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Factor Xa Inhibition Across the Spectrum of ACS:

A New Standard of Care

Dr. Ihab Suliman

Meta-analysis of UFH and LMWH vs Placebo in UA/NSTEMI

Eikelboom J. Lancet 2000;355:1936–42

Petersen, J. L. et al. JAMA 2004;292:89-96.

Intention-to-Treat Population: Efficacy End Points at 30 DaysEnoxaparin vs UFH in UA/NSTEMI

Petersen, J. L. et al. JAMA 2004;292:89-96.

Intention-to-Treat Population: Efficacy End Points at 30 DaysEnoxaparin vs UFH in UA/NSTEMI

C o p y r i g h t r e s t r i c t i o n s m a y a p p l y .

P e t e r s e n , J . L . e t a l . J A M A 2 0 0 4 ; 2 9 2 : 8 9 - 9 6 .

S a f e t y A n a l y s i s : M a j o r B l e e d i n g U p t o 7 D a y s A f t e r R a n d o m i z a t i o n

Summary of Evidence for UFH and LMWH in UA/NSTEMI

UFH or LMWH reduce death or MI compared with no anticoagulant

Enoxaparin is marginally superior to UFH for efficacy

Enoxaparin is associated with a non-significant trend toward increased bleeding vs UFH but is more convenient to use than UFH

Herbert JM et alHerbert JM et al. Cardiovasc Drug Rev. Cardiovasc Drug Rev. 1997;15:1. . 1997;15:1. van Boeckel CAA et alvan Boeckel CAA et al. Angew Chem, Int Ed. Angew Chem, Int Ed EngEngll. 1993;32:1671. . 1993;32:1671.

Once daily administration Highly selective for its target No risk of pathogen contamination 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 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

Turpie AGG Turpie AGG et al. Net al. N EnEngl J Med. 2001;344gl J Med. 2001;344:619.:619.

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

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

Patients with NSTE ACS, Chest discomfort < 24 hoursPatients with NSTE ACS, Chest discomfort < 24 hours2 of 3: Age>60, ST Segment 2 of 3: Age>60, ST Segment ΔΔ, , cardiac markers cardiac markers

Patients with NSTE ACS, Chest discomfort < 24 hoursPatients with NSTE ACS, Chest discomfort < 24 hours2 of 3: Age>60, ST Segment 2 of 3: Age>60, ST Segment ΔΔ, , cardiac markers cardiac markers

FondaparinuxFondaparinux2.5 mg sc once daily2.5 mg sc once daily

FondaparinuxFondaparinux2.5 mg sc once daily2.5 mg sc once daily

Study Design: Randomized, Double Blind

ASA, Clop, GP IIb/IIIa, ASA, Clop, GP IIb/IIIa, planned Cath/PCI as per planned Cath/PCI as per

local practicelocal practice

ASA, Clop, GP IIb/IIIa, ASA, Clop, GP IIb/IIIa, planned Cath/PCI as per planned Cath/PCI as per

local practicelocal practice

RandomizeRandomize

EnoxaparinEnoxaparin1 mg/kg sc twice daily1 mg/kg sc twice daily

EnoxaparinEnoxaparin1 mg/kg sc twice daily1 mg/kg sc twice daily

Primary:Primary: EfficacyEfficacy:: Death, MI, refractory ischemiaDeath, MI, refractory ischemia at 9 days at 9 days

SafetySafety:: Major bleeding at 9 daysMajor bleeding at 9 daysRisk benefitRisk benefit:: Death, MI, refractory ischemia, major bleeds 9 days Death, MI, refractory ischemia, major bleeds 9 days

SecondarySecondary:: Above & each component Above & each component separatelyseparately at day 30 & 6 months at day 30 & 6 monthsHypothesisHypothesis:: First test non-inferiority, then test superiority First test non-inferiority, then test superiority

Primary:Primary: EfficacyEfficacy:: Death, MI, refractory ischemiaDeath, MI, refractory ischemia at 9 days at 9 days

SafetySafety:: Major bleeding at 9 daysMajor bleeding at 9 daysRisk benefitRisk benefit:: Death, MI, refractory ischemia, major bleeds 9 days Death, MI, refractory ischemia, major bleeds 9 days

SecondarySecondary:: Above & each component Above & each component separatelyseparately at day 30 & 6 months at day 30 & 6 monthsHypothesisHypothesis:: First test non-inferiority, then test superiority First test non-inferiority, then test superiority

Outcomes

PCI< 6 hPCI< 6 h,, No additional UFH No additional UFHPCI >6 hPCI >6 h,, IV UFH IV UFHWith IIb/IIIa 65 U/kgWith IIb/IIIa 65 U/kgWithout IIb/IIIa 100 U/kgWithout IIb/IIIa 100 U/kg

