update 2015- what's new from cardiology main congresses jnuc4 2015 final

ESC 2O15

Aldosterone Lethal effects Blockade in Acute myocardial infarction Treated with or without Reperfusion to improve Outcome and Survival at Six months follow-up

F. Beygui, G. Cayla, V. Roule, F. Roubille, N. Delarche, J. Silvain, E. Van Belle, L. Belle, M. Galinier, P. Motreff, L. Cornillet, JP Collet, A. Furber, P.

Goldstein, P. Ecollan, D. Legallois, A. Lebon, H. Rousseau, J. Machecourt, F. Zannad, E. Vicaut, G. Montalescot

on behalf of the ALBATROSS investigators

Years

Tertile 3

Tertile 1

Death according to tertilesof aldosterone in MI

Log rank P = 0.005

Cum

ulat

ive

Surv

ival

Rat

e, %

Beygui F, et al. Circulation. 2006;114:2604-2610.

70

75

80

85

90

95

100

1 11 21 31 41 51 61 71 81 91 101 111 121 131 141 151 161 171 181

Days

Quartile 1Quartile 2Quartile 3Quartile 4

Death according to quartilesof aldosterone in STEMI

Palmer B, et al. Eur Heart J. 2008; 29:2489-96Beygui F, et al. Circulation 2006; 114:2604-10

Aldosterone levels and death in AMI

ALBATROSS study design

1° End Point: death, resuscitated cardiac death, VF/VT, indication for defibrillator, heart failure

up to 6-month FU

controlRandomizedOpen label

N=1600

AMI (ST+ or ST-) in the first 72hrs

clinicaltrials.gov registration number NCT 01059136ALBATROSS study protocol - Beygui et al. Am Heart J 2010

iv K+ canrenoate*then

spironolactone*** Soludactone 200mg

** Aldactone 25mg od

Aldosterone blockade

Standard treatment(N=801)

MRA regimen(N=802)

Age (median) 58 58Current smoking (%) 52 47Diabetes (%) 16 16Hypertension (%) 44 42Dyslipidemia (%) 46 47Prior MI (%) 9 8Prior HF (%) 1 1STEMI (n) 617 612NSTEMI (n) 183 186Killip I (%) 91 93PCI (%) 81 82LV ejection fraction (median in %) 50 50

Baseline characteristics

HR = 0,97 [0,73-1,28]p= 0. 81

Prim

ary

end

poin

t

Nat risks

StandardTherapy 801 687 669645273

MRARegimen 802705683 660 183

Follow-up(days)

InCYP2C19Extensive&

StandardTherapyMRAregimen

Primary End PointDeath, resuscitated death, VF/VT, indication for ICD or heart failure

MRA: Mineralocorticoid Receptor Antagonist; VF: Ventricular Fibrillation; VT: Ventricular Tachycardia; ICD: Implantable Cardioverter Defibrillator

Standard therapy(n=801)

MRA regimen (n=802)

P value

Significant ventricular arrhythmia (%) 6 5.6 0.75

New or worsening heart failure (%) 5.6 5.9 0.85

Death (%) 2.1 1.4 0.26

Death or resuscitated cardiac arrest (%) 2.4 1.6 0.28

Secondary End Points

Hyperkalemia > 5.5mmol.L-1 (%) 0.2 3 <0.0001

HR = 0,20 [0,06-0,69]p= 0. 0044

Death

Nat risks

StandardTherapy 617 587 579556 236

MRARegimen 612 595 587571162

Follow-up(days)

Ine&

StandardTherapyMRAregimen

Death in STEMI patients (n=1229)

DoesCyclosporineImpRoveClinicaloUtcomeinST-elevationmyocardialinfarctionpatients?

(theCIRCUSstudy)

MichelOVIZE,MD,PhDLouisPradelHospital andClaudeBernardUniversity,

Lyon,France

Reperfusion injury contributes to MI

Reperfusion injury

Ca2+Transition pore

REPERFUSION NECROSISIschemia / Reperfusion

-

ATPPiCa2+ROS

Cyclosporine

Mitochondria

Onset ofchest pain

CORONARY ARTERY OCCLUSION - TIMI flow grade =0-1

WINDOW TO STARTTREATMENT OF REPERFUSION INJURY

30 minutes to 12 hours

First medicalcare

Cath labadmission

AMBULANCE PCI CARDIOLOGIST

PCI Reperfusion

Ischemia injury

LAD occluded (TIMI 0-1)

Coronary angiography

e-randomization

CicloMulsion® (Neurovive Pharmaceuticals): lipid emulsion of cyclosporine (no cremophor content)

Initial Echo

Final Echo

Discharge

PCICicloMulsion® :(2.5 mg/kg, IV bolus)

1 year

Anterior STEMI

Experimental design

• > 18 years• symptom onset < 12 hrs• ST shift ≥ 0.2 mV in two contiguous anterior leads• LAD as culprit artery with TIMI flow grade : 0 – 1

ITT Analysis

Primary endpointAnalysis

Anterior STEMIs

Randomized(n= 970)

Control(n=495)

No informed content (n=1)Imprisoned and therefore ineligible (n=1)Did not receive any treatment (n=4) Missing or poor echographic data (n=74)

Did not receive any treatment (n=4) Missing or poor echographic data (n=95)

Cyclosporine(n = 475)

Cyclosporine(n = 395)

Control(n=396)

modified as treatedanalysis

Consort Diagram

(80% power to detect a 20% relative risk reduction)

Primary outcome at 1 year

Combined incidence of [all-cause mortality; worsening of heart failure during initialhospitalization or re-hospitalisation for heart failure ; LV remodeling] within 1 year afteracute MI

(LV remodeling (echo): increase > 15% of LVEDV at 1 year versus initial discharge)

Cyclosporine(n=395)

Control(n=396)

Odds Ratio(95% CI) P value

(Death / HF / LV remodeling) 233 (59.0 %) 230 (58.1%) 1.04 [0.78; 1.39] 0.77

Secondary outcomes at 1 year

Cyclosporine(n=395)

Control(n=396)

Odds Ratio(95% CI) P value

Death: all-cause 7.1 % 6.6 % 1.09[0.63 ; 1.90] 0.76

Death: cardiovascular 6.1 % 6.1 % 1.01[0.56 ; 1.81] 0.98

HF worsening or re-hospitalization for HF 22.8 % 22.7 % 1.01[0.72 ; 1.41] 0.97

HF worsening 15.7 % 16.9 % 0.92[0.63 ; 1.34] 0.65

Re-hospitalization for HF 10.6 % 10.4 % 1.03[0.65 ; 1.63] 0.89

Cardiogenic shock 6.6 % 6.1 % 1.09[0.61 ; 1.94] 0.77

Recurrent Myocardial infarction 2.3 % 3.8 % 0.59[0.26 ; 1.37] 0.22

Stroke 1.8 % 3.0 % 0.58[0.22 ; 1.48] 0.25

Major bleeding 1.8 % 2.3 % 0.73[0.27 ; 2.00] 0.54

HF: heart failure

Results From The Minimizing Adverse Haemorrhagic Events By

Transradial Access Site And Systemic Implementation

of Angiox-MATRIXTreatment Duration Program

M. Valgimigli, MD, PhDSwiss Cardiovascular Center Bern,

Inselspital, Bern, Switzerlandon behalf of the MATRIX Group

NCT01433627

1:1

1:1

NSTEACS or STEMI with invasive managementAspirin+P2Y12 blocker

Trans-Femoral Access

Heparin±GPI

BivalirudinMono-Tx

StopInfusion

Prolong≥ 4 hs infusion

1:1

Trans-Radial Access

MATRIX Program NCT01433627

http://www.cardiostudy.it/matrix

Lancet. 2015; 385(9986):2465-76

ACC 2015, oral presentation

ACCESS

ANTITHROMBINTYPE

TREATMENT DURATION

Primary EP: NACE

11.0%

No post-PCI bivalirudinPost-PCI bivalirudin

RR: 0.91; 95% CI: 0.74-1.11; P=0.34

11.9%

Treatment Duration Study

TCT

Effect of Thrombus Aspiration in Patients With Myocardial

Infarction Presenting Late After Symptom Onset

Steffen Desch, MD Thomas Stiermaier, MD; Suzanne de Waha, MD;

Philipp Lurz, MD, PhD; Matthias Gutberlet, MD; Marcus Sandri, MD; Norman Mangner, MD; Enno Boudriot, MD;

Michael Woinke, MD; Sandra Erbs, MD; Gerhard Schuler, MD; Georg Fuernau, MD; Ingo Eitel, MD; Holger Thiele, MD

Background

• Recent trials on thrombus aspiration in STEMI reported disappointing results with no reduction in mortality and possibly an increase in stroke.

↓

Frobert et al. N Engl J Med 2013;369:1587-97. Jolly et al. N Engl J Med 2015;372:1389-98.

0 12 h 24 h 36 h 48 h

?

Symptom onset:

TASTE TOTAL

Study Flow 152 patients with subacute STEMI t12 and d48 hours after symptom onset

Thrombus aspiration (n=70)

Standard PCI Only (n=74)

No CMR (n=14) No CMR (n=19)

Final diagnosis other than STEMI (n=8)

1:1 randomization

Received allocated treatment (n=70) Received allocated treatment (n=69)

Intention-to-treat (n=56) Intention-to-treat (n=55)

Primary endpoint: Microvascular obstruction

Results Primary Endpoint: Microvascular Obstruction

0 Thrombus aspiration

Mic

rova

scul

ar o

bstr

uctio

n, %

LV

Standard PCI only

p=0.47 5

4

3

1

2

2.5 ± 4.0

3.1 ± 4.4

The-First-In-Man Randomized Trial of a ß3-adrenoceptor Agonist in Chronic Heart Failure

BEAT-HF

Henning Bundgaard, Anna Axelsson, Jakob H Thomsen, Mathias Sørgaard, Klaus Kofoed, Nana Køber, Rasmus B Hasselbalch, Henry Krum, Søren Boesgaard, Finn Gustafsson, Lars Køber, Kasper Iversen,

Helge Rasmussen

• Raised levels of intracellular sodium (Nai) in the cardiomyocytes contribute to contraction abnormalities in heart failure (HF)

• The Na-K pump in the cardiomyocytes mediates Nai export –and evidence-based HF treatments stimulate the Na-K pump (ß blockers, ACE inhibitors, aldosterone antagonists)

• ß3 adrenoceptor (AR) agonists stimulate the Na-K pump through the NO/cGMP/PKG pathway – mediating Nai export (Bundgaard et al, Circulation 2010)

Background – chronic heart failure (HF) and intracellular Na+

BEAT-HF

• Mirabegron; (BETMIGA)- FDA and EMA approved for overactive bladder (OAB)- Dose (25-)50 mg x 1- T1/2 =22-25 h, Cmax 3-4 h

• Side effects; – Increased BP and HR (off-target ß1/2 AR stimulation), – “Cold” symptoms, – Gastrointestinal discomfort

• Maximum reported dosage for OAB over12 weeks: 300 mg/day

• Doses administered in this study:– Start; 25 mg x 2 – then – if tolerated - weekly increases;– 50 mg x 2, 100 mg x 2, 150 mg x 2 (after a week 300 mg x1)

BEAT-HF

Study drug and dose

Study design

BEAT-HF

Screened (n=142)

37 declined participation

33 Screen failure12 ejection fraction ≥ 40%5 Renal failure5 Atrial fibrillation4 BMI > 353 Drug contra-indications6 Other Eligible (n=107)

Randomized (n=70)

Placebo (n=35) Mirabegron (n=35)

2 Deaths1 Adverse effects1Admitted - endocarditis1 Admitted - urinary tract infection 1 Reduced complianceFollow-up data

analyzed (n=29)

1 Adverse effects2 Reduced compliance

Follow-up data analyzed (n=32)

Follow up 6 months

• All 61 patients completing the study were compliant by pill count (> 98%) • 66 patients (94%) reached target dose of 300 mg daily, 3 patients 200 mg

(Mirabegron), 1 patient 100 mg daily (Placebo).

