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OASIS in ACS: with Updates on 2011 ESC Guidelines on Anticoagulation Donato Maranon, MD, FPCP, FPCC, FACC. Dramatic Improvement of Outcome over the Last 30 years. Antiplatelet agents Anticoagulants Revascularization / Reperfusion / Thrombolysis Long term treatment / secondary prevention - PowerPoint PPT Presentation
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OASIS in ACS: with Updates on 2011 ESC Guidelines
on Anticoagulation
Donato Maranon, MD, FPCP, FPCC, FACC
OASIS in ACS: with Updates on 2011 ESC Guidelines
on Anticoagulation
Donato Maranon, MD, FPCP, FPCC, FACC
Antiplatelet agents
Anticoagulants
Revascularization / Reperfusion / Thrombolysis
Long term treatment / secondary prevention
Implementation of guidelines
Antiplatelet agents
Anticoagulants
Revascularization / Reperfusion / Thrombolysis
Long term treatment / secondary prevention
Implementation of guidelines
Dramatic Improvement of Outcome over the Last 30 years
Dramatic Improvement of Outcome over the Last 30 years
Therapeutic Options in Acute Coronary Syndromes
Therapeutic Options in Acute Coronary Syndromes
Anti-ischemic treatment
Antiplatelet agents
Anticoagulants
Revascularization/Reperfusion/Thrombolysis
Long term treatment/secondary prevention
Anti-ischemic treatment
Antiplatelet agents
Anticoagulants
Revascularization/Reperfusion/Thrombolysis
Long term treatment/secondary prevention
Targets for antithromboticsTargets for antithrombotics
Tissue factor
Plasma clottingcascade
Prothrombin
Thrombin
Fibrinogen Fibrin
Thrombus
Platelet aggregation
Conformational activation of GPIIb/IIIa
Collagen
Thromboxane A2
ADP
AT
AT
Aspirin
ClopidogrelPrasugrelAZD 6140
GPIIb/IIIainhibitors
BivalirudinHirudin
Dabigatran
FactorXa
Fondaparinux
LMWHHeparin
Direct Xa inhib
ROADMAP TO UA/NSTEMIEarly Conservative Strategy
• Bedrest, O2 if indicated
• Nitrates, Morphine, BB, ACEi• Aspirin, Clopidogrel• LMWH or UFH or Fondaparinux• Monitor with serial ECG and cardiac biomarkers• Eptifibatide or Tirofiban, if with continuing ischemia,
elevated TnT or TnI, and other high risk factors
ROADMAP TO UA/NSTEMIEarly Invasive Strategy
• Bedrest, O2 if needed
• Nitrates, Morphine, BB, ACEi
• Aspirin, LMWH or UFH
• GP IIb/IIIa, tirofiban, eptifibatide, or abciximab is added to aspirin, clopidogrel and heparin if PCI needed
Guidelines Recommendations for Anticoagulation
• Anticoagulation is recommended for all patients in addition to antiplatelet therapy (I-A)
• Anticoagulation should be selected according to the risk of both ischaemic and bleeding events (I-B)
• Several anticoagulants are available, namely UFH, LMWH, Fondaparinux, bivalirudin. The choice depends on the initial strategy (urgent invasive, early invasive, or conservative strategies (I-B)
• In an urgent invasive strategy UFH (I-C), or enoxaparin (IIa-B) or bivalirudin (I-B) should be immediately started
2007 ESC Guidelines
Guidelines Recommendations for Anticoagulation
• In a non-urgent situation, as long as decision between early invasive or conservative strategy is pending:– Fondaparinux is recommended on the basis of the
most favourable efficacy/safety profile (I-A)– Enoxaparin with a less favourable efficacy/safety
profile than fondaparinux should be used only if the bleeding risk is low (IIa-B)
– As efficacy/safety profile of LMWH (other than enoxaparin) or UFh relative to fondaparinux is unknown; these anticoagulants cannot be recommended over fondaparinux (IIa-B)
2007 ESC Guidelines
