Guidelines nste-acs-slides

ESC Guidelines for the Management of NSTE-ACS (1)ESC Guidelines for the Management of NSTE-ACS (1)

ESC Guidelines for the Management of Non-ST Segment Elevation Acute Coronary

Syndromes

ESC Guidelines for the Management of ESC Guidelines for the Management of NonNon--ST Segment Elevation Acute Coronary ST Segment Elevation Acute Coronary

SyndromesSyndromes

JeanJean--Pierre Bassand, MD, FESCPierre Bassand, MD, FESCCoCo--chairchairUniversity Hospital Jean MinjozUniversity Hospital Jean MinjozBesanBesanççononFranceFrance

Christian Hamm, MD, FESCChristian Hamm, MD, FESCCoCo--chairchairKerckhoffKerckhoff HeartHeart CenterCenterBadBad NauheimNauheimGermanyGermany


Members of the Task ForceMembersMembers of of thethe TaskTask ForceForce

•• JeanJean--Pierre Bassand, Pierre Bassand, France France CoCo--ChairChair

•• Diego Ardissino, Italy Diego Ardissino, Italy •• AndrzejAndrzej BudajBudaj, Poland, Poland•• Eric Boersma, Eric Boersma,

NetherlandsNetherlands•• Francisco FernandezFrancisco Fernandez--

Aviles, SpainAviles, Spain

•• Christian Hamm, Christian Hamm, GermanyGermanyCoCo--chairchair

•• Keith Fox, United Keith Fox, United Kingdom Kingdom

•• David Hasdai, IsraelDavid Hasdai, Israel•• Magnus Ohman, USA Magnus Ohman, USA •• Lars Wallentin, Sweden Lars Wallentin, Sweden •• William Wijns, BelgiumWilliam Wijns, Belgium


EuropeanEuropean HeartHeart Journal Journal AdvanceAdvance Access Access publishedpublished JuneJune 14, 200714, 2007


Trends and Prognosis in NSTE-ACSTrends Trends andand PrognosisPrognosis in NSTEin NSTE--ACSACS

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Trends and Prognosis in NSTE-ACSTrends Trends andand PrognosisPrognosis in NSTEin NSTE--ACSACS

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STEMI STEMI versusversus NSTEMINSTEMIMortalityMortality afterafter DischargeDischarge

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MethodsMethodsMethods



11-- Cost/benefit and cost/risk ratiosCost/benefit and cost/risk ratios in the terms of in the terms of –– Number Needed to TreatNumber Needed to Treat

2 2 -- Class III reClass III re--introduced in the level of recommendationsintroduced in the level of recommendations–– Class III = contraClass III = contra--indication (it goes without saying, indication (it goes without saying,

but itbut it’’s better to say it !)s better to say it !)


RISC ’90

Cohen ’94

Holdright ’94

Gurfinkel ’95

All

399

214

285

143

2859

Theroux ’88

Cohen ’90

243

69

10 102 ∞ 11 101020.25 20% 20% 0.50.1 2 1013%0% 6%

Odds ratio and 95% CI

NNT and 95% CI Odds ratio and 95% CI

Incidence

0.55 (0.39-0.77) 31 (23-62) 2.3 (0.97-5.4)4.7% vs 7.4%

Incidence

1.1% vs 0.5%

Death or MI at end study medicationSize Major bleeds

Heparin+ Ctrl+ Heparin+ Ctrl+ Heparin+ Ctrl+

0.5 140%

FRISC ’96 1506

000

00

0

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Randomized trials of UFH/LMWH (dark bars ) vs Control (open bars)

Randomized trials Randomized trials of UFH/LMWH of UFH/LMWH (dark bars )(dark bars ) vsvs Control Control (open bars)(open bars)



11-- Cost/benefit and cost/risk ratios in the form of Cost/benefit and cost/risk ratios in the form of –– Number Needed to TreatNumber Needed to Treat

2 2 -- Class III reClass III re--introducedintroduced in the level of recommendationsin the level of recommendations–– Class III = contraClass III = contra--indication (it goes without saying, indication (it goes without saying,

but itbut it’’s better in saying !)s better in saying !)


MethodsMethodsMethods33-- Quality level of trials taken into accountQuality level of trials taken into account

–– Double blind, Double blind, randomisedrandomised designdesign–– Use of hard endpoints in the primary endpoint Use of hard endpoints in the primary endpoint

•• death and MI death and MI •• death / MI / stroke and bleeding as net clinical benefitdeath / MI / stroke and bleeding as net clinical benefit

–– Adequate sample size calculationsAdequate sample size calculations–– Contemporary adjunctive treatments (stents, clopidogrel, Contemporary adjunctive treatments (stents, clopidogrel,

IIb/IIIa inhibitorsIIb/IIIa inhibitors……))44-- EfficacyEfficacy / / safetysafety profile profile ofof drugsdrugs / / treatmentstreatments takentaken intointo

accountaccount for for thethe gradation gradation ofof recommendationsrecommendations


Classes of Recommendations Classes of Recommendations Classes of Recommendations

Evidence or general agreement that the given treatment or Evidence or general agreement that the given treatment or procedure is not useful / effective, and in some cases may be procedure is not useful / effective, and in some cases may be harmful. harmful.

Class IIIClass III

Usefulness / efficacy is less well established by evidence / Usefulness / efficacy is less well established by evidence / opinionopinion

Class Class IIbIIb

Weight of evidence / opinion is in favour of usefulness / efficaWeight of evidence / opinion is in favour of usefulness / efficacycyClass Class IIaIIa

Conflicting evidence and/or a divergence of opinion about the Conflicting evidence and/or a divergence of opinion about the usefulness / efficacy of the given treatment or procedureusefulness / efficacy of the given treatment or procedure

Class IIClass II

Evidence and/or general agreement that a given treatment of Evidence and/or general agreement that a given treatment of procedure is beneficial, useful, effectiveprocedure is beneficial, useful, effective

Class IClass I


Levels of EvidenceLevelsLevels ofof EvidenceEvidence

Consensus of opinion of the experts and/or Consensus of opinion of the experts and/or small studies, retrospective studies, small studies, retrospective studies, registries.registries.

Level of Evidence CLevel of Evidence C

Data derived from a single randomized clinical Data derived from a single randomized clinical trial or large nontrial or large non--randomized studies.randomized studies.Level of Evidence BLevel of Evidence B

Data derived from multiple randomized clinical Data derived from multiple randomized clinical trials or metatrials or meta--analyses.analyses.Level of Evidence ALevel of Evidence A


Table of Contents (1)Table of Contents (1)Table of Contents (1)•• Epidemiology and Natural HistoryEpidemiology and Natural History•• PathophysiologyPathophysiology•• Diagnosis & Risk AssessmentDiagnosis & Risk Assessment•• TreatmentTreatment

–– AntiAnti--ischaemic agentsischaemic agents–– AntiAnti--coagulants coagulants –– AntiAnti--platelet agentsplatelet agents–– Resistance to antiplatelet agents/drug interactionsResistance to antiplatelet agents/drug interactions–– Withdrawal of antiplatelet agentsWithdrawal of antiplatelet agents–– Coronary revascularisationCoronary revascularisation–– LongLong--term management and rehabilitationterm management and rehabilitation


Table of Contents (2)Table of Contents (2)Table of Contents (2)

•• Complications and their managementComplications and their management–– BleedingBleeding–– ThrombocytopeniaThrombocytopenia

•• Special Conditions & PopulationsSpecial Conditions & Populations–– ElderlyElderly–– DiabetesDiabetes–– Impact of GenderImpact of Gender–– AnaemiaAnaemia–– Chronic Kidney DiseaseChronic Kidney Disease

•• Management Strategy Management Strategy •• Performance Measures Performance Measures


PathophysiologyPathophysiologyPathophysiology


Troponin elevated Troponins elevated or not

Adapted from Michael Davies Adapted from Michael Davies

ACS without persistentST-segment elevation

ACS with persistentST-segment elevation


Diagnosis & Risk AssessmentDiagnosis & Risk AssessmentDiagnosis & Risk Assessment

Suspicion of Acute Coronary Syndrome

High Risk Low Risk

Troponin positive

Chest PainChest Pain

Troponin2 x negative

Workingdiagnosis

ECG

Bio-chemistry

Riskstratification

Admission

Diagnosis

Treatment Invasive Non-invasiveReperfusion

STEMI NSTEMI Unstable Angina

PersistentST – elevation

ST/T –Abnormalities

Normal or Undetermined

ECG


0,7

0,75

0,8

0,85

0,9

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1

0 30 60 90 120 180

No ST-depression1mm ST-depression2mm ST-depression

Kaul et al. PARAGON Study. JACC 2003

Predictive Value of ST DepressionPredictive Value of ST Depression

Follow-up in days

Surv

ival


Example of Release of Cardiac Markers in a Patient with NSTE-ACS(Shaded Area Indicates Normal Range).

Example of Release of Cardiac Markers in a Patient with NSTEExample of Release of Cardiac Markers in a Patient with NSTE--ACSACS(Shaded Area Indicates Normal Range).(Shaded Area Indicates Normal Range).

0

1

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4

Hours after admission

Multi

ples

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it

0 40 60 10020 80

Myoglobin

cTnl

cTnT

CK-MB


Non-coronary Conditions with Troponin ElevationNonNon--coronary Conditions with Troponin Elevationcoronary Conditions with Troponin Elevation•• Severe congestive heart failure Severe congestive heart failure –– acute and chronicacute and chronic•• Aortic dissection, aortic valve disease or Aortic dissection, aortic valve disease or

hypertrophichypertrophic cardiomyopathycardiomyopathy•• Cardiac contusion, ablation, pacing, Cardiac contusion, ablation, pacing, cardioversioncardioversion, ,

or or endomyocardialendomyocardial biopsy biopsy •• Inflammatory diseases, e.g., Inflammatory diseases, e.g., myocarditismyocarditis, or , or

myocardial extension of myocardial extension of endoendo--/pericarditis/pericarditis•• Hypertensive crisis Hypertensive crisis •• TachyTachy-- or or bradyarrhythmiasbradyarrhythmias•• Pulmonary embolism, severe pulmonary Pulmonary embolism, severe pulmonary

hypertensionhypertension•• HypothyroidismHypothyroidism•• ……//……


Non-coronary Conditions with Troponin Elevation NonNon--coronary Conditions with Troponin Elevation coronary Conditions with Troponin Elevation •• ……//……•• Apical ballooning syndromeApical ballooning syndrome•• Chronic or acute renal dysfunctionChronic or acute renal dysfunction•• Acute neurological disease, including stroke, or Acute neurological disease, including stroke, or

subarachnoidsubarachnoid haemorrhagehaemorrhage•• Infiltrative diseases, e.g., Infiltrative diseases, e.g., amyloidosisamyloidosis, ,

haemochromatosishaemochromatosis, , sarcoidosissarcoidosis, scleroderma, scleroderma•• Drug toxicity, e.g., Drug toxicity, e.g., adriamycinadriamycin, 5, 5--fluorouracil, fluorouracil,

herceptinherceptin, snake venoms, snake venoms•• Burns, if affecting >30% of body surface areaBurns, if affecting >30% of body surface area•• RhabdomyolysisRhabdomyolysis•• Critically ill patients, especially with respiratory Critically ill patients, especially with respiratory

failure, or sepsisfailure, or sepsis


Cardiac and non cardiac conditions that can mimic NSTE-ACS

Cardiac and non cardiac conditions that can Cardiac and non cardiac conditions that can mimic NSTEmimic NSTE--ACSACS

CervicalCervicaldiscopathydiscopathyRib fractureRib fractureMuscle injury/ Muscle injury/ inflammationinflammationCostochondritisCostochondritis

EsophagealEsophagealspasmspasmEsophagitisEsophagitisPeptic ulcerPeptic ulcerPancreatitisPancreatitisCholescystitisCholescystitis

Aortic dissectionAortic dissectionAortic aneurysmAortic aneurysmAortic Aortic coarctationcoarctationCerebrovascularCerebrovasculardiseasedisease

Sickle cell anaemiaSickle cell anaemiaPulmonaryPulmonaryembolismembolismPulmonaryPulmonaryinfarctioninfarctionPneumoniaPneumoniaPleuritisPleuritisPneumothoraxPneumothorax

MyocarditisMyocarditisPericarditisPericarditisMyopericarditisMyopericarditisCardiomyopathyCardiomyopathyValvularValvular diseasediseaseApical ballooningApical ballooning((TakoTako--TsuboTsubosyndrome)syndrome)

OrthopedicOrthopedicGastroGastro--intestinalintestinalVascularVascularHaematologicalHaematologicalPulmonaryPulmonaryCardiacCardiac


ACSInitial Decision-making Algorithm

ACSInitial Decision-making Algorithm

ECGST ST Neg. T

Arrival & > 6-12 hours

Low RiskHigh RiskSTEMI

Troponin

normal

+


Recommendations for Diagnosis and Risk Stratification (1)

Recommendations for Diagnosis and Risk Recommendations for Diagnosis and Risk Stratification (1)Stratification (1)

•• Diagnosis and shortDiagnosis and short--term risk stratification of term risk stratification of NSTENSTE--ACS should be based on a combination of ACS should be based on a combination of clinical history, symptoms, ECG, biomarkers and clinical history, symptoms, ECG, biomarkers and risk score results (Irisk score results (I--B). B).