Compliance and safety

BEAT-HF

mm

Hg

Bea

ts p

r min

MirabegronPlacebo

Baseline 6 months Baseline 6 months Baseline 6 months

Mean difference 2.2 (95% CL, -5.2 to 9.5)P=0.55

Mean difference -0.3 (95% CL, -6.0 to 5.5)P=0.91

Systolic BP Diastolic BP

Mean difference 0.6 (95% CL, -3.2 to 6.3)P=0.52

Heart rate

200

406080

100120140

200

406080

100120140

mm

Hg

20

0

40

60

80

100

Primary endpoint

BEAT-HF

Left ventricular ejection fraction

P= 0.82

Mean difference 0.4% (95% CL, -3.5 to 3.8) LV

EF (

%)

Mirabegron

Placebo

Baseline 6 months

Exploratory analyses

BEAT-HF

Baseline 6 months 6 monthsBaseline

Baseline LVEF (CT) < 40% Baseline LVEF (CT) ≥ 40%

P= 0.40

Mean difference -2.0% (95% CL, -6.8 to 2.8)

P<0.03

Mean difference 5.5% (95% CL, 0.6-10.4)

Mirabegron

Placebo

30

ANNEXA™-R Part 2: A Phase 3 Randomized, Double-Blind, Placebo-Controlled Trial Demonstrating Sustained Reversal of Rivaroxaban-Induced Anticoagulation in Older Subjects by Andexanet alfa (PRT064445), a Universal Antidote for Factor Xa (fXa) Inhibitors

Mark Crowther, MD, MSc, FRCPCProfessor of Medicine, McMaster University, Canada

Co-authorsAlex Gold1, Genmin Lu1, Janet M. Leeds1 , Brian L. Wiens1, Vandana Mathur2, Janice Castillo1, Pamela B. Conley1, Stuart J. Connolly3, John T. Curnutte1

1Portola Pharmaceuticals employee; 2Portola Pharmaceuticals consultant; 3McMaster University, Canada

31

Andexanet: Designed to Reverse Activity of Factor Xa InhibitorsNature Medicine (2013),19(4): 446-51

Factor Xa Andexanet Alfa

Catalytic DomainGla

Recombinant engineered version of human factor Xa produced in CHO cells

S S

S419

S S

A419Factor Xa inhibitor Factor Xa inhibitor

• No known interaction with other coagulation factors except Tissue Factor Pathway Inhibitor (TFPI)

• Retains high affinity for Antithrombin III-inhibitor complex and can reverse ATIII-dependent anticoagulant effects of enoxaparin and fondaparinux in vitro and in vivo

• Acts as a fXa decoy and retains high affinity for all direct fXa inhibitors

• Change of serine to alanine to eliminate catalytic activity and prevent prothrombin cleavage

• GLA domain removed to prevent anticoagulant effect

Gla

32

Andexanet Has Demonstrated Deep and Rapid Reversal of Biomarkers of Anticoagulation for Four fXa Inhibitors to Date

▸ Multiple Phase 2 Proof-of-Concept StudiesApixaban 5 mg PO Q12 – completed; successful

Rivaroxaban 20 mg PO QD - completed; successful

Enoxaparin 40 mg SQ QD – completed; successful

Edoxaban 60 mg PO QD – completed; successful for cohorts analyzed to date

Betrixaban 80 mg PO QD – ongoing

▸ Phase 3 and Confirmatory Registration-enabling Studies

Phase 3 studies: older healthy subjects treated with apixaban or rivaroxaban –completed; successful

Phase 4 “Confirmatory study” with bleeding patients – ongoing

Planning enrollment of bleeding patients with rivaroxaban, apixaban, edoxaban, and enoxaparin

þ

þ

þ

þ

þ

o

þ

33

Andexanet Bolus Only

Placebo

Rn ~ 35 per Xa

Andexanet Bolus + Infusion (x 2hrs)

Placebo

R

apixaban- 400mg andexanetrivaroxaban- 800mg andexanet

Part I: Bolus

Andexanet Alfa: ANNEXA™ Registration-Enabling StudiesAccelerated Approval Phase 3 Design for Apixaban and Rivaroxaban

apixaban- 400mg + 480mg (4mg/min) andexanetrivaroxaban- 800mg + 960mg (8mg/min) andexanet

Anti-fXa levels

(Biomarker endpoint)

n ~ 35 per Xa

þ apixaban________rivaroxabanþ

apixaban________

rivaroxaban

R: Randomization

Part 2: Bolus + Infusion

þþ

34

Anti-fXa (ng/mL)

ANNEXA™-R (Rivaroxaban, Bolus + Infusion) Primary Endpoint: Anti-fXa

Met Primary Endpoint: ▸Mean percent change in anti-fXa from

baseline to post-infusion nadir was 97%▸p< 0.0001 vs. placebo

Met First Secondary Endpoint:▸Mean percent change in anti-fXa from

baseline to post-bolus nadir was 95%▸p< 0.0001 vs. placebo

Met Second Secondary Endpoint:▸Occurrence of subjects with ≥ 80%

reduction in anti-fXa activity post-infusion nadir: AnXa (n= 26/26) vs. Placebo (n=0/13)▸p< 0.0001 vs. placeboTime after bolus (hr)

Ant

i-fX

a (n

g/m

L)

0.0 0.2 0.4 0.60

100

200

300

400

1 2 3 4 5 6 7 8 9 10 11 12

End of Bolus

Placebo (n=13)

800 mg bolus + 960 mg x 2hr infusion (n=26)

End of Infusion

ProvidingRapidOutofHospitalAcuteCardiovascularTreatment:

PROACT-4JustinA.Ezekowitz,RobertC.Welsh,DaleWeiss,MichaelChan,WilliamKeeble,FadiKhadour,SanjaySharma,WayneTymchak,

SunilSookram,NeilBrass,DarrenKnapp,ThomasI.Koshy,YingganZheng,PaulW.Armstrong

onbehalfofthePROACT-4Investigators20November2015

ClinicalTrials.gov NCT01634425

TrialDesign

Arrivalonscene;StandardCare;In/Exclusion;

VerbalConsentPOCrelayedtoERstaff

POC-Troponininambulance

UsualCare

R

9-1-1Call

Ambulance

Ambulance ER

Primaryoutcome:timetodisposition

Firstmedicalcontact

Patientdisposition

Methods:Troponin&Ambulances

• POCdevice(Alere Inc,SanDiego)– Cardio2TroponinI

– analyticalsensitivity=0.01ng/mL– 99th%ile =0.02ng/mL

• assay&deviceHealthCanadaapproved– resultwithin~15-18minutes– Installedon~25ambulances

• Edmonton:3600km2, 1.1mpeople,5hospitals(2PCI)

• EMSSystem: >300paramedics,88ambulances,~4000calls/yr forCP

Assessed foreligibility

Randomized(n=601)

Allocated toPOC-Troponin(n=305)•Received POC-Troponintesting(n=250)•Didnotrec’vPOC-Troponintesting(n=55)

Allocated toUsualCare(n=296)• Received POC-Troponintesting(n=2)

Losstofollow-up(n=0)Withdrewconsent* (n=2)

Losstofollow-up(n=0)Withdrewconsent* (n=2)

ITTAnalysis (n=296)Perprotocolanalysis (n=294)

ITTAnalysis (n=305)Perprotocolanalysis (n=250)

July2013–Feb2015

Results

TroponinresultsUsualcare POC-Troponin

n 296 305Firsttroponin available,minutes 138(101-218) 38(28-55)*POC-troponin I,ng/ml,n(%)

≤0.01 - 196(64.3)>0.01 - 53(17.4)>0.03 - 30(9.8)

Notdone/missing 55(18.4)1st In-Hospital# troponin I,ng/ml,%

>0.1 9.5% 14%

#In-hospital clinicaltroponin istheBeckmanAccuTnI;*p<0.001

Primaryendpoint:ITT

Usualcare POC-Troponin p padj*N 296 305Firstmedicalcontacttofinaldisposition,hours

9.14(9h08)(6.68,11.17)

8.85(8h51)(6.22,10.76)

0.069 0.074

DischargedfromED 9.32(9h19)(7.37,11.00)

8.88(8h50)(6.65,10.23)

0.021 0.017

Admittedtohospital 8.73(5.43,11.95)

8.62(5.25,12.55)

0.959 0.908

72.5%ofallpatientsweredischargedhome.AdjustmentbymodifiedGRACEscore(age,heartrate,systolicbloodpressure,creatinine, cardiacarrestatadmission,elevatedcardiacenzymes,Killip class)

Secondaryendpoints:ITT

Usualcare POC-Troponin pN 296 305Eventswithin30days,n(%)

All-causedeath 4(1.4) 4(1.3) 0.966Re-EDvisit 34(11.6) 43(14.2) 0.338

Re/initialhospitalization 18(6.1) 21(6.9) 0.690EDvisitorrehospitalization 47(16.0) 59(19.5) 0.265

Perprotocolanalysis allnon-significant differences

Results

POC-Troponin>0.03ng/mlin9.8%

ACS:22patients(73.3%)AHF:2patients(6.7%)Other:6patients(20%)

UsingthresholdforPOC-troponin>0.03ng/mlforACS,comparedtoallothergroups:

Sensitivity44%andSpecificity96%PPV73%andNPV87%

Robert W. Yeh, Eric A. Secemsky, Dean J. Kereiakes, Sharon-Lise T. Normand, Anthony H. Gershlick, David J. Cohen, John A. Spertus, P.

Gabriel Steg, Donald E. Cutlip, Michael J. Rinaldi, Edoardo Camenzind, William Wijns, Patricia K. Apruzzese, Yang Song, Joseph M. Massaro,

and Laura Mauri, for the Dual Antiplatelet Therapy (DAPT) Study Investigators

Individualizing Treatment Duration of Dual Antiplatelet Therapy after Percutaneous

Coronary Intervention: An Analysis from the DAPT Study

Background

44

• In the DAPT Study, continuation of dual antiplatelet therapy beyond 12 months reduced ischemic complications after coronary stenting compared with aspirin alone, yet increased moderate or severe bleeding.

Mauri, Kereiakes, Yeh et al. NEJM. 2014 Dec 4:371:2155-66.

-1,0%

-1,6%-2,0%

1,0%0,5%

-3,0%

-2,0%

-1,0%

0,0%

1,0%

2,0%

3,0%

HR0.29(0.17–0.48)P<0.001

HR1.36(1.00–1.85)P=0.05

HR1.61(1.21–2.16)P=0.001

StentThrombosis

Death,MI,OrStroke(MACCE)

MyocardialInfarction

GUSTOMod/Severe

Bleed

Death

HR0.71(0.59–0.85)P<0.001

HR0.47(0.37–0.61)P<0.001

RiskDifferen

ce(Con

tinue

dThieno

pyrid

ine–Placeb

o),1

2-30

M

*The ischemia model C-statistic: 0.70 in DAPT Study; 0.64 in PROTECT**The bleeding model C-statistic: 0.68 in DAPT Study; 0.64 in PROTECT

45

Multivariable Prediction ModelsPredictors of Myocardial

Infarction or Stent ThrombosisPredictors of

Moderate/Severe BleedingPredictors of Events HR (95% CI) P HR (95% CI) PContinued Thienopyridine vs. Placebo

0.52 (0.42 – 0.65) <0.001 1.66 (1.26 - 2.19) <0.001

MI at Presentation 1.65 (1.31 – 2.07) <0.001 - -Prior PCI or Prior MI 1.79 (1.43 – 2.23) <0.001 - -CHF or LVEF < 30% 1.88 (1.35 – 2.62) <0.001 - -Vein Graft PCI 1.75 (1.13 – 2.73) 0.01 - -Stent Diameter < 3 mm 1.61 (1.30 – 1.99) <0.001 - -Paclitaxel-Eluting Stent 1.57 (1.26 – 1.97) <0.001 - -Cigarette Smoker 1.40 (1.11 – 1.76) 0.01 - -Diabetes 1.38 (1.10 – 1.72) 0.01 - -Peripheral Arterial Disease 1.49 (1.05 – 2.13) 0.03 2.16 (1.46, 3.20) <0.001Hypertension 1.37 (1.03 – 1.82) 0.03 1.45 (1.00, 2.11) 0.05Renal Insufficiency 1.55 (1.03 – 2.32) 0.04 1.66 (1.04, 2.66) 0.03Age (per 10 years) - - 1.54 (1.34, 1.78) <0.001

The DAPT Score

46

Variable PointsPatient CharacteristicAge

≥ 75 -265 - <75 -1< 65 0

Diabetes Mellitus 1Current Cigarette Smoker 1Prior PCI or Prior MI 1CHF or LVEF < 30% 2Index Procedure CharacteristicMI at Presentation 1Vein Graft PCI 2Stent Diameter < 3mm 1

Distribution of DAPT Scores among all randomized subjects in the DAPT Study

47

Continued Thienopyridine vs. Placebo DAPT Score <2 (Low); N=5731

1.7%vs.2.3%P=0.07

Continued Thienopyridine Placebo

10%

8%

6%

4%

2%

0%

Cum

ulat

ive

Inci

denc

e of

ST

/MI

12 15 18 21 24 27 30Months After Enrollment

3.7%vs.3.8%P=0.73


10%

8%

6%

4%

2%

0%

Cum

ulat

ive

Inci

denc

e of

M

ACC

E


3.0%vs.1.4%P<0.001


10%

8%

6%

4%

2%

0%

Cum

ulat

ive

Inci

denc

e of

G

UST

O M

oder

ate/

Seve

re B

leed


Myocardial Infarction or Stent Thrombosis Death, MI, or Stroke (MACCE)

GUSTO Moderate/Severe Bleeding

48

Continued Thienopyridine vs. Placebo DAPT Score ≥ 2 (High); N=5917

2.7%vs.5.7%P<0.001


10%

8%

6%

4%

2%

0%

Cum

ulat

ive

Inci

denc

e of

ST

/MI


4.9%vs.7.6%P<0.001


10%

8%

6%

4%

2%

0%

Cum

ulat

ive

Inci

denc

e of

M

ACC

E


1.8%vs.1.4%P=0.26


10%

8%

6%

4%

2%

0%

Cum

ulat

ive

Inci

denc

e of

G

UST

O M

oder

ate/

Seve

re B

leed


Myocardial Infarction or Stent Thrombosis Death, MI or Stroke (MACCE)

GUSTO Moderate/Severe Bleeding

DAPT Score Calculator

DAPT Score calculatorwww.daptstudy.org

Thank you!

49

ESC GUIDELINES

2015 ESC Guidelines for the managementof acute coronary syndromes in patientspresenting without persistent ST-segmentelevation – Web AddendaTask Force for the Management of Acute Coronary Syndromes inPatients Presenting without Persistent ST-Segment Elevation of theEuropean Society of Cardiology (ESC)

Authors/Task Force Members: Marco Roffi* (Chairperson) (Switzerland),Carlo Patrono* (co-Chairperson) (Italy), Jean-Philippe Collet† (France),Christian Mueller† (Switzerland), Marco Valgimigli† (The Netherlands),Felicita Andreotti (Italy), Jeroen J. Bax (The Netherlands), Michael A. Borger (Germany),Carlos Brotons (Spain), Derek P. Chew (Australia), Baris Gencer (Switzerland),Gerd Hasenfuss (Germany), Keld Kjeldsen (Denmark), Patrizio Lancellotti (Belgium),Ulf Landmesser (Germany), Julinda Mehilli (Germany), Debabrata Mukherjee (USA),Robert F. Storey (UK), and Stephan Windecker (Switzerland)Document Reviewers: Helmut Baumgartner (CPG Review Coordinator) (Germany), Oliver Gaemperli (CPG ReviewCoordinator) (Switzerland), Stephan Achenbach (Germany), Stefan Agewall (Norway), Lina Badimon (Spain),Colin Baigent (UK), Hector Bueno (Spain), Raffaele Bugiardini (Italy), Scipione Carerj (Italy), Filip Casselman(Belgium), Thomas Cuisset (France), Çetin Erol (Turkey), Donna Fitzsimons (UK), Martin Halle (Germany),Christian Hamm (Germany), David Hildick-Smith (UK), Kurt Huber (Austria), Efstathios Iliodromitis (Greece),Stefan James (Sweden), Basil S. Lewis (Israel), Gregory Y. H. Lip (UK), Massimo F. Piepoli (Italy), Dimitrios Richter

* Corresponding authors: Marco Roffi, Division of Cardiology, University Hospital, Rue Gabrielle Perret-Gentil 4, 1211 Geneva 14, Switzerland, Tel: +41 22 37 23 743, Fax: +41 22 3727 229, E-mail: [email protected].

