Presenters’ Disclosure Information: Relationships Related to this Presentation Research Grants...

Presenters’ Disclosure Information:Relationships Related to this Presentation

Research Grants and/or Consultant fees:Research Grants and/or Consultant fees:

Mahaffey: Mahaffey: Aventis, AstraZeneca, Berlex, Lilly, Daiichi, Aventis, AstraZeneca, Berlex, Lilly, Daiichi,

Millennium, Merck, Schering-Plough, The Millennium, Merck, Schering-Plough, The Medicines CompanyMedicines Company

Ferguson: Ferguson: Aventis, AstraZeneca, Bristol Myers Squibb, Aventis, AstraZeneca, Bristol Myers Squibb,

Guidant, Merck, Sanofi, Schering-Plough, Guidant, Merck, Sanofi, Schering-Plough, The Medicines CompanyThe Medicines Company

Kenneth W. Mahaffey, M.D.

James J. Ferguson, M.D.

On behalf of the SYNERGY Investigators

The SYNERGY Trial

Superior

Yield of the

New strategy of

Enoxaparin,

Revascularization &

GlYcoprotein IIb/IIIa Inhibitors

The SYNERGY Trial

Key Prior Trials

ESSENCE / TIMI 11b:ESSENCE / TIMI 11b: Superiority of enoxaparin vs UFH Superiority of enoxaparin vs UFH

in conservative management in conservative management strategystrategy

NICE Registries:NICE Registries: Comparable safety and efficacy to Comparable safety and efficacy to

historical controls in PCIhistorical controls in PCI

ACUTE 2 / INTERACT / AtoZACUTE 2 / INTERACT / AtoZ Contemporary trials in higher risk Contemporary trials in higher risk

patientspatients

Key Questions

What is the role of enoxaparin in high-What is the role of enoxaparin in high-risk NSTEMI ACS patients managed with risk NSTEMI ACS patients managed with an early invasive treatment strategy ?an early invasive treatment strategy ?

Can we safely bring patients on Can we safely bring patients on enoxaparin rapidly forward to the enoxaparin rapidly forward to the catheterization laboratory ?catheterization laboratory ?

Study DesignAt least 2 of 3 required:At least 2 of 3 required:

• Age Age 60 60

• ST ST (transient) or (transient) or • (+) CK-MB or Troponin(+) CK-MB or Troponin

Enoxaparin IV Heparin

Primary endpoint: Death or MI at 30 days

High-RiskHigh-RiskACS PatientsACS Patients

RandomizeRandomize(n = 10,000)(n = 10,000)

Early invasive strategyOther therapy per AHA/ACC Guidelines

(ASA, -blocker, ACE, clopidogrel, GP IIb/IIIa)

60 U/kg 60 U/kg 12 U/kg/hr 12 U/kg/hr (aPTT 50-70 sec)(aPTT 50-70 sec)1 mg/kg SC Q12H1 mg/kg SC Q12H

Statistical Assumptions

InferiorityInferiority

NoninferiorityNoninferiority

SuperioritySuperiority

0.60.6 11 1.21.2

Hazard Ratio (95% CI)

Enoxaparin Better UFH Better

Control group 15% death/MIControl group 15% death/MI

17% reduction primary endpoint17% reduction primary endpoint

Type I error of 5% (2-sided)Type I error of 5% (2-sided)

90% power 90% power

Sample size ~10,000 patientsSample size ~10,000 patients

Sample size:

8000 10,000 pts

For crossover and interim event rate

Sample size:

8000 10,000 pts

For crossover and interim event rate

1.1

zone of noninferiority

Europe: 5163

Australia: 253Australia: 253

New Zealand: 160New Zealand: 160

Brazil: 289Brazil: 289

Argentina: 192Argentina: 192

Canada: 1616Canada: 1616

USA: 5702USA: 5702

BelgiumBelgium 355355

GermanyGermany 456456

ItalyItaly 7272

PolandPoland 381381

SpainSpain 412412

TurkeyTurkey 139139

12 Countries. 467 Sites. 10,027 Patients.

Inclusion Criteria

AgeAge

(+) ECG(+) ECG

(+) Biomarkers(+) Biomarkers

20%20%

16%16%

20%20%

44%44%

Enoxaparin UFH(n = 4993) (n = 4985)

Median age (years) 68 68

Female sex (%) 34 34

Hypertension (%) 68 68

Diabetes (%) 29 30

Hypercholesterolemia (%) 58 59

Family history of CAD (%) 46 45

Myocardial infarction (%) 29 28

CHF (%) 9 9

Stroke (%) 5 5

PVD (%) 10 10

CABG (%) 16 17

PCI (%) 21 19

Baseline Characteristics

Concomitant Medications


Aspirin (%) 95 95

Beta blocker (%) 86 86

Ace inhibitor (%) 64 62

Statin (%) 69 70

Clopidogrel (%) 62 63

GP IIb-IIIa inhibitor (%) 56 58

Pre-randomization Therapy

Enoxaparin UFH All Patients(n = 4993) (n = 4985) (n = 9978)

