Prevention of Serious Adverse Outcomes Following Angiography: Primary Trial and Establishment of Biorepository Steven D. Weisbord

Contrast-induced acute kidney injury (CI-AKI) and associated adverse outcomes CI-AKI: – Common and associated with: In-hospital mortality Prolongation in hospitalization Increased costs Progression of CKD Long-term mortality – Preventable Equipoise exists on effectiveness of IV NaHCO 3 and NAC

Our trial VA cooperative study Prospective, double blind, randomized clinical trial using a 2x2 factorial design to assess: – Isotonic bicarbonate v. isotonic saline – Oral NAC v. oral placebo 33 VA sites Enrollment over 2 ½ years

Study hypotheses 1.Compared to isotonic saline, isotonic bicarbonate ↓ morbidity and mortality following angiography - Effect mediated thru ↓ CI-AKI 2.Compared to placebo, NAC ↓ morbidity and mortality following angiography - Effect mediated thru ↓ CI-AKI

Eligibility: inclusion criteria High risk for CI-AKI and adverse outcomes – eGFR ml/min/1.73 m 2 with DM – eGFR < 45 ml/min/1.73 m 2 with or without DM – Undergoing elective or urgent coronary or non- coronary angiography

Exclusion criteria eGFR < 15 ml/min/1.73m 2 time of angio Unstable SCr STEMI Emergent angio Receipt of iodinated contrast w/i 7 days Decompensated CHF Receipt of oral or iv NAC Prisoner Age < 18 Pregnancy Unwillingness to comply with outcome assessment Active in another trial Dementia

Randomization Randomize pts into 4 treatment combinations: – Bicarbonate/NAC – Saline/NAC – Bicarbonate/placebo – Saline/placebo Randomization stratified by study site – Accounts for site specific preventive care – No further stratification due to large sample size

Interventions: IVF and NAC Isotonic bicarbonate or saline pseudo-protocolized – Pre-angio: ≥ 3 ml/kg over ≥ 1 ≥ 1 ml/kg/hr – Intra-angio: ml/kg/hr – Post-angio: ≥ 6 ml/kg over ≥ 4 hrs Permissible for providers to administer additional IVF (≤ 12 ml/kg over ≤ 12 hrs pre and post) Oral NAC – 1200 mg po bid x 5 days starting on day of angio

Study outcomes 1 0 outcome: – Death, dialysis within 90 days and persistent renal injury (↑ SCr ≥ 90 days 2 0 outcomes: – CIAKI (↑ SCr 0.5 mg/dl and/or 96±24 hrs) – Death – Hospitalization with ACS, CVA, CHF within 90 days – All cause 90-day hospitalization 3 0 outcome: – Development of 1 yr – 1 yr } Passive follow up using data registries

Power assumptions and sample size No interaction between our interventions Basal rate of 1 0 outcome in controls 8.7% Effect size of 25% (both interventions) Alpha = 0.025; 1-beta = 0.9 3% loss to follow up Overall 7,680 pts – 1,920 pts in each arm

Established collaboration Investigators from George Institute in Australia funded to enroll 1,000 pts from 10 sites With data sharing – total study 8,680 pts Anticipated start up: – Australia – February 2013 – US – October 2013

Ancillary study - Biomarker collection - CIAKI defined by  SCr at ~ hrs - Renal injury from contrast occurs w/i minutes of contrast administration -Identifying CIAKI in incipient stage with biomarkers will permit: -Early interventions to mitigate further renal damage -Help predict risk for longer-term outcomes -Furthermore, biomarkers measured prior to angiography may: - help predict risk for CIAKI -Stratify pts regarding need for preventive care

Studies of biomarkers of CIAKI to date

Collective findings of prior studies Early (2-4) hr increases in u & s NGAL seen in pts with CI-AKI (moderate sens/spec 70-90%) s CyC and u IL18 increase later (~ 24 hrs) & are moderately predictive of CI-AKI* u L-FABP increases early (2-4 hrs) and peaks later (e.g. 24 hrs) in pts with CI-AKI* Pre-angiography u L-FABP higher in pts who develop CI-AKI* * Findings based on 1-2 studies

Caveats of studies to date Small # pts – Limited power to characterize diagnostic/prognostic capacity of biomarkers ~ 50% of pts had normal kidney function – Small absolute # pts (<200) with CI-AKI – Generalizability of findings to CKD pts unclear Diabetes and GFR affect baseline levels of some biomarkers Few analyses of risk stratification of pre-angio biomarkers Limited analyses of panels of biomarkers Only 2 studies tracked long-term outcomes

PRESERVE as a resource for biomarker analyses Very large number of patients (up to 7,680) Comprehensive assessment of CI-AKI and 90-day outcomes – Minimizes misclassification – Confirm (or refute) association of CI-AKI with longer-term outcomes All patients will have CKD – High incidence of AKI(~ 15%) – High risk for adverse 90-day outcomes (~ 9%) Provides opportunity to investigate fx of preventive interventions on biomarkers All are VA pts  integrated electronic health record

NIH/NIDDK funding for biorepository Recent receipt of funding for collection & storage of blood and urine from PRESERVE pts Blood (20 ml) & urine (10 ml) collected at study sites pre- and 4 hrs post-angiography Spun/aliquoted/labeled and stored locally at & shipped in bulk to Boston VA Shipped ~ quarterly to NIDDK biorepository for long-term storage and future use Samples to be made available to qualified investigators in future

Essential personnel Paul Palevsky – Co-Study chair on parent study and Co-PI on both ancillaries Michael Fine Jim Kaufman Glenn Chertow Chirag Parikh – also co-I on long-term f/u and co- PI on biomarker study Peter McCullough Rick Shunk Mary Brophy Susan Soliva Robert Lew Soe Soe Thwin Ryan Ferguson Todd Conner Maria Mor – co-I and statistician for both ancillaries