PCI <6 hPCI <6 h:: IV Fonda 2.5 mg IV Fonda 2.5 mgwithout IIb/IIIa, 0 with IIb/IIIawithout IIb/IIIa, 0 with IIb/IIIaPCI> 6 hPCI> 6 h:: IV Fonda 2.5 mg with IV Fonda 2.5 mg withand 5.0 mg without IIb/IIIa and 5.0 mg without IIb/IIIa

ExcludeAge < 21Any contra-ind to EnoxHem stroke< 12 mo.Creat> 3 mg/dL/265 umol/L

N=20,000

OASIS 5 Investigators. N Engl J Med 2006

Bleeding Definition – OASIS 5

Major bleeding - defined as clinically overt bleeding with at least one of the following:– fatal, – symptomatic intracranial haemorrhage, – retroperitoneal haemorrhage, – intraocular haemorrhage leading to significant vision loss – a decrease in haemoglobin of 3.0 g/dL (with each

blood transfusion unit counting for 1.0 g/dL of Hb) – requiring transfusion of two or more units of red blood

cells or equivalent of whole blood.

Minor bleeding - any clinically significant bleeding not meeting the definition of major and leading to interruption of study drug, surgical intervention or transfusion of 1 unit blood


Procedures by 9 Days in Centers With or Without Cath Labs in OASIS-5

Cath Lab+ Cath Lab-

No. Centers 420 (73%) 156 (27%)

No. Patients 14,028 (70%) 6050 (30%)

Angiography 73.2% 27.7%

PCI 39.6% 12.5%

CABG 6.8% 1.8%

Revasc. 46.1% 14.1%


Time from Rand to Cath

44.22

17.42

38.4

05

101520253035404550

<24 hrs 24-48 hrs >48

% o

f p

atie

nts

Death/MI/RI: Day 9

Days

Cu

mu

lativ

e H

aza

rd

0.0

0.0

10

.02

0.0

30

.04

0.0

50

.06

0 1 2 3 4 5 6 7 8 9

Enoxaparin

Fondaparinux

HR 1.01 95% CI 0.90-1.13

P for non-inf=0.007


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<<0.00001

Enoxaparin

Fondaparinux


Categories of Major Bleeds at 9 Days

Enox(No. Pts)

Fonda(No. Pts)

P

No. Rand. 10021 10057

Major Bleeding 404 (4.1%) 215 (2.2%) <<0.0001

Fatal Bleeding 22 7 0.005

Intracranial 5 6

Surgery req’d to stop bleed 74 41 0.0001

Retroperitoneal 37 9 0.0001

Hb 3 g/dL 312 150 0.0001

Transfusion 2 units 275 162 0.0001


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 HR 0.83 95% CI 0.71-0.9795% CI 0.71-0.97

P=0.02P=0.02

Enoxaparin

Fondaparinux


Efficacy at 6 Months

0.8 1 1.2

Enox Fonda

Death/MI/RI 13.2% 12.3%

Death/MI 11.4% 10.5%

Death 6.5% 5.8%

MI 6.6% 6.3%

Strokes 1.7% 1.3%

Death/MI/Stroke 12.5% 11.3%

0.055

0.05

0.05

0.33

0.04

0.007

P value


Mortality at 6 Months

Days

Cu

mu

lati

ve H

azar

d0.

00.

020.

040.

06

0 20 40 60 80 100 120 140 160 180

HR 0.89HR 0.8995% CI 0.80-1.00 95% CI 0.80-1.00

P=0.05P=0.05

Enoxaparin

Fondaparinux


Relative Impact of MI, Refractory Ischemia or Bleeding on Mortality

Crude Odds Ratio for Death

(95% CI)

30 Days 30 to 180 Days

180 Days

Nonfatal MI 9.6 (7.7-12.0) 2.2 (1.5-3.3) 5.6 (4.6-6.7)

Refractory Ischemia

4.0 (2.9-5.6) 1.4 (0.8-2.3) 2.6 (2.0-3.5)

Major Bleeds 6.5 (5.1-8.2) 2.1 (1.4-3.0) 4.1 (3.3-5.0)

Minor Bleeds 3.0 (2.1-4.3) 1.5 (0.9-2.4) 2.2 (1.6-2.9)


Relation Between Bleeding Reduction at

9 Days and Long Term Mortality

No. Deaths at 6 months

Patients with Enox Fonda Difference

No. Bleeds 528 518 -10

Minor Bleeds 31 13 -18

Major Bleeds 76 35 -41

Total: 635 566 -69

-59 (85.5%)

85.5% of difference in death at 6 months is explained by bleeding within the first 9 days

Clinical Events after PCI: Day 30

2.1

5.5 5.4

11.3

2

5.8

2.8

9.4

0

2

4

6

8

10

12

Death MI Major Bleeds Death, MI orMajor Bleed

Eve

nt

Rat

e (%

)

Enox (n=3089) Fonda (n=3118)

