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  1. 1. 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
  2. 2. Background <ul><ul><li>Contrast induced renal insufficiency after invasive cardiology procedures has been strongly associated with early and late mortality </li></ul></ul><ul><ul><li>Preclinical and pilot studies have suggested that systemic hypothermia can ameliorate or prevent radiocontrast nephropathy (RCN) </li></ul></ul><ul><ul><li>We therefore performed a prospective, randomized trial to determine the utility of systemic hypothermia in pts receiving iodinated contrast </li></ul></ul>
  3. 3. 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=6 0.0 1.0 2.0 3.0 4.0 5.0 6.0 Dae MW et al. JACC 2004;43:48A Rabbit model N=40 Control Hypothermia
  4. 4. The COOL RCN Pilot <ul><ul><li>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 </li></ul></ul><ul><ul><li>Mean 150 ± 65 [range 49-320] mL contrast used during angiography (60%) or PCI (40%) </li></ul></ul><ul><ul><li>SCr measured at 24, 48 and 72 - 96 hrs </li></ul></ul><ul><ul><li>RCN (SCr ↑>25% from baseline) developed in 3 pts (10%), vs. 40% predicted </li></ul></ul>Stone GW. TCT2006
  5. 5. COOL RCN Randomized Trial Pts at risk for RCN (CrCl 20-50 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 ) SCr measured at 24, 48 and 72-96 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
  6. 6. Key Exclusion Criteria <ul><ul><li>Unstable renal function, acute renal failure or dialysis </li></ul></ul><ul><ul><li>Renal artery angiography, renal drug infusion, or known RAS </li></ul></ul><ul><ul><li>Receiving mannitol or IV diuretics </li></ul></ul><ul><ul><li>Decompensated HF, intubated, or hypotension (SBP <100) </li></ul></ul><ul><ul><li>STEMI within 72 hours </li></ul></ul><ul><ul><li>Severe allergy (contrast, heparin, meperidine, buspirone) or recent MAOI </li></ul></ul><ul><ul><li>Additional contrast within 10 days pre or post procedure </li></ul></ul><ul><ul><li>IVC filter, or height < 4’ 11” </li></ul></ul><ul><ul><li>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 </li></ul></ul>
  7. 7. Reprieve® System Heparin / hydrogel coated PET balloon 12 Fr venous catheter with a 25 cm heat exchange balloon
  8. 8. Cooling Procedures <ul><ul><li>Cooling must be achieved before 1 st contrast </li></ul></ul><ul><ul><li>Target core temp 33ºC; no contrast before 34ºC </li></ul></ul><ul><ul><li>Shivering suppression protocol (45-60’ pre cool): </li></ul></ul><ul><ul><ul><li>Buspirone 60 mg po </li></ul></ul></ul><ul><ul><ul><li>Meperidine 50 mg slow IV bolus; 15’ later 25-50 mg slow IV bolus; 15’ later start 25-35 mg/hr IV infusion </li></ul></ul></ul><ul><ul><ul><li>Surface forced air warming blanket (at high) </li></ul></ul></ul><ul><ul><li>Rewarming initiated 3 hours post procedure towards a target of 36ºC at a rate of 1°C/hr </li></ul></ul>
  9. 9. Study procedures <ul><ul><li>IV Hydration </li></ul></ul><ul><ul><ul><li>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) </li></ul></ul></ul><ul><ul><ul><li>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 </li></ul></ul></ul><ul><ul><li>N-acetylcysteine was allowed per PI discretion </li></ul></ul><ul><ul><li>Low osmolar contrast only; iodixanol preferred </li></ul></ul>
  10. 10. Power Analysis <ul><ul><li>Primary efficacy endpoint </li></ul></ul><ul><ul><ul><li>RCN, defined as a relative SCr ↑ >25% from baseline anytime within 96 hrs) </li></ul></ul></ul><ul><ul><ul><li>Assumed RCN rates: 35% control, 21% Rx (40% treatment effect) </li></ul></ul></ul><ul><ul><ul><li>Randomizing 358 pts provided 80% power (α=0.05) -> 400 pts randomized to allow 10% lost to FU, inadequate samples or study procedures </li></ul></ul></ul>