OASIS 5OASIS 5: An International, Multicenter, Randomized, : An International, Multicenter, Randomized, Double-Blind, Double-Dummy Trial in 41 CountriesDouble-Blind, Double-Dummy Trial in 41 Countries
OASIS 5OASIS 5: An International, Multicenter, Randomized, : An International, Multicenter, Randomized, Double-Blind, Double-Dummy Trial in 41 CountriesDouble-Blind, Double-Dummy Trial in 41 Countries
20,078 patients with 20,078 patients with UA/NSTEMIUA/NSTEMI20,078 patients with 20,078 patients with UA/NSTEMIUA/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
1. Michelangelo OASIS 5 Steering Committee. Am Heart J 2005;150:1107.e1-.e102. OASIS 5 Investigators. N Engl J Med 1464-76
Vital status ascertained in 20,066 (99.9%) Lost to follow-up at day 9: fondaparinux: n=7 and enoxaparin: n=5
Study Objectives and OutcomesStudy Objectives and OutcomesStudy Objectives and OutcomesStudy Objectives and Outcomes
Outcomes (centrally adjudicated)Primary efficacy: 1st occurrence of the composite of death, MI, or refractory
ischemia(RI) up to day 9
Primary safety: Major bleeding up to day 9
Risk benefit: Death, MI, refractory ischemia, major bleeds up to day 9
Secondary: Above & each component separately at days 30 and 180
ObjectivesPrimary efficacy objective: To demonstrate non-inferiority of fondaparinux
compared with enoxaparin
Primary safety objective: To determine whether fondaparinux was superior to enoxaparin in preventing major
bleeding
ObjectivesPrimary efficacy objective: To demonstrate non-inferiority of fondaparinux
compared with enoxaparin
Primary safety objective: To determine whether fondaparinux was superior to enoxaparin in preventing major
bleeding
1. Michelangelo OASIS 5 Steering Committee. Am Heart J 2005;150:1107.e1-.e102. OASIS 5 Investigators. N Engl J Med 2006;354:1464-76
Key Messages from OASIS 5Key Messages from OASIS 5
1.1. Major bleeding risk reductionMajor bleeding risk reduction
2.2. Significant risk reduction for death and death/ Significant risk reduction for death and death/ MI/ stroke 30 days and 6 monthsMI/ stroke 30 days and 6 months
3.3. Consistent effect in every subset of patientsConsistent effect in every subset of patients1.1. PCIPCI2.2. ElderlyElderly3.3. Renal failureRenal failure4.4. Irrespective of initial risk categoryIrrespective of initial risk category
4.4. Excess of catheter thrombus formation during Excess of catheter thrombus formation during PCIPCI
1.1. Major bleeding risk reductionMajor bleeding risk reduction
2.2. Significant risk reduction for death and death/ Significant risk reduction for death and death/ MI/ stroke 30 days and 6 monthsMI/ stroke 30 days and 6 months
3.3. Consistent effect in every subset of patientsConsistent effect in every subset of patients1.1. PCIPCI2.2. ElderlyElderly3.3. Renal failureRenal failure4.4. Irrespective of initial risk categoryIrrespective of initial risk category
4.4. Excess of catheter thrombus formation during Excess of catheter thrombus formation during PCIPCI
Death/MI/RI: Day 9
Days
Cum
ulat
ive
Haz
ard
0.0
0.01
0.02
0.03
0.04
0.05
0.06
0 1 2 3 4 5 6 7 8 9
Enoxaparin
Fondaparinux
HR 1.01 95% CI 0.90-1.13
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 0.53 95% CI 0.45-0.62
P<<0.00001
Enoxaparin
Fondaparinux
Mortality: Day 30
Days
Cu
mu
lati
ve H
aza
rd0.
00.
010.
020.
03
0 3 6 9 12 15 18 21 24 27 30
HR 0.83 HR 0.83 95% CI 0.7195% CI 0.71--0.970.97
P=0.022P=0.022
Enoxaparin
Fondaparinux
Mortality at 6 Months
Days
Cu
mu
lati
ve H
aza
rd0.
