Gregory DucrocqCardiology Departement

Bichat HospitalParis, France

Management of STEMI patientsHow to implement ESC guidelines

What is the purpose of guidelines?

A legal document?

Something to follow in any case?

Something to learn by heart?

« Guidelines summarize and evaluate all available evidence »

« guidelines are not substitutes but are complements for textbooks »

« The guidelines do not however override the responsability of health professionals to make appropriate decisions according to the circumstances of individual patient »

ESC STEMI guidelines.

A summary of available evidence that you should implement

according to your local conditions

How are the guidelines built?

Still a lot of low level recommendations

A majority of low level of evidence

Guidelines are not a monolith

There is room for local interpretation and implementation according to your local practice

Emergency care

Antithrombotic therapy

Post discharge

Guidelines Implementation

A precise analysis of local conditions is key for guidelines implementation

Emergency care

Antithrombotic therapy

Post discharge

Guidelines Implementation

How do we implement in France?

A network of physician-staffed Mobile Intensive CareUnits

What are the results?

Reperfusion therapy in STEMI

FAST MI 2010 registry

STEMI: reperfusion therapy

IV lysis: 57% prehospitalFAST MI 2010 registry

Meeting the ESC requirements of the guidelines influences survival

Time ECG to PPCI within GL Time ECG to PPCI > GL0

0.51

1.52

2.53

3.54

1.1

3.5

% in-hospital death

Adjusted OR: 2.92 (1.17-7.30)P=0.02

Median time from ECG to PCI: 110 min [78; 185]Only 55% met the recommended timelines

FAST MI 2010 registry

A precise analysis of local conditions is key for guidelines implementation

Implementation according to your local conditions?

How many PCI capable centers?Which volume?How distant are they?Experience of operators in primary PCIFinancial issues: can any patient be treated by primary PCI?Transfer: do you have doctors in the ambulances?

Emergency care

Antithrombotic therapy

Post discharge

Guidelines Implementation

What do the trials say?

Clopidogrel on top of ASA in STEMI

(Death, reinfarction, stroke)(CV death, recurrent MI, recurrent ischemia)

Sabatine et al. N Engl J Med. 2005

Prop

ortio

n w

ith E

nd P

oint

, %

N=3491; 75 y/o, lytic, 300 mg load,

75 mg/day, cath in 2-8 days

Day

0

5

10

15

0 5 10 15 20 25 30

Placebo

Clopidogrel

Odds ratio 0.80(95% CI 0.65-0.97)

P=0.026

CLARITY (TIMI 28)

Day (Up to 28 Days)

COMMIT (CCS-2)N=45,852; 50% lytic,75 mg/day x 16 days

9% proportional risk reduction

(P=0.002)

Placebo + ASA: 2310 events (10.1%)

Clopidogrel + ASA2121 events (9.2%)

0

2

4

6

89

1

3

5

7

0 7 14 21 28

1011

COMMIT Collaborative Group Lancet. 2005

Clopidogrel non responders

n=544

1121049688807264564840322416

80

Number of patients

< -20 [-10,0] [11,20] [31,40] [51,60] [71,80] [91,100]

Delta 5µM ADP

Adapted from Serebruany et al. JACC 2005

PrasugrelBrandt et al Am Heart J 2007

Ticagrelor

Gurbel et al Circulation 2009

New oral antiplatelet agents can achieve faster and stronger

platelet inhibition

0

5

10

15

0 30 60 90 180 270 360 450

HR 0.81(0.73-0.90)P=0.0004

Prasugrel

Clopidogrel

Days

Endp

oint

(%)

12.1

9.9

HR 1.32(1.03-1.68)P=0.03

Prasugrel

Clopidogrel1.82.4

138 events

35 events

TRITON: Prasugrel vs clopidogrel in ACS

CV Death / MI / Stroke

TIMI Major NonCABG Bleeds

NNT = 46

NNH = 167

Wiviott S et al NEJM 2007

PLATO: ticagrelor vs clopidogrel in ACSPrimary endpoint time to CV death, MI or stroke

