SYNERGY研究
Presenters’ Disclosure Information: Relationships Related to this Presentation
Research Grants and/or Consultant fees:
Mahaffey:
Aventis, AstraZeneca, Berlex, Lilly, Daiichi, Millennium, Merck, Schering-Plough, The Medicines Company
Ferguson:
Aventis, AstraZeneca, Bristol Myers Squibb, Guidant, Merck, Sanofi, Schering-Plough, The 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:
Superiority of enoxaparin vs UFH in conservative management strategy
NICE Registries:
Comparable safety and efficacy to historical controls in PCI
ACUTE 2 / INTERACT / AtoZ
Contemporary trials in higher risk patients
Key Questions
What is the role of enoxaparin in high-risk NSTEMI ACS patients managed with an early invasive treatment strategy ?
Can we safely bring patients on enoxaparin rapidly forward to the catheterization laboratory ?
Study Design
At least 2 of 3 required:
Age ? 60
ST ? (transient) or ?
(+) CK-MB or Troponin
Enoxaparin
IV Heparin
Primary endpoint: Death or MI at 30 days
High-Risk ACS Patients
Randomize (n = 10,000)
Early invasive strategy
Other therapy per AHA/ACC Guidelines
(ASA, ?-blocker, ACE, clopidogrel, GP IIb/IIIa)
60 U/kg ? 12 U/kg/hr (aPTT 50-70 sec)
1 mg/kg SC Q12H
Statistical Assumptions
12 Countries. 467 Sites. 10,027 Patients.
Inclusion Criteria
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 antithrombin 24 25 24
UFH only 29 30 29
Enoxaparin only 42 42 43
UFH and enoxaparin 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
HR 0.96 (0.87-1.06)
1.1
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
Pre-randomization
No prior
UFH
Enox
Both
Pre-randomization
Randomization
Prior Antithrombin Therapy: Efficacy and Safety
Enox UFH (%) (%)
30-DAY DEATH / MI
BLEEDING
GUSTO Severe
TIMI Major
Enox UFH (%) (%)
No prior
UFH
Enox
Both
Pre-randomization
Randomization
No prior
UFH
Enox
Both
Pre-randomization
Randomization
Crossover
Crossovers: Relation to Bleeding
Crossovers: Relation to Outcome
Enoxaparin
UFH
Systematic Overview: 30-Day Death/MI and In-hospital Transfusions
30-DAY DEATH / MI
IN-HOSPITAL TRANSFUSIONS
Enox UFH
2.6% 3.3%
0.7% 0.6%
2.5% 4.3%
1.0% 0.8%
17.0% 16.0%
0.8% 0.9%
ESSENCE
INTERACT
TIMI 11B
ACUTE 2
AtoZ
SYNERGY
Enox UFH
5.0% 9.0%
7.4% 8.3%
7.9% 8.1%
7.4% 7.9%
14.0% 14.5%
6.2% 7.7%
Systematic Overview: Death/MI and Bleeding
10.1% 11.0%
Enox UFH
8.2% 7.8%
4.8% 4.1%
(n = 21,946)
(n = 22,104)
(n = 22,104)
AtoZ did not include CABG data.
Systematic Overview—No Pre-rando Therapy: Death/MI and Bleeding
8.1% 9.5%
Enox UFH
5.6% 5.5%
3.5% 2.7%
(n = 9835)
(n = 8627)
(n = 8627)
AtoZ did not include CABG data.
Summary
High-risk population treated with an early invasive management strategy
The study
Summary
Efficacy — not superior but at least as effective as UFH in the overall population
The results
met criteria for non-inferiority
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
Bleeding — more frequent with enoxaparin
The results
High-risk population treated with an early invasive management strategy
p = 0.007
p = 0.106
p = 0.155
Summary
Prior antithrombotic therapy
Post-randomization management
B