00.
020.
040.
06
0 20 40 60 80 100 120 140 160 180
HR 0.89HR 0.8995% CI 0.7995% CI 0.79--0.99 0.99
P=0.037P=0.037
Enoxaparin
Fondaparinux
0
0,05
0,1
0,15
0,2
Increased Mortality at Days 30/180 in Patientswith Major Bleeds by Day 9 in OASIS 5
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 30 60 90 120 150 180
Maj Bleed 9 days
No Maj Bleed 9 days
Days
Cum
ulat
ive H
azar
d
Bleeding Rates: Day 9
Outcome Enox(%)
Fonda(%)
HR (95% CI) P value
No. Randomized 10021 10057
Total Bleed 7.3 3.3 0.44 (0.39-0.50) <<0.0001
Major Bleed 4.1 2.2 0.52 (0.44-0.61) <<0.0001
TIMI Major Bleed 1.3 0.7 0.55 (0.41-0.74) <<0.0001
Minor Bleed 3.2 1.1 0.35 (0.28-0.43) <<0.0001
Categories of Major Bleeds at 9 Days
Enox(No. Pts)
Fonda(No. Pts)
P
No. Rand. 10021 10057
Total Bleeding 412 (4.1%) 217 (2.2%) <<0.0001
Intracranial 7 7
Surgery req’d to stop bleed 77 41 0.0001
Retroperitoneal 37 9 0.0001
Hb 3 g/dL 312 150 0.0001
Transfusion 2 units 287 164 0.0001
Does the Lower Bleeding Rate at 9 Days
Translate into Lower Long Term Mortality?
-69566635Total:
-413576Major Bleeds
-181331Minor Bleeds
-10518528No. Bleeds
No. Deaths at 180 Days
-57
-30
-9
-18
Difference
260278No Bleeds
295352Total:
FondaEnoxPatients with
2555Major bleeds
1019Minor Bleeds
No. Deaths at 30 Days
-59 (85.5%)
-39 (68.4%)
Relative Impact of MI, Refractory Ischemiaor Bleeding on Mortality
1.5 (0.9-2.4)
2.1 (1.4-3.0)
1.4 (0.8-2.3)
2.2 (1.5-3.3)
30 to 180 Days
2.2 (1.6-2.9)3.0 (2.1-4.3)Minor Bleeds
4.1 (3.3-5.0)6.5 (5.1-8.2)Major Bleeds
2.6 (2.0-3.5)4.0 (2.9-5.6)Refractory Ischemia
5.6 (4.6-6.7)9.6 (7.7-12.0)Nonfatal MI
180 Days30 Days
Crude Odds Ratio for Death
(95% CI)
OASIS-5
Mehran, R. et al. Eur Heart J 2009 30:1457-1466
Impact of Major Bleeding, Re-MI and Transfusion on risk of Death: ACUITY trial
Myocardial infarction 3.1 (2.4 to 3.9)
3.5 (2.7 to 4.4)
4.5 (3.4 to 5.9)
Major bleeding
Blood transfusion
DeathsHazard Ratio (95% CI)
P value
77
93
70
<0.001
<0.001
<0.001
Hazard ratio (95%CI)
0.5 1 2 4 8
OASIS-5Less Bleeding = Less Deaths
OASIS-5Less Bleeding = Less Deaths
Days
Cu
mu
lativ
e 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<0.001
Enoxaparin
Fondaparinux
Days
Cu
mu
lativ
e 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<0.001
Enoxaparin
Fondaparinux
Days
Cu
mu
lati
ve H
azar
d
0.0
0.01
0.02
0.03
0 3 6 9 12 15 18 21 24 27 30
HR: 0.83 95% CI: 0.71-0.97p=0.02
Enoxaparin
Fondaparinux
Days
Cu
mu
lati
ve H
azar
d
0.0
0.01
0.02
0.03
0 3 6 9 12 15 18 21 24 27 30
HR: 0.83 95% CI: 0.71-0.97p=0.02
Enoxaparin
Fondaparinux
Bleeding Reduced by 50% Deaths Reduced by 17%
Yusuf S, Mehta S, et al. OASIS-5 Investigators NEJM 2006
A Shift in the Paradigm
Fondaparinux makes it possible to reduce both ischemic risk (death, death/MI, death/MI/stroke) and bleeding risk
First ever observed with an anticoagulant in ACS
Comparison of Anticoagulant Activities
of Enoxaparin and Fondaparinux in OASIS 5
Comparison of Anticoagulant Activities
of Enoxaparin and Fondaparinux in OASIS 5
Anderson J. J Thromb Haemostasis 2010; 8: 243-9
Enoxaparin (n=42)Enoxaparin (n=42) Fondaparinux (n=48)Fondaparinux (n=48) P-valueP-value
MeanMean SDSD MeanMean SDSD
6hr anti-Xa 6hr anti-Xa (IU/ml)(IU/ml)
1.21.2 0.450.45 0.50.5 0.20.2 <0.0001<0.0001
6hr Xa-clot 6hr Xa-clot (seconds)(seconds)
111.8111.8 29.629.6 64.964.9 17.717.7 <0.001<0.001
6hr ETP AUC 6hr ETP AUC (mA)(mA)