No. at risk

Clopidogrel

Ticagrelor

9,291

9,333

8,521

8,628

8,362

8,460

8,124

Days after randomisation

6,743

6,743

5,096

5,161

4,047

4,147

0 60 120 180 240 300 360

121110

9876543210

13

Cu

mu

lati

ve in

cid

ence

(%

)

9.8

11.7

8,219

HR 0.84 (95% CI 0.77–0.92), p=0.0003

Clopidogrel

Ticagrelor

Wallentin et al NEJM 2009

Time to major bleeding – primary safety event

No. at risk

Clopidogrel

Ticagrelor

9,186

9,235

7,305

7,246

6,930

6,826

6,670

Days from first IP dose

5,209

5,129

3,841

3,783

3,479

3,433

0 60 120 180 240 300 360

10

5

0

15

Clopidogrel

Ticagrelor

11.2011.58

6,545

HR 1.04 (95% CI 0.95–1.13), p=0.434

K-M

est

imat

ed r

ate

(% p

er y

ear)

0 60 120 180 240 300 360

6

4

3

2

1

0

Clopidogrel (300 or 600)

Ticagrelor

4.0

5.1

HR 0.79 (95% CI 0.69–0.91), p=0.001

7

5

9,291

9,333

8,865

8,294

8,780

8,822

8,589

Days after randomisation

7079

7119

5,441

5,482

4,364

4,4198,626

Cu

mu

lati

ve i

nci

de

nce

(%

)Cardiovascular death over time

Wallentin et al NEJM 2009

Prasugrel or ticagrelor in STEMI patients?

Antithrombotic therapy: What do the Guidelines say?

Prasugrel in ACS

Pro

• Efficacy benefit

• 1 / day

• Possible greater efficacy and safety in diabetic patients

Against

• No cross over with clopidogrel

• Cost

• Restrictions– < 65 kg

– > 75 yo

– Previous stroke

Ticagrelor in ACS

Pro

• Efficacy benefit

• Mortality benefit

• Simplification (relative)

• Reversibility (relative)

Against

• Bid

• Extra-platelet effects– Bradycardia

– Dyspnea

• Cost

Prasugrel vs. Ticagrelor: Weighing pros and cons in order to build

your own algorithm

As simple as possible!

Which anticoagulant in primary PCI?

Antithrombotics in STEMI The Bichat formulary

STEMI – Primary PCI

• Aspirine – Load 500 mg– Maintenance 75 mg/j

• Ticagrelor– Load 180 mg– Maintenance 90 mg bid

• Bivalirudin (prolonged 4 h post PCI)• Abciximab for bailout

If bleeding risk or CI to ticagrelor or association to OAC: Clopidogrel 600/75

Emergency care

Antithrombotic therapy

Post discharge

Guidelines Implementation

Impact of combined secondary prevention therapy after myocardial infarction in USIC

2000

Danchin N et al. Am Heart J 2005

How to implement?

Importance to have a post discharge protocole

Importance to have a post discharge network

A precise analysis of local conditions is key for guidelines implementation

Availability of medications

Cost of medication

Reimbursement system

Compliance of patients

Side effects

Geographic variations

Medication use, no. (%)

North

America

Latin

America

Western

Europe

Eastern

Europe

Middle East

Asia

Japan

No. of patients 9 420 776 8 531 3 194 334 1 860 2 274

≥ 1 antiplatelet drug 7 982 (84.8) 729 (94.1) 7 285 (85.5) 2 807 (87.9) 313 (93.7) 1 686 (90.7) 1 989 (87.5)

Aspirin 7 482 (79.5) 682 (88.0) 6 102 (71.8) 2 539 (79.5) 299 (89.5) 1 383 (74.4) 1 757 (77.3)

Aspirin + another antiplatelet drug 1 580 (16.8) 181 (23.4) 1 190 (14.0) 541 (16.9) 31 (9.3) 264 (14.2) 417 (18.3)