GRACE ACS Risk ModelGRACE ACS GRACE ACS RiskRisk ModelModel


Mortality in hospital and at 6 months in low, intermediate and high risk categories in registry populations according to the

GRACE Risk score http://www.outcomes.org/grace

Mortality in hospital and at 6 months in low, intermediate and Mortality in hospital and at 6 months in low, intermediate and high risk categories in registry populations according to the high risk categories in registry populations according to the

GRACE Risk score GRACE Risk score http://http://www.outcomes.orgwww.outcomes.org/grace/grace

>8>8>118>118HighHigh33--888989--118118IntermediateIntermediate<3<3<=88<=88LowLow

PostPost--discharge to 6 discharge to 6 months deaths (%)months deaths (%)

GRACE Risk ScoreGRACE Risk ScoreRisk categoryRisk category((tertilestertiles))

>3>3>140>140HighHigh11--33109109--140140IntermediateIntermediate<1<1<=108<=108LowLow

InIn--hospital deaths (%)hospital deaths (%)GRACE Risk ScoreGRACE Risk ScoreRisk categoryRisk category((tertilestertiles))



Recommendations for Diagnosis and Risk Stratification Recommendations for Diagnosis and Risk Stratification (2)(2)

•• The evaluation of the individual risk is a dynamic process The evaluation of the individual risk is a dynamic process that is to be updated as the clinical situation evolves.that is to be updated as the clinical situation evolves.

–– A 12A 12--lead ECG should be obtained within 10 minutes after first lead ECG should be obtained within 10 minutes after first medical contact and immediately read by an experienced medical contact and immediately read by an experienced physician. (Iphysician. (I--C) Additional leads (V3C) Additional leads (V3RR and V4and V4RR, V7, V7--V9) should be V9) should be recorded. ECG should be repeated in case of recurrence of recorded. ECG should be repeated in case of recurrence of symptoms, and at 6, 24 hours and before hospital discharge (Isymptoms, and at 6, 24 hours and before hospital discharge (I--C). C).

–– Blood must be drawn promptly for troponin (Blood must be drawn promptly for troponin (cTnTcTnT or or cTnIcTnI) ) measurement. The result should be available within 60 minutes. measurement. The result should be available within 60 minutes. (I(I--C) The test should be repeated after 6C) The test should be repeated after 6--12 hours if the initial 12 hours if the initial test is negative (Itest is negative (I--A).A).

–– ……//……



Recommendations for Diagnosis and Risk Stratification Recommendations for Diagnosis and Risk Stratification (3)(3)

•• The evaluation of the individual risk is a dynamic The evaluation of the individual risk is a dynamic process that is to be updated as the clinical situation process that is to be updated as the clinical situation evolves.evolves.–– ……//……–– Established risk scores (such as GRACE) should be Established risk scores (such as GRACE) should be

implemented for initial and subsequent risk assessment (Iimplemented for initial and subsequent risk assessment (I--B)B)

–– An echocardiogram is recommended to rule out differential An echocardiogram is recommended to rule out differential diagnoses (Idiagnoses (I--C).C).

–– In patients without recurrence of pain, normal ECG findings, In patients without recurrence of pain, normal ECG findings, and negative troponins tests, a nonand negative troponins tests, a non--invasive stress test for invasive stress test for inducible ischaemia is recommended before discharge (Iinducible ischaemia is recommended before discharge (I--A).A).


Recommendations for Diagnosis and Risk stratification (4)Long Term Risk

Recommendations for Diagnosis and Risk stratification (4)Recommendations for Diagnosis and Risk stratification (4)Long Long TermTerm RiskRisk

•• The following predictors of longThe following predictors of long--term death or MI term death or MI should be considered in risk stratification (Ishould be considered in risk stratification (I--B): B):

–– Clinical indicators: age, heart rate, blood pressure, Clinical indicators: age, heart rate, blood pressure, Killip class, diabetes, previous MI/CADKillip class, diabetes, previous MI/CAD

–– ECG markers: STECG markers: ST--segment depressionsegment depression–– Laboratory markers: troponins, GFR/ Laboratory markers: troponins, GFR/ CrClCrCl/ / CystatinCystatin C, C,

BNP/NTBNP/NT--proBNPproBNP, , hsCRPhsCRP–– Imaging findings: low ejection fraction, main stem Imaging findings: low ejection fraction, main stem

lesion, 3lesion, 3-- vessel disease.vessel disease.–– Risk score resultRisk score result


TreatmentTreatmentTreatment


Therapeutic OptionsTherapeuticTherapeutic OptionsOptions•• AntiAnti--ischaemic agentsischaemic agents•• AntiAnti--coagulantscoagulants

–– UFH or UFH or LMWHsLMWHs–– FondaparinuxFondaparinux–– Bivalirudin Bivalirudin

•• AntiAnti--plateletplatelet agentsagents–– ASAASA–– ClopidogrelClopidogrel–– IIbIIIaIIbIIIa InhibitorsInhibitors

•• RevascularisationRevascularisation


Treatment-------

Anti-ischaemic agents

TreatmentTreatment--------------

AntiAnti--ischaemic agentsischaemic agents


Recommendations for Anti-ischaemic DrugsRecommendations for AntiRecommendations for Anti--ischaemic Drugsischaemic Drugs•• BetaBeta--blockers are recommended in the absence of blockers are recommended in the absence of

contraindications, particularly in patients with hypertension contraindications, particularly in patients with hypertension or tachycardia (Ior tachycardia (I--B).B).

•• Intravenous or oral nitrates are effective for symptom relief Intravenous or oral nitrates are effective for symptom relief in the acute management of anginal episodes (Iin the acute management of anginal episodes (I--C).C).

•• Calcium channel blockers provide symptom relief in patients Calcium channel blockers provide symptom relief in patients already receiving nitrates and betaalready receiving nitrates and beta--blockers; they are useful blockers; they are useful in patients with contraindications to betain patients with contraindications to beta--blockade, and in blockade, and in the subgroup of patients with the subgroup of patients with vasovaso--spastic angina (Ispastic angina (I--B).B).

•• Nifedipine, or other dihydropyridines, should not be used Nifedipine, or other dihydropyridines, should not be used (III(III--B), unless combined with betaB), unless combined with beta--blockers (blockers (IIaIIa--B)B)


Treatment------

Anti-coagulants

TreatmentTreatment------------

AntiAnti--coagulantscoagulants


What’s New with Anti-coagulantsWhatWhat’’s New with Antis New with Anti--coagulantscoagulants1 1 -- Pharmacological TreatmentPharmacological Treatment

-- Superior efficacy with equivalent safety of Superior efficacy with equivalent safety of enoxaparinenoxaparin over UFH over UFH (Petersen meta(Petersen meta--analysis) analysis)

-- Fondaparinux nonFondaparinux non--inferior to inferior to enoxaparinenoxaparin in OASISin OASIS--55-- Fondaparinux reduced bleeding rate by ~ 50% in OASISFondaparinux reduced bleeding rate by ~ 50% in OASIS--55-- Reduction in bleeding impacts on outcome (significant risk Reduction in bleeding impacts on outcome (significant risk

reduction for death, MI and stroke)reduction for death, MI and stroke)

2 2 -- AntiAnti--coagulants in the Setting of PCIcoagulants in the Setting of PCI-- Enoxaparin is not superior to UFH in SYNERGYEnoxaparin is not superior to UFH in SYNERGY-- Bivalirudin superior to UFH/LMWH + Bivalirudin superior to UFH/LMWH + GPIIbGPIIb/IIIA /IIIA inhibitors in inhibitors in

ACUITYACUITY


Anticoagulants – New ComersAnticoagulants Anticoagulants –– New ComersNew Comers•• FondaparinuxFondaparinux

–– Unequivocal benefit over Unequivocal benefit over enoxaparinenoxaparin–– Significant RR of both bleeding and ischaemic risksSignificant RR of both bleeding and ischaemic risks–– Closes the loop Closes the loop –– Shift in the paradigmShift in the paradigm–– Catheter thrombi issueCatheter thrombi issue–– Bleeding risk issue with UFH Bleeding risk issue with UFH ‘‘on topon top’’ of of fondafonda. in PCI patients. in PCI patients

•• BivalirudinBivalirudin–– Not double blind trialNot double blind trial–– Non inferiority margin issueNon inferiority margin issue–– Biased comparison of the different regimens Biased comparison of the different regimens –– No impact of bleeding risk reduction on outcome at short and No impact of bleeding risk reduction on outcome at short and

long term FUlong term FU


Death or MI at 30 DaysDeath or MI at 30 Days

Efficacy and Bleeding Complications AmongEfficacy and Bleeding Complications AmongPatients Randomized to Patients Randomized to EnoxEnox or UFH in NSTEor UFH in NSTE--ACSACS

PetersenPetersen.. JAMAJAMA 2004;2004;292292::8989––9696

Trial

ESSENCETIMI 11BACUTE II

INTERACTA to Z

SYNERGYOVERALL

Enoxaparin

94/1607 (5.8)145/1953 (7.4)25/315 (7.9)19/380 (5.0)

137/1852 (7.4)696/4992 (14.0)

1116/11099 (10.1)

UHF

118/1564 (7.5)163/1957 (8.6)17/210 (8.1)33/366 (9.0)

139/1768 (7.9)722/4982 (14.5)

1192/10847 (11.0)

OR (95% CI)

0.76 (0.58-1.01)0.88 (0.70-1.11)0.97 (0.51-1.83)0.54 (0.30-0.96)0.94 (0.73-1.20)0.96 (0.86-1.07)0.91 (0.83-0.99)

FavorsEnoxaparin

FavorUFH

0.2 0.5 1 2

OR (95% CI)

Events, No./Total (%)


Enoxaparin Was Non-Inferior to UFHin Reducing Death or MI in the SYNERGY Trial

Enoxaparin Was NonEnoxaparin Was Non--Inferior to UFHInferior to UFHin Reducing Death or MI in the SYNERGY Trialin Reducing Death or MI in the SYNERGY Trial

0 5 10 15 20 25 30

Free

dom

from

Dea

th / M

I

Days from RandomizationJAMA 2004;292:45-54 Am Heart J 2005;149:581-90

0.8

0.85

0.9

0.95

1Enoxaparin 1 mg sc bidUFH (aPTT 50-70 sec)

Enoxaparinbetter

UFHbetter

Hazard Ratio (95% CI)

0.8 1 1.2

HR 0.96 (0.87-1.06)

30-Day Death/MI30-Day Death/MI

1.1


OASIS 5 TrialDeath, myocardial infarction or refractory ischemia through day 9

OASIS 5 TrialOASIS 5 TrialDeath, myocardialDeath, myocardial infarction or refractory ischemia through day 9infarction or refractory ischemia through day 9

Days

Cum

ulat

ive H

azar

d

Hazard ratio, 1.01 (95% CI, 0.90 - 1.13)

0.00

0.06

0.05

0.04

0.03

0.02

0.01

0 1 2 3 4 5 6 7 8 9

FondaparinuxEnoxaparin

NEJM 2006;354:1464


OASIS 5 TrialMajor bleeding through day 9

OASIS 5 TrialOASIS 5 TrialMajor bleeding through day 9Major bleeding through day 9

Days

Cum

ulat

ive H

azar

d

Hazard ratio, 0.52 (95% CI, 0.44 - 0.61)P<0.001

0.00

0.04

0.03

0.02

0.01

0 1 2 3 4 5 6 7 8 9


NEJM 2006;354:1464


Relation Between Bleeding and Mortality in OASIS-5

Relation Relation BetweenBetween BleedingBleeding andand MortalityMortality in in OASISOASIS--55

NEJM 2006;354:1464

0

0,01

0,02

0,03

0,04

0 3 6 9 12 15 18 21 24 27

Enoxaparin

Fondaparinux

Days

Cum

ulat

ive H

azar

d

HR 0.8395% CI 0.71-0.97

P = 0.022

Mortality: Day 30

30


Days

Cum

ulat

ive H

azar

d

Hazard ratio, 0.89 (95% CI, 0.80 - 1.00)

P=0.050.00

0.08

0.06

0.04

0.02

0 30 60 90 120 150 180


OASIS 5 TrialDeath through day 180

OASIS 5 TrialOASIS 5 TrialDeath through day 180Death through day 180

Hazard ratio, 0.83 (95% CI, 0.71 – 0.97)

P=0.02

NEJM 2006;354:1464


Relation Between Bleeding and Mortality in OASIS-5

Relation Relation BetweenBetween BleedingBleeding andand MortalityMortality in in OASISOASIS--55

