Walking The Tight Rope In ACS: Balancing Safety And Efficacy Stefan - PowerPoint PPT Presentation

UCR Uppsala Clinical Research Center Walking The Tight Rope In ACS: Balancing Safety And Efficacy Stefan James, MD, PhD Associate Professor Head of Interventional Cardiology Uppsala Clinical Research Center University Hospital Uppsala, Sweden Astra Zeneca, Daiichi Sankyo, Eli Lilly, BMS, Terumo, Grant/Research Support Consulting Fees/Honoraria Merck, Medtronic, Boston Scientific

Risk for ischemic events Risk for bleeding

Do we have a balance between thrombosis and bleeding in ACS or… Thrombosis Bleeding Irreversible Reversible Tissue Injury Transfusion … is bleeding the inevitable cost of improved antithrombotic efficacy?

Important issues in ACS and antithrombotic treatment: 1. How common is bleeding? 2. What are the outcomes after bleeding complications? 3. How to identify patients with increased risk? 4. Treatment of bleeding complications?

Frequency of Major Bleeding in ACS GRACE Registry: Worldwide Argentina, Australia, Austria, Belgium, Brazil, Canada, France, Germany, Italy, New Zealand, Poland, Spain, United Kingdom, United States 1999-2002 6 5 % "Major" Bleeding Overall 4 Unstable angina 3 NSTEMI STEMI 2 1 N=24,045 0 GRACE Registry Transfusion ≥2 units PRBC Decrease in hct of ≥10% Moscucci M, et al. Eur Heart J 2003; 24: 1815-1823. Death or hemorrhagic stroke or SDH

Incidence of Major Bleeding in Randomised ACS Trials 12 10 8 % 6 4 2 0 GUSTO IIb OASIS-2 PRISM- PURSUIT PRISM CURE SYNERGY PLATO PLUS

Comparison of incidence of Major Bleeding across the trials Differences in:  Timing of Bleeds  Definitions – TIMI, GUSTO, OASIS, ISTH  Co-interventions – Combination of antithrombotic drugs – Procedures (PCI, CABG)  Transfusion strategies

PLATO Bleedings Ticagrelor Clopidogrel % 14 p=NS 12 10 p=NS 8 p=NS 6 4 2 0 PLATO TIMI Fatal/Life- Major Major threatening Wallentin et al. NEJM Aug 30, 2009

PLATO Bleedings Ticagrelor Clopidogrel % 14 p=NS 12 10 p=NS 8 p=NS 6 p=0.03 4 p=0.03 2 0 PLATO PLATO TIMI TIMI Fatal/Life- Major Major threatening Major Major Non-CABG Non-CABG Wallentin et al. NEJM Aug 30, 2009

Is bleeding dangerous?

GRACE Registry Bleeding Predicts In-hospital Deaths n = 24 045 patients who developed (open bars) or Moscucci M, et al. Eur Heart J 2003; 24: 1815-1823. did not develop major bleeding (closed bars)

OASIS Registry, OASIS-2, CURE “Dose - related” association with mortality N = 34,126 Eikelboom JW, et al. Circulation 2006

PURSUIT, PARAGON, GUSTO IIb Dose-related Association N = 26,452 Kaplan Meier Curves for 30 Day Death, Stratified by Bleed Severity 1 0.95 0.9 0.85 0.8 0.75 0.7 0 5 10 15 20 25 30 Days to Death GUSTO None Mild Moderate Severe Rao SV, et.al. AJC 2005

Why is bleeding dangerous?