Statins 7 681 (81.7) 568 (73.3) 6 772 (79.5) 2 084 (65.3) 299 (89.5) 1 334 (71.7) 1 176 (51.7)

β-blockers 5 942 (63.3) 416 (53.7) 5 712 (67.3) 2 409 (75.5) 237 (71.4) 1 058 (56.9) 697 (30.7)

ACE inhibitors 4 432 (47.3) 376 (48.7) 4 216 (49.7) 2 418 (75.8) 189 (56.8) 712 (38.3) 473 (20.8)

Ducrocq et al EJCPR 2013

Guidelines implementation is part of a global endeavor aiming

to reduce mortality in STEMI

Evolution of 30-day mortality after MI Data from the nationwide french registries

Puymirat et al. JAMA 2012

USIK USIC-2000 FAST-MI FAST-MI-2

Long-term death rates post ACS remain highThe UK–Belgian GRACE experience

Fox KAA, et al. Eur Heart J 2010

Merci!

Total major bleeding

NS

NS

NS

NS

NS

0

K-M

esti

mate

d r

ate

(%

per

year)

PLATO major bleeding

1

2

3

4

5

6

7

8

9

10

1211

13

TIMI major bleeding

Red cell transfusion*

PLATO life-threatening/

fatal bleeding

Fatal bleeding

Major bleeding and major or minor bleeding according to TIMI criteria refer to non-adjudicated events analysed with the use of a statistically programmed analysis in accordance with definition described in Wiviott SD et al. NEJM 2007;357:2001–15; *Proportion of patients (%); NS = not significant

11.6 11.

2

7.9 7.7

8.9 8.9

5.8 5.8

0.3 0.3

TicagrelorClopidogrel

Wallentin et al NEJM 2009

PLATO: CABG and NonCABG Major Bleeding*

*Both groups included aspirin; Patients may be counted in more than 1 bleeding event category. The graded areas in the middle of the columns represent patients with both a CABG bleed and a non-CABG bleed

11.6

4.5

7.4

11.2

3.8

7.9

P=NS

P=0.03

K-M

est

imat

ed r

ate

(% p

er y

ear)

0

1

2

3

4

5

6

7

8

9

10

12

11

13

Ticagrelor/clopidogrelTIMI Major Bleeding

Ticagrelor/clopidogrel PLATO Major Bleeding

NonCABG

CABG

7.9 7.7

5.3

2.8

5.8

2.2

P=0.03

P=NS

NonCABG

CABG

NS

Wallentin et al. N Engl J Med. 2009;361:1045-1057

NS

Minor and minimal bleeding in PLATOE

vent

s (%

pat

ient

s)

4.8 3.8

17.2

10.6

0

10

20

30

40

Ticagrelor Clopidogrel Ticagrelor Clopidogrel

n=442 n=349 n=1587 n=970

Minor bleeding† Minimal bleeding†

*Both groups included aspirin

PLATO: Bradycardia-related Events

All PatientsTicagrelor(n=9,

235)Clopidogrel

(n=9,186) P Value

Bradycardia-related event, n (%)

Pacemaker insertion 82 (0.9) 79 (0.9) 0.87

Syncope 100 (1.1) 76 (0.8) 0.08

Bradycardia 409 (4.4) 372 (4.0) 0.21

Heart Block 67 (0.7) 66 (0.7) 1.00

• Ventricular pauses ≥3 seconds occurred in 5.8% of ticagrelor-treated patients vs 3.6% of clopidogrel-treated patients in the acute phase, and 2.1% and 1.7% after 1 month, respectively

• There were no differences in adverse clinical consequences (ie, pacemaker insertion, syncope, bradycardia, and heart block)

Wallentin L, et al. N Engl J Med. 2009;361:1045–1057.BRILIQUE: Summary of Product Characteristics, 2010.

