shamir mehta, md, msc, frcpc director interventional cardiology associate professor of medicine...

Shamir Mehta, MD, MSc, FRCPCShamir Mehta, MD, MSc, FRCPCDirector Interventional Cardiology

Associate Professor of Medicine

McMaster University

Hamilton, Ontario, Canada

The Balancing Act in ACS Continues – But with BetterOutcomes? 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%Dea

th /

MI

BleedingBleeding

1988ASA

1992ASA+

Heparin

1998 ASA+

Heparin+Anti-

GPIIB/IIIA

2003ASA+

LMWH +Clopidogrel +Intervention

Bleeding is Associated with an Increased 30-Day Mortality in NSTEMI Patients

Rao et al. Am J Cardiol 2005;96:1200-1206

N = 26,452 ACS patients from GUSTO IIb, PURSUIT and PARAGON A&B

Log-rank p values are 0.0001 for all 4 categories, 0.20 for no bleeding vs. mild bleeding, 0.0001 for mild vs. moderate bleeding, and 0.001 for moderate vs. severe bleeding.

Adjusted HR (95% CI)

% Death

2.9% 1.03.5% 1.6 (1.3-1.9)5.9% 2.7 (2.3-3.4)

25.7% 10.6 (8.3-13.6)

GUSTO bleeding None Mild Moderate Severe

0 5 10 15 20 25 30

0.70

0.75

0.80

0.85

0.90

0.95

1.00

Days to Death

Cu

mu

lati

ve s

urv

ival

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;96:1200-1206

Procedure-related GUSTO bleeds

Non-procedure-related GUSTO bleeds

Ris

k o

f d

eath

(H

azar

d R

atio

)

None

1.0

Mild

1.3

Severe

16.5

0

5

20

10

15

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, CUREStrong, Independent Association

OutcomeMajorBleed

No MajorBleed

Hazard (Adjusted)

P-Value

Death 60/470(12.8%)

833/33676(2.5%)

5.37(3.97-7.26)

<0.0001

MI46/436(10.6%)

1375/33710(4.1%)

4.44(3.16-6.24)

<0.0001

Stroke12/469

(2.6%)

187/33677

(0.6%)

6.46

(3.54-11.79)<0.0001

Eikelboom JW et al. Circulation. 2006;114(8):774-82.

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 972-224

Adjusted HR (95% CI) at day 30: 5.06 (4.59-5.62); at day 180: 3.16 (2.92-3.44)

0.00

0.05

0.10

0.15

0.20

0 30 60 90 120 150 180

Major Bleed 9 days

No Major Bleed 9 days

Cu

mu

lati

ve

Ha

zard

Days

Increased Risk of MI at Days 30/180 in Patients with Major Bleeds by Day 9 (All Patients)


Budaj et al. JACC. 2006;abstract 972-224

0 30 60 90 120 150 180

Days

0.00

Cu

mu

lati

ve

Ha

zard

0.05

0.10

0.15

Major Bleed 9 days


Increased Risk of Stroke at Days 30/180 in Patients with Major Bleeds by Day 9 (All Patients)


Budaj et al. JACC. 2006;abstract 972-224.

0 30 60 90 120 150 180

0.00

0.01

0.02

0.03

0.04

0.05

0.06

Cu

mu

lati

ve

Ha

zard

Days

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

FibrinFibrinogen

Clot

XaVa

PLCa2+

IIa

VIIIa

Ca2+

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 (Cmax/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

IIa IIa IIII

FibrinogenFibrinogen Fibrin clotFibrin clot

Extrinsic Extrinsic pathwaypathway

IntrinsicIntrinsicpathwaypathway

AT XaXaAT AT

Fondaparinux Fondaparinux

XaXa

Antithrombin

Fondaparinux Mechanism of Action

Olson et al. J Biol Chem. 1992;267:12528-38.Turpie et al. N Engl J Med. 2001;344:619-25.

THROMBIN

Recycled

EphesusN = 1817

Pentathlon 2000N = 1584

PenthifraN = 1250

PentamaksN = 724

Overall Odds Reduction

% odds reduction

Fondaparinux better Enoxaparin better

-100 -80 -60 -40 -20 200 40 60 80 100

58.5%

28.1%

61.6%

63.1%

55.3%P = 0.000000000000000001

Overall odds reduction for proximal DVT = 57.4% [CI: 72.3 - 35.6]; p = 10-6

Overall Efficacy of Fondaparinux vs Enoxaparin in VTE Prevention: Meta-analysis

Turpie et al. Arch Intern Med. 2002;162:1833-40.