  11. 11. Study Organization <ul><ul><li>Principal Investigator: Gregg W. Stone </li></ul></ul><ul><ul><li>Data Management: Harvard Clinical Research Institute (HCRI) </li></ul></ul><ul><ul><li>Site and Data Monitoring: Radiant Medical </li></ul></ul><ul><ul><li>Clinical Events Committee: HCRI (Don Cutlip, chair) </li></ul></ul><ul><ul><li>Biochem Core Lab: ACM Medical Laboratory </li></ul></ul><ul><ul><li>DSMB: Julian Aroesty, Chair; J. Lopez; F. Ling; J. Orav </li></ul></ul><ul><ul><li>Sponsor: Radiant Medical (subsequently assumed by ZOLL Circulation) </li></ul></ul>
  12. 12. Top Enrolling Sites Site Principal Investigator Owensboro Hospital, Owensboro, KY Kishor Vora UPMC Presbyterian, Pittsburgh, PA John Schindler Methodist North Hospital, Memphis, TN Claro Diaz Wake Med, Raleigh, NC Tiff Mann Columbia University Medical Cntr, NY, NY George Dangas Mayo Clinic, Rochester, Minnesota Patricia Best
  13. 13. 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 70 pts normothermia 58 pts hypothermia 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)
  14. 14. Baseline Features Normothermia N=70 Hypothermia N=58 P value Age (yrs) 72 ± 10 74 ± 10 0.45 Female 31.4% 48.3% 0.07 Diabetes 61.4% 32.8% <0.01 Hypertension 88.6% 91.4% 0.77 Dyslipidemia 91.4% 84.4% 0.27 Current smoking 26.3% 17.5% 0.47 Prior MI 36.2% 36.2% 1.00 Prior CABG 33.3% 29.3% 0.70 Prior PCI 48.6% 43.1% 0.59 Serum creatinine (mg/dL) 1.97 ± 0.8 1.78 ± 0.6 0.16 Creatinine clearance (mL/min) 36.2 ± 8.1 36.8 ± 8.8 0.70
  15. 15. Procedural Summary Normothermia N=70 Hypothermia N=58 P value N-acetylcysteine administered 77.1% 62.1% 0.06 Pre hydration volume (mL) 799 ± 492 1,114 ± 1,556 0.12 Post hydration volume (mL) 854 ± 791 882 ± 760 0.84 Procedure type Diagnostic 58.6% 51.7% 0.45 Interventional 41.4% 48.3% 0.45 Total contrast volume (mL) 138 ± 78.3 150 ± 94.3 0.44 Contrast type* Non-ionic, iso-osmolar 75.4% 79.3% 0.60 Non-ionic, low osmolar 24.3% 24.1% 0.98 Temp. @ 1st contrast (ºC) 36.1 ± 0.7 33.6 ± 0.5 <0.001 * Some pts received 2 types of contrast during the index procedure
  16. 16. 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 ± 16.4 34ºC reached before contrast: 92.5% Meperidine dose (mg, mean) 245 ± 70 Premature cooling cessation: 0% Aggregate cooling data (N=50) 33.0 33.5 34.0 34.5 35.0 35.5 36.0 Time (min) Patient Temperature (ºC) 0 10 20 30 40
  17. 17. 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) 0.16 - 24 hr 1.91 ± 0.77 (n=68) 1.77 ± 0.66 (n=58) 0.30 - 48 hr 2.21 ± 0.94 (n=58) 1.94 ± 0.73 (n=53) 0.09 - 72 – 96 hr 2.11 ± 0.87 (n=68) 1.92 ± 0.72 (n=56) 0.18
  18. 18. Development of RCN Primary endpoint OR [95%CI] = 1.27 [0.53-3.00] P=0.59 OR [95%CI] = 0.83 [0.34-2.05] P=0.69 OR [95%CI] = 1.16 [0.51-2.67] P=0.71
  19. 19. 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 change Odds ratio [95% CI]* P value Relative ↑ >25% 0.83 [0.18 - 3.78] 0.81 Absolute ↑ >0.5 mg/dL 0.57 [0.14 - 2.38] 0.44 Absolute or relative ↑ 0.90 [0.25 - 3.40] 0.87 *<1 -> Hypothermia is protective
  20. 20. Adverse Events at 30 Days Normothermia N=70 Hypothermia N=58 P value Mortality, all cause 1.4% 5.2% 0.22 AMI 1.4% 3.4% 0.45 Dialysis 2.9% 0% 0.50 Ventricular fibrillation 0% 0% 1.0 Venous compl. -> surgery 0% 0% 1.0 Bleeding -> transf. ≥2U 12.9% 6.9% 0.26 Rehospitalization 18.6% 22.4% 0.59 Composite adverse events 37.1% 37.9% 0.93
  21. 21. <ul><ul><li>The observed rate of RCN in the control arm (18.6%) was lower than anticipated (35%) </li></ul></ul><ul><ul><li>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) </li></ul></ul>Limitations
  22. 22. COOL RCN Conclusions <ul><ul><li>In pts at high risk for RCN undergoing invasive cardiology procedures hydrated with NS + NaHCO 3 , systemic hypothermia using the Reprieve® system: </li></ul></ul><ul><ul><ul><li>May be safely achieved and is well tolerated </li></ul></ul></ul><ul><ul><ul><li>Does not result in a significant reduction in RCN </li></ul></ul></ul>

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