1 / 22

Gregg W. Stone, MD Columbia University Medical Center The Cardiovascular Research Foundation

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.

beulah
Download Presentation

Gregg W. Stone, MD Columbia University Medical Center The Cardiovascular Research Foundation

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. COOL RCNA 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. 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

  3. Prevention of Experimental Contrast-Induced Nephropathy with Hypothermia, Fenoldopam, N-Acetylcysteine, and Bicarbonate Rabbit model N=40 6.0 5.0 4.0 Serum Creatinine (mg/dl) 3.0 Control 2.0 1.0 48 hr 24 hr 0.0 Baseline Normo- thermia39ºC, N=6 Bicarb N=6 Fenold-opam N=6 NAC N=6 37ºC N=5 35ºC N=5 32ºC N=6 Hypothermia Dae MW et al. JACC 2004;43:48A

  4. 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 49-320] mL contrast used during angiography (60%) or PCI (40%) SCr measured at 24, 48 and 72 - 96 hrs RCN (SCr ↑>25% from baseline) developed in 3 pts (10%), vs. 40% predicted Stone GW. TCT2006

  5. COOL RCNRandomized 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 R Hypothermia (33-34°C) Pre contrast and 3 hrs post + Hydration (NaCl & NaHCO3 ) Control Hydration (NaCl & NaHCO3 ) 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.) *Pts w/SCr ↑25% or ≥0.5 mg/dL at day 3 had an additional blood draw between day 7 – 10

  6. 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

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

  8. Cooling Procedures • Cooling must be achieved before 1st contrast • Target core temp 33ºC; no contrast before 34ºC • Shivering suppression protocol (45-60’ pre cool): • Buspirone 60 mg po • Meperidine 50 mg slow IV bolus; 15’ later 25-50 mg slow IV bolus; 15’ later start 25-35 mg/hr IV infusion • 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

  9. Study procedures • IV Hydration • 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) • 1 hr pre cath: Stop NS, start NaHCO3 (150 mEq in 1 L D5W): 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

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

  11. 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) Study Organization

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

  14. Normothermia N=70 Hypothermia N=58 P value Baseline Features 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. Normothermia N=70 Hypothermia N=58 P value Procedural Summary 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. Aggregate cooling data (N=50) Cooling Efficiency 36.0 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% 35.5 35.0 Patient Temperature (ºC) 34.5 34.0 33.5 33.0 20 30 40 10 0 Time (min)

  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. Development of RCN 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 Primary endpoint

  19. Randomization to HypothermiaMultivariate Analysis (16 variables) 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 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) Absolute or relative ↑ 0.90 [0.25 - 3.40] 0.87 *<1 → Hypothermia is protective

  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. Limitations 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)

  22. COOL RCNConclusions In pts at high risk for RCN undergoing invasive cardiology procedures hydrated with NS + NaHCO3, systemic hypothermia using the Reprieve® system: May be safely achieved and is well tolerated Does not result in a significant reduction in RCN

More Related