Clots, Contrast Media, and Catheterization

Clots, Contrast Media, and Catheterization
Evolving Science ● New Mechanisms ● Optimal Management Clots, Contrast Media, and Catheterization Maximizing Patient Safety and Outcomes in Coronary Angioplasty Focus on Comparative Effects of Contrast Media on Thrombosis Mitigation, Mortality, and Renal Function Steven V. Manoukian, MD, FACC Program Chairman Director, Cardiovascular Research | Sarah Cannon Research Institute | Centennial Heart Cardiovascular Consultants | Medical Director, Cardiovascular Services | Clinical Services Group | Hospital Corporation of America (HCA) | Nashville, TN

Welcome and Program Overview
CME-accredited symposium jointly sponsored by the University of Massachusetts Medical Center, office of CME and CMEducation Resources, LLC Mission statement: Improve patient care through evidence-based education, expert analysis, and case study-based management Processes: Strives for fair balance, clinical relevance, on-label indications for agents discussed, and emerging evidence and information from recent studies COI: Full faculty disclosures provided in syllabus and at the beginning of the program

Welcome and Program Overview
Commercial Support: This program is sponsored by an independent educational grant from Guerbet, LLC

Program Educational Objectives
As a result of this session, participants will be able to: Discuss the role that cardiovascular contrast media (CM) can play in thrombosis mitigation and renal preservation in the setting of PCI Detail the physical, chemical, and biological properties—ionicity, molecular structure, and viscosity—of contrast agents used in PCI and their potential impact on renal function, thrombosis, and patient safety Apply landmark trials, registry data, and observational studies to optimize selection of CM in patients undergoing PCI Identify high-risk patients that may be appropriate candidates for specific CM shown to decrease risk of thrombotic events and/or renal dysfunction Explain how ionic properties, viscosity, and other chemical features may affect renal function and coagulation in the setting of PCI

Program Faculty Steven V. Manoukian, MD, FACC Roxana Mehran, MD
Program Chairman Director, Cardiovascular Research Sarah Cannon Research Institute Centennial Heart Cardiovascular Consultants Medical Director Cardiovascular Services Clinical Services Group Hospital Corporation of America (HCA) Nashville, TN Frederick Feit, MD Associate Professor Department of Medicine Division of Cardiology New York University School of Medicine Member, NYU Cardiac Catheterization Associates New York, NY USA Roxana Mehran, MD Director of Outcomes Research, Data Coordination and Analysis Center for Interventional Vascular Therapy New York-Presbyterian Hospital Columbia University Medical Center Associate Professor of Medicine Division of Cardiology Columbia University College of Physicians and Surgeons Director of the Clinical Research, Data Coordination and Analysis Center at the Cardiovascular Research Foundation New York City, NY USA

Faculty COI Financial Disclosures
Steven V. Manoukian, MD, FACC Consultant, Educational Grant, Research Support, and/or Employment: BMS, Guerbet LLC, sanofi-aventis, The Medicines Company Frederick Feit, MD Consultant: CV Therapeutics, The Medicines Company Shareholder: Eli Lilly, Johnson and Johnson, The Medicines Company Roxana Mehran, MD Clinical Research Support: sanofi-aventis, Bracco Educational Support: The Medicines Company, Boston Scientific, Abbott, Medtronic, and Cordis Consultant/Honoraria: TMC, BSC, Abbott, Medtronic, sanofi-aventis, Lilly/Diachi Sankyo, Astra Zeneca, Cordis, Therox, Bracco, Guerbert, Regado

Contrast Induced Acute Kidney Injury
Roxana Mehran, MD, FACC, FAHA, FSCAI, FESC Associate Professor of Medicine Columbia University Medical Center Joint Chief Scientific Officer Cardiovascular Research Foundation

How to Assess Renal Function?
Abbreviated Modification of Diet in Renal Disease equations (MDRD) equation: eGFR, ml/min/1.73 m2= 186 x (Serum Creatinine [mg/dL]) x (Age-0.203) x (0.742 if female) x (1.210 if African American) Cockcroft-Gault equation: (140- age) x Body Weight [kg]* Creatinine Clearance, ml/min = * Multiple by 0.8 in female Serum Creatinine mg/dL] x 72

Major Causes of Acute Kidney Injury In Cardiac Patients
Contrast Induced Nephropathy (CIN) AKI after Cardiopulmonary Bypass Procedures The major causes of renal failure in hospitalized patients include development of radiocontrast nephropathy (RCN) and bypass surgery.

Contrast-Induced AKI Definition
New onset or exacerbation of renal dysfunction after contrast administration in the absence of other causes: increase by > 25% or absolute  of > 0.5 mg/dL from baseline serum creatinine There is a variety of definitions of RCN, the most common being an increase of serum creatinine greater than 0.5 mg/dl or increase by >25% of baseline creatinine within 24–48 hours following exposure to contrast without other identifiable causes of ARF. The time course of contrast-induced renal failure is predictable. It occurs within 24–48 hours after exposure, with a typical peak creatinine after 3–5 days and a return to baseline or near baseline in 1 to 2 weeks. Occurs 24 to 48 hrs post–contrast exposure, with creatinine peaking 5 to 7 days later and normalizing within 7 to 10 days in most cases

Composite of all 3 Definitions
Impact of the Definition Utilized on the Rate of Contrast-Induced Nephropathy in PCI 275 consecutive patients undergoing PCI given the contrast agent ioxilan Definitions Rise in SCr ≥0.5 mg/dl (n = 9) Decrease in eGFR ≥25% (n = 21) Rise in SCr ≥25% (n = 28) Composite of all 3 Definitions (n = 29) CIN 3.3% 7.6%* 10.2%# 10.5%† *P=0.37 vs. rise in SCr ≥0.5 mg/dl #P=0.02 vs. rise in SCr ≥0.5 mg/dl †P=0.001 vs. rise in SCr ≥0.5 mg/dl There were no deaths or cases requiring dialysis. Major and minor bleeding rates were 1.5% and 1.8%. Conclusion: The wide variation in CIN and its lack of association with adverse outcomes underscore the need for a standardized, clinically relevant definition. Jabara R, et al. Am J Cardiol. 2009;Epub ahead of print.

Risk Factors for the Development of Contrast-Induced AKI
Fixed (non-modifiable) risk factors Modifiable risk factors Pre-existing renal failure Volume and type of contrast medium Diabetes mellitus Multiple contrast injections within 72 hours Advanced congestive heart failure Hemodynamic instability Reduced left ventricular ejection fraction Dehydration Acute myocardial infarction Anemia Cardiogenic shock Intra-aortic balloon pump Renal transplant Low serum albumin level (<35 g/L) Angiotensin converting enzyme inhibitors Diuretics Nephrotoxic drugs (nonsteroidal anti-inflammatory agents, antibiotics, cyclosporine, etc.)

Scheme to Define CIN Risk Score
Risk Factors Integer Score Hypotension 5 IABP 5 CHF 5 Risk Score Risk of CIN Risk of Dialysis ≤ 5 7.5% 0.04% 6 to 10 14.0% 0.12% 11 to 16 26.1% 1.09% ≥ 16 57.3% 12.6% Age >75 years 4 Anemia 3 Diabetes 3 Calculate Contrast media volume 1 for each 100 cc3 Serum creatinine > 1.5mg/dl 4 Recently, CIN risk score was developed and validated based on the analysis of large prospectively created database. You may see that risk of CIN may be as high as 57% and risk of dialysis maybe as high as 12% in pts with multiple risk factors. OR 2 for 40 – 60 4 for 20 – 40 6 for < 20 eGFR <60ml/min/1.73 m2 eGFR < 60ml/min/1.73 m2 = 186 x (SCr) x (Age)-0.203 X (0.742 if female) x (1.210 if African American) Mehran et al. JACC 2004;44:

Prognostic Impact of CKD and Contrast Induced AKI
What is the Prognostic Impact of CKD and Contrast Induced Nephropathy

Contrast-induced AKI: In-hospital Mortality
% In-hospital Death P<0.001 In-hospital mortality is especially high in pts requiring dialysis. McCullough et al. Am J Med 1997;

Contrast-Induced Nephropathy: Resource Utilization
Endpoint (%) Patients P-value With CIN Without CIN Hospital length of stay (days) <0.001 ICU length of stay (days) <0.0001 Need for hemodialysis (%) 12 Iakovou I et al, J Am Coll Cardiol. 2002;39:2A

Preventive Trials How to prevent CIN?

Prevention of Contrast Induced Nephropathy
Strategies Prevention of Contrast Induced Nephropathy

Effects of Saline, Mannitol, and Furosemide
A total of 78 patients with mean baseline SCR 2.1 mg/dl who underwent coronary angiography/PCI N=78 Randomization 0.45% saline alone 12 hours before and 12 hours after angiography N=28 Saline plus mannitol * N=25 Furosemide* N=25 Primary endpoint: increase in the baseline SCr of at least 0.5 mg/dl within 48 hours after the injection of radiocontrast agents * Given before angiography Solomon R et al, N Engl J Med 1994;331(21):

Effects of Saline, Mannitol, and Furosemide to Prevent Acute Decreases in Renal Function Induced by Radiocontrast Agents P=0.02 for Saline vs. Furosemide group P=NS for Mannitol vs. Furosemide group Solomon R et al, N Engl J Med 1994;331:

Optimal Hydration Regimen
1937 Patients Screened 317 Ineligible or No Consent 1620 Randomized 809 Received 0.9% Saline 811 Received 0.45% Sodium Chloride 124 Excluded From Primary End Point Analysis Repeat Catheterization (n=78) Incomplete Data (n=46) 113 Excluded From Primary End Point Analysis Repeat Catheterization (n=59) Incomplete Data (n=53) Bypass Grafting (n=1) 685 for Primary End Point Analysis 698 for Primary End Point Analysis Mueller et al Arch Intern Med 2002

Optimal Hydration 0.9% NS vs 0.45% NS
3 0.9% Saline 0.45% Sodium Chloride P=.04 2 P=.93 Incidence, % P=.35 1 CN Mortality Vascular Mueller et al Arch Intern Med 2002