NEJM 2006;354:1464

0

0,05

0,1

0,15

0,2

0 30 60 90 120 150 180

Maj Bleed 9 days

No Maj Bleed 9 days

Days

Cum

ulat

ive H

azar

dMortality at Days 30/180 in Patients with Major Bleeds


A New Concept is BornA A NNewew CConceptoncept isis BBornorn1.1. BleedingBleeding carriescarries a a highhigh riskrisk ofof deathdeath, , MIMI and strokeand stroke2.2. Rate of major bleeding is as high as the rate of death at Rate of major bleeding is as high as the rate of death at

the acute phase of NSTEthe acute phase of NSTE--ACSACS3.3. PreventionPrevention ofof bleedingbleeding isis equallyequally asas important as important as

preventionprevention ofof ischemic ischemic eventsevents and results in a and results in a significant risk reduction for death, MI and strokesignificant risk reduction for death, MI and stroke

4.4. RiskRisk stratification for stratification for bleedingbleeding shouldshould bebe part part ofof thethedecisiondecision makingmaking processprocess


0

5

10

15

Days from randomization

Cum

ulat

ive ev

ents

perc

ent

0 5 10 15 20 25 30 35

Estimate P(log rank)11.7%UFH/Enoxaparin + IIb/IIIa (N=4603)

Bivalirudin + IIb/IIIa (N=4604) 0.8911.8%Bivalirudin alone (N=4612) 0.01410.1%

Acuity TrialNet clinical outcome composite end-point

Acuity TrialAcuity TrialNet clinical outcome composite endNet clinical outcome composite end--pointpoint

NEJM 2006;355:2203


Acuity – Primary Endpoint MeasuresAcuityAcuity –– PrimaryPrimary EndpointEndpoint MeasuresMeasures

NEJM 2006;355:2203

Primaryendpoint

0

Net clinicaloutcome

Ischemiccomposite

Majorbleeding

Bivalalone

10.1 %

7.8 %

3.0 %

UFH/Enox+ IIb/IIIa

11.7 %

7.3 %

5.7 %

RR (95% CI)

0.86 (0.77-0.97)

1.08 (0.93-1.24)

0.53 (0.43-0.65)

P value(non inferior)

(superior)

< 0.0010.015

0.020.32

< 0.001< 0.001

Risk Ratio ± 95% CI

0 1 2

UFH/Enoxaparin + GPI vs. Bivalirudin Alone

Bivalirudinalone better

UFH/Enox +IIb/IIIa better

Uppe

r bou

ndar

y non

-infer

iority


RISC ’90

Cohen ’94

Holdright ’94

Gurfinkel ’95

All

399

214

285

143

2859

Theroux ’88

Cohen ’90

243

69

10 102 ∞ 11 101020.25 20% 20% 0.50.1 2 1013%0% 6%



Incidence

0.55 (0.39-0.77) 31 (23-62) 2.3 (0.97-5.4)4.7% vs 7.4%

Incidence

1.1% vs 0.5%


Heparin+ Ctrl+ Heparin+ Ctrl+ Heparin+ Ctrl+

0.5 140%

FRISC ’96 1506

000

00

0

0

Randomized trials of UFH/LMWH (dark bars ) vs Control ( open bars)

Randomized trials of UFH/LMWH Randomized trials of UFH/LMWH (dark bars )(dark bars ) vsvs Control Control ( open bars)( open bars)


ACUTE-II ’02

INTERACT ’03

A to Z ’04

SYNERGY ’04

All

525

746

3620

9974

21946

ESSENCE ’97

TIMI-11B ’99

3171

3910

10 102 ∞ 11 101020.5 2110%0% 20% 0.50.1 2 1015%0% 10%



Incidence

0.91 (0.83-0.99) 113 (61-1438) 1.1 (0.96-1.3)10.1% vs 11.0%

Incidence

3.9% vs 3.7%

Death or MI at 30 daysSize Major bleeds

LMWH+ UFH+ LMWH+ UFH+ LMWH+ UFH+

Randomized trials Enoxaparin (dark bars) vs UFH (open bars)

Randomized trials Randomized trials Enoxaparin (dark bars) Enoxaparin (dark bars) vsvs UFH (open bars)UFH (open bars)


GUSTO-2B ’95

OASIS pilot ’97

OASIS ’99

Klootwijk ’99

All

12142

909

10141

300

32699

10 102 ∞ 11 101020.5 2110%0% 20% 0.50.1 2 1013%0% 6%



Incidence

0.93 (0.85-1.0) 176 (89-∞) 1.0 (0.89-1.2)7.7% vs 8.3%

Incidence

2.3% vs 2.3%


DTI+ UFH+ DTI+ UFH+ DTI+ UFH+

ACUITY ’06 9207

Randomized trials Direct thrombin inhibitors (DTIs) (dark bars) vs UFH/LMWH (open bars)

Randomized trials Randomized trials Direct thrombin inhibitors (Direct thrombin inhibitors (DTIsDTIs) ) (dark bars)(dark bars) vsvs UFH/LMWH UFH/LMWH (open bars)(open bars)


Recommendations for Anticoagulation (1)Recommendations for Anticoagulation (1)Recommendations for Anticoagulation (1)

•• Anticoagulation is recommended for all patients in addition Anticoagulation is recommended for all patients in addition to antiplatelet therapy (Ito antiplatelet therapy (I--A). A).

•• Anticoagulation should be selected according to the risk of Anticoagulation should be selected according to the risk of both ischaemic and bleeding events (Iboth ischaemic and bleeding events (I--B). B). Several Several anticoagulants are available, namely UFH, LMWH, anticoagulants are available, namely UFH, LMWH, fondaparinux, fondaparinux, bivalirudinbivalirudin. The choice depends on the initial . The choice depends on the initial strategy, strategy, urgent invasive, early invasive, or conservative urgent invasive, early invasive, or conservative (I(I--B) (see section Management Strategy).B) (see section Management Strategy).

•• In an urgent invasive strategy UFH (IIn an urgent invasive strategy UFH (I--C), or C), or enoxaparinenoxaparin ((IIaIIa--B) or B) or bivalirudinbivalirudin (I(I--B) should be immediately started. B) should be immediately started.



•• In an nonIn an non--urgent situation, as long as decision between urgent situation, as long as decision between early invasive or conservative strategy is pending :early invasive or conservative strategy is pending :

–– Fondaparinux is recommended on the basis of the most Fondaparinux is recommended on the basis of the most favorable efficacy/safety profile. (Ifavorable efficacy/safety profile. (I--A) A)

–– Enoxaparin with a less favourable efficacy/safety profile than Enoxaparin with a less favourable efficacy/safety profile than fondaparinux should be used only if the bleeding risk is low (fondaparinux should be used only if the bleeding risk is low (IIaIIa--B)B)

–– As efficacy/safety profile of LMWH (other than As efficacy/safety profile of LMWH (other than enoxaparinenoxaparin) or ) or UFH relative to fondaparinux is unknown; these anticoagulants UFH relative to fondaparinux is unknown; these anticoagulants cannot be recommended over fondaparinux (cannot be recommended over fondaparinux (IIaIIa--B)B)



•• At PCI procedures the initial anticoagulant should be At PCI procedures the initial anticoagulant should be maintained also during the procedure regardless whether maintained also during the procedure regardless whether this treatment is UFH (Ithis treatment is UFH (I--C), C), enoxaparinenoxaparin ((IIaIIa--B) or B) or bivalirudinbivalirudin (I(I--B), while B), while addititionaladdititional UFH in standard dose UFH in standard dose (50(50--100 IU/kg bolus) is necessary in case of fondaparinux 100 IU/kg bolus) is necessary in case of fondaparinux ((IIaIIa--C). C).

•• Anticoagulation can be stopped within 24 hours after Anticoagulation can be stopped within 24 hours after invasive procedure (invasive procedure (IIaIIa--C). In a conservative strategy, C). In a conservative strategy, fondaparinux, fondaparinux, enoxaparinenoxaparin or other LMWH may be or other LMWH may be maintained up to hospital discharge (Imaintained up to hospital discharge (I--B). B).


Treatment------

Anti-platelet agents


AntiAnti--platelet agentsplatelet agents


Anti-Platelet TreatmentAntiAnti--Platelet TreatmentPlatelet Treatment

Pharmacological Treatment Pharmacological Treatment

•• Loading dose 600mg Loading dose 600mg vsvs 300mg clopidogrel : unsettled 300mg clopidogrel : unsettled issueissue

•• New ADP receptor antagonists under development New ADP receptor antagonists under development (TRITON, PLATO, CHAMPION: ongoing studies)(TRITON, PLATO, CHAMPION: ongoing studies)

•• GP GP IIbIIb//IIIaIIIa inhibitorsinhibitors–– UpstreamUpstream or or deferreddeferred–– ACUITY Timing ACUITY Timing –– No No unequivocalunequivocal resultsresults


VA ’83

Cairns ’85

Theroux ’88

RISC ’90

All

1266

555

479

796

3096

10 102 ∞ 11 101020.25 2110%0% 20% 0.50.1 2 1013%0% 6%



Incidence

0.47 (0.37-0.61) 17 (14-23) 1.4 (0.68-2.7)6.2% vs 12.2%

Incidence

1.2% vs 0.9%


Aspirin+ Ctrl+ Aspirin+ Ctrl+ Aspirin+ Ctrl+

0.5

0

Four randomised trials of aspirin (dark bars) vscontrol (open bars)

Four randomised trials of aspirin Four randomised trials of aspirin (dark bars)(dark bars) vsvscontrol control (open bars)(open bars)


0.90

0.92

0.94

0.96

0.98

1.00

6 8 10 1241

Prop

ortio

nev

ent

free

0.90

0.92

0.94

0.96

0.98

1.00

0 1 2 3 4

0-30 days 31 days to 12 months

PlaceboPlacebo

Clopidogrel

Clopidogrel

RR: 0.79 (0.67-092)p=0.003

RR: 0.82 (0.70-095)P=0.009

CURE TrialEarly and late effects of Clopidogrel

CURE TrialCURE TrialEarly and late effects of ClopidogrelEarly and late effects of Clopidogrel

Days MonthsNEJM 2001;345:494Circulation 2003;107:966


CURE TrialCURE TrialBleeding Within 7 Days After CABG SurgeryBleeding Within 7 Days After CABG Surgery

Life Life threateningthreatening

OtherOther majormajor

Life Life threateningthreatening or majoror major

TIMI majorTIMI major

GUSTO severe/GUSTO severe/lifelife--threateningthreatening

PP

4.24.2

1.11.1

5.35.3

2.42.4

2.92.9

CC

3.73.7

0.70.7

4.44.4

1.81.8

2.42.4

DrugDrug stoppedstopped > 5 > 5 daysdays priorprior toto CABGCABG

Placebo morePlacebo more ClopidogrelClopidogrel moremore

OR and 95% CIOR and 95% CI

00 11 33

0.470.470.890.89

1.691.69

0.140.14 0.800.802.482.48

0.460.460.830.83

1.481.48

0.290.290.720.72

1.781.78

0.380.380.840.84

1.81.8

Circulation 2004;110:1202


Recommendations for Oral Antiplatelet Drugs (1) Recommendations for Oral Antiplatelet Drugs (1) Recommendations for Oral Antiplatelet Drugs (1) •• Aspirin is recommended for all patients presenting with Aspirin is recommended for all patients presenting with

NSTENSTE--ACS without contraindication at an initial loading ACS without contraindication at an initial loading dose of 160 dose of 160 -- 325mg (non325mg (non--enteric) (Ienteric) (I--A), and at a A), and at a maintenance dose of 75 to 100mg longmaintenance dose of 75 to 100mg long--term (Iterm (I--A). A).

•• For all patients, immediate 300mg loading dose of For all patients, immediate 300mg loading dose of clopidogrel is recommended, followed by 75mg clopidogrel is recommended, followed by 75mg clopidogrel daily (Iclopidogrel daily (I--A). Clopidogrel should be maintained A). Clopidogrel should be maintained for 12 months unless there is an excessive risk of for 12 months unless there is an excessive risk of bleeding (Ibleeding (I--A). A).

•• For all patients with contraindication to aspirin, For all patients with contraindication to aspirin, clopidogrel should be given instead (Iclopidogrel should be given instead (I--B).B).


Recommendations for Oral Antiplatelet Drugs (2) Recommendations for Oral Antiplatelet Drugs (2) Recommendations for Oral Antiplatelet Drugs (2)

•• In patients considered for an invasive In patients considered for an invasive procedure/PCI, a loading dose of 600mg of procedure/PCI, a loading dose of 600mg of clopidogrel may be used to achieve more rapid clopidogrel may be used to achieve more rapid inhibition of platelet function (inhibition of platelet function (IIaIIa--B).B).

•• In patients In patients pretreatedpretreated with clopidogrel who need with clopidogrel who need to undergo CABG, surgery should be postponed to undergo CABG, surgery should be postponed for 5 days for clopidogrel withdrawal if clinically for 5 days for clopidogrel withdrawal if clinically feasible (feasible (IIaIIa--C). C).


