Bleeding and clinical outcomes Sunil Rao DCRI

Importance and Impact of Bleeding on ACS Clinical Outcomes Sunil V. Rao MD Assistant Professor of Medicine Duke University Medical Center Durham VA Medical Center Duke Clinical Research Institute Disclosures  Consultant and/or Speaker’s Bureau  Sanofi-Aventis  The Medicines Company  Pfizer  Cordis Antithrombotic Pharmacotherapy During PCI: 25 Years of Evolving Therapy 1970s Empirical treatment with heparin and aspirin 1980s Randomized and observational studies   aspirin: no  restenosis; but  acute complications heparin: threshold 300 seconds ACT 1990s Era of stents and platelet blockade    stents: “shotgun” approach  ASA + ADP-inhibitors GP IIb/IIIa blockade: antibody and SMI heparin:  doses; LMWH 2000s Targeted anticoagulants (DTIs,Anti-Xa) Challenge of optimal combinations Progressively better outcomes with PCI Unadjusted Outcomes after PCI 8 7 6 5 4 3 2 1 0 19771981 19851986 19901994 19971998 In-hosp Mortality Emer CABG % From the NHLBI(I), NHLBI (II), NACI, and NHLBI Dynamic Registries CRUSADE In-Hospital Outcomes Death (Re)-Infarction CHF 4.3 % 2.5 % 8.0 % Cardiogenic Shock Stroke Non-CABG Transfusion 2.6 % 0.8 % 9.9 % CRUSADE: Quarter 1, 2004-Quarter 4, 2004 (n=39,933) Bleeding and ACS       Older Age Female Gender Renal Failure History of Bleeding Right Heart Catheterization GPIIbIIIa antagonists Independent Predictors of Major Bleeding in Marker Positive Acute Coronary Syndromes Moscucci, GRACE Registry, Eur H J 2003 Excess dosing of Gp IIb/IIIa and bleeding in women N=32,601 patients from CRUSADE Overall Women Men 1.46 (1.22, 1.73) 1.72 (1.30, 2.28) 1.27 (0.97, 1.66) 0.5 1.0 1.5 2.0 2.5 Excess Dosing More Likely to Bleed Alexander KP, et. al. Circulation 2006 Procedural factors Femoral arterial access Sherev DA, CCI 2005 “Major” Bleeding – Incidence in ACS Clinical Trials Bleeding & Outcomes Kaplan Meier Curves for 30-Day Death, Stratified by Bleed Severity log rank p-value for all four categories <0.0001 log-rank p-value for no bleeding vs. mild bleeding = 0.02 log-rank p-value for mild vs. moderate bleeding <0.0001 log-rank p-value for moderate vs. severe <0.001 Rao SV, et al. Am J Cardiol. 2005 Bleeding and Outcomes in NSTE ACS 26,452 patients from PURSUIT, PARAGON A, PARAGON B, GUSTO IIb NST Adjusted Hazard Ratios for Mortality by Bleeding Severity Bleeding severity Mild* Moderate* Severe* Bleeding as a time-dependent covariate 30d Death 1.6 2.7 10.6 6 mo Death 1.4 2.1 7.5 *p<0.0001 Rao SV, et.al. AJC 2005 Bleeding & Outcomes - Data from CURE Trial 25 20 Mortality (%) Life Threatening 15 Major 10 Minor 5 No bleeding 0 0 30 60 90 120 150 180 Eikelboom JW, et. al. Circulation 2006 Bleeding Incidence : Impact of definition N=15,858 ACS pts from PURSUIT & PARAGON B 25 19.2 20 15 % 10 5 0 GUSTO Mild GUSTO Mod GUSTO Sev TIMI Mini TIMI Min TIMI Maj Rao SV, et.al. JACC 2006 11.4 12.7 8.5 8.2 1.2 Effect of bleeding definition on 30d death/MI N=15,858 ACS patients from PURSUIT & PARAGON B Decreased Risk Increased Risk Rao SV, et.al. JACC 2006 Calculating Costs of Ischemia and Bleeding: EPIC EQOL Study (Abciximab in PCI) 30000 27349 Costs 20000 Abciximab versus Placebo  ischemic costs: $523 $$$  major bleed costs: $458 10000 8800 5900 1300 0 Urgent PCI Urgent CABG Minor bleed Major bleed Mark DB, et al. Circ 1996 Risk versus benefit Thrombosis Bleeding Bleeding – Immediate clinical consequences    Cessation of antithrombotic therapy Hypotension Reversal of antithrombotic therapy  Blood transfusion Geographic variation in transfusion relative to U.S. N=24,112 0.24 (0.19 – 0.30) Unadjusted Adjusted 0.19 (0.15 – 0.25) for baseline characteristics Adjusted for baseline characteristics and procedures Adjusted for baseline characteristics, procedures, and bleeding 0.69 (0.54 – 0.88) 0.76 (0.59 – 1.00) Less than US 1.0 More than US Rao SV, et. al. AHA 2005 Variations in Transfusion Rates for NSTE ACS Across Hospitals Percentage of Hospitals (%) 30 Non-CABG 25 20 15 10 5 0 0 4 8 12 16 20 Overall 24 > 28 Percentage of Patients Receiving Blood Transfusions (%) Yang X, et. al. JACC 2005 Cooperative Cardiovascular Project 30 day death by transfusion and Hct 2  Odds ratio for 30 day mortality Higher 78,974 pts > 65 years with confirmed MI Grouped into categories of admission hematocrit Excluded pts with bleeding and those with CABG Primary endpoint: 30-day mortality 1.8 1.6 1.4 1.2 1 0.8 0.6 0.4 0.2 0   HCT< 33 %  Lower <24% 24-27 27-30 30-33 33-36 36-39 >39% Wu W, NEJM 2001 Transfusion in ACS N=24,111 pts from PURSUIT, PARAGON B, GUSTO IIb 30 Day Survival By Transfusion Group 1 No Transfusion Transfusion 0.98 Survival Rates 0.96 0.94 0.92 0.9 0 5 10 15 Days 20 25 30 Rao SV, et. al., JAMA 2004 PRBC Transfusion Among NSTE ACS Patients: Cox model for 30-day Death (N=24,111) Adjusted for transfusion propensity 3.77 (3.14, 4.52) Adjusted for baseline characteristics Adjusted for baseline Characteristics, bleeding propensity, transfusion Propensity, & nadir HCT -4.0 1.0 3.54 (2.96, 4.23) 3.94 (3.26, 4.75) 10 Rao SV, et. al., JAMA 2004 *Transfusion as a time-dependent covariate Adjusted Risk of In-Hospital Outcomes By Transfusion Status* N=74,971 ACS pts. from 478 centers Death Death or Re-MI 1 2.0 * Non-CABG patients only Yang X, et. al. JACC 2005 Properties of PRBCs  Low 2,3 DPG* High O2 affinity*   Depleted of Nitric Oxide  NO plays a fundamental role in O2 exchange† *Welch HG, et. al. Ann Int Med 1992 †Stamler JS, et. al. Science 1997 Effects of Transfusion  Packed red cells  Depleted of NO Function as NO “sinks” Lead to vasoconstriction Platelet aggregation Ineffective O2 delivery  Associated with increases in CRP and IL6* *Fransen E, et. al. Chest 1999 REPLACE-2 ACUITY Bivalirudin STEEPLE IV enoxaparin OASIS 5 Fondaparinux STEEPLE Investigators. NEJM 2006 OASIS Investigators. NEJM 2006 Lincoff AM, et. al. JAMA 2003 Stone GW. ACC 2006 Addressing the challenge of selecting an anticoagulation strategy Age Renal function Bleeding Risk Cost Ischemic Risk Ease of use PCI vs CABG vs Med Rx Time to cath Bleeding and ACS outcomes Conclusions   Bleeding is more common than we think Clinical bleeding and transfusion are associated with worse outcomes and cost Strategies that maintain an adequate antithrombotic effect to reduce ischemia while minimizing the risk of bleeding may improve survival in patients with acute ischemic heart disease  The traditional efficacy-safety relationship has changed 