Carlo Patrono, Istituto di Farmacologia, Universita Cattolica del Sacro Cuore, Largo F. Vito 1, IT-00168 Rome, Italy, Tel: +39 06 30154253, Fax: +39 06 3050159, E-mail: [email protected].† Section Coordinators affiliations listed in the Appendix in the full text document http://www.escardio.org/guidelines.

ESC Committee for Practice Guidelines (CPG) and National Cardiac Societies document reviewers listed in the Appendix in full text document http://www.escardio.org/guidelinesESC entities having participated in the development of this document:

Associations: Acute Cardiovascular Care Association (ACCA), European Association for Cardiovascular Prevention & Rehabilitation (EACPR), European Association of Cardiovas-cular Imaging (EACVI), European Association of Percutaneous Cardiovascular Interventions (EAPCI), Heart Failure Association (HFA).

Councils: Council on Cardiovascular Nursing and Allied Professions (CCNAP), Council for Cardiology Practice (CCP), Council on Cardiovascular Primary Care (CCPC).

Working Groups: Working Group on Cardiovascular Pharmacotherapy, Working Group on Cardiovascular Surgery, Working Group on Coronary Pathophysiology and Microcir-culation, Working Group on Thrombosis.

The content of these European Society of Cardiology (ESC) Guidelines has been published for personal and educational use only. No commercial use is authorized. No part of theESC Guidelines may be translated or reproduced in any form without written permission from the ESC. Permission can be obtained upon submission of a written request to OxfordUniversity Press, the publisher of the European Heart Journal and the party authorized to handle such permissions on behalf of the ESC.

Disclaimer: The ESC Guidelines represent the views of the ESC and were produced after careful consideration of the scientific and medical knowledge and the evidence available atthe time of their publication. The ESC is not responsible in the event of any contradiction, discrepancy and/or ambiguity between the ESC Guidelines and any other official recom-mendations or guidelines issued by the relevant public health authorities, in particular in relation to good use of healthcare or therapeutic strategies. Health professionals are encour-aged to take the ESC Guidelines fully into account when exercising their clinical judgment, as well as in the determination and the implementation of preventive, diagnostic ortherapeutic medical strategies; however, the ESC Guidelines do not override, in any way whatsoever, the individual responsibility of health professionals to make appropriate andaccurate decisions in consideration of each patient’s health condition and in consultation with that patient and, where appropriate and/or necessary, the patient’s caregiver. Nordo the ESC Guidelines exempt health professionals from taking into full and careful consideration the relevant official updated recommendations or guidelines issued by the competentpublic health authorities, in order to manage each patient’s case in light of the scientifically accepted data pursuant to their respective ethical and professional obligations. It is also thehealth professional’s responsibility to verify the applicable rules and regulations relating to drugs and medical devices at the time of prescription.

& The European Society of Cardiology 2015. All rights reserved. For permissions please email: [email protected].

European Heart Journaldoi:10.1093/eurheartj/ehv320

Among the multitude of additional biomarkers evaluated for thediagnosis of NSTE-ACS, only CK-MB and copeptin seem to haveclinical relevance.2,6,8,10,44 – 50 CK-MB shows a more rapid declineafter MI as compared with cardiac troponin and may provide addedvalue for the timing of myocardial injury and the detection of earlyreinfarction.2,6,8,10 Assessment of copeptin, the C-terminal part ofthe vasopressin prohormone, may quantify the endogenous stresslevel in multiple medical conditions including MI. As the level of en-dogenous stress appears to be invariably high at the onset of MI, theadded value of copeptin to conventional (less sensitive) cardiactroponin assays is substantial.44 – 50 Therefore the routine use ofcopeptin as an additional biomarker for the early rule-out of MIis recommended whenever sensitive or high-sensitivity cardiactroponin assays are not available. Copeptin may have some addedvalue even over high-sensitivity cardiac troponin in the early rule-out of MI.44– 48

3.3.3 ‘Rule-in’ and ‘rule-out’ algorithmsDue to the higher sensitivity and diagnostic accuracy for the detec-tion of acute MI at presentation, the time interval to the second car-diac troponin assessment can be shortened with the use ofhigh-sensitivity assays. This may reduce substantially the delay todiagnosis, translating into shorter stays in the emergency depart-ment and lower costs.2,6,8,10,29 – 36 It is recommended to use the0 h/3 h algorithm (Figure 2). As an alternative, 0 h/1 h assessmentsare recommended when high-sensitivity cardiac troponin assayswith a validated algorithm are available (Figure 3). The 0 h/1 h algo-rithms rely on two concepts: first, high-sensitivity cardiac troponin isa continuous variable and the probability of MI increases with in-creasing high-sensitivity cardiac troponin values;39 second, early ab-solute changes of the levels within 1 h can be used as surrogates for

absolute changes over 3 h or 6 h and provide incremental diagnosticvalue to the cardiac troponin assessment at presentation.39 The cut-off levels within the 0 h/1 h algorithm are assay specific.36,39,51 – 55

hs-cTn no change

Discharge/Stress testing

∆ changea

(1 value > ULN)

Invasive management

Painfree, GRACE <140,differential diagnoses excluded Work-up differential

diagnoses

hs-cTn no change

Pain >6h Pain <6h

hs-cTn <ULN hs-cTn >ULN

High

ly ab

norm

al hs

-cTn

+ cli

nica

l pre

sent

atio

n

hs-cTn no change


∆ changea

(1 value > ULN)

Invasive management


diagnoses

hs-cTn no change

Pain >6h

Re-test hs-cTn: 3h

Pain <6h


Acute Chest Pain

GRACE = Global Registry of Acute Coronary Events score; hs-cTn = high sensitivity cardiac troponin; ULN = upper limit of normal, 99th percentile of healthy controls. a

Figure 2 0 h/3 h rule-out algorithm of non-ST-elevation acute coronary syndromes using high-sensitivity cardiac troponin assays.

Suspected NSTEMI

0h <A ng/l Other0h ≥D ng/l

or0-1h ≥E ng/l

ObserveRule-out Rule-in

or0h <B ng/l

and0-1h <C ng/l

A B C D E

hs-cTnT (Elecsys) 5 12 3 52 5

hs-cTnl (Architect) 2 5 2 52 6

hs-cTnl (Dimension Vista) 0.5 5 2 107 19

Figure 3 0 h/1 h rule-in and rule-out algorithms using high-sensitivity cardiac troponins (hs-cTn) assays in patients presentingwith suspected non-ST-elevation myocardial infarction (NSTEMI)to the emergency department. 0 h and 1 h refer to the time fromfirst blood test. NSTEMI can be ruled-out already at presentation,if the hs-cTn concentration is very low. NSTEMI can also be ruled-out by the combination of low baseline levels and the lack of a rele-vant increase within 1 h. Patients have a high likelihood for NSTEMIif the hs-cTn concentration at presentation is at least moderatelyelevated or hs-cTn concentrations show a clear rise within the firsthour. Cut-off levels are assay-specific. Cut-off levels for otherhs-cTn assays are in development.

ESC GuidelinesPage 10 of 59

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(Greece), Thomas Rosemann (Switzerland), Udo Sechtem (Germany), Ph. Gabriel Steg (France), Christian Vrints(Belgium), and Jose Luis Zamorano (Spain)

The disclosure forms of all experts involved in the development of these guidelines are available on the ESC websitehttp://www.escardio.org/guidelines.

Questions and answers companion manuscripts of these guidelines are available at: http://www.escardio.org/Guidelines-&-Education/Clinical-Practice-Guidelines/Acute-Coronary-Syndromes-ACS-in-patients-presenting-without-persistent-ST-segm

- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -Keywords Acute cardiac care † Acute coronary syndrome † Angioplasty † Anticoagulation † Apixaban † Aspirin †

Atherothrombosis † Beta-blockers † Bivalirudin † Bypass surgery † Cangrelor † Chest pain unit †Clopidogrel † Dabigatran † Diabetes † Early invasive strategy † Enoxaparin † European Society ofCardiology † Fondaparinux † Glycoprotein IIb/IIIa inhibitors † Guidelines † Heparin † High-sensitivitytroponin † Myocardial ischaemia † Nitrates † Non-ST-elevation myocardial infarction † Platelet inhibition †Prasugrel † Recommendations † Revascularization † Rhythm monitoring † Rivaroxaban † Statin † Stent †Ticagrelor † Unstable angina † Vorapaxar

The table of contents of these guidelines can be found in thefull text document this addenda refers to.

2.1 Definitions, pathophysiologyand epidemiology2.1.3 Pathophysiology and epidemiologyPlaque rupture or erosion with overlying thrombosis is consideredto be the main initiating mechanism of ACS. Inflammation is believedto play a key role in plaque disruption, although the stimuli that ini-tiate the acute inflammatory process remain elusive.14,15 Platelet ac-tivation and aggregation onto the exposed thrombogenic surface ofa ruptured plaque is an early important event in the pathogenesis ofACS.15,16 Activated platelets release inflammatory and mitogenicsubstances into the microenvironment, primarily altering thechemotactic, adhesive and proteolytic properties of the endo-thelium.16 Healthy vascular endothelium releases prostacyclin andnitric oxide, both of which inhibit platelet activation and aggregation.It is likely that, when intact, these counterregulatory mechanisms ofendothelial thromboresistance limit the extent and duration ofplatelet activation in response to vascular injury.16 This hypothesiswould explain why only a small fraction of disrupted plaques mayelicit symptoms while the majority heal silently. The episodic natureof platelet activation, supported by transient increases in thromb-oxane biosynthesis, is consistent with the concept of coronaryatherothrombosis as a dynamic process, in which repeated episodesof thrombus formation and fragmentation occur over a disruptedplaque.16 Finally, focal or diffuse spasm of normal or atheroscleroticcoronary arteries, predominantly caused by vasoconstrictorstimuli acting on hyperreactive vascular smooth muscle cells, maycause ACS.

While the incidence of STEMI has decreased appreciably over thelast decade, the rate of NSTEMI has slightly increased.17 Overall,NSTEMI patients appear to have lower short-term mortality com-pared with STEMI individuals, while at 1- or 2-years follow-up themortality rates become comparable, likely due to differences inbaseline characteristics, including older age and a greater prevalenceof co-morbidities in the NSTEMI population.18– 20

3.3 Diagnostic tools3.3.3 ‘Rule-in’ and ‘rule-out’ algorithms

5.1 Pharmacological treatmentof ischaemia5.1.4 Other drug classesDiltiazem and verapamil show similar efficacy in relieving symp-toms and appear in this respect equivalent to beta-blockers.121,122

In the 1980s, one study comparing nifedipine and metoprolol in

Table 5 Characteristics of the 0 h/3 h and the 0 h/1 halgorithms

0h/3 h algorithm 0h/1 h algorithm

Negative predictive value for acute MI

98–100% 98–100%

Positive predictive value for acute MI

Unknown, depending on delta change and assay 75–80%

Effectivenessa ++ +++

Feasibility ++requires GRACE score +++

ChallengesPain onset cannot be

patients

Cut-off levels are assay-

from the 99th percentile

Validation in large multicentre studies

+ +++

Additional advantages Already used clinically Shorter time to decision

GRACE ¼ Global Registry of Acute Coronary Events; MI ¼ myocardial infarction.aEffectiveness is quantified by the percentage of consecutive chest pain patientsclearly classified as rule-out or rule-in of acute MI (i.e., approximately 60% for the0 h/3 h algorithm and approximately 75% for the 0 h/1 h algorithm).


Among the multitude of additional biomarkers evaluated for thediagnosis of NSTE-ACS, only CK-MB and copeptin seem to haveclinical relevance.2,6,8,10,44 – 50 CK-MB shows a more rapid declineafter MI as compared with cardiac troponin and may provide addedvalue for the timing of myocardial injury and the detection of earlyreinfarction.2,6,8,10 Assessment of copeptin, the C-terminal part ofthe vasopressin prohormone, may quantify the endogenous stresslevel in multiple medical conditions including MI. As the level of en-dogenous stress appears to be invariably high at the onset of MI, theadded value of copeptin to conventional (less sensitive) cardiactroponin assays is substantial.44 – 50 Therefore the routine use ofcopeptin as an additional biomarker for the early rule-out of MIis recommended whenever sensitive or high-sensitivity cardiactroponin assays are not available. Copeptin may have some addedvalue even over high-sensitivity cardiac troponin in the early rule-out of MI.44– 48

3.3.3 ‘Rule-in’ and ‘rule-out’ algorithmsDue to the higher sensitivity and diagnostic accuracy for the detec-tion of acute MI at presentation, the time interval to the second car-diac troponin assessment can be shortened with the use ofhigh-sensitivity assays. This may reduce substantially the delay todiagnosis, translating into shorter stays in the emergency depart-ment and lower costs.2,6,8,10,29 – 36 It is recommended to use the0 h/3 h algorithm (Figure 2). As an alternative, 0 h/1 h assessmentsare recommended when high-sensitivity cardiac troponin assayswith a validated algorithm are available (Figure 3). The 0 h/1 h algo-rithms rely on two concepts: first, high-sensitivity cardiac troponin isa continuous variable and the probability of MI increases with in-creasing high-sensitivity cardiac troponin values;39 second, early ab-solute changes of the levels within 1 h can be used as surrogates for

absolute changes over 3 h or 6 h and provide incremental diagnosticvalue to the cardiac troponin assessment at presentation.39 The cut-off levels within the 0 h/1 h algorithm are assay specific.36,39,51 – 55

hs-cTn no change


∆ changea

(1 value > ULN)

Invasive management


diagnoses

hs-cTn no change

Pain >6h Pain <6h


High

ly ab

norm

al hs

-cTn

+ cli

nica

l pre

sent

atio

n

hs-cTn no change


∆ changea

(1 value > ULN)

Invasive management


diagnoses

hs-cTn no change

Pain >6h

Re-test hs-cTn: 3h

Pain <6h


Acute Chest Pain

GRACE = Global Registry of Acute Coronary Events score; hs-cTn = high sensitivity cardiac troponin; ULN = upper limit of normal, 99th percentile of healthy controls. a

Figure 2 0 h/3 h rule-out algorithm of non-ST-elevation acute coronary syndromes using high-sensitivity cardiac troponin assays.

