Shamir Mehta, MD, MSc, FRCPC Director Interventional Cardiology Associate Professor of Medicine McMaster University Hamilton, Ontario, Canada The Balancing Act in ACS Continues – But with Better Outcomes? A Critical Appraisal of Recent Clinical Data

Antithrombotics in UA/NSTEMI Patients in the Last Decade: Increased Efficacy at the Price of Increased Bleeding 16-20% 12-15% 8-12% 6-10% 4-8% Death / MIBleeding 1988 ASA 1992 ASA+ Heparin 1998 ASA+ Heparin+ Anti- GPIIB/IIIA 2003 ASA+ LMWH + Clopidogrel + Intervention

Bleeding is Associated with an Increased 30-Day Mortality in NSTEMI Patients Rao et al. Am J Cardiol 2005;96: N = 26,452 ACS patients from GUSTO IIb, PURSUIT and PARAGON A&B Log-rank p values are for all 4 categories, 0.20 for no bleeding vs. mild bleeding, for mild vs. moderate bleeding, and for moderate vs. severe bleeding. Adjusted HR (95% CI) % Death 2.9% %1.6 ( ) 5.9%2.7 ( ) 25.7%10.6 ( ) GUSTO bleedingNoneMildModerateSevere Days to Death Cumulative survival

Procedure-Related and Non-Procedure-Related Bleeds are Associated with an Increased 30-Day Mortality in NSTEMI Patients Rao et al. Am J Cardiol 2005;96: Procedure-related GUSTO bleeds Non-procedure-related GUSTO bleeds Risk of death (Hazard Ratio) None 1.0 Mild 1.3 Severe None 1.0 Mild 2.1 Moderate 2.5 Severe 10.9 Moderate 3.7 N = 26,452 ACS patients from GUSTO IIb, PURSUIT and PARAGON A & B

OASIS Registry, OASIS-2, CURE Strong, Independent Association Outcome Major Bleed No Major Bleed Hazard (Adjusted) P- Value Death 60/470 (12.8%) 833/33676 (2.5%) 5.37 ( ) < MI 46/436 (10.6%) 1375/33710 (4.1%) 4.44 ( ) < Stroke 12/469 (2.6%) 187/33677 (0.6%) 6.46 ( ) < Eikelboom JW et al. Circulation. 2006;114(8): N = 34,126

Increased Mortality at Days 30/180 in Patients with Major Bleeds by Day 9 (All Patients) Budaj et al. JACC. 2006;abstract Adjusted HR (95% CI) at day 30: 5.06 ( ); at day 180: 3.16 ( ) Major Bleed 9 days No Major Bleed 9 days Cumulative Hazard Days

Increased Risk of MI at Days 30/180 in Patients with Major Bleeds by Day 9 (All Patients) Adjusted HR (95% CI) at day 30: 5.01 ( ); at day 180: 2.99 ( ) Budaj et al. JACC. 2006;abstract Days 0.00 Cumulative Hazard Major Bleed 9 days No Major Bleed 9 days

Increased Risk of Stroke at Days 30/180 in Patients with Major Bleeds by Day 9 (All Patients) Adjusted HR (95% CI) at day 30: 4.77 ( ); at day 180: 3.30 ( ) Budaj et al. JACC. 2006;abstract Cumulative Hazard Days Major Bleed 9 days No Major Bleed 9 days

Potential Mechanisms for the Higher Morbidity/Mortality Associated with Bleeding 1.Activation of clotting cascade as a response to bleeding--may lead to recurrent events in at the site of plaque rupture 2.Cessation of antithrombotic therapies (eg. ASA, clopidogrel, heparin) after a bleeding event 3.Adverse effects of hypotension due to the bleed 4.Adverse effects of transfusion 5.Common risk factors for bleeding and adverse outcome

Coagulation Cascade and New Anticoagulants Rosenberg & Aird. N Engl J Med. 1999;340:1555–64. Wessler & Yin. Thromb Diath Haemorrh. 1974;32:71–8. Inhibition of one molecule of factor Xa can inhibit the generation of 50 molecules of thrombin Intrinsic pathway Extrinsic pathway 1 50 Xa X II Fibrin Fibrinogen Clot Xa Va PL Ca 2+ IIa VIIIa Ca 2+ PL IXa Bivalirudin Fondaparinux