206.4206.4 90.690.6 386.7386.7 51.551.5 <0.001<0.001
ETP AUC, endogenous thrombin potential area under the curveETP AUC, endogenous thrombin potential area under the curve
Enoxaparin vs FondaparinuxEnoxaparin vs Fondaparinux
J Eikelboom, in pressJ Eikelboom, in pressJ Eikelboom, in pressJ Eikelboom, in press
Death/MI/RI: Day 9
Days
Cum
ula
tive
Ha
zard
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
OASIS 5OASIS 5
A New Concept is Born
1. Bleeding carries a high risk of death, MI and stroke
2. Rate of major bleeding is as high as the rate of death at the acute phase of NSTE-ACS
3. Prevention of bleeding is equally as important as prevention of ischemic events and results in a significant risk reduction for death, MI and stroke
4. Risk stratification for bleeding should be part of the decision making process
OASIS 5 Conclusions Patients Undergoing PCI OASIS 5 Conclusions Patients Undergoing PCI
1. A lower incidence of vascular access site complications was observed with fondaparinux
2. Fewer bleeding complications with fondaparinux irrespective of the timing of last study drug administration
3. Fewer bleeding complications with fondaparinux irrespective of the use of UFH prior to PCI
4. A higher rate of guiding catheter thrombosis was observed with fondaparinux when PCI was performed without UFH, but this was largely avoided if UFH was used just before/during the procedure
OASIS 5 Investigators. N Engl J Med 2006;354:1464-76
Fondaparinux in PCI
Clinical Events after PCI: Day 30
2,1
5,4 5,4
11,7
2
5,7
2,8
9,5
02468
101214
Death MI Major Bleeds Death,MI,Stroke orMajor Bleed
Eve
nt
Rat
e (%
)
Enox (n=3089) Fonda (n=3118)
P<0.0001
P=0.004
P=0.68
P=0.60
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
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
Mean dose of UFH for PCI used in OASIS 5: 47 IU/kg
EnoxEnox FondaFonda HRHR CICI
No UFH post-RandomizationNo UFH post-Randomization 1.21.2
(n=1,277)(n=1,277)
0.50.5
(n=1,313)(n=1,313)
0.450.45 0.18–1.110.18–1.11
UFH or equivalent placebo UFH or equivalent placebo mandated by protocol during mandated by protocol during PCIPCI
1.11.1
(n=1,229)(n=1,229)
0.40.4
(n=1,279)(n=1,279)
0.340.34 0.12–0.950.12–0.95
Open Label UFHOpen Label UFH 2.72.7
(n=598)(n=598)
1.31.3
(n=543)(n=543)
0.480.48 0.20–1.170.20–1.17
OverallOverall 1.51.5
(n=3,104)(n=3,104)
0.60.6
(n=3,135)(n=3,135)
0.420.42 0.24–0.710.24–0.71
Yusuf S. et al. N Engl J Med. 2006;354:2829
Mean dose of UFH for PCI used in OASIS 5: 47 IU/kg
Adding UFH to Fondaparinux for PCI is Safe and Preserves the Lower Bleeding with Fondaparinux
Adding UFH to Fondaparinux for PCI is Safe and Preserves the Lower Bleeding with Fondaparinux
OASIS 5 PCI: Net Clinical Benefit Favours Fondaparinux in Invasively Managed Patients
OASIS 5 PCI: Net Clinical Benefit Favours Fondaparinux in Invasively Managed Patients
0
2
4
6
8
10
12
Death, MI, Stoke, Major Bleeding (%)
ALL PCI EARLY PCI < 24h
EnoxaparinFondaparinux
RR 0.78P=0.004 RR 0.76
P=0.035
Mehta et al. JACC 2006;abstract 821-5Mehta et. al. JACC 2007, in press
Death/MI/Stroke/Major Bleeding
Conclusions for PCIConclusions for PCI1. Patients who underwent an early invasive strategy in
OASIS 5 trial had superior net benefit with fondaparinux compared to enoxaparin
2. Fondaparinux is safe and effective as upstream therapy in patients undergoing PCI and reduces bleeding by half compared to enoxaparin
