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16th Interventional Cardiology SymposiumMontreal, Quebec / June 14-16, 2007

Adapted from a presentation by:Shamir R. Mehta, MD, MSc, FRCPC, FACC

“Transitioning ACS Patients to the Cath Lab: Optimizing Outcomes with Upstream Fondaparinux and Bivalirudin/UFH”

Friday, June 15, 2007

Shamir R. Mehta, MD, MSc, FRCPC, FACCShamir R. Mehta, MD, MSc, FRCPC, FACCDirector, Interventional Cardiology

Hamilton Health SciencesAssociate Professor of Medicine

McMaster UniversityHamilton, Ontario, Canada

Transitioning ACS Patients to the Cath Lab: Optimizing Outcomes with Upstream Fondaparinux and Bivalirudin/UFH

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%Dea

th /

MI

BleedingBleeding

1988ASA

1992ASA+UFH

1998 ASA+UFH+

GPIIb/IIIaInhib

2003ASA+

LMWH +Clopidogrel +

PCI

Coagulation Cascade and New Anticoagulants

Inhibition of one molecule of factor Xa can inhibit the generation of 50 molecules of thrombin

Intrinsic pathway Extrinsic pathway

1

50

X

II

FibrinFibrinogen

Clot

XaVa

PLCa2+

VIIIaCa2+

PL

IXa

Bivalirudin

FondaparinuxXa

IIa

Rosenberg & Aird. N Engl J Med. 1999;340:1555–64.Wessler & Yin. Thromb Diath Haemorrh. 1974;32:71–8.

OASIS-5: A Randomized, Double-Blind, Double-Dummy Trial

20,078 patients with UA/NSTEMI20,078 patients with UA/NSTEMI

Fondaparinux2.5 mg s.c. od up to 8 days

Aspirin, Clopidogrel, anti-GPIIb/IIIa, planned Cath/PCI as per local practice

Randomization

Enoxaparin1 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. 1464-76.

Majority of Patients Undergoing Catheterizationin OASIS-5 Went Early

Mehta et al. JACC 2006; abstract 821-5

44.2%

17.4%

38.4%

05

101520253035404550

<24 hrs 24-48 hrs >48 hrs

Patie

nts

(%)

N = 14,206

Fondaparinux and Enoxaparin Non-inferiorfor Efficacy at 9 Days

OASIS-5 Investigators. N Engl J Med. 2006;354:1464-76.

5.8%5.7%Death/MI/RI

1.9%1.9%Refractory Ischemia

2.6%2.7%MI

1.8%1.9%Death

4.1%4.1%Death/MI

FondaparinuxEnoxaparin

0.8 1.0 1.2

Non-inferiorityMargin = 1.185

P=0.002

Hazard Ratio

Fondaparinux better Enoxaparin better

Fondaparinux Substantially Reduces Major BleedingCompared with Enoxaparin

Days

Cum

ulat

ive

Haz

ard

0 1 2 3 4 5 6 7 8 9

0.0

0.01

0.02

0.03

0.04HR 0.52

95% CI 0.44-0.61 P<<0.00001 Enoxaparin

Fondaparinux

Fondaparinux Reduces 30-Day all-cause Mortality Compared with Enoxaparin

Days

Cum

ulat

ive

Haz

ard

0.0

0.01

0.02

0.03

0 3 6 9 12 15 18 21 24 27 30

HR 0.83 95% CI 0.71-0.97

P=0.02

Enoxaparin

Fondaparinux

Fondaparinux Superior to Enoxaparin for Efficacy at 6 Months

OASIS 5 Investigators. N Engl J Med. 2006;354:1464-76.

0.8 1.2

11.3%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

0.06

0.05

0.05

0.04

0.007

P value

Fondaparinux better Enoxaparin better

Enoxaparin Fondaparinux Hazard Ratio

Hazard Ratio1

Net Clinical Benefit Favours Fondaparinux in Patients Undergoing PCI and Early PCI

Outcome Day 9 EnoxN = 3072

FondaN = 3105 HR (95% CI) P value

Death, MI or Stroke 6.2 6.3 1.03 0.79

Major Bleeding 5.1 2.4 0.46 <0.00001

Death, MI, stroke, major bleeding 10.4 8.2 0.78 0.004

Mehta et al. JACC. 2006;abstract 821-5.

Death, MI or Stroke 5.4 5.3 0.98 0.89

Major Bleeding 4.9 2.3 0.48 0.0005

Death, MI, stroke, major bleeding 9.5 7.3 0.76 0.035

Early PCI<24 hours

Catheter Thrombus Virtually Eliminated After Protocol Amendment Allowing UFH to be Used for PCI

No UFH Prior to PCI UFH Prior to PCI

Enox(%)

Fonda(%)

HR (95% CI)

Enox(%)

Fonda(%)

HR(95% CI)

No. randomized 810 793 80 75

Death/MI/Stroke 60 (7.4) 57 (7.2) 0.97(0.68-1.40) 5 (6.3) 3 (4.0) 0.62

(0.15-2.61)

Major Bleed 35 (4.3) 26 (3.3) 0.75(0.45-1.25) 5 (6.2) 1 (1.3) 0.21

(0.02-1.79)

Catheter Thrombus 4 (0.5) 9 (1.1) 2.30(0.71-7.4) 0 1 (1.3)* --

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 for PCI is Safe and Preserves the Lower Bleeding with Fondaparinux vs Enoxaparin

Enox Fonda HR CI

No UFH post-Randomization

1.2(n = 1277)

0.5(n = 1313)

0.45 0.18-1.11

UFH or equivalent placebo mandated by protocol during PCI

1.1(n = 1229)

0.4n = 1279)

0.34 0.12-0.95

Open Label UFH 2.7(n = 598)

1.3(n = 543)

0.48 0.20-1.17

Overall 1.5(n = 3104)

0.6(n = 3135)

0.42 0.24-0.71

Yusuf S. et al. N Engl J Med. 2006; 354:2829.