Received pre-randomization (%):

No antithrombinNo antithrombin 2424 25 25 2424

UFH onlyUFH only 2929 30 30 2929

Enoxaparin onlyEnoxaparin only 4242 42 42 4343

UFH and enoxaparinUFH and enoxaparin 3 3 3 3 3 3

No antithrombinNo antithrombin 2424 25 25 2424

UFH onlyUFH only 2929 30 30 2929

Enoxaparin onlyEnoxaparin only 4242 42 42 4343

UFH and enoxaparinUFH and enoxaparin 3 3 3 3 3 3


Cath during baseline hosp (%) 92 92

Time to cath* 22 21 (hours) (6, 44) (6, 43)

Percutaneous intervention 46 47

Time to PCI* 23 22 (hours) (6, 49) (6, 48)

CABG (%) 19 18

Time to CABG* 91 89 (hours) (44, 167) (45, 166)

Days hospitalized* 5 4 (3, 8) (3, 8)

In-hospital Procedures

*Median (25th ,75th)

Kenneth W. Mahaffey, M.D.

James J. Ferguson, M.D.

On behalf of the SYNERGY Investigators

The SYNERGY Trial

Primary Results (30 Days)

Enoxaparin UFH Unadjusted(n = 4993) (n = 4985) P-value

Death and MI (%) 14.0 14.5 0.396

Death (%) 3.2 3.1 0.705

MI (%) 11.7 12.7 0.135

Death and MI at 30 Days

30-Day Death/MI30-Day Death/MI

0.80.8 11 1.21.2


Enoxaparin

Better

UFH

Better0 5 10 15 20 25 30

0.8

0.85

0.9

0.95

1.0

Free

dom

from

Dea

th /

MI

Days from Randomization

UFHUFHEnoxaparinEnoxaparin

HR 0.96 (0.87-1.06)HR 0.96 (0.87-1.06)

1.11.1

In-hospital Cardiac Events


CHF (%) 8.0 7.9

Cardiogenic shock (%) 2.0 2.3

Cardiac arrest (%) 2.0 2.2

Ventricular tachycardia/fib (%) 4.8 4.9

Atrial fib / flutter (%) 8.6 7.7

2nd or 3rd degree heart block (%) 1.0 1.1

Acute mitral regurgitation (%) 0.3 0.3

Pulmonary edema (%) 0.2 0.2

Deep vein thrombosis (%) 0.2 0.2

Ventricular septal defect (%) 0.1 < 0.1

Bleeding Events

Enoxaparin UFH(n = 4993) (n = 4985) P-value

GUSTO severe 2.9 2.4 0.106

TIMI major - clinical: 9.1 7.6 0.008 CABG-related 6.8 5.9 0.081 Non-CABG-related 2.4 1.8 0.025 H/H drop - algorithm 15.2 12.5 0.001

Any RBC transfusion 17.0 16.0 0.155

ICH < 0.1 < 0.1 NS

PCI Patients: Thrombotic Complications


Any unsuccessful PCI 3.6 3.4

Any threatened abrupt closure 1.1 1.0

Any abrupt closure 1.3 1.7

Emergency CABG 0.3 0.3

No prior

UFH

Enox

Both

Pre-randomization

No prior

UFH

Enox

Both

Pre-randomization Randomization


Enox UFHBetter Better

0.60.6 11 22



0.60.6 11 22

Prior Antithrombin Therapy: Efficacy and Safety

Enox UFH (%) (%)Enox UFH (%) (%)

30-DAY DEATH / MI

30-DAY DEATH / MI

BLEEDINGGUSTO Severe

TIMI Major

BLEEDINGGUSTO Severe

TIMI MajorEnox UFH (%) (%)Enox UFH (%) (%)

2.9 2.42.9 2.4Total(n = 9978)

14.0 14.514.0 14.59.1 7.69.1 7.6

3.1 1.83.1 1.8No Prior Rx(n = 2440)

12.6 14.812.6 14.89.7 6.99.7 6.9

3.1 2.23.1 2.2ConsistentTherapy(n = 6138)

13.3 15.913.3 15.99.3 7.99.3 7.9

No prior

UFH

Enox

Both

Pre-randomization Randomization

No prior

UFH

Enox

Both

Pre-randomization Randomization Crossover

Crossovers: Relation to Bleeding

TIMI MajorGUSTO Severe

0

2

4

6

8

10

Total No Crossover Crossover

0

2

4

6

8

10


0

4

8

12

16

20


0

4

8

12

16

20


(n = 9978)(n = 9978) (n = 9180)(n = 9180) (n =798)(n =798) (n = 9978)(n = 9978) (n = 9180)(n = 9180) (n =798)(n =798)