PARAGON-A’98

PURSUIT ’98

GUSTO-IV ’01

PARAGON-B’02

All

2282

10948

7800

5225

31402

PRISM ’98

PRISM-PLUS’98

3232

1915

10 102 ∞ 11 101020.5 2110%0% 20% 0.50.1 2 1012.5%0% 5%



Incidence

0.91 (0.85-0.98) 111 (63-549) 1.6 (1.3-2.0)10.8% vs 11.8%

Incidence

1.6% vs 1.0%


GPIIb/IIIa+ Ctrl+ GPIIb/IIIa+ Ctrl+ GPIIb/IIIa+ Ctrl+

Randomised trials of GP IIb/IIIa inhibitors (dark bars) vscontrol (open bars )

Randomised trials of GP IIb/IIIa inhibitors Randomised trials of GP IIb/IIIa inhibitors (dark bars)(dark bars) vsvscontrol control (open bars )(open bars )


11.7%11.7% 1.00 (0.89-1.11) <0.0010.93

ACUITY Timing ACUITY Timing -- Primary Endpoint MeasuresPrimary Endpoint Measures

Net clinical outcome

Ischemic composite

Major bleeding

7.9%7.1% 1.12 (0.97-1.29) 0.060.13

4.9%6.1% 0.80 (0.67-0.95) <0.0010.01

Routine Upstream IIb/IIIa vs. Deferred PCI IIb/IIIaRoutine Upstream IIb/IIIa vs. Deferred PCI IIb/IIIa

JAMA 2007;297:591JAMA 2007; 297:591

Primaryendpoint

0

Net clinicaloutcome

Ischemiccomposite

Majorbleeding

UpstreamIIb/IIIa

11.7 %

7.1 %

6.1 %

DeferredIIb/IIIa

11.7 %

7.9 %

4.9 %

RR (95% CI)

1.00 (0.89-1.11)

1.12 (0.97-1.29)

0.80 (0.67-0.95)


(superior)

< 0.0010.93

0.060.13

< 0.0010.01


0 1 2DeferredPCI GPIbetter

RoutineUpstream GPI

better

Uppe

r bou

ndar

y non

-infer

iority


Recommendations for GP IIb/IIIa Inhibitors (1)Recommendations for GP IIb/IIIa Inhibitors (1)Recommendations for GP IIb/IIIa Inhibitors (1)

•• In patients at intermediate to high risk, particularly In patients at intermediate to high risk, particularly patients with elevated troponins, STpatients with elevated troponins, ST--depression, or depression, or diabetes, either eptifibatide or tirofiban for initial early diabetes, either eptifibatide or tirofiban for initial early treatment are recommended in addition to oral treatment are recommended in addition to oral antiplatelet agents (antiplatelet agents (IIaIIa--A).A).

•• The choice of combination of antiplatelet agents and The choice of combination of antiplatelet agents and anticoagulants should be made in relation to risk of anticoagulants should be made in relation to risk of ischaemic and bleeding events. (Iischaemic and bleeding events. (I--B)B)

•• Patients who received initial treatment with eptifibatide or Patients who received initial treatment with eptifibatide or tirofiban prior to angiography, should be maintained on tirofiban prior to angiography, should be maintained on the same drug during and after PCI (the same drug during and after PCI (IIaIIa--B) B)


Recommendations for GP IIb/IIIa Inhibitors (2)Recommendations for GP IIb/IIIa Inhibitors (2)Recommendations for GP IIb/IIIa Inhibitors (2)

•• In high risk patients not pretreated with GP IIb/IIIa inhibitorsIn high risk patients not pretreated with GP IIb/IIIa inhibitors and and proceeding to PCI, proceeding to PCI, abciximababciximab is recommended immediately is recommended immediately following angiography. following angiography. (I(I--A) The use of eptifibatide or tirofiban in A) The use of eptifibatide or tirofiban in this setting is less well established (this setting is less well established (IIaIIa--B). B).

•• GP IIb/IIIa inhibitors must be combined with an anticoagulant (IGP IIb/IIIa inhibitors must be combined with an anticoagulant (I--A).A).

•• Bivalirudin may be used as an alternative to GP IIb/IIIa inhibitBivalirudin may be used as an alternative to GP IIb/IIIa inhibitors ors plus UFH/LMWH. (plus UFH/LMWH. (IIaIIa--B) B)

•• When anatomy is known and PCI planned to be performed within When anatomy is known and PCI planned to be performed within 24 hours with GP IIb/IIIa inhibitors, most secure evidence is fo24 hours with GP IIb/IIIa inhibitors, most secure evidence is for r abciximababciximab ((IIaIIa--B)B)


Resistance to Antiplatelet Agents & Drug interactions

Resistance to Antiplatelet Agents & Resistance to Antiplatelet Agents & Drug interactionsDrug interactions


Recommendations for Resistance to Antiplatelet Treatment/Drugs Interactions

Recommendations for Resistance to Recommendations for Resistance to Antiplatelet Treatment/Drugs InteractionsAntiplatelet Treatment/Drugs Interactions

•• Routine assessment of platelet aggregation inhibition in Routine assessment of platelet aggregation inhibition in patients submitted to either aspirin or clopidogrel therapy, patients submitted to either aspirin or clopidogrel therapy, or both, is not recommended (or both, is not recommended (IIbIIb--C).C).

•• NSAID (selective COX 2 inhibitors and nonNSAID (selective COX 2 inhibitors and non--selective NSAID) selective NSAID) should not be administered in combination with either should not be administered in combination with either aspirin or clopidogrel (IIIaspirin or clopidogrel (III--C).C).

•• Clopidogrel can be administered with all statins (IClopidogrel can be administered with all statins (I--B).B).

•• The triple association of aspirin, clopidogrel and VKA The triple association of aspirin, clopidogrel and VKA should only be given if compelling indication exists, in should only be given if compelling indication exists, in which case, the lowest efficacious INR and shortest duration which case, the lowest efficacious INR and shortest duration for the triple association should be targeted (for the triple association should be targeted (IIaIIa--C). C).


Withdrawal of antiplatelet agentsWithdrawalWithdrawal ofof antiplatelet agentsantiplatelet agents


Recommendations for Withdrawal of Antiplatelet Treatment

Recommendations for Withdrawal of Antiplatelet Recommendations for Withdrawal of Antiplatelet TreatmentTreatment

•• Temporary interruption of dual antiplatelet therapy (aspirin Temporary interruption of dual antiplatelet therapy (aspirin and clopidogrel) within the first 12 months after the initial and clopidogrel) within the first 12 months after the initial episode is discouraged (Iepisode is discouraged (I--C). C).

•• Temporary interruption for major or lifeTemporary interruption for major or life--threatening bleeding threatening bleeding or for surgical procedures where even minor bleeding may or for surgical procedures where even minor bleeding may result in severe consequences (brain or spinal surgery) is result in severe consequences (brain or spinal surgery) is mandatory (mandatory (IIaIIa--C).C).

•• Prolonged or permanent withdrawal of aspirin, clopidogrel Prolonged or permanent withdrawal of aspirin, clopidogrel or both is discouraged unless clinically indicated. or both is discouraged unless clinically indicated. Consideration should be given to the risk of recurrence of Consideration should be given to the risk of recurrence of ischaemic events which depends (among other factors), on ischaemic events which depends (among other factors), on initial risk, on presence and type of stent implanted, and on initial risk, on presence and type of stent implanted, and on time window between proposed withdrawal and index event time window between proposed withdrawal and index event and/or revascularisation (Iand/or revascularisation (I--C).C).


Clinical Use of Antithrombotic Therapy. Clinical Use of Clinical Use of AntithromboticAntithrombotic Therapy. Therapy.

•• Abciximab 0.25 mg/kg intravenous bolus followed by infusion oAbciximab 0.25 mg/kg intravenous bolus followed by infusion of 0.125 f 0.125 µµg/kg/min (maximum 10 g/kg/min (maximum 10 µµg/min) g/min) for 12 to 24 hfor 12 to 24 h•• Eptifibatide 180 Eptifibatide 180 µµg/kg intravenous bolus (second bolus after 10 min for PCI) follg/kg intravenous bolus (second bolus after 10 min for PCI) followed by infusion of 2.0 owed by infusion of 2.0 µµg/kg/min for 72 to 96 hg/kg/min for 72 to 96 h•• Tirofiban 0.4 Tirofiban 0.4 µµg/kg/min intravenously for 30 minutes followed by infusion of 0.g/kg/min intravenously for 30 minutes followed by infusion of 0.10 10 µµg/kg/min for 48 to 96 h. g/kg/min for 48 to 96 h. A high dose regimen (bolus 25A high dose regimen (bolus 25µµg/kg + 0.15g/kg + 0.15µµg/kg/min infusion for 18 hours) is tested in clinical trials.g/kg/min infusion for 18 hours) is tested in clinical trials.

GP IIb/IIIa inhibition*GP IIb/IIIa inhibition*

•• Fondaparinux* 2.5mg subcutaneously dailyFondaparinux* 2.5mg subcutaneously daily•• Enoxaparin* 1mg/kg subcutaneously every 12 h Enoxaparin* 1mg/kg subcutaneously every 12 h •• DalteparinDalteparin* 120 IU/kg every 12 h* 120 IU/kg every 12 h•• NadroparinNadroparin* 86 IU/kg every 12 h* 86 IU/kg every 12 h•• UFH intravenous Bolus 60UFH intravenous Bolus 60––70 U/kg (maximum 5000 IU) followed by infusion of 1270 U/kg (maximum 5000 IU) followed by infusion of 12––15 IU/kg/h (maximum 15 IU/kg/h (maximum 1000 U/h) titrated to 1000 U/h) titrated to aPTTaPTT 1.51.5––2.5 times control2.5 times control•• Bivalirudin* intravenous bolus of 0.1 mg/kg and infusion of 0.25Bivalirudin* intravenous bolus of 0.1 mg/kg and infusion of 0.25 mg/kg/hr. Additional intravenous bolus mg/kg/hr. Additional intravenous bolus 0.5 mg/kg and infusion increased to 1.75 mg/kg/hour before PCI0.5 mg/kg and infusion increased to 1.75 mg/kg/hour before PCI

Anticoagulants Anticoagulants

•• Aspirin initial dose: 160Aspirin initial dose: 160––325 mg 325 mg nonentericnonenteric formulation, followed by 75formulation, followed by 75––100mg daily100mg dailyClopidogrel 75 mg/d after a loading dose of 300mg (600mg when Clopidogrel 75 mg/d after a loading dose of 300mg (600mg when rapid onset of action is wanted)rapid onset of action is wanted)

Oral Antiplatelet TherapyOral Antiplatelet Therapy


Treatment------

Coronary revascularisation


Coronary revascularisation Coronary revascularisation


Invasive vs. Conservative StrategiesInvasive vs. Conservative StrategiesInvasive vs. Conservative Strategies

1.1. New data coming fromNew data coming from longlong--term followterm follow--up up of of RITARITA--3, 3, FRISCFRISC--2 2 andand Mehta metaMehta meta--analysisanalysis show significant risk show significant risk reduction for death and death & MI at longreduction for death and death & MI at long--term followterm follow--upup

2.2. Early hazard Early hazard shown inshown in ICTUS trialICTUS trial (excess of death & MI (excess of death & MI observed within 1observed within 1stst month after revascularisation in month after revascularisation in immediate invasive group)immediate invasive group)

3.3. Early hazardEarly hazard shown in shown in Mehta metaMehta meta--analysisanalysis

ICTUS Lancet 2007;369:827RITA-3 Lancet 2005;366:914

FRISC 2 Lancet 2000;356:9-16Mehta JAMA 2005:293:2908


Invasive vs Conservative StrategiesInvasive Invasive vsvs Conservative StrategiesConservative Strategies

Lancet 2005;366:914

0

5

10

15

20

25

0 2 3 4

Conservative 20.0 %

Intervention 16.6 %

Follow-up time (years)

Cum

ulat

ive p

erce

nt

Odds Ratio 0.7895% CI 0.61-0.99

P = 0.044

Death, MI, Rehospitalization for ACS

1 5

RITARITA--33


Invasive vs Conservative StrategiesInvasive Invasive vsvs Conservative StrategiesConservative Strategies

Lancet 2007;369:827

0

10

20

30

100 200 300 400

Early invasive

Selective invasive

Time (days)

Perc

ent

Death, MI, Rehospitalization for ACS

21.2

22.7

RR 1.0795% CI 0.87-1.33

P = 0.33

ICTUSICTUS


-40

-30

-20

-10

0

10

20

30

40

50

60

Relative Mortality Benefit with the Revascularisation vs Gradient in Rates of Revascularisation Between both Randomisation Arms

Relative Mortality Benefit with the Revascularisation Relative Mortality Benefit with the Revascularisation vsvs Gradient in Rates Gradient in Rates of Revascularisation Between both Randomisation Armsof Revascularisation Between both Randomisation Arms

Eur Heart J 2004; 25: 1471-1472

Relat

ive m

orta

lity b

enef

it:In

vasiv

e vs c

onse

rvat

ive st

rate

gies

per

cent

Difference in rate of revascularization: Invasive - Conservative strategies percent

VANQWISH

ICTUS

TIMI IIIb

10 20 30 40 50 60 70 80 90

TACTIS-TIMI 18

RITA 3

FRISC II

GUSTO IV-ACSDatabank analysis


Bavry et al. JACC 2006

Meta-Analysis: Invasive TherapyMetaMeta--AnalysisAnalysis: : InvasiveInvasive TherapyTherapy


Timing of InterventionTiming of InterventionTiming of Intervention

1.1. Few studies have shown superiority of Few studies have shown superiority of veryvery early intervention early intervention vsvsdeferred intervention.deferred intervention.