Suspected NSTEMI

0h <A ng/l Other0h ≥D ng/l

or0-1h ≥E ng/l

ObserveRule-out Rule-in

or0h <B ng/l

and0-1h <C ng/l

A B C D E

hs-cTnT (Elecsys) 5 12 3 52 5

hs-cTnl (Architect) 2 5 2 52 6

hs-cTnl (Dimension Vista) 0.5 5 2 107 19

Figure 3 0 h/1 h rule-in and rule-out algorithms using high-sensitivity cardiac troponins (hs-cTn) assays in patients presentingwith suspected non-ST-elevation myocardial infarction (NSTEMI)to the emergency department. 0 h and 1 h refer to the time fromfirst blood test. NSTEMI can be ruled-out already at presentation,if the hs-cTn concentration is very low. NSTEMI can also be ruled-out by the combination of low baseline levels and the lack of a rele-vant increase within 1 h. Patients have a high likelihood for NSTEMIif the hs-cTn concentration at presentation is at least moderatelyelevated or hs-cTn concentrations show a clear rise within the firsthour. Cut-off levels are assay-specific. Cut-off levels for otherhs-cTn assays are in development.


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European Heart Journal: Acute Cardiovascular Care 1 –23© The European Society of Cardiology 2015Reprints and permissions: sagepub.co.uk/journalsPermissions.navDOI: 10.1177/2048872615604119acc.sagepub.com

EUROPEANSOCIETY OFCARDIOLOGY ®

Pre-hospital management of patients with chest pain and/or dyspnoea of cardiac origin. A position paper of the Acute Cardiovascular Care Association (ACCA) of the ESC.

Writing committee

Farzin Beygui1 (Chair), Maaret Castren2, Natale Daniele Brunetti3, Fernando Rosell-Ortiz4, Michael Christ5, Uwe Zeymer6, Kurt Huber7, Fredrik Folke8, Leif Svensson9, Hector Bueno10, Arnoud van’t Hof11, Nikolaos Nikolaou12, Lutz Nibbe13, Sandrine Charpentier14, Eva Swahn15, Marco Tubaro16 and Patrick Goldstein17

AbstractChest pain and acute dyspnoea are frequent causes of emergency medical services activation. The pre-hospital management of these conditions is heterogeneous across different regions of the world and Europe, as a consequence of the variety of emergency medical services and absence of specific practical guidelines. This position paper focuses on the practical aspects of the pre-hospital treatment on board and transfer of patients taken in charge by emergency medical services for chest pain and dyspnoea of suspected cardiac aetiology after the initial assessment and diagnostic work-up. The objective of the paper is to provide guidance, based on evidence, where available, or on experts’ opinions, for all emergency medical services’ health providers involved in the pre-hospital management of acute cardiovascular care.

KeywordsPre-hospital, chest pain, dyspnoea

Date received: 1 June 2015; accepted: 13 August 2015

1 Department of Cardiology, Interventional Cardiology and Cardiology Research Units, Caen University Hospital, France

2 Department of Emergency Medicine and Services, Helsinki University Hospital and Helsinki University, Finland; Karolinska Institutet, Department of Clinical Science and Education, Stockholm, Sweden

3University of Foggia, Italy 4Empresa Pública de Emergencias Sanitarias de Andalucía, Spain 5Paracelsus Medical University, Nuremberg, Germany 6 Wir leben Medizin, Klinikum der Stadt Ludwigshafen am Rhein

gGmbH, Germany 7 Third Department of Medicine, Cardiology and Emergency Medicine,

Wilhelminenhospital, Vienna, Austria 8 Department of Cardiology, Copenhagen University Hospital,

Gentofte, Denmark 9 Department of Medicine, Centre for Resuscitation Science, Karolinska

Institutet Solna, Sweden10 Centro Nacional de Investigaciones Cardiovasculares and Department

of Cardiology, Hospital 12 de Octubre, Madrid, Spain

604119 ACC0010.1177/2048872615604119European Heart Journal: Acute Cardiovascular CareBeygui et al.research-article2015

Original scientific paper

11 ISALA Academy, Interventional Cardiology, Zwolle, The Netherlands

12 Cardiology Department, Konstantopouleio General Hospital, Athens, Greece

13 Universitätsmedizin Berlin, Charité, Campus Virchow-Klinikum, Medizinische Klinik m.S. Intensivmedizin und Nephrologie, Berlin, Germany

14 Emergency Department, University Hospital of Rangueil, Toulouse, France

15 Department of Cardiology and Department of Medical and Health Sciences, Linköping University, Sweden

16 ICCU, Division of Cardiology, San Filippo Neri Hospital, Rome, Italy17SAMU and Emergency Department, Lille University Hospital, France

Corresponding author:Farzin Beygui, Department of Cardiology, Caen University Hospital, Ave de la Cote de Nacre, Caen 14000, France. Email: [email protected]

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6 European Heart Journal: Acute Cardiovascular Care

evidence for the benefit of pre-hospital versus in-hospital antithrombotic therapy, a fast transfer with no administra-tion of any antithrombotic medication to a PCI-capable centre could be the most reasonable decision in patients with active bleeding or at very high risk of bleeding. Caution should be taken in general, based on the risk assess-ment, not to initiate a treatment pre-hospital which might be administered more safely in the hospital setting after fur-ther evaluation. In such situations a rapid and secure trans-fer in stable conditions to the appropriate facility is the best option.

Reperfusion therapy and STEMI networks. Reperfusion ther-apy is widely discussed in the ESC guidelines for the man-agement of STEMI9 and for myocardial revascularization.18

The care of STEMI in the pre-hospital setting should be based on regional STEMI networks. Such networks include one or more hospitals and EMS organizations which have a shared protocol for the choice of reperfusion strategy adjunctive therapy and patient transfer in order to provide consistent treatment to patients. Such protocols should be formally discussed between all components of the network and be available in writing.

In general, PPCI is the reperfusion modality of choice if it can be performed in a timely manner. However, pre-hos-pital fibrinolysis remains a very important tool if transfer delays are prolonged, particularly among early presenters at low bleeding risk (Figure 1).

Tables 4 and 5 summarize simple examples of treatment protocols recommended by the study group for ‘en route’ therapy for PPCI and pre-hospital fibrinolysis.

Although the ESC guidelines still recommend fibrinoly-sis up to 12 h after symptom onset, the benefit of fibrinoly-sis remains modest >6 h after coronary occlusion.19 EMSs

that can provide both reperfusion strategies should balance the benefit and the risk of pre-hospital fibrinolysis >6 h after symptom onset. The choice between PPCI and fibrinolysis in the individual patient should be based on the estimated time for PCI (first medical contact to balloon time), the patient’s bleeding risk, time since symptom onset, STEMI location and the haemodynamic status of the patient, as outlined in the ESC guidelines.20 It is especially relevant in elderly patients with non-extensive STEMI to consider switching to a PPCI strategy if it can be done with-out an ‘unacceptable’ increase in reperfusion delay.

Direct telephone contact between the pre-hospital team, the emergency medical communication centre and inter-ventional cardiology team, with ECG teletransmission if necessary, may be very useful in planning reperfusion ther-apy in the safest and most efficient way in borderline cases.

The use of nitrates and beta-blockers in the pre-hospital setting has not been studied and may be associated with hypotension and heart failure. The routine use of intrave-nous beta-blockers as well as routine oxygen supplementa-tion early after myocardial infarction are associated with adverse events.21,22 Therefore, the routine use of nitrates, beta-blockers and oxygen supplementation are not recom-mended in the pre-hospital setting.

2.1.2.1. PPCI strategy. PPCI is widely accepted as the preferred method of reperfusion in STEMI and should be preferred to fibrinolysis if it can be performed in a timely fashion.

2.1.2.1.1. Adjunctive therapy prior to PPCI. Unlike the setting of fibrinolysis, there are major gaps in the evidence for the benefit of pre-hospital versus in-hospital administra-tion of adjunctive therapy in patients managed by a PPCI

Table 4. Pre-hospital adjunctive therapy in a primary percutaneous coronary intervention strategy for ST elevation myocardial infarction.

Pain controlTitration of i.v. opioids (limited to the lowest dose required)

AnticoagulantEnoxaparine: 0.5mg/kg or UFH 70–100 IU/kg i.v. bolus only(Bivalirudin may be considered in patients at high risk of bleeding.)

Antiplatelet therapy¾ Aspirin LD 150–300 mg p.o. or 250–500 mg i.v.

And¾ P2Y12 inhibitor¾ Ticagrelora 180 mg LD p.o. Or¾ Prasugrel 60 mg LD p.o. (if no past history of stroke and age <75 years) Or¾ Clopidogrel 600 mg LD p.o. if ticagrelor and prasugrel unavailable or contra-indicated

a Only the pre-hospital administration of ticagrelor has been compared with its in-hospital administration in an adequately sized random controlled trial (RCT) showing its safety. Small RCTs have assessed the pre-hospital administration of clopidogrel, and prasugrel’s pre-hospital use has been assessed only in non-RCT cohort studies.i.v.: intravenous; p.o.: per os; LD: Loading dose.


Beygui et al. 7

strategy. However, early initiation of antiplatelet therapy at the time of PCI is associated with improved outcome and sets the basis of pre-hospital antiplatelet therapy.

2.1.2.1.1.1. Aspirin. Although historically used with high levels of recommendation, there are major gaps of evidence for the pre-hospital use of aspirin before PPCI for STEMI.

A small case versus control study showed that the pre-hospital administration of the combination of aspirin and unfractionated heparin (UFH) improved coronary artery patency when compared with in-hospital administration, although outcome was not affected.23 Despite the lack of evi-dence, in light of its major impact on vascular mortality24 and the low risk of its pre-hospital administration, aspirin’s prompt use in the pre-hospital setting is recommended.

2.1.2.1.1.2. P2Y12 inhibitors. The pre-hospital versus in-hospital administration of clopidogrel has been assessed in two small sized studies showing its safety but no evi-dence of a clinical benefit.25,26 However, a meta-analysis of pre-PCI versus post-PCI (although not pre-hospital versus in-hospital) administration of clopidogrel among STEMI patients has shown a significant reduction of mortality risk without an increase of bleeding risk in association with pre-PCI treatment.27

No study comparing pre-hospital versus in-hospital administration of prasugrel is available. A small sized trial showed the higher platelet reactivity inhibition after pre-PPCI administration of prasugrel compared with clopi-dogrel.28 In the STEMI sub-group of the TRITON trial there was a benefit in favour of prasugrel in terms of the primary endpoint of the study (cardiovascular death, myocardial infarction or stroke) and early mortality without

significant excess in bleeding. These results should be considered with caution as a major part of the benefit was driven by patients undergoing PCI several days after STEMI and most patients in the trial received their first dose of study medication during PCI.29

In the PLATO trial pre-PPCI ticagrelor tended to reduce the triple thrombotic primary endpoint (p=0.05) without significantly increasing bleeding.30 The pre-hospital admin-istration of ticagrelor in the setting of PPCI has been com-pared with its in-hospital administration in the adequately sized (n=1862) ATLANTIC trial.31 Although the trial’s co-primary endpoints – pre-PCI ST segment elevation resolu-tion or TIMI grade 3 flow – were equally distributed between the pre-hospital and in-hospital groups, the pre-hospital administration of ticagrelor was not associated with an excess in bleeding complications, highlighting the safety of such a strategy. Furthermore, there was a marked and significant reduction in rates of definite stent thrombo-sis in the pre-hospital group. Although this finding should be considered more as hypothesis generating than as estab-lished evidence it might support the pre-hospital adminis-tration of ticagrelor in view of the absence of a safety issue with this strategy. Interestingly the crushing of ticagrelor tablets leads to an accelerated drug absorption and subse-quent higher 1 h platelet reactivity inhibition compared with integral tablet administration.32 Administration of crushed tablets may therefore be considered especially in STEMI patients with difficulties with swallowing tablets, such as those with prior stroke or dysphagia and those sedated, especially by opioids, and/or intubated.

Considering the likely benefit and the safety of pre-PCI P2Y12 inhibitors in the setting of STEMI, the extension of their use to the pre-hospital setting is recommended by the study group although the evidence in favour of this strategy

Table 5. Pre-hospital fibrinolysis in ST elevation myocardial infarction.

Pre-hospital fibrinolysis strategy

Pain controlTitration of i.v. opioids (limited to the lowest dose required)

Age <75 years: - Aspirin 150–300 mg p.o. or i.v. - Clopidogrel 300 mg p.o. - Enoxaparin: 30mg i.v. + 1mg/kg s.c. (max 100mg) 15 min after i.v. bolus - Tenecteplase weight adjusted dosea

Age ⩾75: - Aspirin 150–300 mg p.o. or i.v. - Clopidogrel 75 mg p.o. - Enoxaparin: 1mg/kg s.c. (max. 75mg), no i.v. bolus - Tenecteplase half weight adjusted doseb

In all cases a direct transfer to a PCI-capable centre for rescue PCI for fibrinolysis failure or routine PCI should be preferred to transfer to a non-PCI facility.

aWeight adjusted dose: 30mg ⩽60kg, 35mg >60 to ⩽70 kg, 40mg >70 to ⩽80 kg, 45mg >80 to ⩽90kg, 50 mg if >90 kg.bReducing the dose by 50% in elderly patients was associated with an improvement of outcome in the STREAM trial.i.v.: intravenous; p.o.: per os; s.c.: subcutaneous; PCI: percutaneous coronary intervention.