Periprocedural Hydration Protocol
Consider 2 main factors: Baseline CRI (Yes/No) LVEF (Preserved/Impaired) In patients w/o baseline CRI (eGFR>60 ml/min) and w/o CHF with preserved LVEF: IV 0.9% NS at 1cc/kg/hr 12 hours prior to procedure. The patients are encouraged to drink fluids for 24 hours after the procedure. In patients w/o baseline CRI and mild to moderate LV dysfunction: (LVEF 30% to 40%): IV 0.45%NS at 50 cc/hour 12 hrs prior to procedure. The patients are encouraged to drink fluids for 24 hours after the procedure. In patients with baseline CRI and normal LVEF: IV 0.9% NS at 1 cc/kg/hour for 12 hours pre- and post- procedure In patients with baseline CRI and reduced LVEF: IV 0.45% NS at cc/cc replacement (urine output should be match to maintain euvolemic state) for 12 hours pre- and post-procedure

Prevention of CIN with Sodium Bicarbonate
Patients With Baseline Serum Creatinine >1.8 mg/dl who Underwent Contrast Exposure (Iopamidol in All) N=137 Sodium Chloride Hydration (154 mEq/L of Sodium Chloride) N=68 Sodium Bicarbonate Hydration (154 mEq/L of Sodium Bicarbonate) N=69 Primary endpoint: increase in serum creatinine ≥25% within 2 days post-exposure Merten GJ et al. JAMA, 2004;291:

Prevention of CIN with Sodium Bicarbonate: Results
Endpoints Sodium Chloride N=59 Sodium Bicarbonate N=60 P value Incidence of CIN (%) 13.6% 1.7% 0.02 Incidence of CIN (↑SCr 0.5 mg/dL) 11.9% 0.03 Merten GJ et al. JAMA, 2004;291:

REMEDIAL Trial Pts with eGFR<40 N=393 Excluded N=42
Randomized N=351 Saline + NAC N=118 Bicarbonate + NAC N=117 Saline+AA+NAC N=116 7 excluded 9 excluded 9 excluded 111 included into analysis 108 included into analysis 107 included into analysis NAC = N-acetylcysteine, AA = ascorbic acid Briguorio C. et al, Circulation 2007

REMEDIAL Trial: Results
Saline + NAC N=111 Bicarbonate + NAC N=108 Saline + Ascorbic Acid + NAC N=107 P Value Serum creatinine increase by ≥25% 11 (9.9%) 2 (1.9%)* 10 (10.3%) 0.010 Serum creatinine increase by ≥0.5 mg/dL 12 (10.8%) 1 (0.9%)† 12 (11.2%) 0.026 eGFR decrease by ≥25% 10 (9.2%) 0.018 *P=0.019, †P<0.01 vs. saline + NAC group Briguorio C. et al, Circulation 2007

MEENA Design Hydration Protocol
353 patients enrolled between January 2006 and January 2007 DESIGN: Prospective, randomized, parallel-group, single-center clinical evaluation of two hydration strategies for patients undergoing coronary angiography OBJECTIVE: To compare the incidence of CIN between periprocedural hydration with sodium bicarbonate vs. sodium chloride (0.9%, normal saline) PRIMARY ENDPOINT: Decrease in estimated GFR by ≥ 25% within 4 days of coronary angiography 178 patients assigned to sodium bicarbonate 236 patients assigned to sodium chloride 22 excluded 28 excluded 156 evaluable patient 147 evaluable patient Hydration Protocol 3 mL/kg for 1 hr before the procedure 1.5 mL/kg during and for 4hrs post-procedure Brar, S et. al., i2/ACC 2007

MEENA p = 0.82 p = 0.97

Sodium Bicarbonate for the Prevention of CIN
Meta-Analysis Sodium Bicarbonate for the Prevention of CIN Brar et al. cJASN 2009

Meta-Analysis Study Flow 469 Citations Identified Dates: 1996 to 2008
168 from EMBASE 261 from MEDLINE 40 from Cochrane Library 8 Citations identified from conference proceedings Dates: 1996 to 2008 Randomized Trials Number of Patents: 2,290 424 Citations excluded based on screening of titles or abstracts 53 identified for further review 38 Citations excluded after full review 36 Design was not correct 1 Unusual protocol 1 Difference between groups in volume administered & NAC dose 14 articles included in meta-analysis (N=2,290) Brar et al. cJASN 2009

Change in Renal Function
Published Randomized Trials Harm Brar 0.2 0.1 0.0 -0.1 \-0.2 Maioli Adolph Masuda Ozcan ∆ Creatinine Sodium Bicarbonate (mg/dL) Improvement with Bicarb Merten No effect Briguori Deterioration with Chloride Benefit ∆ Creatinine Sodium Chloride (mg/dL) Brar et al. cJASN 2009

Meta-Regression Understanding Sources of Heterogeneity Trial Size
Smaller trials show greater benefit Trial Size “Small Study Effect” Merten Criteria N=290 Large Trials Small Trials N=2290 N=2290 12.6% vs. 10.7% P=0.32 13.5% vs. 6.7% P=0.03 RR 95% CI 0.85 0.50 Summary: Positive effect only observed in small trials Brar et al. cJASN 2009

Forest Plot High Quality Studies
Brigouri, (0.04, 0.82) Chen, (0.02, 1.02) Kim, (0.42, 2.28) Ozcan, (0.11, 0.99) Shaikh, (0.39, 1.44) Brar, (0.56, 1.46) Maioli, (0.52, 1.44) Adolph, (0.27, 9.08) Overall (0.49, 1.03) (I-squared =33.3%, p=0.163) Quality Criteria Similar volume Patients If NAC used, dose & route similar between groups No early termination Note: weights are from random effects analysis Favors Bicarbonate Favors Saline Summary: No overall benefit, but trend driven by studies with extreme treatment effects Brar et al. cJASN 2009

The CONTRAST Trial Algorithm 300 patients Primary endpoint
at increased risk for contrast nephropathy undergoing PCI Hydrate Randomize Fenoldopam Matching placebo 1º prior to and 12 º after cath This is the Bulleted List slide. To create this particular slide, click the NEW SLIDE button on your toolbar and choose the BULLETED LIST format. (Top row, second from left) The Sub-Heading and footnote will not appear when you insert a new slide. If you need either one, copy and paste it from the sample slide. If you choose not to use a Sub-Heading, let us know when you hand in your presentation for clean-up and we’ll adjust where the bullets begin on your master page. Also, be sure to insert the presentation title onto the BULLETED LIST MASTER as follows: Choose View / Master / Slide Master from your menu. Select the text at the bottom of the slide and type in a short version of your presentation title. Click the SLIDE VIEW button in the lower left hand part of your screen to return to the slide show. (Small white rectangle) Primary endpoint Worsening renal insufficiency within hours

CONTRAST STUDY: CIN SCr at both baseline and during the 96° post drug administration period were available and analyzed at the central lab in 283 of 315 randomized patients (90%). P=0.61 P=0.27 P=0.84 This is the Sample Pie Charts slide. To create this particular slide, copy and paste the sample in the Slide Sorter view as follows: Select View / Slide Sorter Highlight the Sample Pie Charts page and select Edit / Copy Place the courser where you want the new slide to be and select Edit / Paste Double-click on the pasted-in slide to return to Slide view To access the column chart, right/click on the chart and select chart object / open from the menu. This will open the chart in Microsoft Graph. You can make any changes to the chart and spreadsheet here. When you are finished making your changes, select File / Exit and return to… from the menu bar. THIS METHOD IS PREFERRED TO DOUBLE-CLICKING THE GRAPH AND OPENING IT IN POWERPOINT. Double-clicking the graph can sometimes reformat the sizes, colors, animations and fonts in your graph. OR [95% CI] = 1.11 [0.79, 1.57] Stone GW, et al. JAMA-2003

CONTRAST: 30-Day Adverse Events
30-day incidence of death, MI or dialysis: With CIN 12.2% Without CIN 4.1% p=0.02 P=NS for all This is the Sample Column Chart slide. To create this particular slide, copy and paste the sample in the Slide Sorter view as follows: Select View / Slide Sorter Highlight the Sample Column Chart page and select Edit / Copy Place the courser where you want the new slide to be and select Edit / Paste Double-click on the pasted-in slide to return to Slide view To access the column chart, right/click on the chart and select chart object / open from the menu. This will open the chart in Microsoft Graph. You can make any changes to the chart and spreadsheet here. When you are finished making your changes, select File / Exit and return to… from the menu bar. THIS METHOD IS PREFERRED TO DOUBLE-CLICKING THE GRAPH AND OPENING IT IN POWERPOINT. Double-clicking the graph can sometimes reformat the sizes, colors, animations and fonts in your graph. Stone GW, et al. JAMA-2003

Targeted Renal Delivery

IV Placebo (no drugs/no device)
FEN-001 Trial Design N=33 IV Placebo (no drugs/no device) 2:1 Randomization IV FEN 0.1 -> 0.2 mcg/kg/min IR FEN 0.2 mcg/kg/min Index angiography +/- interventional procedure (+ contrast) IR = intra-renal IV = intravenous FEN = fenoldopam Washout x 1 hr Patients undergoing elective angiography Moderate CKD defined as CrCl ≤ 70 ml/min (≤ 80 ml/min if diabetic) Anticipated CM volume ≥ 80 cc Teirstein et al, Am J Cardiol 2006.

Glomerular Filtration Rate
GFR Response to IV-FEN and TRT-FEN vs. Control 4.9% 23.6% 25.1% -9.7% 9.6% -14.0% -20% -10% 0% 10% 20% 30% 1 2 3 Study Period6 Percent Change in GFR from Baseline [%] IV FEN (n=22) TRT-FEN (n=22) Control Group (n=11) Pre-procedure (IV-FEN vs. Control) Procedure (TRT-FEN vs. Control) Post-Procedure (Active vs. Control) p=0.0007 p<0.05 p=NS Sustained  GFR for 2+ hrs post d/c 5-fold  GFR TRT vs IV All data based on a Fenoldopam dose of 0.2 mcg/kg/min Teirstein et al, Am J Cardiol 2006.