Transfusion in Acute Coronary Syndromes and 30-day mortality 3.77 (3.14, 4.52) Adjusted for transfusion propensity 3.54 (2.96, 4.23) Adjusted for baseline characteristics Adjusted for baseline 3.94 (3.26, 4.75) characteristics, bleeding propensity, transfusion propensity & nadir HCT -4.0 1.0 10 Rao SV, et. al., JAMA 2004;292:1555-1562

OASIS Registry, OASIS-2, CURE N = 34,126 Major No Major Hazard P- Outcome Bleed Bleed (Adjusted) Value 60/470 833/33676 5  37 <0  0001 Death (12  8%) (2  5%) 4  44 46/436 1375/33710 <0  0001 MI (10  6%) (4  1%) 12/469 187/33677 Stroke 6.46 <0.0001 (2.6%) (0.6%) Eikelboom JW et al, Circulation 2006

Risk stratification

GRACE Risk Score and 1 year Mortality/MI

Risk Assessment GRACE Risk Score CRUSADE Bleeding Score (Death / MI) Age Age Killip class Killip class Heart rate Heart rate SBP SBP (U-shape) Female gender Female gender Creatinine Creatinine clearance Diabetes mellitus Diabetes mellitus Positive biomarkers Hematocrit ST-segment deviation Previous vascular disease Cardiac arrest CRUSADE = Can Rapid risk stratification of Unstable angina patients Suppress ADverse outcomes with Early implementation of the ACC/AHA guidelines, GRACE = Global Resgistry of Acute Coronary Events, MI = myocardial infarction, SBP = systolic blood pressure. Subherwal S, et al. Circulation . 2009;119:1873-82. Granger CB, et al. Arch Intern Med . 2003;163:2345-53. Eagle KA, et al. JAMA . 18 2004;291:2727-33.

Implications?

Optimal therapeutic window for antiplatelet drugs? Becker & Gurbel. Thromb Haemost 2010

OASIS-5 Fondaparinux vs Enoxaparin (2/3 on ASA + Clopidogrel) 0.0 0.01 0.02 0.03 0.04 0.05 0.06 Death/MI/RI: Day 9 Cumulative Hazard HR 1.01 95% CI 0.90-1.13 Enoxaparin Fondaparinux 0 1 2 3 4 5 6 7 8 9 Days N = 20,078 OASIS-5 Investigators NEJM 2006

OASIS-5 Less Bleeding = Less Deaths Bleeding Reduced by 50% Deaths Reduced by 17% 0.04 0.04 Enoxaparin Enoxaparin Enoxaparin Enoxaparin HR: 0.52 HR: 0.52 0.03 0.03 Cumulative Hazard Cumulative Hazard Cumulative Hazard Cumulative Hazard 95% CI: 0.44-0.61 95% CI: 0.44-0.61 0.03 0.03 p<0.001 p<0.001 Fondaparinux Fondaparinux 0.02 0.02 0.02 0.02 0.01 0.01 Fondaparinux Fondaparinux 0.01 0.01 HR: 0.83 HR: 0.83 95% CI: 0.71-0.97 95% CI: 0.71-0.97 p=0.02 p=0.02 0.0 0.0 0.0 0.0 0 0 3 3 6 6 9 9 12 12 15 15 18 18 21 21 24 24 27 27 30 30 0 0 1 1 2 2 3 3 4 4 5 5 6 6 7 7 8 8 9 9 Days Days Days Days OASIS-5 Investigators NEJM 2006

OASIS-5 Less Bleeding = Less Deaths Bleeding Reduced by 50% Deaths Reduced by 17% 0.04 0.04 Enoxaparin Enoxaparin Enoxaparin Enoxaparin HR: 0.52 HR: 0.52 0.03 0.03 Cumulative Hazard Cumulative Hazard Cumulative Hazard Cumulative Hazard 95% CI: 0.44-0.61 95% CI: 0.44-0.61 0.03 0.03 p<0.001 p<0.001 Fondaparinux Fondaparinux 0.02 0.02 0.02 0.02 0.01 0.01 Fondaparinux Fondaparinux 0.01 0.01 HR: 0.83 HR: 0.83 95% CI: 0.71-0.97 95% CI: 0.71-0.97 p=0.02 p=0.02 0.0 0.0 0.0 0.0 0 0 3 3 6 6 9 9 12 12 15 15 18 18 21 21 24 24 27 27 30 30 0 0 1 1 2 2 3 3 4 4 5 5 6 6 7 7 8 8 9 9 Days Days Days Days OASIS-5 Investigators NEJM 2006

Bivalirudin 30-Day Major Adverse CV Events Heparin + GPIIb/IIIa inhibitor (n=1802) Bivalirudin monotherapy (n=1800) 8 Major Adverse CV Events, %* 7 5.5% 6 5.5% 5 4 3 2 HR=1.00 (95% CI, 0.75, 1.32) 1 P =0.98 0 0 5 10 15 20 25 30 Time, Days Bivalirudin Should Probably Always Be Combined with UFH CV = cardiovascular. 24 Stone GW, et al. N Engl J Med . 2008;358:2218-30.