•• ISARISAR--COOL (small sample size) COOL (small sample size)

2.2. Many trials, registries and metaMany trials, registries and meta--analysis have shown early hazardanalysis have shown early hazardwith early intervention with early intervention vsvs deferred intervention deferred intervention

•• ICTUS trialICTUS trial•• Mehta MetaMehta Meta--analysisanalysis•• GRACE & CRUSADE registriesGRACE & CRUSADE registries

3.3. Timing of intervention recommended on the basis of risk Timing of intervention recommended on the basis of risk stratificationstratification

JAMA 2003;290:1593

NEJM 2005;353:1095

JAMA 2005;293:2908Heart 2007;93:177Arch Intern Med 2006;166:2027


Pharmacological Environment of PCIPharmacological Environment of PCIPharmacological Environment of PCI

1.1. Loading dose of clopidogrelLoading dose of clopidogrel•• 300 300 vsvs 600mg 600mg •• prepre--treatment treatment vsvs no preno pre--treatmenttreatment

2.2. AntiAnti--coagulants in the coagulants in the cathlabcathlab•• UFHUFH•• BivalirudinBivalirudin•• Enoxaparin if started in the ward (no crossEnoxaparin if started in the ward (no cross--over)over)•• Fondaparinux cannot be used standFondaparinux cannot be used stand--alone alone

3.3. Triple antiplatelet therapyTriple antiplatelet therapy•• Recommended on the basis of ISARRecommended on the basis of ISAR--REACTREACT--22

JAMA 2006;295:1531


Glycoprotein IIb/IIIa inhibitors: II B or Not II B?Glycoprotein IIb/IIIa inhibitors: II B or Not II B?Glycoprotein IIb/IIIa inhibitors: II B or Not II B?•• ISARISAR--REACT 2 : triple antiplatelet Rx superior to double REACT 2 : triple antiplatelet Rx superior to double

antiplatelet Rx in moderate to high risk patients submitted to Pantiplatelet Rx in moderate to high risk patients submitted to PCICI•• ACUITY* better net clinical outcome (ACUITY* better net clinical outcome (death+MI+urgentdeath+MI+urgent

revasc+bleedingrevasc+bleeding) with ) with bivalirudinbivalirudin alone alone vsvs UFH/LMWH + UFH/LMWH + GPIIb/IIIaGPIIb/IIIa inhibitorsinhibitors

•• BUT, trends towards higher ischemic risk with BUT, trends towards higher ischemic risk with bivalirudinbivalirudin alone alone (significant in patients not (significant in patients not pretreatedpretreated with clopidogrel)with clopidogrel)

•• Beneficial effect in ACUITY* entirely driven by risk reduction fBeneficial effect in ACUITY* entirely driven by risk reduction for or bleeding (no impact on outcome)bleeding (no impact on outcome)

•• Liberal nonLiberal non--inferiority margininferiority margin•• No impact of bleeding risk reduction on short and long term No impact of bleeding risk reduction on short and long term

outcomeoutcome

*Randomised but not double blind study


Double vs Triple Antiplatelet Therapy in the Cathlab – ISAR-REACT-2Double Double vsvs Triple Antiplatelet Therapy in the Triple Antiplatelet Therapy in the CathlabCathlab –– ISARISAR--REACTREACT--22

JAMA 2006;295:1531

0

5

10

15

0 10 15 20

Placebo

Days after randomization

Deat

h, M

I, UTV

R pe

rcen

t

RR 0.7595% CI 0.58-0.97

Primary End Point

5 25 30

11.9

8.9Abciximab


Double vs Triple Antiplatelet Therapy in the Cathlab – ISAR-REACT-2Double Double vsvs Triple Antiplatelet Therapy in the Triple Antiplatelet Therapy in the CathlabCathlab –– ISARISAR--REACTREACT--22

JAMA 2006;295:1531

0

5

10

15

20

0 10 15 20Days after randomization

Deat

h, M

I, UTV

R pe

rcen

tTroponin Level and Benefit with Abciximab

5 25 30

Abciximab vs Placebo

Troponin-Positive RR=0.71 (0.54 - 0.98)

Troponin-Negative RR=0.99 (0.56 - 1.78)


Glycoprotein IIb/IIIa inhibitors: II B or Not II B?Glycoprotein IIb/IIIa inhibitors: II B or Not II B?Glycoprotein IIb/IIIa inhibitors: II B or Not II B?•• ISARISAR--REACT 2 : triple antiplatelet Rx superior to REACT 2 : triple antiplatelet Rx superior to double double

antiplatelet Rx in moderate to high risk antiplatelet Rx in moderate to high risk patients submitted to PCIpatients submitted to PCI•• ACUITYACUITY** better net clinical outcome (better net clinical outcome (death+MI+urgentdeath+MI+urgent

revasc+bleedingrevasc+bleeding) with ) with bivalirudinbivalirudin alone alone vsvs UFH/LMWH + UFH/LMWH + GPIIb/IIIaGPIIb/IIIa inhibitorsinhibitors

•• BUT, trends towards higher ischemic risk with BUT, trends towards higher ischemic risk with bivalirudinbivalirudin alone alone (significant in patients not (significant in patients not pretreatedpretreated with clopidogrel)with clopidogrel)

•• Beneficial effect in ACUITYBeneficial effect in ACUITY** entirely driven by risk reduction for entirely driven by risk reduction for bleeding (no impact on outcome)bleeding (no impact on outcome)

•• Wide nonWide non--inferiority margininferiority margin•• No impact of bleeding risk reduction on short and long term No impact of bleeding risk reduction on short and long term

outcomeoutcome•• ACUITY Timing ACUITY Timing –– Upstream Upstream vsvs deferred IIB/IIIA inhibitorsdeferred IIB/IIIA inhibitors

equivocal resultsequivocal results *Randomised but not double blind study


11.7%11.7% 1.00 (0.89-1.11) <0.0010.93

ACUITY Timing ACUITY Timing -- Primary Endpoint MeasuresPrimary Endpoint Measures

Net clinical outcome

Ischemic composite

Major bleeding

7.9%7.1% 1.12 (0.97-1.29) 0.060.13

4.9%6.1% 0.80 (0.67-0.95) <0.0010.01

Routine Upstream IIb/IIIa vs. Deferred PCI IIb/IIIaRoutine Upstream IIb/IIIa vs. Deferred PCI IIb/IIIa

JAMA 2007;297:591JAMA 2007; 297:591

Primaryendpoint

0

Net clinicaloutcome

Ischemiccomposite

Majorbleeding

UpstreamIIb/IIIa

11.7 %

7.1 %

6.1 %

DeferredIIb/IIIa

11.7 %

7.9 %

4.9 %

RR (95% CI)

1.00 (0.89-1.11)

1.12 (0.97-1.29)

0.80 (0.67-0.95)


(superior)

< 0.0010.93

0.060.13

< 0.0010.01


0 1 2DeferredPCI GPIbetter

RoutineUpstream GPI

better

Uppe

r bou

ndar

y non

-infer

iority


TIMI-18 ’01

VINO ’02

RITA-3 ’02

ICTUS ’05

All

2220

131

1810

1200

7962

FRISC-II ’00

TRUCS ’00

2453

148

10 102 ∞ 11 101020.25 210% 10% 30%


NNT and 95% CIIncidence

0.84 (0.73-0.97) 63 (36-368)9.5% vs 11.1%

Death or MI at 1 yearSize

Invasive+ Cons+ Invasive+ Cons+

0.520%

Randomised trials comparing early invasive (dark bars) vsconservative strategy (open bars)

Randomised trials comparing early invasive Randomised trials comparing early invasive (dark bars)(dark bars) vsvsconservative strategy conservative strategy (open bars)(open bars)


Recommendations for invasive evaluation and revascularisation (1)

Recommendations for invasive evaluation Recommendations for invasive evaluation and revascularisation (1)and revascularisation (1)

•• Urgent coronary angiography is recommended in patients with Urgent coronary angiography is recommended in patients with refractory or recurrent angina associated with dynamic ST refractory or recurrent angina associated with dynamic ST deviation, heart failure, life threatening arrhythmias or deviation, heart failure, life threatening arrhythmias or haemodynamichaemodynamic instability (I instability (I -- C). C).

•• Early (< 72 hours) coronary angiography followed by Early (< 72 hours) coronary angiography followed by revascularisation (PCI or CABG) in patients with intermediate torevascularisation (PCI or CABG) in patients with intermediate tohighhigh--risk features is recommended (I risk features is recommended (I -- A). A).

•• Routine invasive evaluation of patients without intermediate to Routine invasive evaluation of patients without intermediate to high risk features is not recommended (IIIhigh risk features is not recommended (III--C), but nonC), but non--invasive invasive assessment of inducible ischaemia is advised (I assessment of inducible ischaemia is advised (I -- C). C).


Recommendations for invasive evaluation and revascularisation (2)

Recommendations for invasive evaluation Recommendations for invasive evaluation and revascularisation (2)and revascularisation (2)

•• PCI of nonPCI of non--significant lesions by angiography is not significant lesions by angiography is not recommended (III recommended (III -- C). C).

•• After critical evaluation of the risk to benefit ratio, After critical evaluation of the risk to benefit ratio, and depending on known coand depending on known co--morbidities and morbidities and potential need for nonpotential need for non--cardiac surgery in the cardiac surgery in the short/medium term (e.g. planned intervention or short/medium term (e.g. planned intervention or other conditions) requiring temporary withdrawal of other conditions) requiring temporary withdrawal of dual antiplatelet therapy, consideration should be dual antiplatelet therapy, consideration should be given to the type of stent to be implanted (BMS or given to the type of stent to be implanted (BMS or DES) (IDES) (I--C). C).


Invasive vsCons

7962

10 102 ∞ 11 101020.5 215%0% 10% 0.50.1 2 1012.5%0% 5%



Incidence Incidence

Death or MISize Major bleeds

Exp+ Ctrl+ Exp+ Ctrl+ Exp+ Ctrl+

DTI vs UFH 24701

LMWH vs UFH 21946

GP IIb/IIIa vsCtrl

31402

Heparin vs Ctrl 2858

Aspirin vs Ctrl 3096

15%

0.84

0.88

0.91

0.91

0.55

0.47

63

102

113

111

31

17

1.3

1.1

1.6

2.3

1.4

NSTE-ACS – Summary of Treatment ApproachesNSTENSTE--ACSACS –– SummarySummary of of TreatmentTreatment ApproachesApproaches


TreatmentLong-term management &

rehabilitation

TreatmentTreatmentLongLong--term management & term management &

rehabilitationrehabilitation


Recommendations for Long Term DrugTherapy (1)

RecommendationsRecommendations for Long for Long TermTerm DrugDrugTherapyTherapy (1)(1)

Lipid lowering therapyLipid lowering therapy

•• Statins are recommended for all NSTEStatins are recommended for all NSTE--ACS patients ACS patients (in the absence of contraindications), irrespective of (in the absence of contraindications), irrespective of cholesterol levels, initiated early (within 1cholesterol levels, initiated early (within 1--4 days) 4 days) after admission, in the aim of achieving after admission, in the aim of achieving LDLcLDLc levels levels <100mg/dL (< 2.6 <100mg/dL (< 2.6 mmolmmol/L) (I/L) (I--B).B).

•• Intensive lipidIntensive lipid--lowering therapy with target lowering therapy with target LDLcLDLclevels <70 mg/dL (< 1.81 levels <70 mg/dL (< 1.81 mmolmmol/L) initiated within 10 /L) initiated within 10 days after admission, is advisable (days after admission, is advisable (IIaIIa--B).B).




BetaBeta--blockersblockers•• BetaBeta--blockers should be given to all patients with reduced blockers should be given to all patients with reduced

LV function (ILV function (I--A).A).

ACE InhibitorsACE Inhibitors•• ACE inhibitors are indicated longACE inhibitors are indicated long--term in all patients with term in all patients with

LVEF LVEF ≤≤40% and in patients with diabetes, hypertension or 40% and in patients with diabetes, hypertension or CKD, unless contraindicated (ICKD, unless contraindicated (I--A).A).

•• ACE inhibitors should be considered for all other patients to ACE inhibitors should be considered for all other patients to prevent recurrence of ischaemic events (prevent recurrence of ischaemic events (IIaIIa--B). Agents and B). Agents and doses of proven efficacy are recommended (doses of proven efficacy are recommended (IIaIIa--C).C).




AngiotensinAngiotensin--Receptor BlockersReceptor Blockers•• AngiotensinAngiotensin--Receptor Blockers should be Receptor Blockers should be

considered in patients who are intolerant to ACE considered in patients who are intolerant to ACE inhibitors and/ or who have heart failure or MI with inhibitors and/ or who have heart failure or MI with LVEF <40% (ILVEF <40% (I--B). B).

