Importance and Impact of Bleeding on ACS Clinical Outcomes Christopher Granger, MD Director, Cardiac Care Unit

Consequences of Recurrent Ischemia GUSTO IIb Mortality at 1 year (%) Armstrong et al. Circulation. 1998;98:1860-1868.

Focus on the antithrombotic effects direct TIs lytics clopidogrel GP IIb/IIIa inhibitors LMWH Heparin Aspirin

Beware of unintended targets

Net Clinical Benefit Benefit  thrombotic events Risk  bleeding Key factors modifying rates (and balance) Antithrombotics: ASA, UFH, LMWH, GP IIb/IIIa, clopidogrel, lytics, combinations Patient factors (elderly, renal fx) Procedures

Bleeding is Common

CRUSADE Site Distribution Total sites = 463 (Active sites = 409) WA (7) VT (1) ME (0) MT (0) ND (1) MI NH (2) MN (4) OR (5) NY (37) MA (11) ID (0) SD (2) WI (5) MI (22) RI (1) WY (0) PA (37) CT (8) IA (5) NJ (10) NE (4) OH (30) IN (7) NV (1) IL (14) DE (3) UT (1) WV (3) VA (16) MD (13) CO (8) KS (3) MO (12) KY (8) DC (1) CA (35) NC (15) TN (11) OK (9) SC (6) AZ (9) AR (3) NM (2) MS (6) AL (11) GA (15) LA (8) TX (17) FL (33) AK (0) HI (1) 150,00 patients included as of September 2005

CRUSADE Bleeding Risks – Transfusion by Age 14.9% overall 10.3% non-CABG Through Q2 2004 (n=74,271) -- Yang, J Am Coll Cardiol 2005;46:1490-5

Bleeding is Bad

30 Day Death According to Bleeding OASIS Registry, OASIS-2, CURE (n=34,146) 12 10 Bleeding Cumulative Events, % 8 5-fold  risk 6 4 2 No Bleeding 5 10 15 20 25 30 Days No. at Risk No Bleeding 33676 33419 33157 32990 32879 32769 32710 Bleeding 470 459 440 430 420 410 408 Eikelboom Circulation 2006;114: 774 - 782; published online August 14 2006

30 Day to 6 Month Death According to Bleeding Bleeding and Outcomes OASIS Registry, OASIS-2, CURE (n=34,146) Bleeding and 30-Day Risk* Event HR Death 5.37 MI 4.44 Stroke 6.46 Death days bleeding no bleeding 30 Day to 6 Month Death According to Bleeding *adjusted with bleeding as time-dependent covariate, baseline factors, propensity Eikelboom Circulation 2006;114: 774 - 782; published online August 14 2006

Prognostic Implications of Bleeding Risk Ratio of Early Death ACS1 PCI2 CABG3 Bleeding 2 to 8* 3.7* to 8 Transfusion 3.5 to 4.0* 2.4* to 7 1.7 to 1.9* 14 selected studies: 1. Moscucci Eur Heart J 2003, Eikelboom Circulation 2006, Rao Am J Cardiol 2005, Rao JACC 2006, Rao JACC 2005, Yang JACC 2005, Rao JAMA 2005 2. Rao Am J Cardiol 2005, Stone J Invasive Cardiol 2004, Kinnaird Am J Cardiol 2003, Attubato Am J Cardiol 2004, Manoukian 2005 3. Kuduvalli Eur J Cardiothorac Surg 2005 , Engoren Ann Thorac Surg 2002 * adjusted

Transfusion (Blood Cell Allogeneic Transplantation) May Be Part of the Problem

blood saves lives 1948

Transfusion and Outcome (non-CABG population) -- Yang, J Am Coll Cardiol 2005;46:1490-5

Transfusion Post PCI: REPLACE 2 One Year Mortality One-year mortality was also increased in transfused patients, with an OR of 4.26 (95% CI= 2.25-8.08; p<0.0001) after adjusting for differences in baseline demographic variables. P<0.0001 -Manoukian SV et al. 2005

