Prevention of Serious Adverse Outcomes Following Angiography (PRESERVE) Trial Steven D. Weisbord MD, MSc

Contrast-associated AKI is associated with serious, adverse outcomes In-hospital mortality Prolongation in hospitalization Increased costs Progression of CKD Long-term mortality

Published trials of NAC Median sample size = 95 Mean assumed effect size = 66%

Trials of bicarbonate Median sample size = 176 Mean assumed effect size = 73%

Summary of data to date on NAC and NaHCO3 Proliferation of small, clinical trials: –Implausibly large effect sizes –Inadequate power –Designed using surrogate primary end-point (Δ SCr) –Many did not assess pt-centered outcomes Meta-analyses based on these trials unable to draw valid conclusions

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

Eligibility: inclusion criteria High risk for CIAKI 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

Interventions: IVF and NAC Isotonic bicarbonate or saline pseudoprotocolized – 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 No interaction between our interventions Basal rate of 1 0 outcome in controls 8.7% (7.6% overall) 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

Current Status Recruitment began in October 2013 All 33 sites in US enrolling as of Sept 2014 – 11 months to get all sites enrolling Current enrollment US = 2,409 pts Current enrollment Australia = 400

Demographic characteristics

Clinical characteristics

Laboratory characteristics

Procedure characteristics

Study outcome events

Enrollment – current and projections

Biomarker Ancillary study NIH0-funded study establishing a repository of: – Serum, plasma, urine prior to angiography – Serum, plasma, urine 2-4 hrs post-angiography Will be used to analyze blood and urine biomarkers for risk for, diagnosis of, and prognosis associated with CIAKI Currently 443 patients enrolled – ~ 10+ pts enrolled/week

Essential personnel Paul Palevsky – Co-Study chair on parent study and Co-PI on ancillary Jim Kaufman Glenn Chertow Chirag Parikh – also co-PI on biomarker study Rick Shunk Deepak Bhatt Edward McFalls Jo Lee Martin Gallagher Alan Cass Soe Soe Thwin Ryan Ferguson Todd Conner Yara Tayeh Kan Mehta Lee Anne Mandich Jill Schaefer