Be-RITe! Registry: Higher Dose More Effective (TRT-Fenoldopam patients only)
CIN Incidence Stratified by TRT Dose 30.3% 3.7% 28.3% 27.7% 0% 10% 20% 30% 40% 50% 0.2 mcg/kg/min 0.4 mcg/kg/min CIN Incidence or Predicted Incidence [%] CIN Incidence Predicted n=33 n=242 p=0.79 p<0.0001 Predicted values per Mehran et al, JACC 2004.

Renal Protective Effects and the Prevention of Contrast-InducedcNephropathy by Atrial Natriuretic Peptide 261 pts Randomized 14 pts excluded 126 pts ANP plus hydration 128 pts hydration Both ANP(0.042 µg/kg/min) and Hydration (1.3 ml/kg/h of Ringer) infusions were initiated 4 to 6 h before the angiographic and continued for 48 h after Morikawa et al. J Am Coll Cardiol 2009;53:1040–6

Incidence on CIN in the ANP Group Compared with the Control Group
Incidence of CIN (%) Creatinine >0.5 mg/dl Creatinine >25% of baseline Creatinine >0.5 mg/dl or >25% of baseline Morikawa et al. J Am Coll Cardiol 2009;53:1040–6

N-Acetylcysteine (NAC)

CIN: Effect of n-Acetylcysteine
Prospective, randomized 83 high risk patients CrCl < 50 ml/min Diabetes 33% IV CONTRAST for CT (75 ml of Low Osmolar CM) n-AC 600 bid x 2 days pre- CIN definition: creatinine increase of 0.5 mg/dl Hydration with 1 ml/kg/h x 24 h p= 0.01 A prospective randomized trial utilizing the oxygen radical scavenger, acetylcysteine, explored the role of oxidative injury in contrast induced nephropathy. Patients undergoing a contrast CT scan were randomized to usual care or pretreatment with 600 mg bid of acetylcysteine starting 24 hours before the contrast exposure and continuing for 24 hours after the exposure. A marked decrease in the incidence of contrast induced nephropathy (CIN) was noted. Although the study is very exciting, a number of limitations are worth noting. First, the low dose of contrast and the route of administration (intravenous) make it difficult to extrapolate the positive results to patients receiving 2-3 times as much contrast intraarterially. Second, the marked reduction in the incidence of CIN was associated with an actual decrease in serum creatinine in many patient, a finding difficult to explain based on the presumed mechanism of action of acetylcysteine. Finally, a number of other experiments involving animal models of renal injury have failed to produce such dramatic results using other free oxygen radical scavengers. This may simply mean that animal models don’t mimic human pathophysiology accurately. In any case, until additional studies in other clinical situations confirm the dramatic results found here, it should not be assumed that acetylcysteine is a magic bullet. Tepel NEJM 2000

Relative Risk for Developing CIN after NAC
Review: Acetylcysteine and CIN Comparison: 01 NAC on CIN Outcome: 01 CIN Study or substudy NAC n/N Control n/N RR (Random) 95% Cl Risk Ratio (Random) 95% Cl Allaqaband et al 8/45 6/ (0.45, 3.12) Briguori et al 6/92 10/ (0.23, 1.57) Diaz-Sandoval et al 2/25 13/ (0.04, 0.72) Durham et al 10/38 9/ (0.55, 2.63) Goldenberg et al 4/41 3/ (0.30, 5.31) Gomes et al 8/78 8/ (0.40, 2.53) Kay et al 4/102 12/ (0.11, 0.96) Nguyen-Ho et al 9/95 19/ (0.20, 0.89) Oldemeyer 4/49 3/ (0.30, 5.41) Pate et al 57/238 50/ (0.82, 1.60) RAPIDO 2/41 8/ (0.05, 1.05) Shyu 2/60 15/ (0.03, 0.57) Fung et al 8/46 6/ (0.49, 3.46) Total: (95% Cl) (0.46, 1.02) Total events: 124 (NAC), 162 (Control) Test for heterogenety: Ch=27.54 (P0.005), 12=56.4% Test for overall effect: Z=1.88 (P=0.05) 0.1 0.2 0.5 1 2 5 10 Favors treatment Favors control Zagler et al. Am Heart J 2006;151:

NEPHRIC Study: Protocol
Patients with diabetes and serum creatinine mg/dl who underwent coronary or aortofemoral angiography Iso-osmolar, non-ionic Iodixanol [Visipaque] N=64 Mean Contrast Volume = 163 ml PTCA – 17% Low-osmolar, non-ionic Iohexol [Omnipaque] N=65 Mean Contrast Volume = 162 ml PTCA – 25% Randomized, double blind, prospective, multicenter Primary endpoint: peak increase in serum creatinine 3 days after angiography Aspelin P et al, NEJM, 2003; 348:

Primary Endpoint – Peak Increase in Scr from Baseline to Day 3
(µmol/l) p=0.002 Iodixanol (Visipaque) n=62 Iohexol (Omnipaque) n=64 Mean 11.2 ±19.7 41.5 ± 68.6 Minimum - 19.0 - 21.0 Max 74.0 331.0

Sharma et al. Catheter Cardiovasc Interv 2005;65:386-393.
Effect of Nonionic Radiocontrast Agents on Occurrence of CIN in Patients with Mild-moderate CRI: Pooled Analysis of the Randomized Trials Significantly highest incidence of CIN with iohexol then two other agents Incidence of CIN P value Iopamidol (Isovue) Low osmolar Iohexol (Omnipaque) Iodixanol (Visipaque) Iso-osmolar 13.5% 25.0% 11.0% 0.024 0.001 Iopamidol – low osmolar Difference between iopamidol and iodixanol was not statistically significant (P=0.227) Sharma et al. Catheter Cardiovasc Interv 2005;65:

The ICON Trial: Protocol
Patients With Chronic Renal Insufficiency to Undergo Angiography/PCI n=130 Ioxaglate (Hexabrix) Low-osmolar, ionic Iodixanol (Visipaque) Isoosmolar, non-ionic Ioxaglate = Ionic dimeric contrast medium Iodixanol = non-ionic, dimeric, isotonic contrast medium Primary Endpoint: Peak increase in the serum creatinine concentration between day 0 (when contrast medium was administered) and day 3 Mehran et al. TCT 2006

ICON Trial: Increase of Serum Creatinine from Baseline (Secondary Study End Point)
Ioxaglate N=74 Iodixanol N=71 p ≥ 0.5 mg/dL 18.2 % 16.2 % 0.82 ≥ 1 mg/dL 4.5 % 1.5 % 0.36 ≥ 25% 24.2 % 0.29 ≥ 25% or ≥ 0.5 mg/dL JACC Intv 2009

CARE Design 482 patients enrolled between July 2005 and June 2006 in 25 clinical site in North America DESIGN: Prospective, randomized, double-blind, parallel-group, multi-center clinical evaluation ipamidol-370 and iodixanol-320 OBJECTIVE: To compare the incidence of CIN between iopamidol-370 and iodixanol-320 PRIMARY ENDPOINT: Increase in SCr ≥ 0.5 mg/dL from baseline to 45 to 120 hours after administration 14 patients withdrew consent 468 assigned to a treatment arm 230 patients assigned to Iopamidol-370 236 patients assigned to Iodixanol-320 26 excluded 26 excluded 204 evaluable patient 210 evaluable patient Solomon, RJ et. al., Circulation 115, (2007)

CARE p = 0.39 p = 0.44 p = 0.15

CARE Diabetic Subgroup p = 0.11 p = 0.37 p = 0.20

Conclusions (1) CRI is one of the most important independent predictors of poor outcome post PCI CIN remains a frequent source of acute renal failure and is associated with increased morbidity and mortality, and higher resource utilization Several factors predispose patients to CIN Preventive measures pre procedure, as well as careful post procedure management should be routine in all patients This is the Bulleted List slide. To create this particular slide, click the NEW SLIDE button on your toolbar and choose the BULLETED LIST format. (Top row, second from left) The Sub-Heading and footnote will not appear when you insert a new slide. If you need either one, copy and paste it from the sample slide. If you choose not to use a Sub-Heading, let us know when you hand in your presentation for clean-up and we’ll adjust where the bullets begin on your master page. Also, be sure to insert the presentation title onto the BULLETED LIST MASTER as follows: Choose View / Master / Slide Master from your menu. Select the text at the bottom of the slide and type in a short version of your presentation title. Click the SLIDE VIEW button in the lower left hand part of your screen to return to the slide show. (Small white rectangle)

Conclusions (2) Hydration pre-PCI (12 hours recommended)
D/C nephrotoxic drugs (NSAIDS, antibiotics, etc) Role of n-acetylcysteine is disputable No Role for IV Fenoldopam Sodium bicarbonate may be useful, but need more definitive data Limit contrast agent volume Low-osmolar agents are better than high-osmolar Within non-ionic contrast, the data are contradictory Role of local drug delivery for prevention of CIN requires further investigation This is the Bulleted List slide. To create this particular slide, click the NEW SLIDE button on your toolbar and choose the BULLETED LIST format. (Top row, second from left) The Sub-Heading and footnote will not appear when you insert a new slide. If you need either one, copy and paste it from the sample slide. If you choose not to use a Sub-Heading, let us know when you hand in your presentation for clean-up and we’ll adjust where the bullets begin on your master page. Also, be sure to insert the presentation title onto the BULLETED LIST MASTER as follows: Choose View / Master / Slide Master from your menu. Select the text at the bottom of the slide and type in a short version of your presentation title. Click the SLIDE VIEW button in the lower left hand part of your screen to return to the slide show. (Small white rectangle)

Mechanism of Thrombosis Induction and Mitigation with Contrast Media
Comparative Effects, Cautionary Notes and Implications for PCI Frederick Feit, MD, FACC Associate Professor of Medicine New York University School of Medicine Director, Interventional Cardiology New York University School of Medicine New York, NY 58

Thrombosis Induction and Mitigation with Contrast Media: Outline
Thrombin generation, platelet activation and their interrelationship Contrast media: The basics Experimental data exploring the interaction of differing contrast media and thrombosis in animals and humans Potential relevance in clinical practice