3. Catheter thrombus occurs very rarely in comparison with death or re-MI and appears to be avoided with standard UFH for the PCI itself without increasing major bleeding
4. Adjunctive UFH (50 IU/kg) with or without GP IIb/IIIa antagonist is recommended as PCI anticoagulation
1. Patients who underwent an early invasive strategy in OASIS 5 trial had superior net benefit with fondaparinux compared to enoxaparin
2. Fondaparinux is safe and effective as upstream therapy in patients undergoing PCI and reduces bleeding by half compared to enoxaparin
3. Catheter thrombus occurs very rarely in comparison with death or re-MI and appears to be avoided with standard UFH for the PCI itself without increasing major bleeding
4. Adjunctive UFH (50 IU/kg) with or without GP IIb/IIIa antagonist is recommended as PCI anticoagulation
Simple Transition of Patients Initiated on Fondaparinux to the Catheterization Lab
Simple Transition of Patients Initiated on Fondaparinux to the Catheterization Lab
Treat with ASA, clopidogrel and fondaparinux, +/- IV glycoprotein IIb/IIIa inhibitor in the ER
Proceed to Cath Lab as usual*
If PCI needed, give UFH (dose 50 units/kg) +/- glycoprotein IIb/IIIa inhibitor
Post procedure, follow usual practice for sheath removal. Immediate removal if closure device or radial and 6 hours after last fondaparinux subcut dose if no closure device used
Treat with ASA, clopidogrel and fondaparinux, +/- IV glycoprotein IIb/IIIa inhibitor in the ER
Proceed to Cath Lab as usual*
If PCI needed, give UFH (dose 50 units/kg) +/- glycoprotein IIb/IIIa inhibitor
Post procedure, follow usual practice for sheath removal. Immediate removal if closure device or radial and 6 hours after last fondaparinux subcut dose if no closure device used
*May perform cath>6 hours after last subcut dose if this was center’s usual practice with using LMWH
Low vs. Standard Dose Unfractionated Heparin for Percutaneous Coronary Intervention in Acute Coronary Syndromes Patients
treated with Fondaparinux: the FUTURA/OASIS 8 Randomised Trial
Sanjit S. Jolly on behalf of FUTURA/OASIS 8 Trial Group
FUTURA Trial Study Objectives
• Primary Objective: To determine whether Low fixed dose vs. Standard ACT guided unfractionated heparin during PCI reduces the composite of peri-PCI* major, minor bleeding and vascular access site complications in ACS patients treated with fondaparinux
• Secondary Objective: To determine if major bleeding rates in FUTURA (with unfractionated heparin added to fondaparinux) are higher than OASIS 5 PCI (with Fondaparinux used alone)
• *Peri-PCI defined within 48 hours following PCI
Study Design
With at least 2 of following:• Age>60• elevated biomarkers• ECG changes
Patients were not eligible if required urgent coronary angiography (<120 min) due to clinical instability
Adjunctive therapyduring PCI
DoubleBlind
Registry
*ACT Targets consistent with current guidelines
Coronary Angiography/PCI to be performed within 72 hours
Study Outcome DefinitionsMajor Bleeding (OASIS 5)
•Fatal
•Symptomatic ICH
•Retroperitoneal hemorrhage
•Intraocular bleeding leading to significant vision loss
•Requiring surgical intervention
•Hb drop of ≥3 g/dL
• Blood transfusion of > two units RBCs
Minor Bleeding Any other significant bleeding leading to transfusion of one unit of blood or discontinuation of antithrombotic therapy.
