presenters’ disclosure information: relationships related to this presentation research grants...
Post on 13-Jan-2016
213 Views
Preview:
TRANSCRIPT
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
Enoxaparin UFH(n = 4993) (n = 4985)
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
Enoxaparin UFH(n = 4993) (n = 4985)
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
Hazard Ratio (95% CI)
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
Enoxaparin UFH(n = 4993) (n = 4985)
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
Enoxaparin UFH(n = 2321) (n = 2364)
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
Hazard Ratio (95% CI)
Enox UFHBetter Better
0.60.6 11 22
Hazard Ratio (95% CI)
Enox UFHBetter Better
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
Total No Crossover Crossover
0
4
8
12
16
20
Total No Crossover Crossover
0
4
8
12
16
20
Total No Crossover Crossover
(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
Total No Crossover Crossover
0
5
10
15
20
25
Total No Crossover Crossover
0
5
10
15
20
25
Total No Crossover Crossover
Enox UFHBetter Better
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%
Hazard Ratio (95% CI)
Enoxaparin Better UFH Better
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.
Hazard Ratio (95% CI)
Enoxaparin Better UFH Better
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
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
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
High-risk population treated with an early invasive management strategy
High-risk population treated with an early invasive management strategy
Summary
Efficacy — not superior but at least as effective as UFH in the overall population
Efficacy — not superior but at least as effective as UFH in the overall population
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
High-risk population treated with an early invasive management strategy
High-risk population treated with an early invasive management strategy
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
Prior antithrombotic therapy
Post-randomization management
Bleeding definitions
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
Prior antithrombotic therapy
Post-randomization management
Bleeding definitions
Age, renal function
Prior antithrombotic therapy
Post-randomization management
Bleeding definitions
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
top related