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

20,078 patients with UA/NSTEMI20,078 patients with UA/NSTEMI20,078 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 Catheterization in 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

Pa

tie

nts

(%

)N = 14,206

Similar Efficacy Outcome Rates in Both Groups at Day 9

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

Hazard Ratio


Major Bleeding: 9 Days

Days

Cu

mu

lati

ve H

azar

d

0.0

0.01

0.02

0.03

0.04

0 1 2 3 4 5 6 7 8 9

HR 0.52 95% CI 0.44-0.61

P<<0.00001Enoxaparin

Fondaparinux

Mortality: Day 30

Days

Cu

mu

lati

ve H

azar

d0.

00.

010.

020.

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

Efficacy at 6 Months

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

0.8 1 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

NS

0.04

0.007

P value


Enoxaparin Fondaparinux Hazard Ratio

Hazard Ratio

All Types of Bleeding were Reduced in the Fondaparinux Group at Day 9

Outcome Enoxaparin(%)

Fondaparinux(%)

p value

No. Randomized 10,021 10,057

Total bleeds 7.3 3.3 <0.001*

Major bleeds 4.1 2.1 <0.001

TIMI major + fatal bleeds

1.3 0.7 <0.001**

Fatal bleeds 0.2 0.1 0.005

Minor bleeds 3.2 1.1 <0.001

* HR (95% CI): 0.44 (0.39-0.50);**HR (95% CI): 0.55 (0.41-0.74)


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. Randomized 10,021 10,057

Total Major Bleeds 412 (4.1%) 212 (2.1%) <0.001

Intracranial 7 7 NS

Requiring surgery 77 41 <0.001

Retroperitoneal 37 9 <0.001

Transfusion 282 160 <0.001

Associated with death at study end

79 38 <0.001


OASIS-5 – The Reduction in Major Bleeding at Day 9 Was Independent of Renal Function


*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

0.6 1.0 1.2

Interaction p value = 0.71

Hazard Ratio


0.80.4

Major Bleeding was Reduced with Fondaparinux Irrespective of Creatinine Clearance

CrCl(mL/min)

Enoxaparin*(%)

Fondaparinux(%)

P value

< 30 (n = 535) 9.9 2.4 0.001

> 30 (n = 19442) 4.0 2.2 <0.001

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

*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;354:1464-76

Characteristics N Enoxaparin Fondaparinux

% %

Age≥ 65 yr 12,261 5.5 2.7< 65 yr 7814 2.1 1.4 0.11

SexMale 12,379 3.3 2.0Female 7699 5.5 2.5 0.07

CreatinineAt or above median* 11,124 4.7 2.4Less than median* 8871 3.4 1.9 0.71

Heparin at randomizationYes 3566 5.0 3.0No 16,512 4.0 2.0 0.35

Revascularization in 9 daysYes 7372 6.0 4.2No 12,706 3.0 1.0 < 0.001

Catheterization laboratory in centerYes 14,028 5.0 2.6No 6050 2.3 1.2 0.88

1.0 1.40.2


0.4 0.6 0.8 1.2* 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

4.3

8.3

2.7

5.1

0

1

2

3

4

5

6

7

8

9

No GP IIb/IIIa GP IIb/IIIa

Enox

Fonda

HR 0.63P<0.0001

HR 0.60P = 0.0001

N = 16448 N = 3630

Fondaparinux Superior to Enoxaparin for Bleeding Irrespective of Rx Duration

6.8

5.2

3

4.8

2.9

2

0

1

2

3

4

5

6

7

8

0-4 Days 5-6 Days 7-8 Days

Maj

or

Ble

eds

at D

ay30

Enox

Fonda

HR 0.69P = 0.001

HR 0.55P <0.0001

HR 0.67P = 0.018

N = 5581 N = 8712 N = 5785

Incidence of Major Bleeds with Enoxaparin in OASIS-5 is Consistent with Previous Trials

Enoxaparin Enox Fonda Enox Fonda

SYNERGY1

In-hospital

ESSENCE2

Day 30

A to Z3

Day 6

Meta-analysis4

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;292:45-54. 2. Cohen et al. N Engl J Med. 337:447-52.