Extrinsic System Intrinsic System Fibrinogen Prothrombin Thrombin
Injury Tissue thromboplastin XIIa, XIa IX IXa VIII, Ca Intrinsic System X Xa Ca ,V Fibrinogen Fibrin Prothrombin Thrombin Platelet Activation Mature Thrombus XIII XIIIa

Sites of Anti-thrombotic Drug Action
Tissue factor Collagen Aspirin Aspirin Plasma clotting cascade ADP Ticlopidine Clopidogrel Prasugrel Ticlopidine Clopidogrel Prasugrel Thromboxane A2 Prothrombin LMWH Fondaparinux Heparin AT Factor Xa Conformational activation of GPIIb/IIIa AT GPIIb/IIIa inhibitors GPIIb/IIIa inhibitors Bivalirudin Hirudin Argatroban Thrombin Platelet aggregation Bivalirudin Hirudin Argatroban Although there are a variety of approaches to enhancing anticoagulant effects none are completely satisfactory when used as a single agent. Major categories of anticoagulant therapy include agents that target any one of three main components of the thrombotic process; thrombin, platelets, or fibrin. Fibrinogen Fibrin Thrombolytics Thrombo- lytics Thrombus

Active catalytic site Fibrinogen Thrombin Anion binding exosite

Active catalytic site Thrombin Active Fibrin Anion binding exosite

Activation Platelet The Platelet EPI Thrombin ADP Thromboxane Collagen
GPIIb/IIIa ADP EPI Thrombin Thromboxane Fibrinogen COX Collagen

Coagulation – “The Real Story”
Complex interplay on the surface of platelets Thrombin Platelet activation Prothrombin Fibrinogen Fibrin GP2b3a expression & platelet aggregation ADP TXA2 Plasma Clotting cascade Collagen Tissue Factor THROMBUS Thrombin plays a critical and central role in thrombogenesis through: Converting fibrinogen to fibrin strands that hold the clot together, Regulating its own production via positive and negative feedback loops to further promotes thrombin generation, Stabilizing the fibrin clot through activation of factor XIII: Thrombin is the link between tissue injury and cellular response. Thrombin: Is the most effective agonist for platelet activation Elicits multiple responses in platelets, endothelial, and other cells Because of the central role that thrombin plays, and effective thrombin-specific inhibitor is important in thrombosis. Xa Ca Va

Contrast Media: Preconceived Notions
Ionic Contrast: What they used to use Nonionic Contrast: What we use now, because it has lower osmolality (the good stuff) Visipaque: The really good stuff, both theoretically and confirmed by the COURT trial Hexabrix: I heard of that; I think it’s pretty good, too

Contrast Media: More Evolved Notions
Ratio of iodine:osmotically active particles determines osmolality Ioxaglate (Hexabrix), an ionic dimer has lower osmolality than nonionic monomers Iodixanol (Visipaque) a nonionic dimer is isoosmolar to plasma

Basic Structures of Contrast Media
Voeltz MD, et al. J Invasive Cardiol Mar;19(3):1A-9A. Review

Contrast Media: Very Evolved Notions
Ionic contrast: conjugation of the benzene ring structure (anion) with a non-radioopaque cation resulting in a water soluble compound. Ionic monomers dissociate in vivo resulting in an iodine:particle ratio of 3:2; for ionic dimers, 6:2 Nonionic monomers do not dissociate so I:p ratio is 3:1; for nonionic dimers, 6:1

Comparative Characteristics of Contrast Media: Molecular Structures
Osmolality (mOsm/kg) HOCM (>1,500) LOCM (280 – 1,000) 6 cPs 8 cPs 5-10 cPs 11 cPs Viscosity at 370C Diatrizoate ioxaglate Ioxilan Iohexol Iopamidol Iopromide Ioversol Iodixanol Name Monomer Dimer # Benz.Rings Ionicity Ionic Nonionic 7171 14 cPs 16 cPs 10-22 cPs 26 cPs Viscosity at 20°C

Classification and Osmolality
Chemical Name Trade Name and Manufacturer Osmolality (mOsm/kg H20) High-Osmolar (HOCM) Ionic Monomers Diatrizoate Hypaque® (GEH) 2016 RenoCal-76® (B) 1870 MD-76®R (M) 1551 Iothalamate Conray ® (M) 1400 Low-Osmolar (LOCM) High-Viscosity (HVCM) Low-Viscosity (LVCM) Nonionic Dimer Iodoxinal VisipaqueTM 320 (GEH) 290 Nonionic Monomers Iopromide Ultravist® 370 (BR) 774 Iopamidol Isovue® 370 (B) 796 Iohexol OmnipaqueTM 350 (GEH) 844 Ioversol Optiray® 350 (M) 792 Ioxilan Oxilan® 350 (G) 695 Ionic Dimer Ioxaglate Hexabrix® (G-M) 600 Voeltz MD, et al. J Invasive Cardiol Mar;19(3):1A-9A. Review

Methods: Patients Undergoing angiography
Blood drawn from 5F pigtail in aorta utilizing 50cc syringe 5ml blood injected in multiple 10cc syringes 2ml contrast drawn into syringe (no mixing) Inject onto filter paper at 10, 30, 60, 90 min. to assess thrombus Engelhart et al. Invest Radiol 1988;23:922-7

Incubation of Blood with Contrast
Engelhart et al. Invest Radiol 1988;23:922-7

Differential Effects of Contrast Media on Platelet Aggregation
Iopamidol: directly induced platelet aggregation and potentiated that induced by ADP Iodixanol: potentiated aggregation Ioxaglate: inhibited aggregation ADP antagonists, but not ASA inhibited Iopamidol induced platelet aggregation indicating that this phenomenon is not mediated by TXA2 and is at least in part by ADP % Aggregation * Platelet aggregation and P-selectin expression in hirudinized whole blood containing iopamidol, iodixanol, or ioxaglate in the absence (open histograms) or presence (thatched histograms) of AR-C66096 (10 umol/l). Heptinstall et al. British Journal of Haemotology 1998;103:

Platelet studies performed using ELISA tests
In Vitro Comparison of the Effects of Contrast Media on Coagulation and Platelet Activation Methods: Pooled human plasma mixed with saline control or contrast Iohexol (Omnipaque), or Iodixanol (Visipaque), or Ioxaglate (Hexabrix) to a final concentration of 60mg I/ml for aPTT and TT studies Platelet studies performed using ELISA tests Corot et al. Blood Coagulation and Fibrinolysis 1996;7:602-8

In Vitro Comparison of the Effects of Contrast Media on Coagulation and Platelet Activation
NaCL 9 g/l Iodixanol Iohexol Ioxaglate TT (s) 19 ± 2 84 ± 10 110 ± 18 >500 APTT (s) 44 ± 2 74 ± 1 81 ± 2 303 ± 13 P <0.01 P < 0.01 Corot et al. Blood Coagulation and Fibrinolysis 1996;7:602-8

30 min intubation PF4 IU/ml 5-HT Ng/ml PDGF-AB Pg/ml TXB2 FpA Control 786 185 6951 33 >1500 Ioxaglate 43 18 <186 47 9 Iodixanol 209 506 2173 48 35 Iohexol 1446 801 18606 25 5 Thrombin 4061 1378 26421 10614 Corot et al. Blood Coagulation and Fibrinolysis 1996;7:602-8

PF4 IU/ml PF4 determinations (platelet factor 4) which represent platelet degranulation induced by contrast media mixed 1:1 with blood for 1 min (mean ± SD, n=4). Corot et al. Blood Coagulation and Fibrinolysis 1996;7:602-8

Corot et al: Conclusions
Ioxaglate demonstrated the most powerful anticoagulant properties, followed by iohexol and Iodixanol Iohexol resulted in major platelet activation; iodixanol in less platelet activation, only with 30 minutes of incubation; ioxaglate did not activate platelets

Differential Effects on Thrombus Formation
Methods: Contrast agent added to blood collected from normal volunteers in ratio of either 20% or 50% Mixed for 1 min. Thrombi formed in vitro by adding 1ml recalcified blood/contrast to the chandler loop (45 cm long, 3 mm inner circumference) PVC tubing Rotated at 37 rpm for 90 mins Thrombus analyzed by immunofluorescence and weighed Thrombolysis over 24 hours, both spontaneous and by tPA assessed, by weight of thrombus and measuring free FITC in supernatant (a product of lysis of FITC-labeled fibrinogen Jones C et al. Thrombosis Research 2003;112:65-71

Differential Effects on Thrombus Formation
P<0.0005 Weight (mg) Saline 20% Ioxaglate - 50% 20% Iobexol % 20% - - Iodixanol % 20% Jones C et al. Thrombosis Research 2003;112:65-71

Differential Effects on Platelet Degranulation
Percentage of platelets positive for P-selectin expression in the presence of CM P<0.02 P<0.03 Percent Positive Saline 50% Ioxaglate - 50% 20% Iobexol % 20% - - Iodixanol % 20% Jones C et al. Thrombosis Research 2003;112:65-71

Fibrinolysis: Spontaneous or with tPA
Weight (mg) Floresence (arbitrary U) Saline 20% 20% Iohexol % 20% - - Iodixanol % 20% tPA Saline 20% 20% Iohexol % 20% - - Iodixanol % 20% tPA Jones C et al. Thrombosis Research 2003;112:65-71

Thrombus Histopathology
Head and tail regions of thrombi for Saline control (top), Iohexol (mid), Iodixanol (bot). Thrombi formed in the presence of either contrast had larger, more platelet-rich heads and much larger tails, composed of an open irregular meshwork of fibrinogen/fibrin enclosing large dense RBC areas and scattered WBC. Iohexol thrombi had larger “heads” than iodixanol thrombi, which had a much more irregular structure with areas of very strong fibrinogen antibody binding interspersed with WBC aggregates. Jones C et al. Thrombosis Research 2003;112:65-71

Differential Effects on Thrombus Formation Conclusions
No thrombi formed from blood incubated with Ioxaglate Thrombi formed with Iohexol or Iodixanol weighed >10x more than those formed with saline controls, had different structure and were more resistant to thrombolysis Iohexol, but neither Iodixanol nor Ioxaglate increased platelet degranulation