Mean Dose of UFH for PCI Used in OASIS 5: 47 IU/Kg

OASIS 5: Using UFH for PCI Reduces Angiographic Complications with Enoxaparin without Increasing Bleeding

Mehta et al. Presented at WCC/ESC Hotline Session, Barcelona, 2006

RR 0.4295% CI 0.26-0.65

P <0.0001

RR 0.9695% CI 0.73-1.26

P = 0.78

RR 0.3995% CI 0.22-0.67

P <0.0001

RR 1.4095% CI 1.00-1.97

P = 0.048

Major Bleeding 48 hours after PCI

Abrupt/threatened abrupt closure

N = 1277 N = 1275 N =

1633

N = 1648

N = 1275

RR 0.94 95% CI 0.63-1.33

P=0.62

RR 0.70 95% CI 0.51-0.96

P=0.026

3.8 3.4

6.2

4.3

1.3

5.9 6

0

2

4

5

6

7

% E

vent

s

Fonda FondaEnox alone

UFH+

Enox

Fonda FondaEnoxalone

UFH+

Enox1

N= 1633

N = 1648

1.63

N = 1277

N = 1633

N = 1648

N = 1277

N = 1275

OASIS 5: Fondaparinux Reduces Major Bleeding with or without Concomittant Use of IV GP IIb/IIIa Inhibitors

HR 0.63P<0.0001

HR 0.60P = 0.0001

N = 16448 N = 3630

Fondaparinux Superior to Enoxaparin Even with Very Short Durations of Treatment

HR 0.69P = 0.001

HR 0.55P <0.0001

HR 0.67P = 0.018

N = 5581 N = 8712 N = 5785

How to Transition Patients Initiated on Fonda to the Cath Lab

• Treat with ASA, Clopidogrel, Statin and Fondaparinux +/- IV nitro in the ER

• Proceed to Cath Lab as usual*

• If PCI needed, give bivalirudin or UFH (dose 50 IU/kg) +/- IIb/IIIa

• Post procedure, follow usual practice for sheath removal. Immediate removal if closure device or radial and 6 hours after last fonda sc dose if no closure device used

*May perform cath>6 hours after last sc dose if this was center’s usual practice with using LMWH

ACUITY Study Design – Patient Flow

UFH/Enox+ GP IIb/IIIa(N = 4,603)

Bivalirudin+ GP IIb/IIIa(N = 4,604)

BivalirudinAlone

(N = 4,612)

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 allClopidogrel

dosing and timingper local practice

* Stratified by pre-angiography thienopyridine use or administration

Moderate-high risk

ACS

Stone GW, et al. N Engl J Med. 2006 Nov 23;355(21):2203-16.

R*

ACUITY Primary Endpoint: Lower Bleeding with BIV vs Hep+IIb/IIIa

PSup = 0.015 PSup = 0.32 PSup <0.0001

Stone GW, et al. N Engl J Med. 2006;355:2203-16.

Thienopyridine Exposed* Not Thienopyridine Exposed

ACUITY PCI: Influence of Thienopyridine Exposure – PCI pts

RR [95%CI]0.81 (0.68-0.96)

RR [95%CI] 0.96 (0.77-1.20)

RR [95%CI] 0.50 (0.37-0.67) RR [95%CI]

1.07 (0.83-1.39)RR [95%CI]

1.37 (1.00-1.88)RR [95%CI]

0.61 (0.39-0.97)

Interaction P values = 0.17, 0.19 and 0.65 respectively*Thienopyridine at any time, any dose, up to time of PCI

RR [95%CI]1.00 [0.67-1.49]

RR [95%CI]0.53 [0.34-0.83]

RR [95%CI]0.84 [0.62-0.1.13]

Troponin+ PCI pts, Thienopyridine use prior to PCIGPI started after angiography but before PCI (N=1358)

ACUITY PCI: “ISAR-REACT-2 Like” Patients

• Anticoagulation is recommended for all patients in addition to antiplatelet therapy (I-A)

• Anticoagulation should be selected according to the risk of both ischaemic and bleeding events (I-B)

• Several anticoagulants are available, namely UFH

Evidence-Based Risk Stratification to Target Therapies in UA/NSTEMI

Recurrent Ischemia or high risk stress test

Aspirin, Clopidogrel, Fondaparinux (Class 1A)

β-blocker, Nitrates

Higher Risk +Troponin, ST s, TRS 3, Recurrent Ischemia, CHF,Prior Revascularization

Lower Risk– ECG, – Markers, TRS 0-2

Invasive Strategy Conservative Strategy

PCIBivalirudin or

UFH (+IV GP IIb/IIIa)UFH dose 50 IU/kg

No PCIMedical Rx or CABG

(hold fonda and clopidogrel)

Summary

• Fondaparinux reduces bleeding and mortality in patients with NSTEACS compared with enoxaparin including those undergoing early intervention (<24 hours)

• Bivalirudin with a thienopyridine reduces bleeding compared with UFH/enox + GPI

• Fondaparinux and bivalirudin are likely to be complementary—fondaparinux for initial upstream therapy of ACS and bivalirudin in place of UFH+GP IIb/IIIa in those undergoing PCI

• This strategy has the potential to lead to the lowest rates of bleeding (and enhanced efficacy) we have ever seen in ACS