30 Day Survival By Transfusion Group GUSTO IIb, PURSUIT, PARAGON B (n=24,000; 10% transfused) 0.9 0.92 0.94 0.96 0.98 1 5 10 15 20 25 30 35 Days Survival Rates No Transfusion Transfusion OR 3.9, time-dependent covariate analysis adjusted for baseline characteristics, bleeding propensity, transfusion propensity, & nadir HCT -- Rao SV, et. al., JAMA 2004

Cochrane Collaboration Risk reduction with restrictive transfusion strategy N=10 randomized trials Hill SR, et. al. Cochrane Database of Systematic Reviews 2004

Properties of packed RBCs Low 2,3 DPG* High O2 affinity* Depleted of Nitric Oxide NO plays a fundamental role in O2 exchange† Effects of Transfusion *Welch HG, et. al. Ann Int Med 1992 †Stamler JS, et. al. Science 1997 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

Does Prevention of Bleeding Improve Long-term Outcome?

Cumulative Percentage of Events Time from randomization in days 1-Year Mortality All patients 3.0 Heparin+GPIIb/IIIa N=3008 Bivalirudin 2.5 N=2994 2.5% 2.0 1.9% Cumulative Percentage of Events 1.5 1.0 p-value=0.16 0.5 0.0 60 120 180 240 300 360 Time from randomization in days

Bleeding vs. MI – Risk for mortality Multivariable analysis of predictors of 1-year mortality Independent Variable Odds Ratio (95% CI) P Value CrCl <30 mL/min 10.28 (3.84-27.49) <0.001 CHF 4.26 (2.75-6.58) <0.0001 Major hemorrhage 3.53 (1.91-6.53) MI at 30 days 2.59 (1.52-4.45) 0.0005 Hx angina 2.11 (1.22-3.62) 0.007 Diabetes 1.59 (1.08-2.36) 0.018 Key Message: The REPLACE-2 regression analysis indicates that major bleeding was a significant predictor of mortality at 1 year, more so than MI or urgent revascularization. Attubato MJ et al. Am J Cardiol. 2004;94(6 suppl 1):39E.

Major Bleeding: 9 Days HR 0.53 95% CI 0.45-0.62 P<<0.00001 Enoxaparin 0.04 HR 0.53 95% CI 0.45-0.62 P<<0.00001 0.03 Cumulative Hazard 0.02 Fondaparinux 0.01 0.0 1 2 3 4 5 6 7 8 9 NEJM 2006;354: March 14 Days

Mortality: Day 30 HR 0.83 95% CI 0.71-0.97 P=0.022 Enoxaparin 0.03 Fondaparinux 0.02 Cumulative Hazard HR 0.83 95% CI 0.71-0.97 P=0.022 0.01 0.0 3 6 9 12 15 18 21 24 27 30 NEJM 2006;354: March 14 Days

Relation Between Bleeding Reduction at 9 Days and Long Term Mortality Deaths at 6 months Patients with Enox Fonda Difference No Bleed 526 523 -3 Minor Bleed 33 13 -20 Major Bleed 79 38 -41 Total Deaths: 638 574 -64 - 61 (95.3%) 95.3% of difference in death at 6 months is explained by bleeding within the first 9 days NEJM 2006;354: March 14

Impact on Ischemic and Bleeding Endpoints and Long-term Mortality Early Late (re)-MI bleeding mortality GUSTO V   = REPLACE-2 =   SYNERGY =  = OASIS-5 =   EXTRACT   ? ACUITY =  ? death/MI

How Might Bleeding Increase Long-Term Mortality? Hemodynamic compromise Hyperadrenergic state Transfusion-induced microcirculatory disorder, NO depletion, immunologic effects Inflammatory response Discontinuation of antithrombotics

What else can be done to reduce bleeding?

Excessive Dosing of Anticoagulants by Age 42% of patients got excess -- Alexander JAMA 2005;294:3108-3116

Dosing Combinations and Transfusions: Heparin + GP IIb-IIIa Inhibitors* * Among patients receiving both Heparin (UFH or LMWH) and GP IIb-IIIa Inhibitors -- Alexander JAMA 2005;294:3108-3116

ACS: Importance of Bleeding Bleeding is at least as bad as recurrent MI with respect to long term impact Each is associated with worse long term outcome and should be prevented Strategies are needed to prevent thrombosis AND to prevent (or minimize) bleeding