Beygui et al. 21

x Upstream GP2b3a inhibition may be considered prior to PPCI in high risk patients (extensive infarct) presenting early (<2 h) after symptom onset, in self-presenters to spoke centres who satisfy the above-mentioned conditions and who are to be transferred to hub centres for PPCI, and as an antiplatelet ther-apy bridge in patients unable to swallow oral P2Y12 inhibitors.

x The use of GP2b3a is only recommended in patients at low risk of bleeding.

x The pre-hospital use of enoxaparin as a first line therapy, or UFH if enoxaparin is not available, dur-ing the transfer for PPCI is recommended.

x Bivalirudin is recommended as a first line anticoagu-lation regimen in the setting of STEMI among patients at high bleeding risk and/or the elderly.

x A >4h infusion of bivalirudin is highly recommended after PPCI in such patients.

x Fondaprinux is not recommended for use in PPCI. x The routine transfer to facilities with 24/7 PPCI is

mandatory. x The routine transfer to facilities with onsite surgery

is not recommended. x Transfer of unstable patients with cardiogenic shock

or suspicion of mechanical complication to centres with onsite PCI and possibility of circulatory assis-tance implantation in the ICU and optimally onsite cardiac surgery is recommended if such a transfer destination will not delay revascularization.

Pre-hospital fibrinolysis strategy x A recommended pre-hospital fibrinolysis regimen is

reported in Table 5. x Pre-hospital fibrinolysis is highly recommended

over in-hospital fibrinolysis. x Pre-hospital fibrinolysis with immediate transfer to a

PCI-capable centre is highly recommended. x Aspirin administration at the time of fibrinolysis is

mandatory. x Clopidogrel (300 mg loading dose in <75 years old

and 75 mg dose in ≥ 75 years old) in combination with pre-hospital fibrinolysis is mandatory.

x A weight adjusted dose of tenecteplase as the first line pre-hospital fibrinolytic regimen is recom-mended with a half dose regimen in > 75 years old.

x Anticoagulation is mandatory at the time of pre-hos-pital fibrinolysis with fibrin specific agents.

x Enoxaparin is highly recommended as the anticoagu-lant of choice in this setting.

x Bivalirudin and fondaparinux are not recommended in combination with pre-hospital fibrinolysis.

NSTE-ACS x Thrombotic and bleeding risk assessment is highly

recommended in the setting of NSTE-ACS.

x Point of care troponin tests may be considered in the setting of NSTE-ACS.

x In the case of chest pain at first medical contact, sub-lingual or intravenous nitrates titrated to blood pres-sure are recommended.

x Transfer to the appropriate facility without any ‘en route’ treatment or aspirin alone is recommended in the absence of need for urgent (<2 h) invasive assessment.

x In EMSs where emergency physicians are on board and in the case of an early invasive strategy (<2 h), an antithrombotic therapy including aspirin, ticagre-lor or clopidogrel loading dose and anticoagulation by enoxaparin or UFH may be considered.

x The use of prasugrel in the pre-hospital setting is not recommended.

x A management similar to STEMI is recommended in NSTE-ACS patients with cardiogenic shock, life-threatening arrhythmias or persistent ischaemia despite initial management, with an antithrombotic regimen including aspirin, ticagrelor or clopidogrel loading dose and anticoagulation by enoxaparin or UFH, and immediate invasive strategy.

x In the case of stable NSTE-ACS, transfer to an emer-gency department or a chest pain unit is recom-mended for patients with suspected NSTE-ACS.

x In high-risk patients with haemodynamic instability or signs of heart failure a transfer to emergency departments with possibility of critical care or inten-sive cardiac care units is recommended. In such patients a transfer to facilities with on-site 24/7 inter-ventional cardiology capability is recommended.

x In patients with persistent symptoms despite initial therapy a direct transfer to a catheterization labora-tory is recommended.

x In the case of NSTE-ACS with cardiogenic shock transfer to centers with onsite interventional cardiology, intensive cardiac care and possibility of circulatory support and cardiac surgery is recommended.

Aortic dissection x The use of ADD score in the pre-hospital setting is

highly recommended. x FoCUS echocardiography may be considered to

support the diagnosis of aortic dissection in the pre-hospital setting.

x A treatment limited to pain relief and blood pressure control is recommended in suspected aortic dissection.

x The recommended target heart rate and systolic blood pressure are <60 beats/min and between 100 and 120 mmHg respectively in the absence of neuro-logical complications.


Beygui et al. 21

x Upstream GP2b3a inhibition may be considered prior to PPCI in high risk patients (extensive infarct) presenting early (<2 h) after symptom onset, in self-presenters to spoke centres who satisfy the above-mentioned conditions and who are to be transferred to hub centres for PPCI, and as an antiplatelet ther-apy bridge in patients unable to swallow oral P2Y12 inhibitors.

x The use of GP2b3a is only recommended in patients at low risk of bleeding.

x The pre-hospital use of enoxaparin as a first line therapy, or UFH if enoxaparin is not available, dur-ing the transfer for PPCI is recommended.

x Bivalirudin is recommended as a first line anticoagu-lation regimen in the setting of STEMI among patients at high bleeding risk and/or the elderly.

x A >4h infusion of bivalirudin is highly recommended after PPCI in such patients.

x Fondaprinux is not recommended for use in PPCI. x The routine transfer to facilities with 24/7 PPCI is

mandatory. x The routine transfer to facilities with onsite surgery

is not recommended. x Transfer of unstable patients with cardiogenic shock

or suspicion of mechanical complication to centres with onsite PCI and possibility of circulatory assis-tance implantation in the ICU and optimally onsite cardiac surgery is recommended if such a transfer destination will not delay revascularization.

Pre-hospital fibrinolysis strategy x A recommended pre-hospital fibrinolysis regimen is

reported in Table 5. x Pre-hospital fibrinolysis is highly recommended

over in-hospital fibrinolysis. x Pre-hospital fibrinolysis with immediate transfer to a

PCI-capable centre is highly recommended. x Aspirin administration at the time of fibrinolysis is

mandatory. x Clopidogrel (300 mg loading dose in <75 years old

and 75 mg dose in ≥ 75 years old) in combination with pre-hospital fibrinolysis is mandatory.

x A weight adjusted dose of tenecteplase as the first line pre-hospital fibrinolytic regimen is recom-mended with a half dose regimen in > 75 years old.

x Anticoagulation is mandatory at the time of pre-hos-pital fibrinolysis with fibrin specific agents.

x Enoxaparin is highly recommended as the anticoagu-lant of choice in this setting.

x Bivalirudin and fondaparinux are not recommended in combination with pre-hospital fibrinolysis.

NSTE-ACS x Thrombotic and bleeding risk assessment is highly

recommended in the setting of NSTE-ACS.

x Point of care troponin tests may be considered in the setting of NSTE-ACS.

x In the case of chest pain at first medical contact, sub-lingual or intravenous nitrates titrated to blood pres-sure are recommended.

x Transfer to the appropriate facility without any ‘en route’ treatment or aspirin alone is recommended in the absence of need for urgent (<2 h) invasive assessment.

x In EMSs where emergency physicians are on board and in the case of an early invasive strategy (<2 h), an antithrombotic therapy including aspirin, ticagre-lor or clopidogrel loading dose and anticoagulation by enoxaparin or UFH may be considered.

x The use of prasugrel in the pre-hospital setting is not recommended.

x A management similar to STEMI is recommended in NSTE-ACS patients with cardiogenic shock, life-threatening arrhythmias or persistent ischaemia despite initial management, with an antithrombotic regimen including aspirin, ticagrelor or clopidogrel loading dose and anticoagulation by enoxaparin or UFH, and immediate invasive strategy.

x In the case of stable NSTE-ACS, transfer to an emer-gency department or a chest pain unit is recom-mended for patients with suspected NSTE-ACS.

x In high-risk patients with haemodynamic instability or signs of heart failure a transfer to emergency departments with possibility of critical care or inten-sive cardiac care units is recommended. In such patients a transfer to facilities with on-site 24/7 inter-ventional cardiology capability is recommended.

x In patients with persistent symptoms despite initial therapy a direct transfer to a catheterization labora-tory is recommended.

x In the case of NSTE-ACS with cardiogenic shock transfer to centers with onsite interventional cardiology, intensive cardiac care and possibility of circulatory support and cardiac surgery is recommended.

Aortic dissection x The use of ADD score in the pre-hospital setting is

highly recommended. x FoCUS echocardiography may be considered to

support the diagnosis of aortic dissection in the pre-hospital setting.

x A treatment limited to pain relief and blood pressure control is recommended in suspected aortic dissection.

x The recommended target heart rate and systolic blood pressure are <60 beats/min and between 100 and 120 mmHg respectively in the absence of neuro-logical complications.



x Intravenous beta-blockers, nitrates, sodium nitro-prusside or calcium channel blockers are recom-mended for blood pressure control.

x Starting beta-blockers before other antihypertensive drugs is highly recommended.

x In the case of complications life support and rapid transfer are recommended.

x Withholding antithrombotic therapy in suspected aortic dissection is mandatory.

x Transfer of patients with a very high probability of aortic dissection (ADD score ≥ 1) to a centre with 24/7 available aortic imaging and cardiac surgery is mandatory.

x Activation of aortic imaging and cardiac surgery and admission directly to radiology before proceeding to the operating theatre may be considered.

x Transfer to a non-surgical centre for imaging before transfer to a facility with cardiac surgery is not recommended.

Pulmonary embolism x The use of clinical prediction scores developed to

determine the likelihood of pulmonary embolism is highly recommended.

x The use of point of care D-dimer, troponin and BNP tests is not recommended.

x In patients with suspected pulmonary embolism con-tinuous ECG and blood oxygen saturation monitor-ing, and an intravenous access during transfer are highly recommended.

x Point of care FoCUS echocardiography may be considered in the pre-hospital setting for evaluation of the severity of pulmonary embolism.

x Transfer to emergency departments or chest pain units is recommended for stable patients with suspi-cion of pulmonary embolism.

x Transfer of patients with severe symptoms or haemo-dynamic instability (cardiac arrest, syncope, shock) or right ventricular enlargement on echocardiography – if performed – to intensive care units in centres equipped for thrombectomy is highly recommended.

x Echocardiography guided reperfusion therapy in the pre-hospital setting may be considered, if expertise is available, in patients with haemodynamic instability.

Pericarditis x It is recommended to consider pericarditis in every

patient in whom fibrinolysis is considered for pre-sumed STEMI.

x Specific management of stable uncomplicated peri-carditis during the pre-hospital transportation is not recommended.

x Pain relief by intravenous minor (paracetamol) or major (opioids) analgesics may be considered.

x Transfer to appropriate units (emergency depart-ment, chest pain unit, cardiology unit) in facilities where echocardiography and pericardiocentesis are available is recommended.

AHF x Risk assessment in the pre-hospital setting based on

the following characteristics is mandatory:�c Presence of cardiogenic shock; haemodynamic

instability (heart rate > 130 beats/min or <40, systolic blood pressure <90 mmHg); respi-ratory distress (respiration rate > 25, blood oxygen saturation <90%); ECG findings (ven-tricular or supraventricular arrhythmia, bra-dycardia, on-going ischaemia (i.e. STEMI, NSTE-ACS)).

x FoCUS pulmonary and cardiac ultrasound may be considered in the pre-hospital setting if competent staff are on board.

x The point-of care BNP tests may be considered in the pre-hospital setting.

x Delaying transfer for ultrasound or BNP testing in the pre-hospital setting is not recommended.

x In the absence of cardiogenic shock the recom-mended treatment is:�c Oxygen with a target saturation >94%;�c Sublingual/intravenous nitrates titrated accord-

ing to blood pressure;�c Intravenous diuretics (furosemide).

x In the case of haemodynamic compromise and res-piratory distress the recommended treatment is:�c Non-invasive ventilation;�c Invasive ventilation in the case of unsuccessful

or contra-indicated non-invasive ventilation;�c Inotropic or vasopressor support.

x Specific management of precipitating or causal fac-tors is mandatory:�c Electrical cardioversion in the case of ventricular

arrhythmia or rapid supraventricular tachycardia associated with haemodynamic and/or neurolog-ical compromise;

�c Intravenous atropine and/or isoprenaline and/or external pacemaker if available in the case of severe bradycardia;

�c Specific treatment of STEMI or NSTE-ACS. x Transfer to emergency departments, chest pain units,

cardiology or medicine wards is recommended in stable patients who respond rapidly to initial treatment.

x Transfer to emergency departments with critical care facilities and/or to intensive cardiac care units is



x Intravenous beta-blockers, nitrates, sodium nitro-prusside or calcium channel blockers are recom-mended for blood pressure control.

x Starting beta-blockers before other antihypertensive drugs is highly recommended.

x In the case of complications life support and rapid transfer are recommended.

x Withholding antithrombotic therapy in suspected aortic dissection is mandatory.

x Transfer of patients with a very high probability of aortic dissection (ADD score ≥ 1) to a centre with 24/7 available aortic imaging and cardiac surgery is mandatory.

x Activation of aortic imaging and cardiac surgery and admission directly to radiology before proceeding to the operating theatre may be considered.

x Transfer to a non-surgical centre for imaging before transfer to a facility with cardiac surgery is not recommended.