PLATO: Dyspnoea

• Ticagrelor-associated dyspnoea was mostly mild to moderate in severity and did not reduce efficacy

• Most events were reported as single episode occurring early after starting treatment• Not associated with new or worsening heart or lung disease• In 2.2% of patients, investigators considered dyspnoea causally related to treatment with

BRILIQUE • Label precautions and warnings: use with caution in patients with history of asthma and

COPD

BRILIQUE: Summary of Product Characteristics, 2010.Wallentin L, et al. N Engl J Med. 2009;361:1045–1057.Storey R, et al. J Am Coll Cardio. 2010;55(Suppl 1):A108.E1007.

Dyspnoea in the PLATO trial Ticagrelor Clopidogrel P Value

Incidence of dyspnoea adverse events (%) 13.8 7.8 <0.001

Patients who discontinued treatment due to dyspnoea (%) 0.9 0.1 <0.001

Landmark analyses of the incidence of new dyspnoea AE post randomization showing (A) onset of any dyspnoea AE in the first 30 days; (B) onset of any dyspnoea AE from 31

days onwards; (C) onset of a dyspnoea AE judged to be unexplained or unknown aetiology in the first 30 days; and (D) onset of a dyspnoea AE judged to be unexplained

or unknown aetiology from 31 days onwards.

Storey R F et al. Eur Heart J 2011;32:2945-2953

Pulmonary function results according to treatment with either ticagrelor 90 mg twice daily (T) or clopidogrel 75 mg daily (C)

RF.Storey , et al. Am J Cardiol 2011;108:1542-6

Pulmonary Function in Patients With Acute Coronary Syndrome Treated With Ticagrelor or Clopidogrel (from the PLATO Pulmonary Function Substudy)

Study Day

*

Tic

agre

lor

Clo

pid

og

rel

10 15 20 25 30 35 40 45 50 551 5

Study Drug Administration Period (42 3 days)

Pla

ceb

o

Individual Profiles for Patients With Dyspnea

Mild dyspnea

Moderate dyspnea

Mild dyspnea of 4 hours

Moderate dyspnea lasting 5 minutes

*

Prematurely discontinued drug

Storey RF et al. J Am Coll Cardiol 2010

Each line or symbol

represents individual

patient data and duration of

event.

PLATO: Laboratory Parameters

All PatientsBRILIQUE (n=9,235)

Clopidogrel (n=9,186) P Value

Mean % increase (± SD) in serum creatinine from baseline

At 1 month 10 ± 22 8 ± 21 <0.001

At 12 months 11 ± 22 9 ± 22 <0.001

1 month after end of treatment 10 ± 22 10 ± 22 0.59

Mean % increase (± SD) in serum uric acid from baseline

At 1 month 14 ± 46 7 ± 44 <0.001

At 12 months 15 ± 52 7 ± 31 <0.001

1 month after end of treatment 7 ± 43 8 ± 48 0.56

Wallentin L, et al. N Engl J Med. 2009;361:1045–1057.BRILIQUE: Summary of Product Characteristics, 2010.

• Creatinine levels may increase during treatment with BRILIQUE; renal function should be checked after 1 month and thereafter according to medical practice

• Label precautions and warnings: as a precautionary measure, the use of BRILIQUE in patients with uric acid nephropathy is discouraged

Ticagrelor (742/9235)

Days from First IP DoseNo. at RiskTicagrelor 9235 8380 7740 7470Clopidogrel 9186 8644 8053 7844

Kap

lan

–Mei

er P

erce

nta

ge,

% 8.29%

3.84%

AE, adverse event; CI, confidence interval; HR, hazard ratio; IP, investigational productStorey RF et al. Eur Heart J 2011

PLATO: Any Dyspnoea AE (≤30 Days)9

8

7

6

5

4

3

2

1

00 10 20 30

HR: 2.24 (95% CI 1.97–2.54), P<0.001

Clopidogrel (339/9186)

Clopidogrel: Total Death in Patients with Dyspnoea AE Within 30 Days

8.51%

3.39%

No. at RiskDyspnoea Event 331 319 314 264 240 191No Dyspnoea Event 8557 8419 8344 7036 6608 4853

