Transcript OASIS in ACS
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
Implementation of guidelines
Therapeutic Options in Acute Coronary Syndromes
Anti-ischemic treatment
Antiplatelet agents
Anticoagulants
Revascularization/Reperfusion/Thrombolysis
Long term treatment/secondary prevention
Targets for antithrombotics
Direct Xa inhib Fondaparinux LMWH Heparin AT AT Bivalirudin Hirudin Tissue factor Collagen Aspirin Plasma clotting cascade Prothrombin Factor Xa Thrombin ADP Thromboxane A 2 Clopidogrel Prasugrel AZD 6140 Conformational activation of GPIIb/IIIa GPIIb/IIIa inhibitors Platelet aggregation Fibrinogen Fibrin Dabigatran Thrombus
Net Clinical Benefit of Anticoagulants
ROADMAP TO UA/NSTEMI
Early Conservative Strategy
• Bedrest, O 2 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/NSTEMI
Early Invasive Strategy
• Bedrest, O 2 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 5
: An International, Multicenter, Randomized, Double-Blind, Double-Dummy Trial in 41 Countries 20,078 patients with
UA/NSTEMI
Aspirin, Clopidogrel, anti-GPIIb/IIIa, planned Cath/PCI as per local practice Randomization Fondaparinux 2.5 mg s.c. od up to 8 days Enoxaparin 1 mg/kg s.c. bid for 2-8 days 1 mg/kg s.c. od if ClCr<30mL/min
Vital status ascertained in 20,066 (99.9%) Lost to follow-up at day 9: fondaparinux: n=7 and enoxaparin: n=5 1. Michelangelo OASIS 5 Steering Committee. Am Heart J 2005;150:1107.e1-.e10
2. OASIS 5 Investigators. N Engl J Med 1464-76
Study Objectives and Outcomes
Objectives Primary 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 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: Secondary: Death, MI, refractory ischemia, major bleeds up to day 9 Above & each component separately at days 30 and 180
1. Michelangelo OASIS 5 Steering Committee. Am Heart J 2005;150:1107.e1-.e10
2. OASIS 5 Investigators. N Engl J Med 2006;354:1464-76
Key Messages from OASIS 5
1.
Major bleeding risk reduction 2.
Significant risk reduction for death and death/ MI/ stroke 30 days and 6 months 3.
Consistent effect in every subset of patients 1.
PCI 2.
3.
4.
Elderly Renal failure Irrespective of initial risk category 4.
Excess of catheter thrombus formation during PCI
Death/MI/RI: Day 9
0 1 2 3
HR 1.01 95% CI 0.90-1.13
4 5 Days 6 Enoxaparin Fondaparinux 7 8 9
Major Bleeding: 9 Days
Enoxaparin HR 0.53 95% CI 0.45-0.62
P<<0.00001
Fondaparinux 0 1 2 3 4
Days
5 6 7 8 9
Mortality: Day 30
Enoxaparin Fondaparinux 95% CI 0.71
0.97
0 3 6 9 12 15
Days
18 21 24 27 30
Mortality at 6 Months
Enoxaparin Fondaparinux 95% CI 0.79
0.99 0 20 40 60 80 100
Days
120 140 160 180
Increased Mortality at Days 30/180 in Patients with Major Bleeds by Day 9 in OASIS 5
0,2
Maj Bleed 9 days
0,15 0,1
No Maj Bleed 9 days
0,05 0
0 Adjusted HR (95% CI) at day 30: 5.06 (4.59-5.62); at day 180: 3.16 (2.92-3.44) 30 60 90 Days 120 150
Budaj et al. JACC 2006;abstract 972-224
180
Bleeding Rates: Day 9
Outcome
No. Randomized Total Bleed Major Bleed TIMI Major Bleed Minor Bleed
Enox (%)
10021 7.3
4.1
1.3
3.2
Fonda (%)
10057 3.3
2.2
0.7
1.1
HR (95% CI) P value
0.44 (0.39-0.50) <<0.0001
0.52 (0.44-0.61) <<0.0001
0.55 (0.41-0.74) <<0.0001
0.35 (0.28-0.43) <<0.0001
Categories of Major Bleeds at 9 Days
No. Rand.
Total Bleeding Intracranial Surgery req ’d to stop bleed Retroperitoneal Hb 3 g/dL Transfusion 2 units
Enox (No. Pts)
10021 412 (4.1%) 7 77 37 312 287
Fonda (No. Pts)
10057 217 (2.2%) 7 41 9 150 164
P
<<0.0001
0.0001
0.0001
0.0001
0.0001
Does the Lower Bleeding Rate at 9 Days Translate into Lower Long Term Mortality?