Major Vascular Access Site Complications
•Large hematoma (≥5 cm or requiring intervention)
•Pseudoaneurysm requiring treatment
•Arterio-venous fistula
•Other vascular surgery related to the access site
Baseline and Procedural Characteristics
Standard Dose UFHStandard Dose UFH
N=1002N=1002
Low Dose UFHLow Dose UFH
N=1024N=1024
Age (years) 65.5 65.3
Male (%) 68.5 67.3
Diabetes (%) 27.9 26.1
ECG changes (%) 74.6 75.3
Elevated Troponin I or T (%) 78.8 81.3
Aspirin (%) 96.1 95.4
Clopidogrel (%) 96.3 94.6
Procedural GP IIb/IIIa (%) 26.4 25.8
Femoral Access (%) 62.4 64.2
Any Stents placed (%) 94.0 93.7
Primary Outcome at 48 h
Standard Standard Dose UFH Dose UFH (n=1002)(n=1002)
LowLowDose UFH Dose UFH (n=1024)(n=1024)
OROR 95% CI95% CI PP
Peri-PCI major, minor bleeds and vascular access complications 5.8% 4.7% 0.80 0.54-1.19 0.27
Primary Outcome at 48 h
Standard Standard Dose UFH Dose UFH (n=1002)(n=1002)
LowLowDose UFH Dose UFH (n=1024)(n=1024)
OROR 95% CI95% CI PP
Peri-PCI major, minor bleeds and vascular access complications 5.8% 4.7% 0.80 0.54-1.19 0.27
Components of primary outcome (Peri-PCI)
Major bleeds 1.2% 1.4% 1.14 0.53-2.49 0.730.73
Minor bleeds 1.7% 0.7% 0.40 0.16-0.97 0.040.04
Major vascular access site complications 4.3% 3.2% 0.74 0.47-1.18 0.210.21
Secondary Outcomes at 30 days
Standard Standard Dose UFH Dose UFH (n=1002)(n=1002)
Low Low Dose UFH Dose UFH (n=1024)(n=1024)
OROR 95% CI95% CI PP
Key Secondary outcome: Peri-PCI major bleeding, death, MI, TVR
3.9% 5.8% 1.51 1.00-2.28 0.05
Death, MI, TVR 2.9% 4.5% 1.58 0.98-2.53 0.06
Death 0.6% 0.8% 1.31 0.45-3.78
MI 2.5% 3.0% 1.22 0.72-2.08
TVR 0.3% 0.9% 2.95 0.80-10.9
Stent thrombosis 0.5% 1.2% 2.36 0.83-6.73 0.110.11
Catheter thrombosis 0.1% 0.5%* 4.91 0.57-42.1 0.150.15
* One event occurred during coronary angiography after randomization
Outcomes to 30 days
Subgroup analysis showed consistent results for primary outcome and for death/MI/TVR for pre-specified subgroups of: Age, Sex,
GP IIb/IIIa, BMI, CrCl, Arterial access site
Subgroup analysis showed consistent results for primary outcome and for death/MI/TVR for pre-specified subgroups of: Age, Sex,
GP IIb/IIIa, BMI, CrCl, Arterial access site
Low dose 2.2% vs. Standard dose 1.8%, HR 1.20 (95% CI 0.64-2.23, p=0.57)
Major Bleed at 30 days
Days
3 6 9 12 15 18 21 24 27 303 6 9 12 15 18 21 24 27 3000
0.0
0.01
0.02
0.03
0.04
0.05
Standard DoseLow Dose
No. at Risk
Standard Dose
Low Dose
1002 986 981 980 980 978
1024 1002 1001 998 997 994
Days
0 3 6 9 12 15 18 21 24 27 300 3 6 9 12 15 18 21 24 27 30
0.0
0.01
0.02
0.03
0.04
0.05 Death/MI/TVR at 30 days
Standard DoseLow Dose
No. at Risk
Standard Dose
Low Dose
1002 980 975 975 974 971
1024 997 988 982 981 978