AldosteroneAldosterone receptor antagonists:receptor antagonists:•• AldosteroneAldosterone blockade should be considered in blockade should be considered in

patients after MI who are already treated with ACE patients after MI who are already treated with ACE inhibitors and betainhibitors and beta--blockers, and who have a LVEF blockers, and who have a LVEF <40% and either diabetes or heart failure, without <40% and either diabetes or heart failure, without significant renal dysfunction or significant renal dysfunction or hyperkaleamiahyperkaleamia (I(I--B). B).


Recommendations for Rehabilitation and Return to Physical Activity

Recommendations for Rehabilitation and Recommendations for Rehabilitation and Return to Physical ActivityReturn to Physical Activity

•• After NSTEAfter NSTE--ACS, assessment of functional capacity is ACS, assessment of functional capacity is recommended (Irecommended (I--C).C).

•• Every patient after NSTEEvery patient after NSTE--ACS should undergo an ECGACS should undergo an ECG--guided exercise test (if technically feasible), or an equivalentguided exercise test (if technically feasible), or an equivalentnonnon--invasive test for ischemia, within 4invasive test for ischemia, within 4--7 weeks after 7 weeks after discharge (discharge (IIaIIa--C)C)

•• Based on cardiovascular status and on the results of Based on cardiovascular status and on the results of functional physical capacity assessment, patients should be functional physical capacity assessment, patients should be informed about the timing of resumption and the informed about the timing of resumption and the recommended level of physical activity, including leisure, recommended level of physical activity, including leisure, work and sexual activities (Iwork and sexual activities (I--C).C).


Complications and their managementBleeding

Thrombocytopenia

Complications and their managementComplications and their managementBleedingBleeding

ThrombocytopeniaThrombocytopenia


TIMI and GUSTO Bleeding DefinitionsTIMI and GUSTO Bleeding DefinitionsTIMI and GUSTO Bleeding Definitions

Bleeding that does not meet criteria for either severe or Bleeding that does not meet criteria for either severe or moderate bleedingmoderate bleeding

MildMild

Bleeding that requires blood transfusion but does not result in Bleeding that requires blood transfusion but does not result in haemodynamichaemodynamic compromisecompromise

ModerateModerate

Either intracranial haemorrhage or bleeding that causes Either intracranial haemorrhage or bleeding that causes haemodynamichaemodynamic compromise and requires interventioncompromise and requires intervention

Severe or life threateningSevere or life threateningGUSTO Bleeding Classification GUSTO Bleeding Classification

Clinically overt bleeding (including imaging) with a < 3 g/dL Clinically overt bleeding (including imaging) with a < 3 g/dL decrease in the haemoglobin concentrationdecrease in the haemoglobin concentration

MinimalMinimal

Clinically overt bleeding (including imaging) with 3 to < 5 g/dClinically overt bleeding (including imaging) with 3 to < 5 g/dL L decrease in the haemoglobin concentrationdecrease in the haemoglobin concentration

MinorMinor

Intracranial haemorrhage or clinically overt bleeding (includingIntracranial haemorrhage or clinically overt bleeding (includingimaging) imaging) ≥≥ 5 g/dL decrease in the haemoglobin 5 g/dL decrease in the haemoglobin concentrationconcentration

MajorMajor

TIMI Bleeding Classification TIMI Bleeding Classification


Hospital Outcome byHospital Outcome byFinal DiagnosisFinal Diagnosis

8

4

1,3

5

3

0,9

3

2

0,5

0

2

4

6

8

10

Patie

nts p

erce

nt

Death Major Bleed Stroke

STEMI (13,862)NSTEMI (11,316)UA (12,509)

Am J Cardiol 2002; 90: 358


Multivariate Model for Major Bleeding in Patients with NSTE-ACS

Multivariate Model for Major Bleeding in Patients with Multivariate Model for Major Bleeding in Patients with NSTENSTE--ACSACS

0.00030.00031.381.38--2.912.912.012.01RightRight--heart catheterisationheart catheterisation

0.00020.00021.351.35--2.622.621.881.88IV IV inotropicinotropic agentsagents

0.0020.0021.681.68--10.410.44.194.19Thrombolytics and GP IIb/IIIa inhibitorsThrombolytics and GP IIb/IIIa inhibitors

<0.0001<0.00011.431.43--2.432.431.861.86GP IIb/IIIa inhibitors onlyGP IIb/IIIa inhibitors only

0.0350.0350.520.52--0.980.980.720.72LMWH and UFH*LMWH and UFH*

0.0120.0120.500.50--0.920.920.680.68LMWH onlyLMWH only

<0.0001<0.00011.461.46--2.492.491.911.91DiureticsDiuretics

0.0190.0191.021.02--1.271.271.141.14Mean arterial pressure (per 20mmHg decrease)Mean arterial pressure (per 20mmHg decrease)

0.0140.0141.141.14--4.084.082.182.18History of bleedingHistory of bleeding

0.00620.00621.131.13--2.082.081.531.53History of renal insufficiencyHistory of renal insufficiency

0.01160.01161.071.07--1.731.731.361.36Female sexFemale sex

0.00020.00021.101.10--1.351.351.221.22Age (per 10Age (per 10--year increase)year increase)

PP--valuevalue95%CI95%CIAdjusted ORAdjusted ORVariableVariable

Moscucci. Eur Heart J 2003;24:1815


Moscucci. Eur Heart J 2003;24:1815

<0.001<0.001<0.0001<0.0001

1.861.862.242.24

GPIIb/IIIa blockers GPIIb/IIIa blockers PercutaneousPercutaneous interventionsinterventions

0.0140.0142.182.18History of bleedingHistory of bleeding

0.00620.00621.531.53History of renal insufficiencyHistory of renal insufficiency0.01160.01161.361.36Female sexFemale sex0.00020.00021.221.22Age (per 10y increase)Age (per 10y increase)

PP--valuevalueAdjusted ORAdjusted ORVariableVariable

Multivariate Model for Major Bleeding in Patients with NSTEMI

Multivariate Model for Major Bleeding in Patients Multivariate Model for Major Bleeding in Patients with NSTEMIwith NSTEMI


5,13

5,37

18,616,1 15,3

22,8

0

10

20

30

40

50

Patie

nts p

erce

nt

Overall STEMI UA

No Major BleedMajor Bleed

** ****

**

Moscucci MMoscucci M et al. et al. EurEur Heart J 2003;24:1815Heart J 2003;24:1815--23.23.

In-Hospital Death Rates in Patients Accordingto Major Bleeding

InIn--Hospital Death Rates in Patients AccordingHospital Death Rates in Patients Accordingto Major Bleedingto Major Bleeding

** p < 0.001

NSTEMI


0

2

4

6

8

10

12

14

30 Day Death According to BleedingOASIS Registry, OASIS-2, CURE

30 Day Death According to Bleeding30 Day Death According to BleedingOASIS Registry, OASISOASIS Registry, OASIS--2, CURE 2, CURE

Cum

ulat

ive E

vent

s, pe

rcen

t

DaysEikelboom Circulation 2006;114: 774 - 782

5-fold ↑ risk

0 10 15 205 25 30

Bleeding

No Bleeding


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

Increased Mortality at Days 30/180 in PatientsIncreased Mortality at Days 30/180 in Patientswith Major Bleeds by Day 9 in OASIS 5 with 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

May Bleed 9 days

No May Bleed 9 days

Days

Cum

ulat

ive H

azar

d


0

5

10

15

20

25

30

35

Dosage of Drugs and Major BleedingDose Group

Dosage of Drugs and Major BleedingDosage of Drugs and Major BleedingDose GroupDose Group

2074 2063

714

5879

1955

178

UFH LMWH GP IIb/IIIa Treatment

Majo

r Ble e

ding

pe r

cen t

Alexander JAMA 2004;294:3108

20732327

3998

237922

UnderdosedRecommendedMild ExcessMajor Excess


30 Day Survival by Transfusion GroupGUSTO IIb, PURSUIT, PARAGON B

( n=24,000 10% transfused )

30 Day Survival by Transfusion Group30 Day Survival by Transfusion GroupGUSTO GUSTO IIbIIb, PURSUIT, PARAGON B , PURSUIT, PARAGON B

( n=24,000 10% transfused )( n=24,000 10% transfused )

Rao SV, JAMA 2004;292:1555

0,9

0,92

0,94

0,96

0,98

1

No Transfusion

Transfusion

Days

Surv

ival R

Ates

0 5 10 15 20 25 30 35


Recommendations for Bleeding Complications (1)

Recommendations for Bleeding Recommendations for Bleeding Complications (1)Complications (1)

•• Assessment of bleeding risk is an important component of Assessment of bleeding risk is an important component of the decision making process. Bleeding risk is increased with the decision making process. Bleeding risk is increased with higher or excessive doses of antihigher or excessive doses of anti--thrombotic agents, length thrombotic agents, length of treatment, combinations of several antiof treatment, combinations of several anti--thrombotic drugs, thrombotic drugs, switch between different anticoagulant drugs, as well as switch between different anticoagulant drugs, as well as with older age, reduced renal function, low body weight, with older age, reduced renal function, low body weight, female gender, baseline female gender, baseline haemoglobinhaemoglobin and invasive and invasive procedures (Iprocedures (I--B).B).

•• Bleeding risk should be taken into account when deciding Bleeding risk should be taken into account when deciding for a treatment strategy. Drugs, combination of drugs and for a treatment strategy. Drugs, combination of drugs and nonnon--pharmacological procedures (vascular access) known pharmacological procedures (vascular access) known to carry a reduced risk of bleeding should be preferred in to carry a reduced risk of bleeding should be preferred in patients at high risk of bleeding (Ipatients at high risk of bleeding (I--B)B)


Recommendations for Bleeding Complications (2)

Recommendations for Bleeding Recommendations for Bleeding Complications (2)Complications (2)

•• Minor bleeding should preferably be managed without Minor bleeding should preferably be managed without interruption of active treatments (Iinterruption of active treatments (I--C).C).

•• Major bleeding requires interruption and/or neutralisation Major bleeding requires interruption and/or neutralisation of both anticoagulant and antiplatelet therapy, unless of both anticoagulant and antiplatelet therapy, unless bleeding can be adequately controlled by specific bleeding can be adequately controlled by specific haemostatic intervention (Ihaemostatic intervention (I--C).C).

•• Blood transfusion may have deleterious effects on Blood transfusion may have deleterious effects on outcome, and should therefore be considered individually, outcome, and should therefore be considered individually, but withheld in but withheld in haemodynamicallyhaemodynamically stable patients with stable patients with haematocrithaematocrit >25% or haemoglobin level > 8g/L (I>25% or haemoglobin level > 8g/L (I--C).C).


Recommendations for ThrombocytopeniaRecommendations for ThrombocytopeniaRecommendations for Thrombocytopenia

•• Significant thrombocytopenia (<100,000/Significant thrombocytopenia (<100,000/µµL or >50% drop in platelet count) L or >50% drop in platelet count) occurring during treatment with GP IIb/IIIa inhibitors and/or heoccurring during treatment with GP IIb/IIIa inhibitors and/or heparin (LMWH or parin (LMWH or UFH) requires the immediate interruption of these drugs. (IUFH) requires the immediate interruption of these drugs. (I--C)C)

•• Severe thrombocytopenia (<10,000/Severe thrombocytopenia (<10,000/µµL) induced by GP IIb/IIIa inhibitors requires L) induced by GP IIb/IIIa inhibitors requires platelet transfusion with or without fibrinogen supplementation platelet transfusion with or without fibrinogen supplementation with fresh with fresh frozen plasma or cryoprecipitate in case of bleeding. (Ifrozen plasma or cryoprecipitate in case of bleeding. (I--C)C)

•• Interruption of heparin (UFH or LMWH) is warranted in case of doInterruption of heparin (UFH or LMWH) is warranted in case of documented or cumented or suspected HIT. In case of thrombotic complications, anticoagulatsuspected HIT. In case of thrombotic complications, anticoagulation can be ion can be achieved with DTI (Iachieved with DTI (I--C).C).

•• Prevention of HIT can be achieved with use of anticoagulants devPrevention of HIT can be achieved with use of anticoagulants devoid of risk of oid of risk of HIT, such as fondaparinux or HIT, such as fondaparinux or bivalirudinbivalirudin, or by brief prescription of heparin , or by brief prescription of heparin (UFH or LMWH) in case these compounds are chosen as anticoagulan(UFH or LMWH) in case these compounds are chosen as anticoagulant (It (I--B).B).