Herbert JM et al. Cardiovasc Drug Rev. 1997;15:1. van Boeckel CAA et al. Angew Chem, Int Ed Engl. 1993;32:1671.  Once daily administration  Rapid onset (C max /2=25 min)  Effects reversible with administration of activated Factor VII (Novoseven®)  No liver metabolism  No protein binding (other than AT)  No risk of pathogen contamination  No reported cases of HIT  No dose adjustment necessary in elderly Fondaparinux: A Synthetic Inhibitor of Factor Xa

IIaII Fibrinogen Fibrin clot Extrinsic pathway Intrinsicpathway AT Xa Fondaparinux Xa Antithrombin Fondaparinux Mechanism of Action Olson et al. J Biol Chem. 1992;267: Turpie et al. N Engl J Med. 2001;344: THROMBIN Recycled

Ephesus N = 1817 Pentathlon 2000 N = 1584 Penthifra N = 1250 Pentamaks N = 724 Overall Odds Reduction % odds reduction Fondaparinux better Enoxaparin better % 28.1% 61.6% 63.1% 55.3% P = Overall odds reduction for proximal DVT = 57.4% [CI: ]; p = Overall Efficacy of Fondaparinux vs Enoxaparin in VTE Prevention: Meta- analysis Turpie et al. Arch Intern Med. 2002;162:

OASIS-5: A Randomized, Double-Blind, Double-Dummy Trial 20,078 patients with UA/NSTEMI Fondaparinux 2.5 mg s.c. od up to 8 days Aspirin, Clopidogrel, anti-GPIIb/IIIa, planned Cath/PCI as per local practice Randomization Enoxaparin 1 mg/kg s.c. bid for 2-8 days 1 mg/kg s.c. od if ClCr<30mL/min Michelangelo OASIS-5 Steering Committee. Am Heart J. 2005;150:1107.e1-.e10. OASIS 5 Investigators. I

Majority of Patients Undergoing Catheterization in OASIS-5 Went Early Mehta et al. JACC 2006; abstract % 17.4% 38.4% <24 hrs24-48 hrs>48 hrs Patients (%) N = 14,206

Similar Efficacy Outcome Rates in Both Groups at Day 9 OASIS-5 Investigators. N Engl J Med. 2006;354: %5.7%Death/MI/RI 1.9% Refractory Ischemia 2.6%2.7%MI 1.8%1.9%Death 4.1% Death/MI FondaparinuxEnoxaparin Non-inferiority Margin = Hazard Ratio Fondaparinux better Enoxaparin better

Major Bleeding: 9 Days Days Cumulative Hazard HR % CI P<< Enoxaparin Fondaparinux

Mortality: Day 30 Days Cumulative Hazard HR % CI P=0.02 Enoxaparin Fondaparinux

Efficacy at 6 Months OASIS 5 Investigators. N Engl J Med. 2006;354: %12.5% Death/MI/Stroke 12.3%13.2%Death/MI/RI 1.3%1.7%Stroke 6.3%6.6%MI 5.8%6.5%Death 10.5%11.4%Death/MI NS P value Fondaparinux betterEnoxaparin better Enoxaparin FondaparinuxHazard Ratio

All Types of Bleeding were Reduced in the Fondaparinux Group at Day 9 OutcomeEnoxaparin (%) Fondaparinux (%) p value No. Randomized10,02110,057 Total bleeds7.33.3<0.001* Major bleeds4.12.1<0.001 TIMI major + fatal bleeds <0.001** Fatal bleeds Minor bleeds3.21.1<0.001 * HR (95% CI): 0.44 ( );**HR (95% CI): 0.55 ( ) OASIS-5 Investigators. N Engl J Med. 2006;354:

The Reduction in Major Bleeding with Fondaparinux was Consistent in Almost All Categories Major bleeding at day 9 Enoxaparin (No. patients) Fondaparinux (No. Patients) p value No. Randomized10,02110,057 Total Major Bleeds412 (4.1%)212 (2.1%)<0.001 Intracranial77NS Requiring surgery7741<0.001 Retroperitoneal379<0.001 Transfusion282160<0.001 Associated with death at study end 7938<0.001 OASIS-5 Investigators. N Engl J Med. 2006;354:

OASIS-5 – The Reduction in Major Bleeding at Day 9 Was Independent of Renal Function OASIS-5 Investigators. N Engl J Med. 2006;354: *88 µmol/L Creatinine 1.9%3.4% <1.04 mg/dL* (n = 8871) 2.4%4.7% >1.04 mg/dL* (n = 11,124) FondaparinuxEnoxaparin Interaction p value = 0.71 Hazard Ratio Fondaparinux betterEnoxaparin better

Major Bleeding was Reduced with Fondaparinux Irrespective of Creatinine Clearance CrCl (mL/min) Enoxaparin* (%) Fondaparinux (%) P value < 30 (n = 535) > 30 (n = 19442) <0.001 OASIS 5 Investigators. N Engl J Med. 2006;354: *Enoxaparin dose reduced to 1 mg/kg od according to label if clearance of creatinine was below 30 mL/min

The Reduction in Major Bleeding at Day 9 with Fondaparinux was Consistent in All Subgroups OASIS-5 Investigators. N Engl J Med 2006;354: Characteristics N Enoxaparin Fondaparinux % Age ≥ 65 yr12, < 65 yr Sex Male12, Female Creatinine At or above median*11, Less than median* Heparin at randomization Yes No16, Revascularization in 9 days Yes No12, < Catheterization laboratory in center Yes 14, No Fondaparinux betterEnoxaparin better * The median value for creatinine was 88 µmol/L (1.04 mg/dL) Interaction p value

Major Bleeding at Day 30 and GP IIb/IIIa Use HR 0.63 P< HR 0.60 P = N = 16448N = 3630

Fondaparinux Superior to Enoxaparin for Bleeding Irrespective of Rx Duration HR 0.69 P = HR 0.55 P < HR 0.67 P = N = 5581N = 8712N = 5785

Incidence of Major Bleeds with Enoxaparin in OASIS-5 is Consistent with Previous Trials EnoxaparinEnoxFondaEnoxFonda SYNERGY 1 In-hospital ESSENCE 2 Day 30 A to Z 3 Day 6 Meta- analysis 4 Day 7 OASIS 5 Day 9 OASIS 5 Day 9 OASIS 5 Day 30 OASIS 5 Day 30 TIMI major+ fatal bleeds 9.1%-0.9%- 1.3%0.7%1.5%1.0% Major bleeds -6.5%-4.7% 4.1%2.2%5.0%3.1% 1.SYNERGY Investigators. JAMA. 2004;292: Cohen et al. N Engl J Med. 337: Blazing et al. JAMA 2004;292: Petersen et al. JAMA. 2004;292:89-96.

Fondaparinux-Associated Reduction of Bleeding Translated into Long-Term Mortality Benefit Patients withEnoxaparinFondaparinuxDifference No Bleed Minor Bleeds Major Bleeds Total No. of deaths at 180 days OASIS-5 Investigators. N Engl J Med. 2006;354:

Days Cumulative Hazard Enoxaparin Fondaparinux HR % CI P<< Net Clinical Benefits at 6 Months (Death, MI, RI, Major Bleeding)

Efficacy and Safety in PCI Patients Outcome Day 9Enox N = 3072 Fonda N = 3105 HR (95% CI)P value Death, MI or Stroke190 (6.2)197 (6.3)1.03 ( ) 0.79 Death38 (1.2)37 (1.2)0.96 ( ) 0.87 MI154 (5.0)160 (5.2)1.03 ( ) 0.80 Stroke13 (0.4)12 (0.4)0.91 ( ) 0.82 Major Bleeding155 (5.1)73 (2.4)0.46 ( ) < Death, MI, stroke, major bleeding 318 (10.4)255 (8.2)0.78 ( ) Mehta et al. JACC. 2006;abstract

PCI < 24 Hours of Randomization Outcome Day 9 Enox N = 1420 Fonda N = 1414 HR (95% CI)P value Death, MI or Stroke77 (5.4)75 (5.3)0.98 ( ) 0.89 Death19 (1.3) 1.01 ( ) 0.98 MI55 (3.9)53 (3.8)0.97 ( ) 0.86 Stroke8 (0.6)6 (0.4)0.76 ( ) 0.60 Major Bleeding69 (4.9)33 (2.3)0.48 ( ) Death, MI, stroke, major bleeding 135 (9.5)103 (7.3)0.76 ( ) Mehta et al. JACC. 2006;abstract 821-5

