COOL RCN A Prospective, Randomized Trial Examining the Safety and Efficacy of Systemic Hypothermia for the Prevention of Radiocontrast Nephropathy Gregg W. Stone, MD Columbia University Medical Center The Cardiovascular Research Foundation

Background Contrast induced renal insufficiency after invasive cardiology procedures has been strongly associated with early and late mortality Preclinical and pilot studies have suggested that systemic hypothermia can ameliorate or prevent radiocontrast nephropathy (RCN) We therefore performed a prospective, randomized trial to determine the utility of systemic hypothermia in pts receiving iodinated contrast

Prevention of Experimental Contrast-Induced Nephropathy with Hypothermia, Fenoldopam, N- Acetylcysteine, and Bicarbonate Serum Creatinine (mg/dl) Baseline 24 hr 48 hr Normo- thermia 39ºC, N=6 Bicarb N=6 Fenold- opam N=6 NAC N=6 37ºC N=5 35ºC N=5 32ºC N= Dae MW et al. JACC 2004;43:48A Rabbit model N=40 Control Hypothermia

The COOL RCN Pilot 30 pts (median age 71, 50% diabetes) with estimated CrCl 20 – 50 mL/min (mean 35.2 ± 8.9) were hydrated and cooled to 33 – 34ºC >90 mins prior to and for 3 hrs after contrast Mean 150 ± 65 [range ] mL contrast used during angiography (60%) or PCI (40%) SCr measured at 24, 48 and hrs RCN (SCr ↑>25% from baseline) developed in 3 pts (10%), vs. 40% predicted Stone GW. TCT2006

Pts at risk for RCN (CrCl mL/min) Undergoing diagnostic and/or interventional cath with >50 cc dye N = 400 pts at up to 35 sites Hypothermia (33-34°C) Pre contrast and 3 hrs post + Hydration (NaCl & NaHCO 3 ) COOL RCN Randomized Trial SCr measured at 24, 48 and hrs* (core lab) 1º efficacy endpoint = RCN (SCr ↑ >25% from baseline) 1º safety endpoint = 30d AE (death, MI, dialysis, VF, venous compl requiring surgery, bleed requiring ≥ 2U transf., rehosp.) Control Hydration (NaCl & NaHCO 3 ) R *Pts w/SCr ↑25% or ≥0.5 mg/dL at day 3 had an additional blood draw between day 7 – 10

Key Exclusion Criteria Unstable renal function, acute renal failure or dialysis Renal artery angiography, renal drug infusion, or known RAS Receiving mannitol or IV diuretics Decompensated HF, intubated, or hypotension (SBP <100) STEMI within 72 hours Severe allergy (contrast, heparin, meperidine, buspirone) or recent MAOI Additional contrast within 10 days pre or post procedure IVC filter, or height < 4’ 11” Hypersensitivity to hypothermia (Raynaud’s), bleeding diathesis, coagulopathy, sickle cell disease, severe hepatic impairment, cryoglobulinemia, untreated hypoth, Addison’s, BPH or urethral stricture, or will refuse blood transfusions

Reprieve® System Heparin / hydrogel coated PET balloon 12 Fr venous catheter with a 25 cm heat exchange balloon

Cooling Procedures Cooling must be achieved before 1 st contrast Target core temp 33ºC; no contrast before 34ºC Shivering suppression protocol (45-60’ pre cool): o Buspirone 60 mg po o Meperidine 50 mg slow IV bolus; 15’ later mg slow IV bolus; 15’ later start mg/hr IV infusion o Surface forced air warming blanket (at high) Rewarming initiated 3 hours post procedure towards a target of 36ºC at a rate of 1°C/hr

Study procedures IV Hydration o 2-12 hrs pre cath: NS 1.5 cc/kg/hr (1.0 cc/kg/hr of ½ NS for pts with CHF or LV dysfunction) o 1 hr pre cath: Stop NS, start NaHCO 3 (150 mEq in 1 L D 5 W): bolus of 0.45mEq/kg (3mL/kg/hr) for the first hour, then 0.15 mEq/kg/hr (1 mL/kg/hr) during the cath and for 5-7 hrs post procedure N-acetylcysteine was allowed per PI discretion Low osmolar contrast only; iodixanol preferred

Power Analysis Primary efficacy endpoint o RCN, defined as a relative SCr ↑ >25% from baseline anytime within 96 hrs) o Assumed RCN rates: 35% control, 21% Rx (40% treatment effect) o Randomizing 358 pts provided 80% power (α=0.05) → 400 pts randomized to allow 10% lost to FU, inadequate samples or study procedures

Study Organization Principal Investigator: Gregg W. Stone Data Management: Harvard Clinical Research Institute (HCRI) Site and Data Monitoring: Radiant Medical Clinical Events Committee: HCRI (Don Cutlip, chair) Biochem Core Lab: ACM Medical Laboratory DSMB: Julian Aroesty, Chair; J. Lopez; F. Ling; J. Orav Sponsor: Radiant Medical (subsequently assumed by ZOLL Circulation)