30 Day Major Bleeding (non-CABG) Heparin + GPIIb/IIIa inhibitor (n=1802) Bivalirudin monotherapy (n=1800) Major Bleeding (%) Primary Endpoint 8.4% 5.0% HR [95%CI] = 0.59 [0.45, 0.76] P<0.0001 Time in Days Number at risk Bivalirudin 1800 1697 1675 1668 1664 1653 1590 Heparin + GPIIb/IIIa 1802 1651 1617 1606 1598 1581 1511

30 Day Mortality Heparin + GPIIb/IIIa inhibitor (n=1802) Bivalirudin monotherapy (n=1800) Death (%) 3.1% 2.1% HR [95%CI] = 0.66 [0.44, 1.00] P=0.048 Time in Days Number at risk Bivalirudin 1800 1758 1751 1746 1742 1729 1666 Heparin + GPIIb/IIIa 1802 1764 1748 1736 1728 1707 1630

Ticagrelor vs. Clopidogrel Primary Endpoint 12 Clopidogrel HR 0.84 (CV death, MI, Stroke) 11.7 11 (0.77 – 0.92) 10 9.8 p=0.0003 Cumulative incidence (%) 9 NNT = 54 Ticagrelor 8 7 CV death 6 Clopidogrel 5 5.1 HR 0.79 4 (0.69 – 0.91) 4.0 Ticagrelor 3 p=0.001 2 NNT = 90 1 0 0 60 120 180 360 Days after randomization Wallentin L, et al. N Engl J Med. 2009;361:1045-57.

Primary safety event: Major bleeding * 15 K-M estimated rate (% per year) Clopidogrel 11.6 Ticagrelor 11.5 10 5 HR 0.99 (95% CI = 0.89 – 1.10), p=0.88 0 0 60 120 180 240 300 360 Days after randomization No. at risk Ticagrelor 6,651 5,235 4,947 4,755 3,726 2,741 2,503 Clopidogrel 6,585 5,215 4,984 4,786 3,753 2,754 2,496 * PLATO definitions

Consistency Across Subgroups Major Bleeding KM % at Month 12 Hazard Ratio Total P Value Characteristic (95% CI) Patients Ti. Cl. HR (95% CI) (Interaction) New ST elevation / LBBB at rand. No 10949 13.4 12.6 1.07 (0.95, 1.19) 0.30 Yes 7471 9.0 9.2 0.98 (0.83, 1.14) Age Group <75 Years 15574 11.1 10.8 1.04 (0.94, 1.15) 1.00 ≥ 75 Years 2846 14.2 13.3 1.04 (0.84, 1.29) Weight Group <60 kg 1296 12.6 15.2 0.82 (0.60, 1.12) 0.12 ≥60 kg 17086 11.5 10.9 1.06 (0.96, 1.16) Sex Male 13184 11.9 11.4 1.05 (0.94, 1.16) 0.76 Female 5237 10.7 10.5 1.01 (0.85, 1.21) Planned Treatment Approach Invasive 13236 11.5 11.6 0.99 (0.89, 1.10) 0.12 Medically managed 5185 11.9 10.3 1.17 (0.98, 1.39) Previous TIA / Non-hemorrhagic Stroke No 17284 11.4 11.0 1.04 (0.95, 1.14) 0.77 Yes 1136 14.6 14.9 0.99 (0.71, 1.37) Medical History of DM No 13800 10.8 10.0 1.08 (0.97, 1.20) 0.21 Yes 4621 14.1 14.8 0.95 (0.81, 1.12) 0.2 1.0 2.0 0.5 Ticagrelor better Clopidogrel better Wallentin L, et al. N Engl J Med. 2009;361:1045-57. (suppl. material)