Patients with
No Bleeds Minor Bleeds Major bleeds Total: No. Bleeds Minor Bleeds Major Bleeds Total:
No. Deaths at 30 Days Enox
278
Fonda
260 19 55 10 25 352
No. Deaths at 180 Days
528 518 31 295 13 76 635 35 566
Difference
-18 -9 -30 -57 -39 (68.4%) -10 -18 -41 -69 -59 (85.5%)
OASIS-5 Nonfatal MI Refractory Ischemia Major Bleeds Minor Bleeds
Relative Impact of MI, Refractory Ischemia or Bleeding on Mortality Crude Odds Ratio for Death (95% CI) 30 Days
9.6 (7.7-12.0)
30 to 180 Days
2.2 (1.5-3.3)
180 Days
5.6 (4.6-6.7) 4.0 (2.9-5.6) 1.4 (0.8-2.3) 2.6 (2.0-3.5) 6.5 (5.1-8.2) 3.0 (2.1-4.3) 2.1 (1.4-3.0) 1.5 (0.9-2.4) 4.1 (3.3-5.0) 2.2 (1.6-2.9)
Impact of Major Bleeding, Re-MI and Transfusion on risk of Death: ACUITY trial
Myocardial infarction Hazard Ratio (95% CI) 3.1 (2.4 to 3.9) Deaths
P
value 77 <0.001
Major bleeding Blood transfusion 3.5 (2.7 to 4.4) 93 <0.001
4.5 (3.4 to 5.9) 70 <0.001
0.5
1 2 4 Hazard ratio (95%CI) 8 Mehran, R. et al. Eur Heart J 2009 30:1457-1466
OASIS-5 Less Bleeding = Less Deaths
Bleeding Reduced by 50% Deaths Reduced by 17%
HR: 0.52 95% CI: 0.44-0.61 p<0.001
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
Anderson J. J Thromb Haemostasis 2010; 8: 243-9
OASIS 5
Death/MI/RI: Day 9
Enoxaparin vs Fondaparinux
6hr anti-Xa (IU/ml) Enoxaparin (n=42) Mean 1.2
SD 0.45
Fondaparinux (n=48) Mean 0.5
SD 0.2
P-value <0.0001
6hr Xa-clot (seconds) 111.8
29.6
64.9
<0.001
95% CI 0.90-1.13
6hr ETP AUC (mA) 206.4
0
90.6
386.7
51.5
Fondaparinux 1 2 3 4 5 Days 6 7 J Eikelboom, in press 8 9
A New Concept is Born
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Bleeding carries a high risk of death, MI and stroke
Rate of major bleeding is as high as the rate of death at the acute phase of NSTE-ACS
Prevention of bleeding is equally as important as prevention of ischemic events and results in a significant risk reduction for death, MI and stroke
Risk stratification for bleeding should be part of the decision making process
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OASIS 5 Conclusions Patients Undergoing PCI
A lower incidence of vascular access site complications was observed with fondaparinux Fewer bleeding complications with fondaparinux irrespective of the timing of last study drug administration Fewer bleeding complications with fondaparinux irrespective of the use of UFH prior to PCI 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
14 12 10 8 6 4 2 0
Clinical Events after PCI: Day 30
P=0.004
11,7 9,5
P=0.68
2,1 2
P=0.60
5,4 5,7
P<0.0001
5,4 2,8 Death MI Major Bleeds Enox (n=3089) Fonda (n=3118) Death, MI,Stroke or Major Bleed
4 3 2 1 0 9 8 7 6 5 Vascular Access Site Complications, Large Hematomas and Pseudo-aneurysms 8,1
HR 0.41
P<<0.0001
Enox Fonda 3,3
HR 0.63
P=0.033
1,6 1
HR 0.36
P<<0.0001
4,4 1,6 Vasc Access Site Complication Pseudo-aneurysm Large Hematoma
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 ascertained Fondaparinux 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
Adding UFH to Fondaparinux for PCI is Safe and Preserves the Lower Bleeding with Fondaparinux Enox Fonda HR No UFH post-Randomization UFH or equivalent placebo mandated by protocol during PCI Open Label UFH Overall 1.2
(n=1,277) 1.1
(n=1,229) 2.7
(n=598) 1.5
(n=3,104) 0.5
(n=1,313) 0.4
(n=1,279) 1.3
(n=543) 0.6
(n=3,135) 0.45
0.34
0.48
0.42
Mean dose of UFH for PCI used in OASIS 5: 47 IU/kg
CI 0.18
–1.11
0.12
–0.95
0.20
–1.17
0.24
–0.71
Yusuf S. et al.