P<0.0001

P=0.01

P=0.68

P=0.60


Coronary and Vascular Access Site Complications

Events at 30 days Enox(%)

Fonda(%)

HR (95% CI) P value

No. Rand. 3089 3118

Coronary--Any Complicatn 8.6 9.6 1.11 (0.95-1.30) 0.18

Abrupt Closure 1.1 1.5 1.33 (0.86-2.06) 0.20

Threatened Abrupt Closure

4.7 5.2 1.12 (0.90-1.39) 0.31

Vascular Access Site 8.1 3.3 0.40 (0.32-0.50) <<0.0001

Pseudo-aneurysm 1.6 1.0 0.63 (0.40-0.98) 0.039

Large Hematoma 4.4 1.6 0.35 (0.26-0.49) <<0.0001


Catheter-Related Thrombus with Enoxaparin and Fondaparinux

Enoxaparin 8 cases total: 6 when PCI performed within 6 h of last enox

dose where no UFH was given Rate is 6/1431=0.42% In Enoxaparin patients receiving study UFH, there was 1

case. 1 case time of PCI not ascertainedFondaparinux 29 cases (UFH was not routinely given to fonda group) Rate is 29/3135=0.9% When open label UFH was used prior to PCI (5000 U

mean), only 1 case of catheter thrombus was reported

Mehta SR et al. ACC 2006

PCI Using Blinded Study Drug: Effect of UFH Before PCI

on Major Bleeding

23

1.82.4

0

2

4

6

8

10

Major Bleeds Major Bleeds

Po

st P

CI

even

ts u

p t

o 4

8 h

rs (

%)

Enox Fonda

No UFH Prior With UFH Prior

UFH Prior


Major Bleeding 48 hours after PCI According to Time From Last Enox Dose

3.5 3.5

1.4 1.3

0

0.5

1

1.5

2

2.5

3

3.5

4

<6 hours >6 hours

Eve

nt

Rat

e (%

)

Enox Fonda

RR 0.39P<0.00001

RR 0.36P<0.00001

Study Protocol

< 6 hours No UFH given in Enox group

>6 hours UFH given in Enox group

N=1431 N=1460 N=1425 N=1411


Effect of UFH on Enox PCI complications

Time of PCI from Last Enox Dose

Outcome < 6 hours

Enox alone

>6 hours

UFH Given

No. Rand. 1431 1427

Abrupt Closure 1.4 1.0

Threatened Abrupt Closure

6.4 3.2

No Reflow 1.5 0.8

Angio thrombus 2.5 1.1

Major Bleeding 3.6 3.6

Prior PCI 16.1 16.9


Vascular Access Site Complications, Large Hematomas and Pseudo-aneurysms

8.1

1.6

4.4

3.3

11.6

0123456789

Vasc Access SiteComplication

Pseudo-aneurysm Large Hematoma

Enox

Fonda

HR 0.41P<<0.0001

HR 0.63P=0.033

HR 0.36P<<0.0001


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

16

20.618.1

12.6

16.613.7

0

5

10

15

20

25

Any PCIComplication

Any PCIComplication or

MACE

Any PCIcomplication or

Major Bleed

Enox

FondaHR 0.79

P<<0.0001

HR 0.81P<0.0001 HR 0.75

P<<0.0001


Conclusions1.1. Fondaparinux is non-inferior compared with enoxaparin at Fondaparinux is non-inferior compared with enoxaparin at

9 days, with 9 days, with substantiallysubstantially lower rates of important bleeds. lower rates of important bleeds. The net benefit-risk balance clearly favors fondaparinux.The net benefit-risk balance clearly favors fondaparinux.

2.2. Bleeding increases the risk of death significantly. Bleeding increases the risk of death significantly.

3.3. At one month and at 6 months there is At one month and at 6 months there is a significant a significant reduction in mortality with fondaparinux.reduction in mortality with fondaparinux.

4.4. Strokes are also significantly reduced, so that there is Strokes are also significantly reduced, so that there is a a clear reduction in death, MI, and strokes with fondaparinuxclear reduction in death, MI, and strokes with fondaparinux

5.5. Consistent results are observed in those undergoing PCI Consistent results are observed in those undergoing PCI (including early PCI)(including early PCI) and in every other subgroup and in every other subgroup examined.examined.

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

Enoxaparin Enox Fond Enox Fond

SYNERGY1

Day 9

ESSENCE2

Day 30

A to Z3

Day 30

Meta-analysis4

Day 7

OASIS 5

Day 9

OASIS 5

Day 9

OASIS 5

Day 30

OASIS 5

Day 30

TIMI major bleed

9.1% 3.0% 1.3% 0.7% 1.5% 1.0%

Major bleed 6.5% 4.7% 4.0% 2.1% 4.9% 3.1%

1. SYNERGY investigators JAMA 2004;2. Cohen JAMA 2004; 3. Blazing JAMA 2004; 4. Petersen JAMA 2004