Pulmonary embolism x The use of clinical prediction scores developed to

determine the likelihood of pulmonary embolism is highly recommended.

x The use of point of care D-dimer, troponin and BNP tests is not recommended.

x In patients with suspected pulmonary embolism con-tinuous ECG and blood oxygen saturation monitor-ing, and an intravenous access during transfer are highly recommended.

x Point of care FoCUS echocardiography may be considered in the pre-hospital setting for evaluation of the severity of pulmonary embolism.

x Transfer to emergency departments or chest pain units is recommended for stable patients with suspi-cion of pulmonary embolism.

x Transfer of patients with severe symptoms or haemo-dynamic instability (cardiac arrest, syncope, shock) or right ventricular enlargement on echocardiography – if performed – to intensive care units in centres equipped for thrombectomy is highly recommended.

x Echocardiography guided reperfusion therapy in the pre-hospital setting may be considered, if expertise is available, in patients with haemodynamic instability.

Pericarditis x It is recommended to consider pericarditis in every

patient in whom fibrinolysis is considered for pre-sumed STEMI.

x Specific management of stable uncomplicated peri-carditis during the pre-hospital transportation is not recommended.

x Pain relief by intravenous minor (paracetamol) or major (opioids) analgesics may be considered.

x Transfer to appropriate units (emergency depart-ment, chest pain unit, cardiology unit) in facilities where echocardiography and pericardiocentesis are available is recommended.

AHF x Risk assessment in the pre-hospital setting based on

the following characteristics is mandatory:�c Presence of cardiogenic shock; haemodynamic

instability (heart rate > 130 beats/min or <40, systolic blood pressure <90 mmHg); respi-ratory distress (respiration rate > 25, blood oxygen saturation <90%); ECG findings (ven-tricular or supraventricular arrhythmia, bra-dycardia, on-going ischaemia (i.e. STEMI, NSTE-ACS)).

x FoCUS pulmonary and cardiac ultrasound may be considered in the pre-hospital setting if competent staff are on board.

x The point-of care BNP tests may be considered in the pre-hospital setting.

x Delaying transfer for ultrasound or BNP testing in the pre-hospital setting is not recommended.

x In the absence of cardiogenic shock the recom-mended treatment is:�c Oxygen with a target saturation >94%;�c Sublingual/intravenous nitrates titrated accord-

ing to blood pressure;�c Intravenous diuretics (furosemide).

x In the case of haemodynamic compromise and res-piratory distress the recommended treatment is:�c Non-invasive ventilation;�c Invasive ventilation in the case of unsuccessful

or contra-indicated non-invasive ventilation;�c Inotropic or vasopressor support.

x Specific management of precipitating or causal fac-tors is mandatory:�c Electrical cardioversion in the case of ventricular

arrhythmia or rapid supraventricular tachycardia associated with haemodynamic and/or neurolog-ical compromise;

�c Intravenous atropine and/or isoprenaline and/or external pacemaker if available in the case of severe bradycardia;

�c Specific treatment of STEMI or NSTE-ACS. x Transfer to emergency departments, chest pain units,

cardiology or medicine wards is recommended in stable patients who respond rapidly to initial treatment.

x Transfer to emergency departments with critical care facilities and/or to intensive cardiac care units is


Beygui et al. 23

highly recommended for unstable patients and/or those who fail to respond to initial treatment.

x Transfer to centres with onsite possibility of circula-tory assistance may be considered in patients with refractory heart failure and cardiogenic shock.

Tamponade x The pre-hospital risk assessment based on the fol-

lowing characteristics is mandatory:�c Presence of cardiogenic shock; haemodynamic

instability (heart rate > 130 beats/min or <40, sys-tolic blood pressure <90 mmHg); signs of acute right ventricular compression and increased sys-temic venous pressure (jugular vein distension); respiratory distress (respiration rate > 25, blood oxygen saturation <90%); low voltage, and/or electrical alternans on the ECG.

x The pre-hospital use of echocardiography in this set-ting may be considered if expertise is available and if it does not delay patient transfer.

x Ultrasound-guided pericardiocentesis may be consid-ered in the pre-hospital setting if ultrasound devices and medical expertise are available on board.

x Blind pericardiocentesis may be considered by highly trained medical operators in the absence of ultrasound in severe cases with refractory cardiac or ‘near- cardiac’ arrest with very high likelihood of tamponade.

x Rapid transfer of patients with suspicion of tam-ponade to the nearest centre with the possibility of ultrasound-guided pericardiocentesis and/or cardiac surgery on-site is mandatory.

Chest pain or dyspnoea in relation with cardiac arrhythmia

x Continuous ECG monitoring and venous access are mandatory in all patients with any type of cardiac arrhythmia.

x Specific ECG training and ECG tele-transmission by EMS teams not including emergency physicians skilled in identification of dysrhythmias is highly recommended.

x Pre-hospital electrical cardioversion is recom-mended in patients with rapid ventricular or supraventricular arrhythmias associated with haemo-dynamic instability, loss of consciousness or resist-ant angina pectoris.

x Pharmacological treatment of cardiac arrhythmias in the pre-hospital setting may be considered in selected conditions.

x Intravenous amiodarone may be considered for patients with resuscitated cardiac arrest as a pre-vention of recurrent life-threatening ventricular arrhythmia.

x Intravenous amiodarone may be considered in pre-vention of recurrent supraventricular arrhythmia with haemodynamic compromise after urgent elec-trical cardioversion.

x Intravenous adenosine may be considered in selected cases of re-entrant supraventricular tachycardia.

x In the case of very rapid, irregular wide QRS tachycardia – possible atrial fibrillation with pre-excitation – the use of AV slowing agents is not recommended (contraindicated). In these patients electrical cardioversion is recommended.

x Atropine, adrenaline, isoprenaline and external pac-ing are recommended in the pre-hospital setting in patients with severe bradycardia associated with haemodynamic instability (hypotension, shock) and/or loss of consciousness.

x A direct transfer of well tolerated arrhythmia with-out any specific treatment to adequate structures is recommended.

x Transfer to a facility with continuous ECG monitor-ing (emergency department, chest pain unit, inten-sive or continuous care unit) is mandatory for all patients with symptomatic cardiac arrhythmia.


Beygui et al. 23

highly recommended for unstable patients and/or those who fail to respond to initial treatment.

x Transfer to centres with onsite possibility of circula-tory assistance may be considered in patients with refractory heart failure and cardiogenic shock.

Tamponade x The pre-hospital risk assessment based on the fol-

lowing characteristics is mandatory:�c Presence of cardiogenic shock; haemodynamic

instability (heart rate > 130 beats/min or <40, sys-tolic blood pressure <90 mmHg); signs of acute right ventricular compression and increased sys-temic venous pressure (jugular vein distension); respiratory distress (respiration rate > 25, blood oxygen saturation <90%); low voltage, and/or electrical alternans on the ECG.

x The pre-hospital use of echocardiography in this set-ting may be considered if expertise is available and if it does not delay patient transfer.

x Ultrasound-guided pericardiocentesis may be consid-ered in the pre-hospital setting if ultrasound devices and medical expertise are available on board.

x Blind pericardiocentesis may be considered by highly trained medical operators in the absence of ultrasound in severe cases with refractory cardiac or ‘near- cardiac’ arrest with very high likelihood of tamponade.

x Rapid transfer of patients with suspicion of tam-ponade to the nearest centre with the possibility of ultrasound-guided pericardiocentesis and/or cardiac surgery on-site is mandatory.

Chest pain or dyspnoea in relation with cardiac arrhythmia

x Continuous ECG monitoring and venous access are mandatory in all patients with any type of cardiac arrhythmia.

x Specific ECG training and ECG tele-transmission by EMS teams not including emergency physicians skilled in identification of dysrhythmias is highly recommended.

x Pre-hospital electrical cardioversion is recom-mended in patients with rapid ventricular or supraventricular arrhythmias associated with haemo-dynamic instability, loss of consciousness or resist-ant angina pectoris.

x Pharmacological treatment of cardiac arrhythmias in the pre-hospital setting may be considered in selected conditions.

x Intravenous amiodarone may be considered for patients with resuscitated cardiac arrest as a pre-vention of recurrent life-threatening ventricular arrhythmia.

x Intravenous amiodarone may be considered in pre-vention of recurrent supraventricular arrhythmia with haemodynamic compromise after urgent elec-trical cardioversion.

x Intravenous adenosine may be considered in selected cases of re-entrant supraventricular tachycardia.

x In the case of very rapid, irregular wide QRS tachycardia – possible atrial fibrillation with pre-excitation – the use of AV slowing agents is not recommended (contraindicated). In these patients electrical cardioversion is recommended.

x Atropine, adrenaline, isoprenaline and external pac-ing are recommended in the pre-hospital setting in patients with severe bradycardia associated with haemodynamic instability (hypotension, shock) and/or loss of consciousness.

x A direct transfer of well tolerated arrhythmia with-out any specific treatment to adequate structures is recommended.

x Transfer to a facility with continuous ECG monitor-ing (emergency department, chest pain unit, inten-sive or continuous care unit) is mandatory for all patients with symptomatic cardiac arrhythmia.


S146

IntroductionSince 2000, the International Liaison Committee on Resuscitation (ILCOR) has published the International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations (CoSTR) every 5 years based on review of cardiopulmonary resuscitation (CPR) science. Seven task forces with representatives from the 7 member resuscitation organizations create the CoSTR that enables regional resusci-tation organizations to create their individual guidelines. The different guidelines are based on the scientific evidence and incorporate or adjust for regional considerations.

Why Acute Coronary Syndromes?Coronary heart disease remains among the leading causes of mortality globally. There is considerable research focus world-wide on improving outcomes in patients with acute coronary syndromes (ACS). Undoubtedly, this has led to improved health and dramatically improved morbidity and mortality in much of the world. Indeed, timely and appropriate care of ACS can reduce and prevent cardiac arrest. Some of the rec-ommended interventions for ACS, however, are considered resource intensive and/or require significant infrastructure, such as well-trained emergency medical services personnel to administer fibrinolysis, and cardiac catheterization laborato-ries that require capital and experienced staff. These regional disparities present challenges to regional and national health authorities as guidelines evolve and become more complex.

The American College of Cardiology with the American Heart Association, European Society of Cardiology, and other organizations have developed guidelines for treatment and management of patients with ST-segment elevation myocardial infarction (STEMI) and non-STEMI ACS. These guidelines primarily focus on the hospital setting, and, for many years, the prehospital and emergency department (ED) management

of patients was based on extrapolation of in-hospital evidence. There is now increasing interest and evidence on the prehos-pital decisions and management of ACS. The time-sensitive nature of ACS forces us to scrutinize not only the time goals to deliver the interventions but also the proper sequencing of them. For these reasons, the ACS Task Force emphasized the evidence review for 2015 on the management of ACS before the patient is admitted.

There has been renewed interest of late in focusing less on the individual aspects of STEMI care and more on the systems of care. This is in recognition that the system may be more than the sum of its parts. In STEMI care, this system integrates awareness and prevention, prehospital care, in-hospital care, specialty centers, and rehabilitation and secondary prevention. The ACS Task Force concentrated on the questions that will inform regional systems-of-care decisions. If a patient with ACS or STEMI presents to prehospital care, a local hospital, or a specialty center, there needs to be a common but nuanced approach to diagnosis and treatment. However, the specifics of that treatment may depend on local resources. The questions covered were intentionally focused to answer questions based on different community resources.

Evidence Evaluation and GRADE ProcessEach task force performed a detailed systematic review based on the recommendations of the Institute of Medicine of the National Academies1 and using the methodological approach proposed by the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) Working Group.2 After identification and prioritization of the questions to be addressed (using the PICO [population, intervention, com-parator, outcome] format),3 with the assistance of information specialists, a detailed search for relevant articles was per-formed in each of 3 online databases (PubMed, Embase, and the Cochrane Library).

(Circulation. 2015;132[suppl 1]:S146–S176. DOI: 10.1161/CIR.0000000000000274.)© 2015 American Heart Association, Inc., European Resuscitation Council, and International Liaison Committee on Resuscitation.

Circulation is available at http://circ.ahajournals.org DOI: 10.1161/CIR.0000000000000274

The American Heart Association requests that this document be cited as follows: Welsford M, Nikolaou NI, Beygui F, Bossaert L, Ghaemmaghami C, Nonogi H, O’Connor RE, Pichel DR, Scott T, Walters DL, Woolfrey KGH; on behalf of the Acute Coronary Syndrome Chapter Collaborators. Part 5: acute coronary syndromes: 2015 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations. Circulation. 2015;132(suppl 1):S146–S176.

*Co-chairs and equal first co-authors.This article has been co-published in Resuscitation. Published by Elsevier Ireland Ltd. All rights reserved.

Part 5: Acute Coronary Syndromes2015 International Consensus on Cardiopulmonary Resuscitation

and Emergency Cardiovascular Care Science With Treatment Recommendations

Michelle Welsford, Co-Chair*; Nikolaos I. Nikolaou, Co-Chair*; Farzin Beygui; Leo Bossaert; Chris Ghaemmaghami; Hiroshi Nonogi; Robert E. O’Connor; Daniel R. Pichel; Tony Scott;

Darren L. Walters; Karen G. H. Woolfrey; on behalf of the Acute Coronary Syndrome Chapter Collaborators

by guest on November 30, 2015http://circ.ahajournals.org/Downloaded from

Circulation. 2015;132[suppl 1]:S146–S176. DOI: 10.1161/CIR.0000000000000274.

Resuscitation 95 (2015) 264–277

Contents lists available at ScienceDirect

Resuscitationjou rn al hom epage : w ww.elsev ie r .com/ locate / resusc i ta t ion

European Resuscitation Council Guidelines for Resuscitation 2015Section 8. Initial management of acute coronary syndromesNikolaos I. Nikolaoua,∗, Hans-Richard Arntzb, Abdelouahab Bellouc, Farzin Beyguid,Leo L. Bossaerte, Alain Cariouf, on behalf of the Initial management of acute coronarysyndromes section Collaborator1

a Cardiology Department, Konstantopouleio General Hospital, Athens, Greeceb Department of Emergency Medicine, Charité, University Medicine Berlin, Campus Benjamin Franklin, Berlin, Germanyc University of Rennes, France & Department of Emergency Medicine, Beth Israel Deaconnes Medical Center, Harvard Medical School,Boston, MA, USAd Interventional Cardiology Unit, Caen University Hospital, Caen, Francee Department of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgiumf Medical Intensive Care Unit, Cochin University Hospital (APHP) & Paris Descartes University, Paris, France

Summary of main changes since 2010 guidelines

The following is a summary of the most important views andchanges in new recommendations for the diagnosis and treatmentof acute coronary syndromes (ACS) since the last ERC guidelines in2010.

