ACS Management and ESC Guidelines

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


LowLowDose UFH Dose UFH (n=1024)(n=1024)


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


Low Low Dose UFH Dose UFH (n=1024)(n=1024)


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 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)



Recommendation for Invasive evaluations and revascularization



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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ACS Management and ESC Guidelines

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Transcript of ACS Management and ESC Guidelines