Low dose 4.5% vs. Standard dose 2.9%HR 1.56 (95% CI 0.98-2.48, p=0.06)
Comparison to OASIS 5 Major Bleeding
Adjusted Major
bleeding* rate (95% CI)
OASIS 5 PCI Fondaparinux
Major bleeding*
OASIS 5 PCI Enoxaparin
Major bleeding*
FUTURA standard dose UFH
1.1% (0.6-2.1)
1.5% 3.6%FUTURA low dose UFH
1.2 % (0.6-2.2)
• Adding unfractionated heparin during PCI to fondaparinux does not appear to increase peri-PCI major bleeding
*Major bleeding rates within 48 hours following PCI
Conclusions • No significant difference in major/minor bleeding or
vascular complications between Low fixed dose and Standard dose unfractionated heparin
• While low dose heparin reduced minor bleeding there was a trend towards reduced efficacy
• The use of unfractionated heparin for PCI on a background of fondaparinux did not increase major bleeding when compared to fondaparinux alone and lower than that previously observed with enoxaparin
Implications
• ACS patients treated with fondaparinux can undergo PCI safely with unfractionated heparin
• No evidence to depart from guideline recommended standard dose regimen of unfractionated heparin during PCI
• Adding unfractionated heparin during PCI to fondaparinux preserves the benefits and safety of fondaparinux (ie. reduced bleeding) while minimizing catheter thrombus
Highlights of the Latest European Society of Cardiology Guidelines on
Anticoagulants
ESC Guidelines 2011 European Heart Journal
ESC Guidelines European Heart Journal
doi:10.1093/eurheart/ehr236
ESC 2011 Guidelines in ACS in patients without presenting persistent ST-segment elevation
Fondaparinux (2.5mg subcutaneously daily) is recommended as having the
most favourable efficacy – safety profile with respect to
anticoagulation GRADE 1 A
ESC Guidelines European Heart Journal
doi:10.1093/eurheart/ehr236
ESC 2011 Guidelines in ACS in patients without presenting persistent ST-segment elevation
Fondaparinux
Contraindicated in severe renal failure
(CrCl<20mL/min). Drug of choice in patients with moderately reduced
renal function (CrCl 30 – 60 mL/min)
ESC Guidelines European Heart Journal
doi:10.1093/eurheart/ehr236
Recommendation for Invasive evaluations and revascularization
ESC Guidelines European Heart Journal
doi:10.1093/eurheart/ehr236
How Should Fondaparinux Be Used in Patients with UA/NSTEMI?
Administer fondaparinux (2.5 mg sc od) for up to 8 days or until hospital discharge if earlier
If a patient needs to undergo an invasive procedure during the treatment period, the following is recommended:
– PCI: UFH should be used during the procedure
– CABG surgery: fondaparinux where possible should not be given during the 24 h before surgery and may be restarted 48 h post-operatively
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