RR % CI P < RR % CI P = 0.78 RR % CI P < RR % CI P = Major Bleeding 48 hours after PCI Abrupt/threatened abrupt closure N = 1277 N = 1275 N = 1633 N = 1648 N = 1275 RR % CI P=0.62 RR % CI P=0.026 OASIS 5: Fonda vs Enox alone and vs UFH + Enox Mehta et al. Presented at WCC/ESC Hotline Session, Barcelona, % Events Fonda Enox alone UFH + Enox Fonda Enox alone UFH + Enox 1 N = 1633 N = N = 1277 N = 1633 N = 1648 N = 1277 N = 1275

Open Label UFH Prior to PCI Data After Protocol Amendment No UFH Prior to PCIUFH Prior to PCI Enox (%) Fonda (%) HR (95% CI) Enox (%) Fonda (%) HR (95% CI) Number randomized Death/MI/Stroke/Maj or Bleed 90 (11.1)80 (10.1)0.90 ( ) 9 (11.2)4 (5.3)0.45 ( ) Death/MI/Stroke60 (7.4)57 (7.2)0.97 ( ) 5 (6.3)3 (4.0)0.62 ( ) Major Bleed35 (4.3)26 (3.3)0.75 ( ) 5 (6.2)1 (1.3)0.21 ( ) Abrupt Closure13 (1.6)15 (1.9)1.18 ( ) 01 (1.3)-- Threatened abrupt closure 38 (4.7)31 (3.9)0.83 ( ) 2 (2.5)4 (5.3)2.13 ( ) Catheter Thrombus4 (0.5)9 (1.1)2.30 ( ) 01 (1.3)*-- Vascular Access Site complication 56 (6.9)22 (2.8)0.40 ( ) 5 (6.3)1 (1.3)0.21 ( ) Final 1758 patients randomized *represents 1 patient with low dose of UFH 5 IU/kg vs mean dose of 47 IU/kg Mehta et al. JACC. 2006;abstract 821-5

Adding UFH to Fondaparinux is Safe and Preserves the Lower Bleeding with Fondaparinux vs Enoxaparin EnoxFondaHRCI No UFH post- Randomization 1.2 (n = 1277) 0.5 (n = 1313) UFH or equivalent placebo mandated by protocol during PCI 1.1 (n = 1229) 0.4 n = 1279) Open Label UFH2.7 (n = 598) 1.3 (n = 543) Overall1.5 (n = 3104) 0.6 (n = 3135) Yusuf S. et al. N Engl J Med. 2006; 354:2829.

PCI-Related Complications and MACE (death, MI or stroke) HR 0.79 P<< HR 0.81 P< HR 0.75 P<< Mehta et al. JACC 2006;abstract 821-5

Advantage of a Single Dose with Fondaparinux The advantage of a single dose for all patients is clear; in this era of recognition of the common occurrence of medical errors that lead to harm, a single dose would result in fewer medical errors because complex calculations of the type identified in the CRUSADE registry would not be needed Califf. JAMA. 2006;295:

ACUITY Study Design – Patient Flow UFH/Enox + GP IIb/IIIa (N = 4,603) Bivalirudin + GP IIb/IIIa (N = 4,604) Bivalirudin Alone (N = 4,612) R* Moderate-high risk unstable angina or NSTEMI undergoing an invasive strategy GPI upstream (N = 2294) GPI CCL for PCI (N = 2309) GPI upstream (N = 2311) GPI CCL for PCI (N = 2293) Aspirin in all Clopidogrel dosing and timing per local practice Aspirin in all Clopidogrel dosing and timing per local practice *Stratified by pre-angiography thienopyridine use or administration Moderate- high risk ACS Stone GW, et al. N Engl J Med Nov 23;355(21):

ACUITY Primary Outcome: No Difference in Ischemic Outcomes or Major Bleeding with Bivalirudin vs Heparin in Presence of GPI P Sup = 0.93P Sup = 0.39 P Sup = 0.38 Stone GW, et al. N Engl J Med Nov 23;355(21):

ACUITY Primary Endpoint: Lower Bleeding with BIV vs Hep+IIb/IIIa P NI < P Sup = P NI = P Sup = 0.32 P NI < P Sup < Stone GW, et al. N Engl J Med Nov 23;355(21):