N Engl J Med.
2006;354:2829
OASIS 5 PCI: Net Clinical Benefit Favours Fondaparinux in Invasively Managed Patients
Death/MI/Stroke/Major Bleeding RR 0.78
P=0.004
RR 0.76
P=0.035
12 10 Death, MI, Stoke, Major Bleeding (%) 8 6 4 2 0 Enoxaparin Fondaparinux ALL PCI EARLY PCI < 24h
Mehta et al. JACC 2006;abstract 821-5 Mehta et. al. JACC 2007, in press
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4.
Conclusions for PCI
Patients who underwent an early invasive strategy in OASIS 5 trial had
superior net benefit
with fondaparinux compared to enoxaparin Fondaparinux is safe and effective as upstream therapy in patients undergoing PCI and
reduces bleeding by half
compared to enoxaparin 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
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
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
Coronary Angiography/PCI to be performed within 72 hours Double Blind Adjunctive therapy during PCI Std Dose UFH
(85 U/kg or 60 U/kg with GP IIb/IIIa) ACT guided*
NSTEACS
Fonda 2.5 mg sc Angio with PCI
R
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 Angio No PCI
Low Dose UFH
(50 U/kg irrespective of GP IIb/IIIa) – without ACT
Registry
30 Day Follow-Up 30 Day Follow-Up 30 Day Follow-Up *ACT Targets consistent with current guidelines
Study Outcome Definitions
Major Bleeding (OASIS 5) Minor Bleeding Major Vascular Access Site Complications
•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 Any other significant bleeding leading to transfusion of one unit of blood or discontinuation of antithrombotic therapy.
•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
Age (years) Male (%) Diabetes (%) ECG changes (%) Elevated Troponin I or T (%) Aspirin (%) Clopidogrel (%) Procedural GP IIb/IIIa (%) Femoral Access (%) Any Stents placed (%)
Standard Dose UFH N=1002
65.5
68.5
27.9
74.6
78.8
96.1
96.3
26.4
62.4
94.0
Low Dose UFH N=1024
65.3
67.3
26.1
75.3
81.3
95.4
94.6
25.8
64.2
93.7
Primary Outcome at 48 h
Standard Dose UFH (n=1002) Low Dose UFH (n=1024) OR Peri-PCI major, minor bleeds and vascular access complications
5.8% 4.7% 0.80
95% CI
0.54-1.19
P
0.27
Primary Outcome at 48 h
Standard Dose UFH (n=1002) Low Dose UFH (n=1024) OR Peri-PCI major, minor bleeds and vascular access complications
5.8% 4.7% Components of primary outcome (Peri-PCI) Major bleeds Minor bleeds Major vascular access site complications 1.2% 1.7% 4.3% 1.4% 0.7% 3.2% 0.80
1.14
0.40
0.74
95% CI
0.54-1.19
0.53-2.49
0.16-0.97
0.47-1.18
P
0.27
0.73
0.04
0.21
Secondary Outcomes at 30 days
Key Secondary outcome:
Peri-PCI major bleeding, death, MI, TVR
Death, MI, TVR Death MI TVR Stent thrombosis Catheter thrombosis
Standard Dose UFH (n=1002) Low Dose UFH (n=1024) OR 95% CI
3.9% 2.9% 0.6% 2.5% 0.3% 0.5% 0.1% 5.8% 4.5% 0.8% 3.0% 0.9% 1.2% 0.5%* 1.51
1.00-2.28
1.58
1.31
1.22
2.95
2.36
4.91
0.98-2.53
0.45-3.78
0.72-2.08
0.80-10.9
0.83-6.73
0.57-42.1
P
0.05
0.06
0.11
0.15
* One event occurred during coronary angiography after randomization
Outcomes to 30 days
0.05
0.04
0.03
0.02
0.01
0.0
No. at Risk Standard Dose 1002 Low Dose 1024 Low dose 2.2% vs. Standard dose 1.8%, HR 1.20 (95% CI 0.64-2.23, p=0.57) 986 1002 Major Bleed at 30 days 981 1001 Days 980 998 Standard Dose Low Dose 980 997 978 994 0.05
0.04
0.03
0.02
0.01
0.0
No. at Risk Standard Dose 1002 Low Dose 1024 Death/MI/TVR at 30 days 980 997 Low dose 4.5% vs. Standard dose 2.9% HR 1.56 (95% CI 0.98-2.48, p=0.06) Standard Dose Low Dose 975 988 Days 975 982 974 981 971 978 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
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 FUTURA low dose UFH 1.1% (0.6-2.1) 1.2 % (0.6-2.2) 1.5% 3.6% • 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