Diagnostic interventions in ACS

• Pre-hospital recording of a 12-lead electrocardiogram (ECG) isrecommended in patients with suspected ST segment elevationacute myocardial infarction (STEMI). For those with STEMI thisexpedites prehospital and in-hospital reperfusion and reducesmortality for both those planned for primary percutaneouscoronary intervention (PPCI) and those who receive fibrinolytictherapy.

• Non-physician ECG STEMI interpretation with or without the aidof computer interpretation is suggested if adequate diagnosticperformance can be maintained through carefully monitoredquality assurance programs.

• Pre-hospital STEMI activation of the catheterisation laboratorymay not only reduce treatment delays but may also reducepatient mortality.

• The use of negative high-sensitivity cardiac troponins (hs-cTn)during initial patient evaluation cannot be used as a standalonemeasure to exclude an ACS, but in patients with very low riskscores may justify early discharge.

Therapeutic interventions in ACS

• Adenosine diphosphate (ADP) receptor antagonists (clopidogrel,ticagrelor, or prasugrel-with specific restriction), may be given

∗ Corresponding author.E-mail address: [email protected] (N.I. Nikolaou).

1 The Initial management of acute coronary syndromes section Collaborator islisted in the Collaborator section.

either pre-hospital or in the ED for STEMI patients planned forprimary PCI.

• Unfractionated heparin (UFH) can be administered either in thepre-hospital or in-hospital setting in patients with STEMI and aplanned primary PCI approach.

• Pre-hospital enoxaparin may be used as an alternative to pre-hospital UFH for STEMI.

• Patients with acute chest pain with presumed ACS do not needsupplemental oxygen unless they present with signs of hypoxia,dyspnoea, or heart failure.

Reperfusion decisions in STEMI

• Reperfusion decisions have been reviewed in a variety of possiblelocal situations.

• When fibrinolysis is the planned treatment strategy, we recom-mend using pre-hospital fibrinolysis in comparison to in-hospitalfibrinolysis for STEMI where transport times are >30 min andpre-hospital personnel are well trained.

• In geographic regions where PCI facilities exist and are available,direct triage and transport for PCI is preferred to pre-hospitalfibrinolysis for STEMI.

• Patients presenting with STEMI in the emergency department(ED) of a non-PCI capable hospital should be transported imme-diately to a PCI centre provided that treatment delays for PPCIare less than 120 min (60 to 90 min for early presenters and thosewith extended infarctions), otherwise patients should receive fib-rinolysis and be transported to a PCI centre.

• Patients who receive fibrinolytic therapy in the emergencydepartment of a non-PCI centre should be transported if possiblefor early routine angiography (within 3 to 24 h from fibrinolytictherapy) rather than be transported only if indicated by the pres-ence of ischemia.

• PCI in less than 3 h following administration of fibrinolytics isnot recommended and can be performed only in case of failedfibrinolysis.

http://dx.doi.org/10.1016/j.resuscitation.2015.07.0300300-9572/© 2015 European Resuscitation Council. Published by Elsevier Ireland Ltd. All rights reserved.

Welsford et al Part 5: Acute Coronary Syndromes S151

context of strong initial education programs, quality assurance programs, and ongoing oversight.

As was pointed out in the public comments, it is difficult to perform head-to-head comparisons or combine data from these studies, because they have used different proprietary computer interpretation algorithms and different gold stan-dards. It is likely that different algorithms perform differently. Computer interpretation algorithms can be updated periodi-cally, which may change their effectiveness, making previ-ous studies less relevant unless the algorithm and version are the same as is used in your setting. Last, some of the algo-rithms can now be adjusted to favor either lower FP results or lower FN results, depending on the needs or how it is used. Therefore, in choosing to use such a computer algorithm as an adjunct, careful consideration of the individual algorithm’s reported performance and evaluation of this in your own set-ting are key.

The use of computer ECG interpretation did not yield equally effective performances across the various systems of care where it has been used with observed sensitivities rang-ing from 0.58 to 0.78 and specificity ranging from 0.91 to 1. This may be due to the algorithm performance (different per-formance with different types of STEMI), but it may also be related to the quality of obtained ECG and the level of training and individual expertise in acquiring the ECG. It is possible that the performance characteristics of a computer algorithm are different in controlled, in-hospital settings in stable patients compared with prehospital settings. Therefore, each system of care has to evaluate performance of any specific algorithm in the particular context where the algorithm is used. Diagnostic performance should always be considered in conjunction with local STEMI prevalence, because very high or low prevalence rates may lead to unacceptable FP and/or FN rates despite sensitivity and specificity rates that may seem satisfactory as stand-alone values. This approach may give important clues as to whether this method fits best in comparison with other

existing options of ECG interpretation such as transmission of ECG for interpretation by an experienced provider.

Knowledge Gaps

Different computer algorithms have not been compared. The optimal ECG computer algorithm for implemen-tation with adjunctive nonexpert interpretation has not been determined.

Nonphysician STEMI ECG Interpretation (ACS 884)Among adult patients with suspected STEMI outside of a hos-pital (P), do nonphysicians (eg, nurses and paramedics) (I), compared with physicians (C), change identification of STEMI on an ECG with acceptable rates of FNs to allow earlier iden-tification and FPs, minimizing unnecessary angiography (O)?

Consensus on ScienceFor the important outcomes of FP and FN results, we have identified very-low-quality evidence (downgraded for risk of bias, inconsistency, and publication bias) from 3 studies34–36 including 1360 ECGs of FP results of STEMI recognition ranging from 0.3% to 30.5% (under the assumption of a dis-ease prevalence of 5% [highest expected FP results]), and FN results did not exceed 4% (under the assumption of 20% prev-alence [highest expected FN results]). Sensitivity ranged from 80% to 99.6%, and specificity ranged from 68% to 96.8%.

For the important outcome of FP/all positive tests, we have identified very-low-quality studies (downgraded for risk of bias and inconsistency) from 9 observational studies34–41 including 900 ECGs of FP/all positive tests for STEMI recog-nition ranging from 8% to 40%.

Treatment RecommendationWe suggest that in adult patients with suspected STEMI outside of a hospital, nonphysicians may perform ECG interpretation to recognize STEMI in a system where the FP and FN rates are low (weak recommendation, very-low-quality evidence).

Figure 1. Thirty-day mortality in STEMI patients undergoing PPCI with and without prehospital ECG and hospital notification (random effects model). Intervention = prehospital ECG; control = without prehospital ECG.

Figure 2. Thirty-day mortality in STEMI patients undergoing fibrinolysis with and without prehospital ECG and hospital notification (fixed effects model). Experimental = prehospital ECG; control = without prehospital ECG.


S152 Circulation October 20, 2015

Values, Preferences, and Task Force InsightsIn making this recommendation, we adopt a balanced approach in between minimizing treatment delays of patients with STEMI and avoiding excess waste of resources resulting from FP system activations.

It is recognized that in many prehospital systems, physi-cians will not be available on-site, and the evidence indicates that highly trained paramedics and nurses can reliably recog-nize STEMI. This should occur in an organized system of pre-hospital care where there is a strong initial education program, ongoing oversight, possible adjunctive computer interpreta-tion, and a quality assurance program.

It is impossible to provide pooled estimates from the reviewed data, because different study methods and/or gold standards have been used. Nonphysician STEMI ECG rec-ognition was not equally reliable across the various reporting systems of care. This may be relevant to the quality of the ECG obtained and the ECG findings but also to the level of training and individual expertise of healthcare providers. Therefore, each system of care should make every effort to assure opti-mal diagnostic accuracy from healthcare providers by main-taining adequate training programs and meticulous care for quality control. Timely feedback from STEMI receiving cen-ters, including performance benchmarks, prehospital and in-hospital ECGs, and catheterization findings, may be essential in this regard. Diagnostic performance should always be con-sidered in conjunction with local STEMI prevalence as very high or low prevalence rates may lead to unacceptable FP and/or FN rates despite sensitivity and specificity rates that may seem satisfactory as stand-alone values. This may give important clues as to whether nonphysician STEMI interpre-tation fits best in the setting of a particular system of care in comparison with other existing options of on-site ECG inter-pretation such as transmission of ECG for interpretation by an experienced provider or computer-assisted interpretation.

Knowledge Gaps

We did not find evaluation of nonphysician ECG inter-pretation initial and maintenance training programs or measurement of ECG interpretation performance based on specific education or experience.

Prehospital STEMI Activation of the Catheterization Laboratory (ACS 873)Among adult patients with suspected STEMI outside of a hospital (P), does prehospital activation of catheterization laboratory (I), compared with no prehospital activation of the

catheterization laboratory (C), change mortality, major bleed-ing, stroke, reinfarction (O)?

IntroductionPrompt restoration of coronary flow in the affected area is key to treatment of STEMI. Several system-related strategies have been developed to minimize system-related delays to reperfusion. For patients with suspected STEMI in the pre-hospital setting, the above strategies for ECG interpretation are used to ensure prehospital STEMI recognition. Where prehospital fibrinolysis is not possible or appropriate, the focus should then be on prompt patient triage for transfer to the medical institution where the most appropriate treat-ment would be offered in a timely manner. Advance hospital notification and early activation of the catheterization labora-tory can expedite invasive revascularization. This review has focused on the potential of prehospital STEMI activation of the catheterization laboratory to improve patient safety and efficacy outcomes.

Consensus on ScienceFor the critical outcome of 30-day mortality, we have identi-fied moderate-quality evidence (upgraded for large effect size) from 6 observational studies13,14,16,42–44 enrolling 1805 patients in favor of prehospital activation of the catheterization labo-ratory over no activation of catheterization laboratory (odds ratio [OR], 0.41; 95% CI, 0.30–0.56) (Figure 3).

For the important outcome of major bleeding, we have identified very-low-quality evidence (downgraded for impre-cision) from 1 observational study43 enrolling 188 patients showing no benefit of prehospital activation of catheteriza-tion laboratory over no activation of catheterization laboratory (OR, 0.68; 95% CI, 0.04–10.68).

For the important outcome of nonfatal stroke, we have identified very-low-quality evidence (downgraded for impre-cision) from 1 observational study13 enrolling 301 patients showing no benefit of prehospital activation of catheteriza-tion laboratory over no activation of catheterization laboratory (OR, 0.06; 95% CI, 0.00–1.13).

For the important outcome of nonfatal reinfarction, we have identified very-low-quality evidence (downgraded for imprecision) from 3 observational studies13,43,44 enrolling 748 patients showing no benefit of prehospital activation of cath-eterization laboratory over no activation of catheterization laboratory (OR, 0.48; 95% CI, 0.22–1.03).

Treatment RecommendationWe recommend that when primary PCI is the planned strategy, that prehospital activation of catheterization laboratory for

Figure 3. Thirty-day mortality for prehospital STEMI activation of the catheterization laboratory versus no prehospital activation. Experimental = prehospital STEMI activation of the catheterization laboratory; control = no prehospital STEMI activation of the catheterization laboratory.


Pre-hospital ECG

Pre-hospital cathlab activation


a topic requiring further research. Our a priori outcomes did not include stent thrombosis; thus, this was not included in the 2015 consensus on science. However, where post hoc evidence of increased stent thrombosis rates were available, inclusion in treatment recommendations was considered.

The concomitant administration of adjunctive anti-thrombotic therapy in association with reperfusion therapy is recommended widely based on consistent evidence in international specialty guidelines.56,57 Nevertheless, whether effort should be undertaken to include such additional therapy in the prehospital management of STEMI patients, particu-larly in a planned primary PCI strategy, remains to be evalu-ated and is the subject of this section. Two related questions reviewed the evidence for administration of anticoagulants in the prehospital setting. One reviewed prehospital versus in-hospital use, and the other reviewed prehospital adminis-tration of different agents. Interestingly, only UFH has been evaluated directly in a comparison of prehospital versus in-hospital use despite other agents being used in the prehospi-tal setting. We encourage prospective RCTs on the relative benefits of prehospital versus in-hospital administration of anticoagulants. While stent thrombosis was not an a priori outcome in our evaluations, it remains a major complication of PCI, and, thus, where post hoc evidence of increased stent thrombosis rates were available, this was considered for the treatment recommendations and is discussed further in the comments section.

In addition to the prehospital antiplatelet and anticoagu-lant treatments for STEMI patients above, this section also includes oxygen supplementation in ACS patients. Although the use of supplementary oxygen (regardless of oxygen satu-ration) had previously been considered standard of care, its routine use for ACS patients (and postarrest patients, patients with chronic obstructive pulmonary disease, etc) has more recently been questioned. Most of the literature on this topic is relatively old, some before reperfusion therapy for STEMI (1970s) and, thus, this limits its generalizability. These studies also used different nonstandardized outcomes, which limits the ability to combine the studies. Despite these numerous methodological concerns, in 2010 the ILCOR ACS Task Force stated that the routine use of supplemen-tary oxygen in ACS was not recommended. The review did cite gaps in prospective studies of oxygen use in ACS in the modern era. Since 2010, 3 prospective research studies on the use of supplementary oxygen use in STEMI were started. Therefore, this topic was reviewed for 2015 to update the review with the use of the new GRADE methodology and in anticipation of additional evidence in the near future. At the time of final manuscript preparation, the published results

were available for only 1 of these trials. The other 2 studies were not yet published.

