting for catheter config and contrast type (Easier to use)

• Diverts excess contrast while maintaining image quality

• Fully disposable

• Saves on all injections (also saves on puffs)

DyeVert Clinical Study Activity

• DyeVert Pilot Study – 2 sites• Results being presented at EuroPCR,

May 2016

• DyeVert RCT – Single center• Currently enrolling