Special Conditions & PopulationsElderly

Impact of Gender

Special Conditions & PopulationsSpecial Conditions & PopulationsElderlyElderly

Impact of GenderImpact of Gender


Clinical Outcomes for Patients Stratified by Age(Invasive Vs Conservative Strategies) from TACTICS–TIMI-18 Trial

Clinical Outcomes for Patients Stratified by AgeClinical Outcomes for Patients Stratified by Age(Invasive Vs Conservative Strategies) from TACTICS(Invasive Vs Conservative Strategies) from TACTICS––TIMITIMI--18 Trial 18 Trial

Am J Cardiol 2003;91:1466

0 0.5 1 1.5 20 0.5 1 1.5 2

≤ 55 y

> 55-65 y

> 65-75 y

> 75 y

1.3

2.0

4.8

10.1

1.2

2.2

4.7

7.9

0.90

1.11

0.97

0.77

≤ 55 y

> 55-65 y

> 65-75 y

> 75 y

3.4

7.4

7.6

13.7

4.2

5.7

4.7

4.3

1.22

0.75

0.60

0.28*

* P = 0.010

Invasivebetter

Conservativebetter

Death

Invasivebetter

Conservativebetter

Nonfatal MI

Age GroupManagement %

Cons. Inv. ORCons. Inv. OR Age GroupManagement %


Clinical Outcomes for Patients Stratified by Age(Invasive Vs Conservative Strategies) from TACTICS–TIMI-18 Trial

Clinical Outcomes for Patients Stratified by AgeClinical Outcomes for Patients Stratified by Age(Invasive Vs Conservative Strategies) from TACTICS(Invasive Vs Conservative Strategies) from TACTICS––TIMITIMI--18 Trial 18 Trial

Am J Cardiol 2003;91:1466

0 0.5 1 1.5 20 0.5 1 1.5 2

≤ 55 y

> 55-65 y

> 65-75 y

> 75 y

4.8

9.1

10.3

21.6

5.0

7.6

7.8

10.8

1.07

0.82

0.73

0.44†

≤ 55 y

> 55-65 y

> 65-75 y

> 75 y

16.4

19.5

18.2

30.2

13.1

18.0

14.9

20.1

0.77

0.90

0.79

0.58†

† P = 0.016

Invasivebetter

Conservativebetter

Death or Nonfatal MI

Invasivebetter

Conservativebetter

Death, MI or Rehospitalization

Age GroupManagement %

Cons. Inv. ORCons. Inv. OR Age GroupManagement %

† P = 0.05


Recommendations for Special PopulationsRecommendationsRecommendations for for SpecialSpecial PopulationsPopulationsElderlyElderly•• Elderly patients (>75 years) often have atypical symptoms. ActivElderly patients (>75 years) often have atypical symptoms. Active screening for e screening for

NSTENSTE--ACS should be initiated at lower levels of suspicion than among ACS should be initiated at lower levels of suspicion than among younger younger (<75 years) patients (I(<75 years) patients (I--C).C).

•• Treatment decisions in the elderly should be tailored according Treatment decisions in the elderly should be tailored according to estimated life to estimated life expectancy, patient wishes and coexpectancy, patient wishes and co--morbidities to minimize risk and improve morbidities to minimize risk and improve morbidity and mortality outcomes in this frail but highmorbidity and mortality outcomes in this frail but high--risk population. (I risk population. (I –– C)C)

•• Elderly patients should be considered for routine early invasiveElderly patients should be considered for routine early invasive strategy, after strategy, after careful evaluation of their inherent raised risk of procedurecareful evaluation of their inherent raised risk of procedure--related related complications, especially during CABG (I complications, especially during CABG (I –– B).B).

WomenWomen•• Women should be evaluated and treated in the same way as men, wiWomen should be evaluated and treated in the same way as men, with special th special

attention to coattention to co--morbidities (Imorbidities (I--B).B).


Special Conditions & PopulationsDiabetes

Special Conditions & PopulationsSpecial Conditions & PopulationsDiabetesDiabetes


Treatment Effect on 30-day Mortality Among Diabetic Patientswith NSTE ACS from Six Randomised Clinical Trials

Treatment Effect on 30Treatment Effect on 30--day Mortality Among Diabetic Patientsday Mortality Among Diabetic Patientswith NSTE ACS from Six Randomised Clinical Trials with NSTE ACS from Six Randomised Clinical Trials

Circulation 2001;104:2767

PURSUIT

PRISM

PRISM-PLUS

GUSTO IV

PARAGON A

PARAGON B

Pooled

2163

687

362

1677

412

1157

6458

6.1

4.2

6.7

7.8

6.2

4.8

6.2

5.1

1.8

3.6

5.0

4.6

4.9

4.6

IIb/IIIa better Placebo better

Trial N Placebo % IIb/IIIa %

0 0.5 1 1.5 2

p = 0.33

p = 0.07

p = 0.17

p = 0.022

p = 0.51

p = 0.93

p = 0.007

Odds Ratio & 95% CI


Recommendations for DiabetesRecommendations for DiabetesRecommendations for Diabetes•• Tight Tight glycaemicglycaemic control to achieve control to achieve normoglycaemianormoglycaemia as soon as soon

as possible is recommended in all diabetic patients with as possible is recommended in all diabetic patients with NSTENSTE--ACS in the acute phase (IACS in the acute phase (I--C).C).

•• Insulin infusion may be needed to achieve Insulin infusion may be needed to achieve normoglycaemianormoglycaemiain selected NSTEin selected NSTE--ACS patients with high blood glucose ACS patients with high blood glucose levels at admission (levels at admission (IIaIIa--C) C)

•• Early invasive strategy is recommended for diabetic patients Early invasive strategy is recommended for diabetic patients with NSTEwith NSTE--ACS (I ACS (I –– A).A).

•• Diabetic patients with NSTEDiabetic patients with NSTE--ACS should receive intravenous ACS should receive intravenous GP IIb/IIIa inhibitors as part of the initial medical GP IIb/IIIa inhibitors as part of the initial medical management which should be continued through the management which should be continued through the completion of PCI (completion of PCI (IIaIIa--B).B).


Special Conditions & PopulationsAnaemia

Special Conditions & PopulationsSpecial Conditions & PopulationsAnaemiaAnaemia


Recommendations for AnaemiaRecommendations for AnaemiaRecommendations for Anaemia

•• Low baseline haemoglobin is an independent marker of the Low baseline haemoglobin is an independent marker of the risk of ischaemic and bleeding events at 30 days. It should risk of ischaemic and bleeding events at 30 days. It should be taken into consideration in assessing initial risk (Ibe taken into consideration in assessing initial risk (I--B).B).

•• All necessary measures should be taken during the course All necessary measures should be taken during the course of initial management to avoid worsening of anaemia by of initial management to avoid worsening of anaemia by bleeding (Ibleeding (I--B). B).

•• Well tolerated anaemia at baseline in patients with NSTEWell tolerated anaemia at baseline in patients with NSTE--ACS should not lead to systematic blood transfusion which ACS should not lead to systematic blood transfusion which should be considered only in case of compromised should be considered only in case of compromised haemodynamichaemodynamic status (Istatus (I--C). C).


Special Conditions & PopulationsChronic Kidney Disease

Special Conditions & PopulationsSpecial Conditions & PopulationsChronic Kidney DiseaseChronic Kidney Disease


Stages of CKD, according to the National Kidney Foundation

Stages of CKD, according to the National Stages of CKD, according to the National Kidney Foundation Kidney Foundation

<15 (or dialysis)<15 (or dialysis)Kidney failureKidney failure55

1515--2929Severe decrease in GFRSevere decrease in GFR44

3030--5959Moderate decrease in GFRModerate decrease in GFR33

6060--8989Kidney damage with mild decrease Kidney damage with mild decrease in GFRin GFR

22

≥≥9090Kidney damage with normal or Kidney damage with normal or increased GFRincreased GFR

11

GFR GFR (mL/min/1.73m(mL/min/1.73m²²))

DescriptionDescriptionStageStage


In-hospital Mortality or Bleeding According to the Level of CrClin Patients Treated with UFH or LMWH

InIn--hospital Mortality or Bleeding According to the Level of hospital Mortality or Bleeding According to the Level of CrClCrClin Patients Treated with UFH in Patients Treated with UFH or LMWHor LMWH

EHJ 2005;26:2285

0

0,05

0,1

0,15

0,2

Creatinine clereance (mL / min)

Estim

ated

pro

babi

lity o

f in-

hosp

ital e

vent

s

30 60 90 120 150 180 210 240 270 300 330

In-hospital mortality UFHBleeding UFHIn-hospital Mortality LMWH Bleeding LMWH


Outcomes According to Degree of Renal Function Impairment in NSTE-ACS Patients in GRACE Registry

Outcomes According to Degree of Renal Function Outcomes According to Degree of Renal Function Impairment in NSTEImpairment in NSTE--ACS Patients in GRACE Registry ACS Patients in GRACE Registry

Heart 2003;89:1003

8,57,9

0,9

7,3

3,8

5,9

0,9

4

0,9

6

0,4

1,8

0

5

10

15

Patie

nts p

erce

nt

Mortality MI Stroke Major bleeding

SevereModerateNormal / minimally impaired* *

* *

*


Recommendations for the Use of Drugs in Case of CKDRecommendations for the Use of Drugs in Case of CKDRecommendations for the Use of Drugs in Case of CKD

Half dose recommended for patients with Half dose recommended for patients with CrClCrCl between 15 and 35ml/min (50mg/day). Quarter dose (25mg/day) between 15 and 35ml/min (50mg/day). Quarter dose (25mg/day) recommended if recommended if CrClCrCl <15ml/min. <15ml/min.

AtenololAtenolol

No specific recommendations for the use of No specific recommendations for the use of abciximababciximab, or for dose adjustment in case of renal failure. Careful , or for dose adjustment in case of renal failure. Careful evaluation of haemorrhagic risk is needed before using the drug evaluation of haemorrhagic risk is needed before using the drug in case of renal failure. in case of renal failure.

AbciximabAbciximab

As 50% of eptifibatide is cleared through the kidney in patientsAs 50% of eptifibatide is cleared through the kidney in patients with renal failure, precautions must be taken with renal failure, precautions must be taken in patients with impaired renal function (in patients with impaired renal function (CrClCrCl <50ml/min). The infusion dose should be reduced to <50ml/min). The infusion dose should be reduced to 11µµg/kg/min in such patients. The dose of the bolus remains unchangg/kg/min in such patients. The dose of the bolus remains unchanged at 180ed at 180µµg/kg. Eptifibatide is g/kg. Eptifibatide is contracontra--indicated in patients with creatinine clearance <30mL/min.indicated in patients with creatinine clearance <30mL/min.

EptifibatideEptifibatideDose adaptation required in patients with renal failure. 50% of Dose adaptation required in patients with renal failure. 50% of the dose only if the dose only if CrClCrCl <30ml/min. <30ml/min. TirofibanTirofiban

If the If the CrClCrCl < 30 < 30 mLmL/min, reduction of the infusion rate to 1.0 mg/kg/h should be co/min, reduction of the infusion rate to 1.0 mg/kg/h should be considered. If a patient is on nsidered. If a patient is on haemodialysis, the infusion should be reduced to 0.25 mg/kg/h. Nhaemodialysis, the infusion should be reduced to 0.25 mg/kg/h. No reduction in the bolus dose is o reduction in the bolus dose is needed.needed.

BivalirudinBivalirudin

Contraindicated in severe renal failure (Contraindicated in severe renal failure (CrClCrCl <30ml/min). However, as much lower risk of bleeding <30ml/min). However, as much lower risk of bleeding complications were observed in Oasiscomplications were observed in Oasis--5 with fondaparinux as compared with 5 with fondaparinux as compared with enoxaparinenoxaparin, even in , even in patients with severe renal failure, this drug might be the anticpatients with severe renal failure, this drug might be the anticoagulant of choice in this situation.oagulant of choice in this situation.

FondaparinuxFondaparinux

In case of severe renal failure (In case of severe renal failure (CrClCrCl<30mL/min), either contraindicated or dose adjustment required, <30mL/min), either contraindicated or dose adjustment required, according to countryaccording to country--specific labelling.specific labelling.

Enoxaparin*Enoxaparin*No information in patients with renal failureNo information in patients with renal failureClopidogrelClopidogrel

Recommended for the treatment of hypertension or renal failure iRecommended for the treatment of hypertension or renal failure in diabetes type 2 with n diabetes type 2 with microalbuminuriamicroalbuminuria 5050--100mg per day. Regular monitoring of electrolyte balance and ser100mg per day. Regular monitoring of electrolyte balance and serum creatinine is recommended. um creatinine is recommended.

LosartanLosartan**Dose adaptation required if Dose adaptation required if CrClCrCl <30ml/min (initial dose 1.25mg daily). Dose must not exceed 5mg<30ml/min (initial dose 1.25mg daily). Dose must not exceed 5mg per day.per day.RamiprilRamipril**Low renal elimination. In patients with severe renal failure (Low renal elimination. In patients with severe renal failure (CrClCrCl <30ml/min), careful with doses >10mg<30ml/min), careful with doses >10mgSimvastatinSimvastatin**Recommendations in case of CKDRecommendations in case of CKDDrugDrug


Recommendations for Patients with CKD (1) Recommendations for Patients with CKD (1) Recommendations for Patients with CKD (1)

•• CrClCrCl and/or GFR should be calculated for every patient hospitalised and/or GFR should be calculated for every patient hospitalised for NSTEfor NSTE--ACS (IACS (I--B). Elderly people, women and low body weight B). Elderly people, women and low body weight patients merit special attention as near normal serum creatininepatients merit special attention as near normal serum creatininelevels may be associated with lower than expected levels may be associated with lower than expected CrClCrCl and GFR and GFR levels (Ilevels (I--B).B).