3. Blazing et al. JAMA 2004;292:55-64 • 4. Petersen et al. JAMA. 2004;292:89-96.

Fondaparinux-Associated Reduction of Bleeding Translated into Long-Term Mortality Benefit

Patients with Enoxaparin Fondaparinux Difference

No Bleed 526 523 -3

Minor Bleeds 33 13 -20

Major Bleeds 79 38 -41

Total 638 574 -64

No. of deaths at 180 days


Days

Cu

mu

lati

ve H

azar

d0.

00.

050.

100.

15

0 20 40 60 80 100 120 140 160 180

Enoxaparin

Fondaparinux

HR 0.8695% CI 0.81-0.93P<<0.00001

Net Clinical Benefits at 6 Months(Death, MI, RI, Major Bleeding)

Efficacy and Safety in PCI PatientsOutcome Day 9 Enox

N = 3072Fonda

N = 3105HR (95% CI) P value

Death, MI or Stroke 190 (6.2) 197 (6.3) 1.03 (0.84-1.25)

0.79

Death 38 (1.2) 37 (1.2) 0.96 (0.61-1.52)

0.87

MI 154 (5.0) 160 (5.2) 1.03 (0.82-1.28)

0.80

Stroke 13 (0.4) 12 (0.4) 0.91 (0.42-2.00)

0.82

Major Bleeding 155 (5.1) 73 (2.4) 0.46 (0.35-0.61)

<0.00001

Death, MI, stroke, major bleeding

318 (10.4) 255 (8.2) 0.78 (0.67-0.93)

0.004

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

PCI < 24 Hours of RandomizationOutcomeDay 9

EnoxN = 1420

FondaN = 1414

HR (95% CI) P value

Death, MI or Stroke 77 (5.4) 75 (5.3) 0.98 (0.71-1.34)

0.89

Death 19 (1.3) 19 (1.3) 1.01 (0.53-1.90)

0.98

MI 55 (3.9) 53 (3.8) 0.97 (0.66-1.41)

0.86

Stroke 8 (0.6) 6 (0.4) 0.76 (0.23-2.18)

0.60

Major Bleeding 69 (4.9) 33 (2.3) 0.48 (0.31-0.72)

0.0005

Death, MI, stroke, major bleeding

135 (9.5) 103 (7.3) 0.76 (0.59-0.98)

0.035

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

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

OASIS 5: Fonda vs Enox alone and vs UFH + Enox

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

3.83.4

6.2

4.3

1.3

5.9 6

0

2

4

5

6

7

% E

ven

ts

FondaFonda

Enox alone

UFH+

EnoxFonda

Fonda

Enoxalone UFH

+Enox

1

N = 1633

N = 1648

1.6

3 N = 1277

N = 1633

N = 1648

N = 1277

N = 1275

Open Label UFH Prior to PCI Data After Protocol Amendment

No UFH Prior to PCI UFH Prior to PCI

Enox(%)

Fonda(%)

HR (95% CI)

Enox(%)

Fonda(%)

HR(95% CI)

Number randomized 810 793 80 75

Death/MI/Stroke/Major Bleed

90 (11.1) 80 (10.1) 0.90(0.67-1.22)

9 (11.2) 4 (5.3) 0.45(0.14-1.47)

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)

Abrupt Closure 13 (1.6) 15 (1.9) 1.18(0.56-2.5)

0 1 (1.3) --

Threatened abrupt closure

38 (4.7) 31 (3.9) 0.83 (0.52-1.32)

2 (2.5) 4 (5.3) 2.13(0.40-11.3)

Catheter Thrombus 4 (0.5) 9 (1.1) 2.30(0.71-7.4)

0 1 (1.3)* --

Vascular Access Site complication

56 (6.9) 22 (2.8) 0.40(0.25-0.65)

5 (6.3) 1 (1.3) 0.21(0.03-1.8)

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

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)

0.4

n = 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.

PCI-Related Complications and MACE (death, MI or stroke)

16

20.618.1

12.6

16.6

13.7

0

5

10

15

20

25

Any PCI Complication Any PCI Complicationor MACE

Any PCI complicationor Major Bleed

Enox

Fonda

HR 0.79P<<0.0001

HR 0.81P<0.0001

HR 0.75P<<0.0001

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;295:1579-80.

ACUITY Study Design – Patient Flow

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

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

BivalirudinAlone

(N = 4,612)

R*

Moderate-high risk unstable angina or NSTEMI undergoing an invasive strategyModerate-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

Aspirin in allClopidogrel

dosing and timingper local practice

*Stratified by pre-angiography thienopyridine use or administration*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.