Contrast Media: Mechanistic Assessment of Thrombin Generation
Methods: Pooled plasma from healthy donors to prepare PRP and PPP Thrombograms obtained by mixing PPP or PRP with activator (TF for extrinsic system and kaolin for intrinsic system) plus ioxaglate, iodixanol, abciximab (as shown) Thrombograms assessed by lag time (clotting time), peak height (maximal velocity of net thrombin production, area under the curve (endogenous thrombin potential) Al Dieri R et al. J of Thombosis and Hemostasis, 2003, 1:

Thrombogram: Iodixanol vs. Ioxaglate
Influence of the contrast media addition on the thrombogram in PPP and PRP. (a) In defibrinated PPP initiated with rTF. (b) In defibrinated PPP initiated with contact activator. (c) In PRP initiated only with CA 2+ ●control; ○iodixanol (5% v/v); ioxaglate (5%, v/v). Data represent median of four independent experiments Al Dieri R et al. J of Thombosis and Hemostasis, 2003, 1:

Abciximab + Iodixanol or Ioxaglate
Effect of abciximab on the thrombogram in PRP in the absence and presence of CM (5% v/v ). ●control; ○abciximab alone (40 ug mL-1);  abciximab + iodixanol;  abciximab + ioxaglate. Data represent median of three independent experiments Al Dieri R et al. J of Thombosis and Hemostasis, 2003, 1:

Al Dieri et al: Conclusions
Ioxaglate is a potent inhibitor of thrombus formation in prp and ppp. Effects of iodixanol are to slightly enhance thrombin generation Ioxaglate amplifies the effect of abciximab Ioxaglate inhibits activation of factors V and VIII (thrombograms not shown) and of platelets by thrombin These data suggest that ioxaglate interferes with binding of substrates to exosite I of thrombin and inhibits thrombin generation via inhibition of thrombin-mediated feedback activation

Healthy baboons with chronic AV (femoral) shunts
Antithrombotic Effects of Ionic and Non-Ionic Contrast Media in Nonhuman Primates Methods: Healthy baboons with chronic AV (femoral) shunts PS 153 stent deployed at 10 atm in AV shunt Labeled platelets used Saline control or contrast (Iodixanol, Isovue, Ioxaglate) locally infused The fluid mechanics and mass transfer characteristics of the infused contrast were modeled using computational fluid dynamics Markou et al. Thromb Haemost 2001;85:488-93

Antithrombotic Effects of Ionic and Non-Ionic Contrast Media in Nonhuman Primates
Schematic of the local infusion system, stented segment, and expanded diameter chamber region of the thrombogenic device showing their relative placement in the A-V baboon shunt. The top panel shows an in-platelet image of platelet deposition on a control stent and within chamber region of flow recirculation. Markou et al. Thromb Haemost 2001;85:488-93

Platelet Deposition in the Expanded Region
Platelets Deposited x 10-6 Platelets Deposited x 10-6 A Time (min) B Time (min) Time course of platelet deposition within the chamber regions of expanded diameter (9.0 mm i.d.) exhibiting low shear blow flow recirculation and stasis. The blood flow rate was 100 ml/min. Platelet deposition was monitored by measuring the accumulation of 111Indium-radiolabeled platelets. A) CM infusion rate = 0.1 ml/min. B) CM infusion rate = 0.3 ml/min. Values are mean ± 1 SEM Markou et al. Thromb Haemost 2001;85:488-93

Platelet Deposition in the Stented Region
Platelets Deposited x 10-6 Platelets Deposited x 10-6 A Time (min) B Time (min) Time course of platelet deposition onto 4.0 mm i.d. metallic stents (Palmaz-Schatz) deployed into A-V shunts in baboons. The blood flow rate was 100 ml/min. Platelet deposition was monitored by measuring the accumulation of 111Indium-radiolabeled platelets. A) CM infusion rate = 0.1 ml/min. B) CM infusion rate = 0.3 ml/min. Values are mean ± 1 SEM Markou et al. Thromb Haemost 2001;85:488-93

Fibrin Deposition on Stented Segment
Deposition of fibrin on the stented segment Fibrin (mg) 4 2 Fibrin (mg) 7 4 4 The blood flow rate was 100 ml/mi. Fibrin deposition was determined by measuring the accumulation of 125iodine-labeled fibrinogen. A) CME infusion rate = 0.1 ml/min. B. CME infusion rate = 0.3 ml/min. Values are mean ± 1 SEM Markou et al. Thromb Haemost 2001;85:488-93

Photographs of Thrombus Formed in Stents
. 9696 Markou et al. Thromb Haemost 2001;85:488-93

Antithrombotic Effects of Ionic and Non-Ionic Contrast Media in Nonhuman Primates
Ioxaglate reduced both platelet and fibrin deposition on stents by 75-80% (p<0.005), while the non-ionic agents reduced platelet deposition by 52% (p<0.05) In the regions of low shear flow, only ioxaglate (0.3ml/min) reduced platelet deposition sgnificantly (by 52%; p<0.05) In this model, while all three agents were inherently antithrombotic, the most striking effects were seen with ioxaglate

Primary endpoint: In-Lab Thrombus
All Comers PTCA All Comers PTCA Iohexol Ioxaglate Randomized Blinded UFH: 10,000 u IV Aspirin Iohexol Ioxaglate Primary Endpoint: In-Lab Thrombus Primary endpoint: In-Lab Thrombus SYNERGY was a prospective, randomized, open-label study evaluating 10,027 patients for the efficacy and safety of enoxaparin versus UFH in high-risk patients presenting with UA/NSTEMI and treated with an early invasive strategy SYNERGY is the largest trial ever conducted in UA/NSTEMI involving a low-molecular-weight heparin High-risk ACS patients were required to have at least of two of the following: Age ≥ 60 years ST  or transient ST  +CK-MB or troponin All patients enrolled received treatment with enoxaparin or UFH and aspirin Enoxaparin: 1 mg/kg SQ q 12 hours If PCI within 8 hours of last SC dose, no drug added If PCI within 8-12 hours of last SC, enoxaparin was given as a 0.3mg/kg IV bolus Unfractionated heparin: 60 U/kg bolus (max 4000 U) 12 U/kg infusion (max 1000 U) Per ACC/AHA guidelines for non-ST  MI Goal aPTT seconds Additional medications, including GP IIb/IIIa inhibitors, were administered at the treating physician's discretion (according to current ACC/AHA guidelines) The primary endpoint was death or nonfatal MI during the first 30 days after randomization Selected additional inclusion criteria: Age ≥18; chest pain ≥10 minutes within 24 hours; signed informed consent Selected additional exclusion criteria: Increased bleeding risk; impaired hemostasis; recent (<48 hours) spinal/epidural procedure; other serious disease (e.g. renal insufficiency - calculated CrCl < 30ml/min) Plessens et al. Cathet Cardiovasc Diagn 1993;28:99-105 24

Coronary Angioplasty: In-Lab Thrombus
Iohexol (Omnipaque) vs Ioxaglate (Hexabrix) For PTCA P = 0.04 Even in lower risk patients, such as those undergoing elective PCI, there is a relationship between transfusion and long-term mortality that persists after adjustment for confounders. Plessens et al. Cathet Cardiovasc Diagn 1993;28:99-105

Primary endpoint: Thrombus During Angiography
All Comers PTCA All Comers PTCA Iohexol Ioxaglate Randomized UFH: 10,000 u IV Aspirin Iohexol Ioxaglate Primary Endpoint: Thrombus During Angiography Primary endpoint: Thrombus During Angiography SYNERGY was a prospective, randomized, open-label study evaluating 10,027 patients for the efficacy and safety of enoxaparin versus UFH in high-risk patients presenting with UA/NSTEMI and treated with an early invasive strategy SYNERGY is the largest trial ever conducted in UA/NSTEMI involving a low-molecular-weight heparin High-risk ACS patients were required to have at least of two of the following: Age ≥ 60 years ST  or transient ST  +CK-MB or troponin All patients enrolled received treatment with enoxaparin or UFH and aspirin Enoxaparin: 1 mg/kg SQ q 12 hours If PCI within 8 hours of last SC dose, no drug added If PCI within 8-12 hours of last SC, enoxaparin was given as a 0.3mg/kg IV bolus Unfractionated heparin: 60 U/kg bolus (max 4000 U) 12 U/kg infusion (max 1000 U) Per ACC/AHA guidelines for non-ST  MI Goal aPTT seconds Additional medications, including GP IIb/IIIa inhibitors, were administered at the treating physician's discretion (according to current ACC/AHA guidelines) The primary endpoint was death or nonfatal MI during the first 30 days after randomization Selected additional inclusion criteria: Age ≥18; chest pain ≥10 minutes within 24 hours; signed informed consent Selected additional exclusion criteria: Increased bleeding risk; impaired hemostasis; recent (<48 hours) spinal/epidural procedure; other serious disease (e.g. renal insufficiency - calculated CrCl < 30ml/min) Esplugas et al. Am J Cardiol 1991;68:1020-4 24

In-Lab Angiographic Thrombus
Iohexol (Omnigraf) vs Ioxaglate (Hexabrix) For PTCA P < 0.005 Even in lower risk patients, such as those undergoing elective PCI, there is a relationship between transfusion and long-term mortality that persists after adjustment for confounders. Esplugas et al. Am J Cardiol 1991;68:1020-4