Enoxaparin

UFH

Crossovers: Relation to Outcome

Enoxaparin

UFH Consistent RxDeath / MI

Total PopulationDeath / MI

(n = 9978)(n = 9978) (n = 9180)(n = 9180) (n =798)(n =798) (n = 6130)(n = 6130) (n = 5637)(n = 5637) (n =493)(n =493)

0

5

10

15

20

25


0

5

10

15

20

25


0

5

10

15

20

25



SYNERGYSYNERGY

AtoZAtoZ

ACUTE 2ACUTE 2

TIMI 11BTIMI 11B

INTERACTINTERACT

ESSENCEESSENCE

0.50.5 11 22Enox UFHBetter Better

SYNERGYSYNERGY

AtoZAtoZ

ACUTE 2ACUTE 2

TIMI 11BTIMI 11B

INTERACTINTERACT

ESSENCEESSENCE

0.50.5 11 22

Systematic Overview:30-Day Death/MI and In-hospital Transfusions

30-DAY DEATH / MI

30-DAY DEATH / MI

IN-HOSPITALTRANSFUSIONS

IN-HOSPITALTRANSFUSIONS Enox UFHEnox UFH

2.6% 3.3%2.6% 3.3%

0.7% 0.6%0.7% 0.6%

2.5% 4.3%2.5% 4.3%

1.0% 0.8%1.0% 0.8%

17.0% 16.0%17.0% 16.0%

0.8% 0.9%0.8% 0.9%ESSENCEESSENCE

INTERACTINTERACT

TIMI 11BTIMI 11B

ACUTE 2ACUTE 2

AtoZAtoZ

SYNERGYSYNERGY

Enox UFHEnox UFH

5.0% 9.0%5.0% 9.0%

7.4% 8.3%7.4% 8.3%

7.9% 8.1%7.9% 8.1%

7.4% 7.9%7.4% 7.9%

14.0% 14.5%14.0% 14.5%

6.2% 7.7%6.2% 7.7%



TIMI Major (All Trials)TIMI Major (All Trials)

Transfusions (All Trials)Transfusions (All Trials)

30-Day Death/MI (All Trials)30-Day Death/MI (All Trials)

0.60.6 11 22

Systematic Overview:Death/MI and Bleeding

10.1% 11.0%10.1% 11.0%

Enox UFHEnox UFH

8.2% 7.8%8.2% 7.8%

4.8% 4.1%4.8% 4.1%

(n = 21,946)(n = 21,946)

(n = 22,104)(n = 22,104)

(n = 22,104)(n = 22,104)

AtoZ did not include CABG data.



TIMI Major (All Trials)TIMI Major (All Trials)

Transfusions (All Trials)Transfusions (All Trials)

30-Day Death/MI (All Trials)30-Day Death/MI (All Trials)

0.60.6 11 22

Systematic Overview—No Pre-rando Therapy: Death/MI and Bleeding

8.1% 9.5%8.1% 9.5%

Enox UFHEnox UFH

5.6% 5.5%5.6% 5.5%

3.5% 2.7%3.5% 2.7%

(n = 9835)(n = 9835)

(n = 8627)(n = 8627)

(n = 8627)(n = 8627)

AtoZ did not include CABG data.

Summary

High-risk population treated with an early invasive management strategy


The studyThe studyThe studyThe study

Summary

Efficacy — not superior but at least as effective as UFH in the overall population


The resultsThe resultsThe resultsThe results

met criteria for non-inferiority met criteria for non-inferiority



Summary



Bleeding — more frequent with enoxaparin Bleeding — more frequent with enoxaparin

The resultsThe resultsThe resultsThe results

UFHUFH

EnoxaparinEnoxaparin

7.6 %7.6 %

9.1 %9.1 %

2.4 %2.4 %

2.9 %2.9 %

16.0 %16.0 %

17.0 %17.0 %

TIMI TIMI MajorMajor

GUSTO GUSTO SevereSevere TransfusionTransfusion



p = 0.007p = 0.007 p = 0.106p = 0.106 p = 0.155p = 0.155

Summary

Prior antithrombotic therapy

Post-randomization management

Bleeding definitions

Age, renal function




Age, renal function

Issues to Issues to considerconsiderIssues to Issues to considerconsider

Summary

An overview of all recent RCTs comparing enoxaparin and UFH shows a consistent effect across the management spectrum

An overview of all recent RCTs comparing enoxaparin and UFH shows a consistent effect across the management spectrum

The study in contextThe study in contextThe study in contextThe study in context




Age, renal function




Age, renal function

Summary

Current role — enoxaparin is an effective

and safe alternative to UFH for the early

invasive management of high risk ACS

patients.

Current role — enoxaparin is an effective

and safe alternative to UFH for the early

invasive management of high risk ACS

patients.

The The messagemessage

The The messagemessage

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