ACUITY Primary Outcome: No Difference in Ischemic Outcomes or Major Bleeding with Bivalirudin vs Heparin in Presence of GPI

11.7%

7.3%5.7% 5.3%

11.8%

7.7%

Net clinicaloutcome

Ischemiccomposite

Major bleeding

30

da

y e

ve

nts

(%

)

UFH/Enoxaparin+GPI (N=4603) Bivalirudin+GPI (N=4604)

PSup = 0.93 PSup = 0.39 PSup = 0.38


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

11.7%

7.3%5.7%

3.0%

10.1%

7.8%

Net clinicaloutcome

Ischemiccomposite

Major bleeding

30

da

y e

ve

nts

(%

)

UFH/Enoxaparin+GPI (N=4603) Bivalirudin alone (N=4612)

PNI <0.0001PSup = 0.015

PNI = 0.011PSup = 0.32

PNI <0.0001PSup <0.0001


ACUITY: Components of the Ischemic Composite

7.3%

1.3%

4.9%

2.3%2.7%2.4%

5.0%

7.7%

1.5% 1.6%

7.8%

5.4%

Ischemiccomposite

Death Myocardialinfarction

Unplannedrevasc forischemia

30

da

y e

ve

nts

(%

)

UFH/Enox+GPI (N=4603) Bivalirudin+GPI (N=4604) Bivalirudin alone (N=4612)

UFH/Enoxaparin + GPI vs. Bivalirudin + GPI vs. Bivalirudin AloneUFH/Enoxaparin + GPI vs. Bivalirudin + GPI vs. Bivalirudin Alone

PSup = 0.32 PSup = 0.34 PSup = 0.35 PSup = 0.78


0 1 2

ACUITY: Net Clinical Outcome CompositeUFH/Enoxaparin + IIb/IIIa vs. Bivalirudin AloneUFH/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

BivalAlone

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%

10.9%13.5%

P Pint

0.86 (0.71-1.03)0.88 (0.75-1.02)

0.90 (0.77-1.05)0.82 (0.68-0.98)

0.86 (0.74-0.99)0.96 (0.77-1.19)

0.79 (0.64-0.97)0.90 (0.78-1.04)

0.87 (0.75-1.00)0.86 (0.70-1.04)

0.090.09

0.160.03

0.030.71

0.020.16

0.050.12

0.89

0.47

0.43

0.28

0.91

RR (95% CI)

Bivalirudin alone betterBivalirudin alone better UFH/Enox + IIb/IIIa betterUFH/Enox + IIb/IIIa better


0 1 2


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

BivalAlone

UFH/Enox+ IIb/IIIa

9.2%11.3%

12.2%11.1%

P Pint

0.76 (0.65-0.89)1.02 (0.86-1.21)

12.2%7.1%

13.3%9.4%

0.92 (0.80-1.06)0.75 (0.61-0.93)

0.230.01

<0.0010.83

0.35

0.02

0.18

13.0%8.6%

13.7%10.6%

0.96 (0.80-1.14)0.81 (0.69-0.95)

0.610.01 0.42

Biomarkers (CK/Trop)

ST Deviation

TIMI Risk Score

Pre Thienopyridine

6.4% 10.2% 0.63 (0.43-0.91) 0.019.4% 10.2% 0.92 (0.77-1.10) 0.34

13.9% 15.2% 0.92 (0.76-1.11) 0.36

Yes (n = 5192)No (n = 4023)

RR (95% CI)



0 1 2



BivalAlone

UFH/Enox+ IIb/IIIa

P Pint

0.59

11.6% 13.3% 0.87 (0.75-1.00) 0.09

10.6% 18.2% 0.97 (0.75-1.26) 0.84

5.1% 6.5% 0.78 (0.58-1.04) 0.09

0.62

8.3% 9.8% 0.85 (0.67-1.06) 0.15

9.2% 9.4% 0.98 (0.78-1.23) 0.86

12.5% 14.4% 0.87 (0.73-1.05) 0.14

0.56

9.1% 10.0% 0.91 (0.73-1.12) 0.36

6.7% 7.1% 0.94 (0.80-1.10) 0.46

10.6% 12.6% 0.84 (0.65-1.10) 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 (3.0-19.7 h)

Late (≥19.7 h)

Risk ratio±95% CI

Risk ratio±95% CI

Actual treatment

Rand. to angio/interv.tertiles


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.

shamir mehta, md, msc, frcpc director interventional cardiology associate professor of medicine...

Documents

day mortality

increased mortality

acs patients

moderate bleeding

mild bleeding

major bleeds

increased risk of stroke

increased risk of mi