All Comers PCI Patients
Iodixanol Ioxaglate Sequential Design Enoxaparin 1 mg/kg SC Q12 h, or 0.5 mg/kg 5 min prior to PCI Iodixanol Ioxaglate ASA, 250 mg PO OD, clopidogrel 300 mg PO >6h GP IIb/IIIa in 43% (operator discretion) (Peak anti Xa > 0.5 IU/ml in 97% of patients) SYNERGY was a prospective, randomized, open-label study evaluating 10,027 patients for the efficacy and safety of enoxaparin versus UFH in high-risk patients presenting with UA/NSTEMI and treated with an early invasive strategy SYNERGY is the largest trial ever conducted in UA/NSTEMI involving a low-molecular-weight heparin High-risk ACS patients were required to have at least of two of the following: Age ≥ 60 years ST  or transient ST  +CK-MB or troponin All patients enrolled received treatment with enoxaparin or UFH and aspirin Enoxaparin: 1 mg/kg SQ q 12 hours If PCI within 8 hours of last SC dose, no drug added If PCI within 8-12 hours of last SC, enoxaparin was given as a 0.3mg/kg IV bolus Unfractionated heparin: 60 U/kg bolus (max 4000 U) 12 U/kg infusion (max 1000 U) Per ACC/AHA guidelines for non-ST  MI Goal aPTT seconds Additional medications, including GP IIb/IIIa inhibitors, were administered at the treating physician's discretion (according to current ACC/AHA guidelines) The primary endpoint was death or nonfatal MI during the first 30 days after randomization Selected additional inclusion criteria: Age ≥18; chest pain ≥10 minutes within 24 hours; signed informed consent Selected additional exclusion criteria: Increased bleeding risk; impaired hemostasis; recent (<48 hours) spinal/epidural procedure; other serious disease (e.g. renal insufficiency - calculated CrCl < 30ml/min) Primary Endpoint: In-Hospitral MACE (cardiac death, MI, TVR, CVA, systemic embolic event) Secondary endpoint: Angiographic outcomes (large thrombus > 2 vessel diameters) Le Feuvre et al. Cath and Cardiovasc Int. 2006;67:852-8 24

Le Feuvre et al: Intraprocedural Large Thrombus
Iodixanol vs. Ioxaglate for PCI Stent in 91% P < Even in lower risk patients, such as those undergoing elective PCI, there is a relationship between transfusion and long-term mortality that persists after adjustment for confounders. Le Feuvre et al. Cath and Cardiovasc Int. 2006;67:852-8

Thrombosis Induction and Mitigation with Contrast Media: Conclusions
Data from in vitro studies and from animal models indicate significant differences in the effects of different contrast media on thrombin generation, thrombolysis and platelet activation. Among commonly used agents, the ionic dimer, Ioxaglate (Hexabrix) inhibits both thrombin generation and platelet activation Non-ionic monomers activate platelets, enhance thrombin generation and inhibit thrombolysis The non-ionic dimer, Iodixanol (Visipaque) has intermediate results

Thrombosis Induction and Mitigation with Contrast Media: Conclusions
There are some provocative clinical data, but are they relevant in the current era? Stay Tuned!

The Role of Contrast Media (CM) on Clinical Outcomes in Patients with STEMI and High-Risk ACS: The Evidence-Based Case for Risk-Directed Selection of CM in PCI The Journey from Clinical Trials to Choices for CM in the Cardiac Catheterization Laboratory: How Should Recent Evidence and Trials Affect Our Choices? Steven V. Manoukian, MD, FACC Program Chairman Director, Cardiovascular Research | Sarah Cannon Research Institute | Centennial Heart Cardiovascular Consultants | Medical Director, Cardiovascular Services | Clinical Services Group | Hospital Corporation of America (HCA) | Nashville, TN

Clots, Contrast Media, and Catheterization Outline
PCI ischemic complications Anticoagulation in PCI Bleeding complications of PCI anticoagulation Impact of PCI periprocedural MI Clinical trials of contrast media in PCI Conclusions

Ischemic Complications of PCI
30-Day Event Rates Adapted from REPLACE-2, ACUITY-PCI, HORIZONS PCI Subset Lincoff AM et al. JAMA 2003;289: Stone GW et al. Lancet 2007;369: Stone GW et al. NEJM 2008;358:

EPILOG: 30-Day Primary Efficacy Endpoint
0.12 0.10 0.08 0.06 0.04 0.02 0.01 Urgent Revascularization Probability of Death, Myocardial Infarction, or Days After Randomization P<0.001 Placebo Abciximab + standard-dose heparin Abciximab + low-dose heparin EPILOG Investigators. NEJM 1997;336:

EPILOG: 30-Day Individual Endpoints
Efficacy End Point Placebo + Standard-Dose Heparin (n=939) Abciximab + Low-Dose Heparin (n=935) P Value Abciximab + Standard-Dose Heparin (n=918) No. of patients (%) No. patients (%) Composite 109 (11.7) 48 (5.2) <0.001 49 (5.4) Death 7 (0.8) 3 (0.3) 0.21 4 (0.4) 0.39 Myocardial infarction 81 (8.7) 34 (3.7) 35 (3.8) Q-wave 0.36 4 (0.5) 0.38 Non-Q-wave 74 (7.9) 30 (3.2) 31 (3.4) Large non-Q-wave (CK MB > 5 x control) 53 (5.6) 19 (2.0) 23 (2.5) Small non-Q-wave (CK MB 3-5x control) 18 (1.9) 11 (1.2) 0.26 8 (0.9) 0.07 Non-Q-wave after hospitalization 3(0.03) 0.25 Urgent revascularization 15 (1.6) 21 (2.3) 0.001 Repeated percutaneous intervention 14 (1.5) 0.003 Coronary-artery bypass grafting 16 (1.7) 0.007 0.11 Death or myocardial infarction 85 (9.1) 38 (4.2) EPILOG Investigators. NEJM 1997;336:

ACUITY: Early Composite Ischemia
Days After Randomization 15 10 5 Bivalirudin alone, 8.0%, P=0.30 Bivalirudin + GP IIb/IIIa inhibitor, 7.9%, P=0.37 Heparin + GP IIb/IIIa inhibitor, 7.4% Stone GW et al. NEJM 2006;355:

ACUITY: Major Bleeding
Days After Randomization 15 10 5 Heparin + GP IIb/IIIa inhibitor, 5.7% Bivalirudin + GP IIb/IIIa inhibitor, 5.3%, P=0.41 Bivalirudin alone, 3.1%, P<0.001 Stone GW et al. NEJM 2006;355:

ACUITY: Major Bleeding and Mortality
Long rank p Value: <0.0001 7.3% Patients with major bleeding Patients without major bleeding Percent Mortality Days After Randomization 8 7 6 5 4 3 2 1 1.2% Manoukian SV et al. JACC 2007;49:

ACUITY: Predictors of Major Bleeding
Odds Ratio ± 95% CI OR (95% CI) p value Age > 75 years 1.64 ( ) <0.0001 Female gender 1.92 ( ) Diabetes 1.20 ( ) 0.057 Hypertension 1.24 ( ) 0.040 No prior PCI 1.32 ( ) 0.006 Anemia 1.87 ( ) Renal insufficiency 1.53 ( ) Baseline ST-segment deviation > 1 mm 1.35 ( ) 0.0008 Baseline cardiac biomarker elevation 1.43 ( ) 0.0002 Heparin plus GPI vs bivalirudin monotherapy 1.95 ( ) Manoukian SV et al. JACC 2007;49:

Clinical Classification of MI
Type 1 Spontaneous myocardial infarction related to ischaemia due to primary coronary event such as plaque erosion and/or rupture, fissuring, or dissection Type 2 Myocardial infarction secondary to ischaemia due to either increased oxygen demand or decreased supply, e.g. coronary artery spasm, coronary embolism, anaemia, arrhythmias, hypertension, or hypotension Type3 Sudden unexpected cardiac death, including cardiac arrest, often with symptoms suggestive of myocardial ischaemia, accompanied by presumably new ST-elevation, or new LBB,B, or evidence of fresh thrombus in a coronary artery by angiography and/or at autopsy, but death occurring before blood samples could be obtained, or at a time before the appearance of cardiac biomarkers in the blood Type 4a Myocardial infarction associated with PCI Type 4b Myocardial infarction associated with stent thrombosis as documented by angiography or at autopsy Type 5 Myocardial infarction associated with CABG Thygesen K et al. J Am Coll Cardiol 2007;50:

ACUITY: Periprocedural MI and Mortality
30-Day Event Rates, PCI Population P<0.0001 P=0.8 P<0.0001 P=0.41 P<0.0001 P<0.0001 30-day events (%) P=0.0004 P=0.27 P<0.0001 Prasad A et al. J Am Coll Cardiol 2009;54:

ACUITY: Periprocedural MI and 1-Year Mortality
PCI Population HR ± 95% CI HR (95% CI) P-value Age (> 75 years) 2.53 ( ) <0.0001 Anemia 1.51 ( ) 0.0002 Prior stroke 1.29 ( ) 0.02 Male 1.53 ( ) 0.0001 Diabetes 1.51 ( ) Baseline CrCl <60 mL/min 1.43 ( ) 0.003 Pre-randomization UFH 1.25 ( ) 0.03 Prior MI 1.33 ( ) 0.005 CKMB/troponin+ at baseline 1.70 ( ) ECG changes at baseline 1.76 ( ) 30-day major bleed 3.03 ( ) 30-day revascularization 1.76 ( ) 0.008 Periprocedural MI 1.30 ( ) 0.22 Spontaneously occurring MI 7.49 ( ) Prasad A et al. J Am Coll Cardiol 2009;54:

Periprocedural Troponin and Mortality
Meta-Analysis, n=15,581 Fuchs Cantor Gruberg Nallamothu Ricciardi Kini Natarajan Cavallini Okmen Shyu Hermann Kizer Miller Prasad All trials ( ) Nienhuis NB et al. Catheter Cardiovasc Interv 2008;71:325-6.

The Impact of Cardiac Contrast Media on MACE End Points In ACS
What do the Vascular Biology and Clinical Trials Teach Us?