ACUITY: Components of the Ischemic Composite UFH/Enoxaparin + GPI vs. Bivalirudin + GPI vs. Bivalirudin Alone P Sup = 0.32P Sup = 0.34P Sup = 0.35P Sup = 0.78 Stone GW, et al. N Engl J Med Nov 23;355(21):

ACUITY: Net Clinical Outcome Composite UFH/Enoxaparin + IIb/IIIa vs. Bivalirudin Alone Men (n = 6444) Women (n = 2771) Diabetes (n = 2585) No diabetes (n = 6630) CrCl ≥60 (n = 6993) CrCl <60 (n = 1644) Age <65 (n = 5051) Age ≥65 (n = 4164) Risk ratio ±95% CI Risk ratio ±95% CI Bival Alone UFH/Enox + IIb/IIIa 7.8% 12.9% US (n = 5224) OUS (n = 3991) 10.6% 9.5% 8.9% 16.1% 10.8% 9.8% 9.5% 11.6% 9.2% 14.7% 11.8% 11.5% 10.4% 16.8% 13.7% 10.9% 13.5% PP int 0.86 ( ) 0.88 ( ) 0.90 ( ) 0.82 ( ) 0.86 ( ) 0.96 ( ) 0.79 ( ) 0.90 ( ) 0.87 ( ) 0.86 ( ) RR (95% CI) Bivalirudin alone better UFH/Enox + IIb/IIIa better Stone GW, et al. N Engl J Med Nov 23;355(21):

ACUITY: Net Clinical Outcome Composite UFH/Enoxaparin + IIb/IIIa vs. Bivalirudin Alone Yes (n = 3197) No (n = 6008) Low (0-2) (n = 1291) Intermed (3-4) (n = 4407) High (5-7) (n = 2449) Elevated (n = 5368) Normal (n = 3841) Risk ratio ±95% CI Risk ratio ±95% CI Bival Alone UFH/Enox + IIb/IIIa 9.2% 11.3% 12.2% 11.1% PP int 0.76 ( ) 1.02 ( ) 12.2% 7.1% 13.3% 9.4% 0.92 ( ) 0.75 ( ) < % 8.6% 13.7% 10.6% 0.96 ( ) 0.81 ( ) Biomarkers (CK/Trop) ST Deviation TIMI Risk Score Pre Thienopyridine 6.4%10.2%0.63 ( ) %10.2%0.92 ( ) %15.2%0.92 ( )0.36 Yes (n = 5192) No (n = 4023) RR (95% CI) Bivalirudin alone better UFH/Enox + IIb/IIIa better Stone GW, et al. N Engl J Med Nov 23;355(21):

ACUITY: Net Clinical Outcome Composite UFH/Enoxaparin + IIb/IIIa vs. Bivalirudin Alone Bivalirudin alone better UFH/Enox + IIb/IIIa better Bival Alone UFH/Enox + IIb/IIIa PP int %13.3%0.87 ( ) %18.2%0.97 ( ) %6.5%0.78 ( ) %9.8%0.85 ( ) %9.4%0.98 ( ) %14.4%0.87 ( ) %10.0%0.91 ( ) %7.1%0.94 ( ) %12.6%0.84 ( )0.21 RR (95% CI) PCI (n = 5170) CABG (n = 1048) Medical (n = 2989) No prior AT (n = 3290) Consistent Rx (n = 5519) Crossover (n = 3211) A-thrombin crossover Early (<3.0 h) Intermediate ( h) Late (≥19.7 h) Risk ratio ±95% CI Risk ratio ±95% CI Actual treatment Rand. to angio/interv. tertiles Stone GW, et al. N Engl J Med Nov 23;355(21):

Summary Fondaparinux reduces bleeding and mortality in patients with NSTEACS compared with enoxaparin including those undergoing early intervention (<24 hours) Standard UFH +/- GPI is recommended in those receiving a PCI Bivalirudin is no different than UFH/enoxaparin in reducing ischemic outcomes or bleeding in presence of a GPI Bivalirudin reduces bleeding compared with UFH/enox + GPI but patients need to be pre-treated with a thienopyridine to maintain efficacy The two agents may be complementary—fondaparinux for initial upstream therapy and bivalirudin in those needing a PCI.