Prehospital ADP-Receptor Antagonists in STEMI (ACS 335)Among adult patients with suspected STEMI outside of the hospital (P), does prehospital administration of an ADP-receptor antagonist (clopidogrel, prasugrel, or ticagrelor) in addition to usual therapy (I), compared with administration of an ADP-receptor antagonist in-hospital (C), change death, intracranial hemorrhage, revascularization, stroke, major bleeding, reinfarction (O)?

Consensus on ScienceFor the critical outcome of 30-day mortality, we have identi-fied very-low-quality evidence (downgraded for imprecision and reporting bias) from 3 RCTs58–60 enrolling 2365 patients showing no additional benefit with prehospital administra-tion of an ADP-receptor antagonist compared with in-hospital administration (OR, 1.58; 95% CI, 0.90–2.78) (Figure 4).

For the important outcome of major bleeding, we have identified very-low-quality evidence (downgraded for impre-cision and reporting bias) from 3 RCTs58–60 enrolling 2365 patients showing no additional benefit with prehospital administration of an ADP-receptor antagonist compared with in-hospital administration (OR, 1.12; 95% CI, 0.72–1.74).

Treatment RecommendationWe suggest that when ADP-receptor antagonists are given to suspected STEMI patients with a planned primary PCI approach, administration can occur in either the prehospital or in-hospital setting, but there is insufficient evidence to change existing practice (very-low-quality evidence, weak recommendation).

Values, Preferences, and Task Force InsightsIn making this recommendation we place a higher value on not recommending adding complexity to prehospital treat-ment regimens over uncertain benefits.

There was no difference in mortality or major bleed-ing with either prehospital or in-hospital administration. We acknowledge, however, that although stent thrombosis was not considered as an outcome a priori, 1 study did report lower early (≤24 hours) stent thrombosis rates with prehospi-tal (0.8%) versus in-hospital administration (0%).60 However, there were no differences in mortality, or their composite isch-emic end points in this trial. The relevance of this very rare occurrence of early stent thrombosis in balance with the rare occurrence of additional bleeding if the patient underwent an emergency surgical strategy rather than PCI will need to

Figure 4. Thirty-day mortality for prehospital versus in-hospital ADP-antagonist administration. Experimental = prehospital ADP-antagonist administration; control = in-hospital ADP-antagonist administration.



elevation after OHCA may be temporary and does not always correlate with an acute coronary artery occlusion.

In 2010, ILCOR completed a single evidence review to examine all adult patients with OHCA and ROSC, inclusive of patients with and without ST elevation. In clinical practice, ACS with and without ST elevation are clinically distinct syn-dromes that are managed with guidelines that promote specific time to intervention targets for STEMI, while less time-sensi-tive strategies are recommended for non–ST elevation ACS. For this reason, the evidence review of this topic has been stratified to reflect the need to give guidance specific to each subset (ST elevation and no ST elevation) of the post-OHCA population.

PCI After ROSC With ST Elevation (ACS 340)Among adult patients with ROSC after cardiac arrest with evidence of ST elevation on ECG (P), does emergency car-diac catheterization laboratory evaluation* (I), compared with cardiac catheterization later in the hospital stay or no cath-eterization (C), change hospital mortality and neurologically favorable survival (O)?

Consensus on ScienceFor the critical outcome of hospital mortality in patients with ROSC after cardiac arrest with ST elevation on ECG, we have identified very-low-quality evidence (down-graded for serious risk of bias and inconsistency and upgraded for large treatment effect) from 15 observational studies112–126 enrolling 3800 patients showing benefit of emergency cardiac catheterization versus cardiac catheterization later in the hos-pital stay or no catheterization (OR, 0.35; 95% CI, 0.31–0.41) (Figure 13).

For the critical outcome of neurologically favorable sur-vival in patients with ROSC after cardiac arrest with ST elevation on ECG, we have identified very-low-quality evi-dence (downgraded for serious risk of bias and inconsistency and upgraded for large treatment effect) from 9 observational studies,112–114,117,119–122,124 enrolling 2919 patients showing

benefit of emergency cardiac catheterization versus cardiac catheterization later in the hospital stay or no catheterization (OR, 2.54; 95% CI, 2.17–2.99).

Treatment RecommendationWe recommend emergency† cardiac catheterization labora-tory evaluation in comparison with cardiac catheterization later in the hospital stay or no catheterization in select†† adult patients with ROSC after OHCA of suspected cardiac origin with ST elevation on ECG (strong recommendation, low-qual-ity evidence).

†Time Frame for TreatmentThe time frame for emergency catheterization has been vari-ably defined in the evidence reviewed. In general, patients were managed to minimize door-to-reperfusion times in a manner similar to the general STEMI patient population. The complexity and heterogeneity of this patient group may delay their resuscitation and management.

††Patient SelectionThe evidence base was nonrandomized case-control studies that were subject to a high level of selection bias. The deci-sion to undertake emergency cardiac catheterization was fre-quently made at the discretion of the treating physician, and the patient’s likelihood of survival is likely to have influenced the decision to undertake the intervention. A variety of factors were more likely to be associated with cardiac catheterization (Table 4): male gender, younger age, ventricular fibrillation as the presenting cardiac arrest rhythm; witnessed arrest; and bystander CPR, being supported with vasopressors or left ven-tricular assist devices. Those patient characteristics that were less likely to be associated with angiography were diabetes mellitus, renal failure, and heart failure.

Values, Preferences, and Task Force InsightsIn making this recommendation, we placed a higher value on survival and good neurologic outcome over resource utiliza-tion. Although the evidence was low-quality because it involved observational studies of selected patients, the strength of the benefit was large and consistent in numerous studies. Given that the evidence derives from selected patients, this recommenda-tion is not intended to apply to all post-ROSC patients with ST

Figure 13. Hospital mortality for patients with ROSC after cardiac arrest with ST elevation: emergency cardiac catheterization versus delayed or no cardiac catheterization. Experimental = emergency cardiac catheterization; control = delayed or no cardiac catheterization.

*Catheterization laboratory evaluation included coronary angiography and early revascularization of acute coronary occlusions or significant stenosis as indicated.



body of evidence for emergency intervention in patients without ST elevation after OHCA with ROSC in compari-son to those with ST elevation: The population studied was smaller, the magnitude of the effect was slightly smaller, and the proportion of patients that went on to have PCI was smaller. Therefore, we believed that a weak recommendation was appropriate. We understand that this recommendation represents a departure from most existing guidelines for the treatment of the general population of non–ST elevation ACS patients without OHCA.

Catheterization laboratory evaluation included coronary angiography and early revascularization of acute coronary occlusions or significant stenosis as indicated.

Knowledge Gaps

Further investigation is needed to confirm the benefit seen in the initial 2 observational studies. Ideally, randomized

studies would help identify if there are certain subgroups of patients that would benefit most or least from angiog-raphy after ROSC.

AcknowledgmentsWe thank the following individuals (the Acute Coronary Syndrome Chapter Collaborators) for their collaborations on the systematic reviews contained in this section: Abdulaziz S. Ali; Chi Keong Ching; Michael Longeway; Catherine Patocka; Vincent Roule; Simon Salzberg; Anthony V. Seto.

The task force members are grateful for the expertise and late-night assistance of the evidence evaluation experts and GRADE experts Eddy Lang and Peter Morley. In addition to our chapter collaborators, Anthony Camuglia and Julian Nam also assisted with insights from their previous work on related meta-analyses. Last, our final work is only as good as the foundation of the initial comprehensive search strategy and, thus, we thank the experienced St Michael’s Hospital Information Specialist group: Teruko Kishibe, Christine Neilson, Carolyn Ziegler, and Sandy Iverson.

Figure 14. Hospital mortality for patients with ROSC after cardiac arrest without ST elevation: emergency cardiac catheterization versus delayed or no cardiac catheterization. Experimental = emergency cardiac catheterization; control = delayed or no cardiac catheterization.


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AHA/ACC guidelines STEMI update 2015

Levine GN, et al. 2015 ACC/AHA/SCAI Focused Update on Primary PCI

Page 9 of 28

2. Culprit Artery–Only Versus Multivessel PCI (See Section 5.2.2.2 of 2011 PCI guideline and Section 4.1.1 of 2013 STEMI guideline for additional recommendations.)

2013 Recommendation 2015 Focused Update Recommendation Comment

Class III: Harm PCI should not be performed in a noninfarct artery at the time of primary PCI in patients with STEMI who are hemodynamically stable (11-13). (Level of Evidence: B)

Class IIb PCI of a noninfarct artery may be considered in selected patients with STEMI and multivessel disease who are hemodynamically stable, either at the time of primary PCI or as a planned staged procedure (11-24). (Level of Evidence: B-R)

Modified recommendation (changed class from “III: Harm” to “IIb” and expanded time frame in which multivessel PCI could be performed).

PCI indicates percutaneous coronary intervention; and STEMI, ST-elevation myocardial infarction. Approximately 50% of patients with STEMI have multivessel disease (25,26). PCI options for patients with

STEMI and multivessel disease include: 1) culprit artery–only primary PCI, with PCI of nonculprit arteries only

for spontaneous ischemia or intermediate- or high-risk findings on predischarge noninvasive testing; 2)

multivessel PCI at the time of primary PCI; or 3) culprit artery–only primary PCI followed by staged PCI of

nonculprit arteries. Observational studies, randomized controlled trials (RCTs), and meta-analyses comparing

culprit artery–only PCI with multivessel PCI have reported conflicting results (11,12,14-24,27,28), likely because

of differing inclusion criteria, study protocols, timing of multivessel PCI, statistical heterogeneity, and variable

endpoints (Data Supplement).

Previous clinical practice guidelines recommended against PCI of nonculprit artery stenoses at the time of

primary PCI in hemodynamically stable patients with STEMI (9,10). Planning for routine, staged PCI of

noninfarct artery stenoses on the basis of the initial angiographic findings was not addressed in these previous

guidelines, and noninfarct artery PCI was considered only in the limited context of spontaneous ischemia or high-

risk findings on predischarge noninvasive testing. The earlier recommendations were based in part on safety

concerns, which included increased risks for procedural complications, longer procedural time, contrast

nephropathy, and stent thrombosis in a prothrombotic and proinflammatory state (9,10), and in part on the

findings from many observational studies and meta-analyses of trends toward or statistically significant worse

outcomes in those who underwent multivessel primary PCI (12-16,21-23). Four RCTs have since suggested that a strategy of multivessel PCI, either at the time of primary PCI or as

a planned, staged procedure, may be beneficial and safe in selected patients with STEMI (17,18,24,27) (Data

Supplement). In the PRAMI (Preventive Angioplasty in Acute Myocardial Infarction) trial (n=465) (24), the

composite primary outcome of cardiac death, nonfatal myocardial infarction (MI), or refractory angina occurred in

21 patients (9%) treated with multivessel primary PCI, compared with 53 patients (22%) treated with culprit

artery–only PCI (HR: 0.35; 95% CI: 0.21 to 0.58; p<0.001). In the CvLPRIT (Complete Versus Culprit-Lesion

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2011/2013 Recommendation 2015 Focused Update Recommendations Comments

Class IIa Manual aspiration thrombectomy is reasonable for patients undergoing primary PCI (29-32). (Level of Evidence: B)

Class IIb The usefulness of selective and bailout aspiration thrombectomy in patients undergoing primary PCI is not well established (33-37). (Level of Evidence: C-LD) Class III: No Benefit Routine aspiration thrombectomy before primary PCI is not useful (33-37). (Level of Evidence: A)

Modified recommendation (Class changed from “IIa” to “IIb” for selective and bailout aspiration thrombectomy before PCI). New recommendation (“Class III: No Benefit” added for routine aspiration thrombectomy before PCI).

PCI indicates percutaneous coronary intervention; and LD, limited data.

The 2011 PCI and 2013 STEMI guidelines’ (9,10) Class IIa recommendation for aspiration thrombectomy before

primary PCI was based on the results of 2 RCTs (29,31,32) and 1 meta-analysis (30) and was driven in large

measure by the results of TAPAS (Thrombus Aspiration During Primary Percutaneous Coronary Intervention in

Acute Myocardial Infarction Study), a single-center study that randomized 1,071 patients with STEMI to

aspiration thrombectomy before primary PCI or primary PCI only (29,32). Three multicenter trials, 2 of which

enrolled significantly more patients than prior aspiration thrombectomy trials, have prompted reevaluation of this

recommendation. In the INFUSE-AMI (Intracoronary Abciximab and Aspiration Thrombectomy in Patients With

Large Anterior Myocardial Infarction) trial (37) of 452 patients with anterior STEMI due to proximal or mid-left

anterior descending occlusion, infarct size was not reduced by aspiration thrombectomy before primary PCI. The

TASTE (Thrombus Aspiration During ST-Segment Elevation Myocardial Infarction) trial (n=7,244) incorporated

a unique design that allowed randomization within an existing national registry, resulting in enrollment of a

remarkably high proportion of eligible patients (34,36). No significant 30-day or 1-year differences were found

between the group that received aspiration thrombectomy before primary PCI and the group that received primary

PCI only with regard to death, reinfarction, stent thrombosis, target lesion revascularization, or a composite of

major adverse cardiac events. The TOTAL (Trial of Routine Aspiration Thrombectomy With PCI Versus PCI

Alone in Patients With STEMI) trial randomized 10,732 patients with STEMI to aspiration thrombectomy before

primary PCI or primary PCI only (35). Bailout thrombectomy was performed in 7.1% of the primary PCI–only

group, whereas the rate of crossover from aspiration thrombectomy before primary PCI to primary PCI only was

4.6%. There were no differences between the 2 treatment groups, either in the primary composite endpoint of

cardiovascular death, recurrent MI, cardiogenic shock, or New York Heart Association class IV heart failure at

180 days, or in the individual components of the primary endpoint, stent thrombosis, or target-vessel

revascularization. There was a small but statistically significant increase in the rate of stroke in the aspiration

thrombectomy group. An updated meta-analysis that included these 3 trials among a total of 17 trials (n=20,960)

found no significant reduction in death, reinfarction, or stent thrombosis with routine aspiration thrombectomy.

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