AE, adverse event; CI, confidence interval; HR, hazard ratioStorey RF et al. Eur Heart J 2011

Days from Randomisation

Kap

lan

–Mei

er P

erce

nta

ge,

%

9

8

7

6

5

4

3

2

1

031 90 150 330210 270

HR: 2.73 (95% CI 1.82–4.09), P<0.001

Dyspnoea Event (26/331)

No Dyspnoea Event (250/8557)

82

3.04%2.54%

Days from Randomisation

Kap

lan

–Mei

er P

erce

nta

ge,

%

9

8

7

6

5

4

3

2

1

090 150 330210 270

Dyspnoea Event (19/726)

31

HR: 1.11 (95% CI 0.69–1.78), P=0.659

AE, adverse event; CI, confidence interval; HR, hazard ratioStorey RF et al. Eur Heart J 2011

No. at RiskDyspnoea Event 726 717 713 628 582 431No Dyspnoea Event 8221 8089 8004 6711 6220 4666

Ticagrelor: Total Death in Patients with Dyspnoea AE Within 30 Days

No Dyspnoea Event (190/8221)

83

Forest plot of Log of HRs by

country

Ticagrelor better Clopidogrel better

Ti. Cl.Total

Patients

KM % atMonth 12

HR (95% CI)Hazard Ratio

(95% CI)

Yes

Yes

Revascularization History of CABG

Sex

Weight Group

≥65 Years

Characteristic

0.5 1.0 2.0

17,256 9.5 11.2 0.86 (0.78, 0.94)<80 kg

1312 13.1 17.3 0.75 (0.60, 0.99)≥60 kg

5288 11.2 13.2 0.83 (0.71, 0.97)

<60 kg

13,336 9.2 11.1 0.85 (0.76, 0.95)Female

2878 16.8 18.3 0.94 (0.78, 1.12)

Male

15,744 8.6 10.4 0.82 (0.74, 0.91)≥75 Years

7979 13.2 16.0 0.83 (0.74, 0.94)<75 Years

10,643 7.2 8.5 0.85 (0.74, 0.97)<65 Years

1152 19.0 20.8 0.87 (0.66, 1.13)Age Group

17,462 9.2 11.1 0.84 (0.76, 0.93)No

1106 19.5 21.7 0.88 (0.67, 1.15)Previous TIA/Non-hemorrhagic Stroke

17,518 9.2 11.0 0.84 (0.77, 0.93)No

Yes

≥80 kg

4662 14.1 16.2 0.88 (0.76, 1.03)13,962 8.4 10.2 0.83 (0.74, 0.92)No

9513 8.3 10.5 0.79 (0.69, 0.90)Medical History of DM

9055 11.4 12.8 0.90 (0.79, 1.01)

0.2

P value(Interaction)

0.76

0.84

0.86

0.22

0.82

0.36

0.17

0.49

PLATO primary endpoint in predefined subgroupsNo interaction with prior stroke/TIA, age or body weight

Wallentin L, et al. N Engl J Med. 2009;361:1045-1057 and supplementary tables

The adenosine hypothesis

The formation of adenosine increases in response to, for example:

Hypoxia Tissue damage

Adenosine has been attributed a number of potential positive effects including:

Vasodilation Cardiac pre-conditioning Antiplatelet activity Immuno-modulation

...but is also implicated in dyspnea, ventricular pauses and renal function

Importance of pre-treatment with clopidogrel in ACS

Bellemain-Appaix A, et al. JAMA. 2012;308:2507-16.

Contraindications• Contraindications specific to BRILIQUE

– Hypersensitivity to the active substance (BRILIQUE) or to any of the excipients

– Active pathological bleeding– History of intracranial haemorrhage– Moderate-to-severe hepatic impairment– Combination with strong CYP3A4 inhibitors such

as ketoconazole, clarithromycin, nefazodone, ritonavir and atazanavir is contraindicated, as co-administration may lead to substantial increases in exposure to BRILIQUE

BRILIQUE: Summary of Product Characteristics, 2010.