Ioxaglate Characteristics: Thrombotic Risk and MACE
Ioxaglate has been shown to reduce platelet accumulation in stents (in animals)* * The clinical significance of this data is not known. Markou CP et al, Thromb and Haemost, 2001, 85:

Antithrombotic and Anticoagulant Properties of Ioxaglate
So what happens? Vessel Injured Exposes endothelial proteins, including collagen Collagen Activates Resting Platelets Thrombin Fibrinogen Thrombin helps convert another protein, fibrinogen, into fibrin Activated Platelets Aggregate and adhere to the exposed collagen on the vessel wall, forming the initial clot Fibrin forms mesh which encapsulates the clot R. Al Dieri Journal of Thrombosis and Haemostasis, 1: Heptinstall et al. British Journal of Haemotology 1998;103: Corot et al. Blood Coagulation and Fibrinolysis 1996;7:602-8 Jones C et al. Thrombosis Research 2003;112:65-71

Blood Vessel Endothelium Subendothelium INJURY Collagen VWF Tissue Factor Vaso-constriction Vaso- constriction Platelet adhesion and secretion Platelet Adhesion & Secretion Coagulation Cascade Coagulation Cascade Thrombin Thrombin Platelet aggregation Fibrin Haemostatic plug Dr Isobel Ford

What are issues and concerns for interventional cardiologists? This process can lead to occlusion of the vessels, such as coronary arteries during PCI End point includes mortality End point includes NSTEMI and STEMI R. Al Dieri Journal of Thrombosis and Haemostasis, 1: Heptinstall et al. British Journal of Haemotology 1998;103: Corot et al. Blood Coagulation and Fibrinolysis 1996;7:602-8 Jones C et al. Thrombosis Research 2003;112:65-71

So what role does ioxaglate play? Vessel Injured Exposes endothelial proteins, including collagen 2 3 Collagen Activates Resting Platelets Thrombin Activates Resting Platelets 1 Activated Platelets Aggregate and adhere to the exposed collagen on the vessel wall, forming the initial clot Fibrinogen Thrombin helps convert another protein, fibrinogen, into fibrin 4 Fibrin forms mesh which encapsulates the clot R. Al Dieri Journal of Thrombosis and Haemostasis, 1: Heptinstall et al. British Journal of Haemotology 1998;103: Corot et al. Blood Coagulation and Fibrinolysis 1996;7:602-8 Jones C et al. Thrombosis Research 2003;112:65-71

Interface of ioxaglate with thrombosis generation 1 Ioxaglate, does not activate resting platelets, unlike nonionic monomers. Doesn’t direct platelets to change shape, release pro-coagulant mediators or to adhere to anything. This prevents/delays formation of the platelet clot. 2 Ioxaglate binds w/thrombin, preventing it from activating platelets; therefore preventing/delaying the formation of the platelet plug. 3 Ioxaglate inhibits the generation of thrombin, reducing the amount of thrombin: inhibits the formation of fibrin. 4 Mechanisms that may be responsible for preventing/delaying formation of the fibrin mesh. R. Al Dieri Journal of Thrombosis and Haemostasis, 1: Heptinstall et al. British Journal of Haemotology 1998;103: Corot et al. Blood Coagulation and Fibrinolysis 1996;7:602-8 Jones C et al. Thrombosis Research 2003;112:65-71

Low-Osmolar Ionic (Ioxaglate) vs
Low-Osmolar Ionic (Ioxaglate) vs. Nonionic (Iohexol) Contrast in Patients with MI/UA Undergoing PTCA Baseline Demographic Characteristics Low Osmolar Ionic Contrast Media (n=106) Nonionic Contrast Media (n=105) Age (yr) (mean ± SD) 63.7 ± 12.7 61.9 ± 12 Male patients (%) 64 62 Clinical history (%) Hypertension 51.9 50.5 Diabetes 24.5 21.0 Smoking 56.6 67.6 Prior MI 40.6 39.1 Prior PTCA 15.1 17.1 Treatment history (%) Aspirin 68.9 61.0 Heparin 53.8 59.1 Nitrates 67.0 66.7 Tissue plasminogen activator 3.8 8.6 Indication for PTCA, % Acute MI 44.4 40.9 Post-MI ischemia 33.9 33.4 Unstable angina 21.7 25.7 Grines CL et al. J Am Coll Cardiol 1996;27:

Low-Osmolar Ionic (Ioxaglate) vs. Nonionic (Iohexol) Contrast in Patients with MI/UA Undergoing PTCA Conclusions Ioxaglate Significant reductions in: Ischemic complications acutely and at one month Decreased blood flow during PTCA Recurrent ischemia with repeat catheterization Repeat PTCA Angina Risk of CABG Authors: “Strongly consider for unstable angina/MI PTCA.” Grines CL et al. J Am Coll Cardiol 1996;27:

Low-Osmolar Ionic (Ioxaglate) vs. Isosmolar Nonionic (Iodixanol) Contrast in PTCA Baseline Clinical Characteristics Iodixanol (Nonionic; n=697) Ioxaglate (Ionic; n=714) Age, y 61.6 ± 10.6 62.3 ± 10.2 Male, % 78.2 76.2 Weight, kg 75.9 ± 12.2 76.2 ± 12.4 Height, cm 168.2 ± 8.6 168.0 ± 8.6 Diabetes, % 20.2 15.8 Current smokers, % 23.2 22.1 Former smokers, % 35.0 36.3 Obesity, % 20.1 Family history of CAD, % 30.7 26.3 Prior MI, % 19.1 18.5 Prior PTCA, % 16.1 14.7 Prior CAG, % 7.1 6.7 History of allergy/hypersensitivity, % 4.7 5.7 Indication for PTCA, % Unstable angina 51.9 49.3 Stable angina 38.3 40.1 Silent ischemia 9.5 10.1 Bertrand ME et al. Circulation 2000;101:

Low-Osmolar Ionic (Ioxaglate) vs. Isosmolar Nonionic (Iodixanol) Contrast in PTCA MACE at 2-Day Follow-Up Iodixanol (Nonionic; n=697) Ioxaglate (Ionic; n=714) p During hospital stay (2 days) 33 (4.7%) 28 (3.9%) 0.45 Death 2 N Stroke 1 NS Q-wave MI 3 NQWMI 24 17 0.24 CABG Re-PTCA 4 Bertrand ME et al. Circulation 2000;101:

Low-Osmolar Ionic (Ioxaglate) vs. Isosmolar Nonionic (Iodixanol) Contrast in PTCA Conclusions No significant difference in in-hospital MACE between ioxaglate and iodixanol. Bertrand ME et al. Circulation 2000;101:

Low-Osmolar Ionic (Ioxaglate) vs. Isosmolar Nonionic (Iodixanol) Contrast in PTCA Iodixanol (n=405) Ioxaglate (n=410) N % N% Average age, y 61±12 62±12 Male 280 69 270 66 Hypertension 240 59 249 61 Diabetes mellitus 110 27 Current smoker 129 32 137 33 Past smoker 238 251 Previous MI 142 35 168 41 Hyperlipidemia 157 63 Angina 353 87 383 93 Angina CHS class IV 290 72 311 76 Family CAD history 242 60 Prior intervention 128 133 Demographics Davidson CJ et al. Circulation 2000;101:

Low-Osmolar Ionic (Ioxaglate) vs. Isosmolar Nonionic (Iodixanol) Contrast in PTCA Hospital Stay Primary Clinical Outcomes Iodixanol (n=405) Ioxaglate (n=410) P N % N% Emergent recatheterization 5 1.2 9 2.2 0.29 Repeat revascularization 4 1.0 8 2.90 0.25 In-hospital abrupt closure 3 0.7 10 2.4 0.05 Stroke/TIA 1 0.2 0.99 Thromboembolic event 2 0.5 0.42 Cardiac death 0.10 Nonfatal MI 2.0 18 4.4 Emergent CABG .07 0.66 Composite outcome 22 5.4 39 9.5 0.027 Davidson CJ et al. Circulation 2000;101:

Low-Osmolar Ionic (Ioxaglate) vs. Isosmolar Nonionic (Iodixanol) Contrast in PTCA Events from Hospital Discharge to 30 Days Iodixanol (n=390) Ioxaglate (n=400) P N % N% Emergent recatheterization or revascularization 13 3.3 12 3.0 0.79 Abrupt closure 2 0.5 0.16 Stroke/TIA 1 0.3 0.99 Thromboembolic event Cardiac death 0.32 Nonfatal MI Emergent CABG Composite outcome 15 3.8 0.94 Davidson CJ et al. Circulation 2000;101:

Low-Osmolar Ionic (Ioxaglate) vs. Isosmolar Nonionic (Iodixanol) Contrast in PTCA Angiographic and Procedural Outcome Iodixanol (n=400) Ioxaglate (n=396) P N % N% Abrupt closure 2 0.5 7 1.8 0.09 Prolonged no-reflow 3 0.8 0.99 Distal embolization 1 0.3 0.57 Side-branch occlusion 6 1.5 Development of moderate to large thrombus -- Dissection 18 4.5 25 6.3 0.25 Unplanned IABP 4 1.0 0.37 Unplanned abciximab 29 7.3 32 8.1 0.66 Procedural success 369 92.2 340 85.9 0.004 >20% absolute decrease 375 93.9 355 90.0 --- <50% residual stenosis 389 97.3 379 94.9 TIME-3 flow 397 99.3 391 98.8 Composite outcome 69 17.3 87 22.0 0.093 Davidson CJ et al. Circulation 2000;101:

Iodixanol, significant
Low-Osmolar Ionic (Ioxaglate) vs. Isosmolar Nonionic (Iodixanol) Contrast in PTCA Conclusions Regarding Ionic Contrast Iodixanol, significant Reduction in in-hospital adverse composite Increase in angiographic success Davidson CJ et al. Circulation 2000;101:

Low-Osmolar Ionic (Ioxaglate) vs. Nonionic Contrast in Coronary Stenting n=3,990 Ioxaglate (Hexabrix® 320) Dimer, ionic Iobitridol (Xenetix® 350) Monomer, non-ionic Iomeprol (Imeron® 400) Monomer, non-ionic Iopamidol (Solutrast® 370) Monomer, non-ionic Iopromid (Ultravist® 370) Monomer, non-ionic Ioversol (Optiray® 350) Monomer, non-ionic Iodixanol (Visipaque® 320) Dimer, non-ionic Scheller B et al. Eur Heart J 2001;22:

Low-Osmolar Ionic (Ioxaglate) vs. Nonionic Contrast in Coronary Stenting Demographic Data, n=3,990 Non-ionic CM Ioxaglate p N 1808 2182 Gender (male) 76% 74% NS Age 63.9 ± 10.3 years Diabetes 18.9% 17.2% Angina pectoris CCS 0-I 22.8% CCS 0-I 26.4% CCS II 36.6% CCS II 37.5% CCS III 28.2% CCS III 25.3% CCS IV 12.5% CCS IV 10.9% Acute coronary syndrome 34.2% 32.3% Unstable angina 24.9% 21.3% AMI 9.3% 11.0% Known CM intolerance 4.1% 4.3% Scheller B et al. Eur Heart J 2001;22:

