AVERT System in PCI Procedures for the Reduction of Contrast Volume - - PowerPoint PPT Presentation

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, , MD

Professo sor of

• f Medicine (Ca

(Cardiolo logy) an and Popula lation He Health Evid idence an and Polic licy Di Director of

• f In

Interv rventional Car Cardio iovascular Rese esearch an and Clin Clinic ical l Tria ials The Ica Icahn Sc School of

• f Medicine at Mount Sin

Sinai, New York

• rk, NY
• n
• n beh

ehalf of

• f AVERT In

Inves esti tigators

Conflict of f In 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.

Backg kground: Contr trast-Induced Acute Kid idney In Inju jury ry

Minimizing Contrast Usage

Insights 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 Pil ilot 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 – Stu tudy Objectives

Primary

• 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 PCI

w/ 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 CIN

within 5 days post-procedure

TREATMENT CONTROL

Randomized 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 In 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
• NYHA III/IV
• Diabetes: type I or II requiring insulin or type II on oral medications
• Albuminuria (+2)
• Anemia (<12 mg/ml female; <13 mg/ml male)
• Medically treated hypertension
• > 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

Stu tudy Organization

Principal 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 Sit ites - 39

Site Principal 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

Site Principal Investigator Total # 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 Completed Evaluated for Contrast Reduction N=283 Procedure Completed Evaluated 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 Characteristic ics 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) ) Pri rimary Endpoint – Contrast Volume Results

Control (N=284) AVERT (N=283) Relative Reduction (AVERT vs. Control) P-value based on t-test P-value based

• n Wilcoxon

P-value based

• n 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

i

• I

n s s l a l

{

p=0.002

Subgroup analysis – Contrast Volu lume

Diagnostic PCI 1 lesion 2 lesions ≥3 lesions

50

• 50
• 100
• 150
• 200

p=0.51

Change in Contrast (mls) Radial Femoral

p<.0001 Change in contrast and 95% CI’s are based Hodges-Lehmann location shift P-values based on interaction term from regression model with a 0.15 alpha level

Favors Avert Favors Control

{ {

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 f 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=0.72 All 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

0.01 0.1 10 100 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=283

Number 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 Events

AVERT N= 292 Number of Events Number of Subjects with Event (%) Confidence Limits Device Related Events 1 1 (0.3%) 0.1%, 1.9%

Secondary ry Endpoint - Results

Adju judic icated Adverse Events through 30 days

Control N= 286 AVERT N= 292 Event Type Number of Events Number of Subjects with Event (%) Confidence Limits Number

• f

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%, 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%, 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%, 1.3% 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

• ccurred 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 Flo low - Per Protocol Post Hoc Analysis

No Procedure (N=2) N=578 Randomized N=286 Control Group N=292 AVERT Group N=284 Procedure Completed Evaluated for Contrast Reduction N=283 Procedure Completed Evaluated for Contrast Reduction N=282* Evaluated for CI-AKI Endpoint Discharge to 5 Days N=281 Evaluated for CI-AKI Endpoint Discharge to 5 Days 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 N=232 Evaluated for Contrast Reduction N=242 Evaluated for Contrast Reduction N=230 Evaluated for CI-AKI Endpoint N=240 Evaluated 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 Patients 99.1 + 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

Co Contrast Resu sult lts Per r Protocol l Post Hoc Analy lysis is

Contrast Volume Reduction (N=474)

Left shift towards lower contrast volume with AVERT

CI 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 0.025 2P-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 Stu tudy Activity

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

May 2016

• DyeVert RCT – Single center
• Currently enrolling