•• Patients with CKD should receive the same firstPatients with CKD should receive the same first--line treatment as line treatment as any other patient, in the absence of contraany other patient, in the absence of contra--indications (Iindications (I--B).B).

•• In patients with In patients with CrClCrCl < 30ml/min or GFR <30ml/min/1.73m², a careful < 30ml/min or GFR <30ml/min/1.73m², a careful approach to the use of anticoagulants is recommended, since doseapproach to the use of anticoagulants is recommended, since doseadjustment is necessary with some, while others are adjustment is necessary with some, while others are contraindicated. (Icontraindicated. (I--C)C)


Recommendations for Patients with CKD (2)Recommendations for Patients with CKD (2)Recommendations for Patients with CKD (2)•• UFH infusion adjusted according to UFH infusion adjusted according to aPTTaPTT is recommended when is recommended when

CrClCrCl < 30ml/min or GFR <30ml/min/1.73m< 30ml/min or GFR <30ml/min/1.73m²² (I(I--C).C).

•• GP IIb/IIIa inhibitors can be used in case of renal failure. DosGP IIb/IIIa inhibitors can be used in case of renal failure. Dose e adaptation is needed with eptifibatide and tirofiban. Careful adaptation is needed with eptifibatide and tirofiban. Careful evaluation of the bleeding risk is recommended for evaluation of the bleeding risk is recommended for abciximababciximab (I(I--B).B).

•• Patients with CKD with Patients with CKD with CrClCrCl < 60 ml/min are at high risk of < 60 ml/min are at high risk of further ischaemic events and therefore should be submitted to further ischaemic events and therefore should be submitted to invasive evaluation and revascularisation whenever possible invasive evaluation and revascularisation whenever possible ((IIaIIa--B). B).

•• Appropriate measures are advised to reduce the risk of contrast Appropriate measures are advised to reduce the risk of contrast induced nephropathy (Iinduced nephropathy (I--B). B).


Management Strategy Management Strategy Management Strategy

Quality of chest painQuality of chest painAssessment of likelihood of CADAssessment of likelihood of CADECG (ST elevation or other ECG abnormalities)ECG (ST elevation or other ECG abnormalities)

Diagnosis and risk stratificationDiagnosis and risk stratification

BiochemistryBiochemistryResponsiveness to Responsiveness to antianginalantianginal treatmenttreatmentECG (repeat, continuous monitoring)ECG (repeat, continuous monitoring)Echocardiography, MRI, CTEchocardiography, MRI, CTRisk scoreRisk score

TreatmentTreatment

EmergentEmergentEarlyEarlyNo/electiveNo/elective

11stst step: Initial Evaluationstep: Initial Evaluation

22ndnd step: Validation & Risk Assessmentstep: Validation & Risk Assessment

44thth step: Revascularisationstep: Revascularisation

33rdrd step: Invasive Managementstep: Invasive Management

55thth step: Longstep: Long--term managementterm management

STRATEGYSTRATEGYSTRATEGY


Risk StratificationRiskRisk StratificationStratification1.1. FeaturesFeatures ofof highhigh riskrisk thatthat mandates urgent mandates urgent

angiography / revascularizationangiography / revascularization–– Refractory angina (e.g. evolving MI without ST Refractory angina (e.g. evolving MI without ST abnormaltiesabnormalties))–– Recurrent angina despite intense Recurrent angina despite intense antianginalantianginal treatment treatment

associated with ST depression (associated with ST depression (>> 2 mm) or deep negative T 2 mm) or deep negative T waves.waves.

–– Clinical symptoms of heart failure or Clinical symptoms of heart failure or haemodynamichaemodynamicinstability (instability (““ shockshock””))

–– Life threatening arrhythmias (ventricular fibrillation or Life threatening arrhythmias (ventricular fibrillation or ventricular tachycardia)ventricular tachycardia)


Risk StratificationRiskRisk StratificationStratification

2 2 -- FeaturesFeatures ofof highhigh riskrisk thatthat mandates mandates earlyearly (<72 (<72 hourshours) ) angiography / revascularizationangiography / revascularization–– Elevated troponin levels Elevated troponin levels –– Dynamic ST or T wave changes (symptomatic or silent) (Dynamic ST or T wave changes (symptomatic or silent) (>> 0.5mm)0.5mm)–– Diabetes mellitus Diabetes mellitus –– Reduced renal function (GFR < 60 ml/min/1.73mReduced renal function (GFR < 60 ml/min/1.73m²²) ) –– Depressed LVEF < 40%Depressed LVEF < 40%–– Early post MI angina Early post MI angina –– PCI within 6 monthsPCI within 6 months–– Prior CABGPrior CABG–– Intermediate to high risk according to a risk scoreIntermediate to high risk according to a risk score


GRACE ACS Risk ModelGRACE ACS GRACE ACS RiskRisk ModelModel


Risk StratificationRiskRisk StratificationStratification

3 3 -- No No featuresfeatures ofof highhigh riskrisk–– No recurrence of chest painNo recurrence of chest pain–– No signs of heart failureNo signs of heart failure–– No abnormalities in the initial ECG or a second No abnormalities in the initial ECG or a second

ECG (6 to 12 hours)ECG (6 to 12 hours)–– No elevation of troponins (arrival and at 6 No elevation of troponins (arrival and at 6 –– 12 12

hours)hours)


Primary therapeutic measuresPrimary therapeutic measuresPrimary therapeutic measures

0.5 0.5 -- 1 mg intravenously, if 1 mg intravenously, if bradycardiabradycardia or or vagalvagal reactionreactionAtropineAtropine

Particularly, if tachycardia or hypertension without sign of heaParticularly, if tachycardia or hypertension without sign of heart failurert failureOral Oral betablockerbetablocker

3 to 5 mg intravenous or subcutaneous, depending on pain severit3 to 5 mg intravenous or subcutaneous, depending on pain severityyMorphineMorphine

Choice between Choice between differrentdifferrent options depends on strategy:options depends on strategy:•• UFH intravenous Bolus 60UFH intravenous Bolus 60––70 IU/kg (maximum 5000 IU) followed by infusion of 1270 IU/kg (maximum 5000 IU) followed by infusion of 12––15 IU/kg/h 15 IU/kg/h

(IU/h maximum 1000) titrated to (IU/h maximum 1000) titrated to aPTTaPTT 1.51.5––2.5 times control2.5 times control•• Fondaparinux 2.5 mg/daily subcutaneously Fondaparinux 2.5 mg/daily subcutaneously •• Enoxaparin 1 mg/kg twice/daily subcutaneously Enoxaparin 1 mg/kg twice/daily subcutaneously •• DalteparinDalteparin 120 IU/kg twice/daily subcutaneously 120 IU/kg twice/daily subcutaneously •• NadroparinNadroparin 86 IU/kg twice/daily subcutaneously86 IU/kg twice/daily subcutaneously•• Bivalirudin 0.1 mg/kg bolus followed by 0.25 mg/kg/hBivalirudin 0.1 mg/kg bolus followed by 0.25 mg/kg/h

AnticoagulationAnticoagulation

Loading dose of 300mg (or 600mg for rapid onset of action) folloLoading dose of 300mg (or 600mg for rapid onset of action) followed by 75 mg dailywed by 75 mg dailyClopidogrelClopidogrel

Initial dose of 160Initial dose of 160––325mg non325mg non--enteric formulation followed by 75enteric formulation followed by 75––100 mg/d (intravenous 100 mg/d (intravenous administration is acceptable)administration is acceptable)

AspirinAspirin

Sublingually or intravenously (caution if systolic blood pressurSublingually or intravenously (caution if systolic blood pressure < 90mmHg)e < 90mmHg)NitratesNitrates

InsufflationInsufflation (4 to 8 L/min) if oxygen saturation is < 90%(4 to 8 L/min) if oxygen saturation is < 90%OxygenOxygen


Management StrategyManagement Management StrategyStrategyOrientationOrientation

•• Quality of chest pain and a symptomQuality of chest pain and a symptom--oriented physical oriented physical examination examination

•• Assessment of the likelihood of CAD (e.g. age, risk Assessment of the likelihood of CAD (e.g. age, risk factors, previous MI, CABG, PCI)factors, previous MI, CABG, PCI)

•• ECG (ST deviation or other ECG abnormalities)ECG (ST deviation or other ECG abnormalities)

No CADNo CAD NSTNST--ACSACSpossiblepossible

STEMI STEMI immediateimmediatereperfusionreperfusion

ValidationValidation


Management StrategyManagement Management StrategyStrategyValidationValidation

•• Routine clinical chemistry, particularly troponins (on presentatRoutine clinical chemistry, particularly troponins (on presentation and after 6 to 12 hours) and other ion and after 6 to 12 hours) and other markers according to working diagnoses (e.g. Dmarkers according to working diagnoses (e.g. D--dimersdimers, BNP, NT, BNP, NT--proBNPproBNP))

•• Repeat, preferably continuous ST segment monitoring (when availaRepeat, preferably continuous ST segment monitoring (when available)ble)•• Echocardiogram, MRI, CT or nuclear imaging for differential diagEchocardiogram, MRI, CT or nuclear imaging for differential diagnoses (e.g. aortic dissection, noses (e.g. aortic dissection,

pulmonary embolism), pulmonary embolism), •• Responsiveness to Responsiveness to antianginalantianginal treatmenttreatment•• Risk score assessmentRisk score assessment•• Bleeding risk assessmentBleeding risk assessment

Urgent < 120 minUrgent < 120 min11-- Refractory angina Refractory angina 22--Recurrent angina despite intense Recurrent angina despite intense

antianginalantianginal treatment treatment associated with ST depression associated with ST depression ((>> 2 mm) or deep negative T 2 mm) or deep negative T waves.waves.

33--Clinical symptoms of heart failure Clinical symptoms of heart failure or or haemodynamichaemodynamic instability instability

44--Life threatening arrhythmias Life threatening arrhythmias (ventricular fibrillation or (ventricular fibrillation or ventricular tachycardia)ventricular tachycardia)

EarlyEarly < 72 < 72 hourshoursElevated troponin levels Elevated troponin levels Dynamic ST or T wave changesDynamic ST or T wave changesDiabetes mellitus Diabetes mellitus Reduced renal function Reduced renal function

(GFR < 60 ml/min/1.73m²) (GFR < 60 ml/min/1.73m²) Depressed LVEF < 40%Depressed LVEF < 40%Early post MI angina Early post MI angina PCI within 6 monthsPCI within 6 monthsPrior CABGPrior CABGIntermediate to high risk Intermediate to high risk

( GRACE risk score )( GRACE risk score )

ElectiveElectiveNo recurrence of chest painNo recurrence of chest painNo signs of heart failureNo signs of heart failureNo abnormalities in the initial No abnormalities in the initial ECG or a second ECG (6 to 12 ECG or a second ECG (6 to 12 hours)hours)No elevation of troponins No elevation of troponins (arrival and at 6 (arrival and at 6 –– 12 hours)12 hours)


urgent

early(< 72 hrs)

no/elective

1. First Contact 2. Diagnosis/Risk Assessment 3. Invasive Strategy

Quality of chest pain Symptom-orientedphysical examinationLikelihood of CADElectrocardiogram (ST-elevation or other abnormalities)

InitialEvaluation

Response to antianginal treatmentRoutine biochemistry, including troponins (on presentation and after 6 to 12 hours), poss. special markers (e.g. D-dimers, BNP/ NT-proBNP)Repeat or continuous ST segment monitoring Risk score assessment Bleeding risk assessmentDifferential diagnosis exclusion: echocardiogram, CT, MRI, nuclear imaging.

Validation

No recurrence of chest pain

No signs of heart failure

No new ECG changes

(Arrival and at 6 – 12 hours)

No elevation of troponins

(Arrival and at 6 – 12 hours)

ACS possible

Other diagnosis

STEMI

Persistent or recurrent angina with/ without ST

changes (≥ 2 mm) or deep neg. T resistant to

antianginal treatment

Clinical symptoms of heart failure or progressing

haemodynamic instability

Life threatening arrhythmias (VF,VT)

Elevated troponin levels

Dynamic ST or T wave changes

(symptomatic or silent)

Diabetes mellitus

Renal dysfunction (GFR<60ml/min/1.73m² )

Reduced left ventricular function (EF <40%)

Early post-infarction angina

Prior MI

PCI within 6 months

Prior CABG

Intermediate to high GRACE risk score


Performance Measures Performance Measures Performance Measures


Recommendations for Performance Measures

Recommendations for Performance Recommendations for Performance MeasuresMeasures

•• Development of regional and/or national Development of regional and/or national programmes to systematically measure programmes to systematically measure performance indicators and provide feedback performance indicators and provide feedback to individual hospitals is strongly to individual hospitals is strongly encouraged (Iencouraged (I--C). C).

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