Low-Osmolar Ionic (Ioxaglate) vs. Nonionic Contrast in Coronary Stenting Angiographic Data, n=3,990 Non-ionic CM Ioxaglate p N 1808 2182 LVEF 55 ± 15.9% 54.8 ± 17.8% NS Vessels diseased Single vessel 26% Single vessel 28% Two vessel 35% Three vessel 39% Three vessel 37% Stented vessel LCA 1.4% LCA 1.2% LAD 35.5% LAD 34.4% CX 19.8% CX 26.4% <0.05 RCA 36.5% RCA 32.8% ACB 6.7% ACB 5.2% Stented vessel localization Proximal 31.5% Proximal 28.8% Scheller B et al. Eur Heart J 2001;22:

Low-Osmolar Ionic (Ioxaglate) vs. Nonionic Contrast in Coronary Stenting Angiographic Data, n=3,990 Non-ionic CM Ioxaglate p Stented vessel localization Proximal 31.5% Proximal 28.8% NS Middle 60.5% Middle 62.2% Distal 8.0% Distal 9.0% Restenotic lesion 18.6% 17.4% RFD 3.37 ± 0.43 mm 3.37 ± 0.81 mm MLD 0.68 ± 0.63 mm 0.67 ± 0.58 mm Diameter stenosis 79.7 ± 17.8% 80.1 ± 5.5% Volume of CME 280.9 ± ml 257.8 ± ml 0.001 Heparin dose 12901 ± 4640 IU 11938 ± 3914 IU ReoPro® 4.9% 5.3% Scheller B et al. Eur Heart J 2001;22:

Primary Endpoint: 12-Month Acute and Subacute Stent Occlusion
Low-Osmolar Ionic (Ioxaglate) vs. Nonionic Contrast in Coronary Stenting Primary Endpoint: 12-Month Acute and Subacute Stent Occlusion n=3,990 Patients Event Non-Ionic CM Ioxaglate P AOS and SAT All patients n=3990 AOS 24/1808 (1.3%) 7/2182 (0.3%) 0.001 SAT 44/1808 (2.45)% 16/2182 (0.7%) Restonosis Reangiography 968/1808 (53.5%) 1062/2182 (48.7%) 0.002 Restenosis 329/968 (34.0%) 296/1062 (27.8%) 0.003 Combined clinical end point (TLR, CABG, death) Combined 414/1808 (22.9%) 356/2182 (16.3%) TLR 301/1808 (16.6%) 229/2182 (10.5%) CABG 22/1808 (1.2%) 31/2182 (1.4%) NS Death 110/1808 (6.1%) 109/2182 (5.0%) 0.007 Scheller B et al. Eur Heart J 2001;22:

Multivariate Analysis of Acute and Subacute Stent Thrombosis
Low-Osmolar Ionic (Ioxaglate) vs. Nonionic Contrast in Coronary Stenting Multivariate Analysis of Acute and Subacute Stent Thrombosis Variable, n=3990 Wald P CME 5.8681 0.0154 Age 0.0013 0.9707 LVEF 1.6027 0.2055 CAD 1.5391 0.2147 CM side effect 0.1368 0.7115 ReoPro® 0.1482 0.7003 Unstable AP 0.1742 0.6764 AMI 2.1049 0.1468 CCS 3.2512 0.0714 MLD 2.7256 0.0988 Heparin 1.9842 0.1589 Localization 0.0108 0.9173 Vessel diameter 0.6186 0.4316 Scheller B et al. Eur Heart J 2001;22:

Low-Osmolar Ionic (Ioxaglate) vs. Nonionic Contrast in Coronary Stenting n=3,990 Ioxaglate, significant reductions in: Acute stent thrombosis Subacute stent thrombosis Reangiography Restenosis Target lesion revascularization Death Scheller B et al. Eur Heart J 2001;22:

Low-Osmolar Ionic (Ioxaglate) vs. Isosmolar Nonionic (Iodixanol) Contrast in PCI Baseline Clinical Characteristics Iodixanol Ioxaglate P N 231 267 Age (y) 64 ± 12 63 ± 11 NS Male gender, n 189 (82) 211 (79) Diabetes mellitus, n 64 (28) 92 (34) Hypertension, n 121 (53) 133 (50) Smoking history, n 94 (41) 97 (36) LDL cholesterol > 3.3 mmol/l 162 (70) 184 (69) Family history of CAD, n 46 (20) 51 (19) Prior CABG, n 16 (7) 23 (9) Prior MI, n 63 (24) Chronic renal failure 35 (15) 44 (16) Statin treatment before PCI 120 (52) 136 (51) Prior left ventricular failure, n 29 (13) 27 (10) PCI for acute MI, n 57 (25) 74 (28) PCI for unstable angina, n 37 (16) 58 (22) PCI for silent myocardial ischemia, n Le Feuvre C et al. Catheter Cardiovasc Interv 2006;67:852-8.

Low-Osmolar Ionic (Ioxaglate) vs. Isosmolar Nonionic (Iodixanol) Contrast in PCI Angiographic Baseline Characteristics and Procedural Data Iodixanol Ioxaglate p Volume of contrast media (ml) 267 ± 125 276 ± 120 NS Peak anti-Xa >0.5 IU/ml, n 224 (97) 259 (97) Peak anti-Xa > 1 IU/ml, n 67 (29) 72 (27) Intravenous antiplatelet therapy, n 99 (43) 112 (42) Planned, n 88 (38) 93 (35) Rescue, n 11 (5) 19 (7) Bifurcation/ostial lesion, n 23 (10) 29 (11) Number of vessel PCI per patient One vessel, PCI, n 192 (83) 219 (82) Two vessel PCI, n 37 (16) 43 (16) Three vessel PCI, n 2 (1) 5 (2) Le Feuvre C et al. Catheter Cardiovasc Interv 2006;67:852-8.

Low-Osmolar Ionic (Ioxaglate) vs. Isosmolar Nonionic (Iodixanol) Contrast in PCI Angiographic Baseline Characteristics and Procedural Data (continued) Iodixanol Ioxaglate p Treatment device Failure to cross the lesion, n 6 (3) 10 (4) NS Balloon, n 17 (6) Stent, n 215 (93) 240 (90) Number of stent used per patient One stent, n 143 (62) 162 (61) Two stents, n 47 (20) 54 (20) Three stents 16 (7) 15 (6) Four stents or more, n 9 (4) 9 (3) Direct stenting, n 159 (69) 187 (70) Drug eluting stent, n 69 (30) 72 (27) Use of intra-aortic balloon pump, n 11 (4) Le Feuvre C et al. Catheter Cardiovasc Interv 2006;67:852-8.

Low-Osmolar Ionic (Ioxaglate) vs. Isosmolar Nonionic (Iodixanol) Contrast in PCI Clinical Events Iodixanol Ioxaglate p Procedural events Cardiac death, n 2 (0.8) NS Non fatal MI or reinfarction, n 7 (3) 1 (0.3) 0.05 Emergency CABG, n 1 (0.4) Stroke or systemic thromboembolic event, n In-hospital events 7(3) Emergency repeat PCI, n 3 (1.3) Composite outcome, n 11 (4.8) 0.005 Le Feuvre C et al. Catheter Cardiovasc Interv 2006;67:852-8.

Low-Osmolar Ionic (Ioxaglate) vs. Isosmolar Nonionic (Iodixanol) Contrast in PCI Clinical Events (continued) Iodixanol Ioxaglate p 30-day events Cardiac death, n 3 (1.3) NS Non fatal MI or reinfarction, n 7 (3) 1 (0.3) 0.05 Emergency repeat PCI, n 5 (2.2) Emergency CABG, n 1 (0.4) Stroke or systemic thromboembolic event, n Composite outcome, n 14 (6) 2 (0.7) 0.002 Le Feuvre C et al. Catheter Cardiovasc Interv 2006;67:852-8.

Low-Osmolar Ionic (Ioxaglate) vs. Isosmolar Nonionic (Iodixanol) Contrast in PCI Angiographic and Procedural Complications During or Immediately After PCI Iodixanol Ioxaglate p Appearance of a large thrombus, n 14 (6) 1 (0.3) 0.0001 Target vessel occlusion, n 12 (5.2) 0.003 Side branch (> 2 mm) occlusion, n 2 (0.9) NS Composite endpoint, n Sustained ventricular arrhythmia Hypotension with intervention 4 (1.7) 4 (1.5) Renal failure requiring treatment 3 (1) Contrast induced nephropathy 2 (1) 7 (2.6) Large thrombus, largest dimension greater than two vessel diameters; Contrast induced nephropathy, > 0.5 mg/dl and/or 25% increase in creatinine levels from day 0 to day 3 Le Feuvre C et al. Catheter Cardiovasc Interv 2006;67:852-8.

Ioxaglate: Iodixanol:
Low-Osmolar Ionic (Ioxaglate) vs. Isosmolar Nonionic (Iodixanol) Contrast in PCI Conclusions Regarding Ionic Contrast Ioxaglate: Thrombus-related events significantly less likely. In-hospital MACE Large thrombus Iodixanol: Independent predictor of in-hospital MACE. Le Feuvre C et al. Catheter Cardiovasc Interv 2006;67:852-8.

Non-Ionic Contrast Prescribing Information
Isovue Omnipaque Optiray Oxilan Ultravist Visipaque Prescribing Information.

Clots, Contrast Media, and Catheterization Conclusions
In PCI, ischemic complications are associated with adverse outcomes Aggressive PCI anticoagulation regimens are effective in reducing ischemic events but increase bleeding complications Active decision-making with regard to the type of contrast media may: Favorably impact rates of ischemic complications Not adversely affect rates of bleeding complications Obviate the need for aggressive anticoagulation regimens Improve overall PCI outcomes

Clots, Contrast Media, and Catheterization

Similar presentations

Presentation on theme: "Clots, Contrast Media, and Catheterization"— Presentation transcript:

Similar presentations

About project

Feedback

Log in

Auth with social network:

Clots, Contrast Media, and Catheterization

Similar presentations

Presentation on theme: "Clots, Contrast Media, and Catheterization"— Presentation transcript:

Similar presentations

About project

Feedback