Top Enrolling Sites SitePrincipal Investigator Owensboro Hospital, Owensboro, KYKishor Vora UPMC Presbyterian, Pittsburgh, PAJohn Schindler Methodist North Hospital, Memphis, TNClaro Diaz Wake Med, Raleigh, NCTiff Mann Columbia University Medical Cntr, NY, NYGeorge Dangas Mayo Clinic, Rochester, MinnesotaPatricia Best

70 pts normothermia 58 pts hypothermia 136 pts randomized between March 2006 and August 2007 Study terminated early due to financial insolvency of Radiant; Radiant assets were purchased by ZOLL Circulation, who funded completion of the study 136 pts randomized 128 pts evaluable 4 pts – Withdrawn prior to initiating study procedures* Sites did not turn in CRFs – 4 pts 73 pts normothermia 63 pts hypothermia *Pul edema (1); IV diuretics (1); polycythemia (1); pt withdrew (1)

Baseline Features Normothermia N=70 Hypothermia N=58 P value Age (yrs)72 ± 1074 ± Female31.4%48.3%0.07 Diabetes61.4%32.8%<0.01 Hypertension88.6%91.4%0.77 Dyslipidemia91.4%84.4%0.27 Current smoking26.3%17.5%0.47 Prior MI36.2% 1.00 Prior CABG33.3%29.3%0.70 Prior PCI48.6%43.1%0.59 Serum creatinine (mg/dL)1.97 ± ± Creatinine clearance (mL/min)36.2 ± ±

Procedural Summary Normothermia N=70 Hypothermia N=58 P value N-acetylcysteine administered77.1%62.1%0.06 Pre hydration volume (mL)799 ± 4921,114 ± 1, Post hydration volume (mL)854 ± ± Procedure type Diagnostic58.6%51.7%0.45 Interventional41.4%48.3%0.45 Total contrast volume (mL)138 ± ± Contrast type* Non-ionic, iso-osmolar75.4%79.3%0.60 Non-ionic, low osmolar24.3%24.1%0.98 1st contrast (ºC)36.1 ± ± 0.5<0.001 * Some pts received 2 types of contrast during the index procedure

Cooling Efficiency Baseline temp (ºC) 36.8 ± 8.8 Time to 35ºC (mins): 6.2 ± 3.7 Time to 34ºC (mins): 13.0 ± 5.5 Time to 33ºC (mins): 29.4 ± ºC reached before contrast: 92.5% Meperidine dose (mg, mean) 245 ± 70 Premature cooling cessation: 0% Aggregate cooling data (N=50) Time (min) Patient Temperature (ºC)

Results Normothermia N=70 Hypothermia N=58 P value Serum creatinine (mg/dL) - Baseline 1.97 ± 0.80 (n=70) 1.78 ± 0.60 (n=58) hr1.91 ± 0.77 (n=68) 1.77 ± 0.66 (n=58) hr2.21 ± 0.94 (n=58) 1.94 ± 0.73 (n=53) – 96 hr2.11 ± 0.87 (n=68) 1.92 ± 0.72 (n=56) 0.18

Development of RCN Primary endpoint OR [95%CI] = 1.27 [ ] P=0.59 OR [95%CI] = 0.83 [ ] P=0.69 OR [95%CI] = 1.16 [ ] P=0.71

Randomization to Hypothermia Multivariate Analysis (16 variables) Logistic regression adjusted for: age, gender, total contrast volume, renal medications, pre hydration time, post hydration time, pre hydration volume, post hydration volume, dyslipidemia, weight, baseline SCr and CrCl, cath vs. PCI, and anemia (variables selected from Mehran RCN Risk Score) Serum creatinine changeOdds ratio [95% CI]* P value Relative ↑ >25%0.83 [ ]0.81 Absolute ↑ >0.5 mg/dL0.57 [ ]0.44 Absolute or relative ↑0.90 [ ]0.87 *<1 → Hypothermia is protective

Adverse Events at 30 Days Normothermia N=70 Hypothermia N=58 P value Mortality, all cause1.4%5.2%0.22 AMI1.4%3.4%0.45 Dialysis2.9%0%0.50 Ventricular fibrillation0% 1.0 Venous compl. → surgery0% 1.0 Bleeding → transf. ≥2U12.9%6.9%0.26 Rehospitalization18.6%22.4%0.59 Composite adverse events37.1%37.9%0.93

The observed rate of RCN in the control arm (18.6%) was lower than anticipated (35%) This fact, coupled with the enrollment of only 136 of a planned 400 pts (34%), resulted in a wide point estimate for the treatment effect of systemic hypothermia (odds 47% better to 200% worse) Limitations

COOL RCN Conclusions In pts at high risk for RCN undergoing invasive cardiology procedures hydrated with NS + NaHCO 3, systemic hypothermia using the Reprieve® system: o May be safely achieved and is well tolerated o Does not result in a significant reduction in RCN