Surveying the Landscape of NSTE ACS - icep.org€¦ · Surveying the Landscape of ... UA/NSTEMI †...

Surveying the Landscape of Therapy in NSTE‐ACS

Yanina Purim-Shem-Tov, MD, MS, FACEPAssociate Professor

Medical Director, Chest Pain Center

Medical Director of Clinical Practice, Emergency Department

Rush University Medical Center

Chicago, IL

Disclosure

• No financial conflicts of interest

2

Goals and Objectives

• Epidemiology/ pathophysiology (brief)

• Recognize the clinical features of low, intermediate and high risk ACS

• Discuss pharmacological treatments (focus on antiplatelet therapy)

• Be able to identify and treat patients appropriate for a conservative or invasive strategy

3

Overview of ACS

Acute Coronary Syndromes*

1.57 Million Hospital Admissions - ACS

UA/NSTEMI† STEMI

1.24 millionAdmissions per year

0.33 millionAdmissions per year

*Primary and secondary diagnoses. †About 0.57 million NSTEMI and 0.67 million UA.Heart Disease and Stroke Statistics – 2007 Update. Circulation 2007; 115:69–171.

4

Pathophysiology of ACSEvolution of Coronary Thrombosis

Davies MJ. Circulation. 1996;94:2013

Pathogenesis of Acute Coronary Syndromes: The “Ruptured” Plaque

Fissures inthe fibrous cap

6

Distal embolization in the setting of a ruptured plaque is the most likely cause of troponin elevation

Greater troponin elevation is associated with a more extensive plaque rupture event and more associated thrombus

Distal Embolization:Pathogenesis of Troponin Elevation in

NSTEMI

7

Evidence for Distal EmbolizationArteriole 100% occluded by a platelet thrombus

8

Unstable Angina STEMINSTEMI

Non occlusive thrombus

Non specific ECG

Normal cardiac enzymes

Non-occlusive thrombus sufficient to cause tissue damage & mild myocardial necrosis

ST depression +/-T wave inversion on ECG

Elevated cardiac enzymes

Complete thrombus occlusion

ST elevations on ECG or new LBBB

Elevated cardiac enzymes

More severe symptoms

Initial Evaluation and management of Non ST‐elevation ACS

Initial Evaluation and Management

•History and Physical•ECG•Cardiac Biomarkers

Establish the Likelihood thatClinical PresentationRepresents an ACSSecondary to CAD

Risk Stratify for Short-termAdverse Outcomes

10

Clinical Features of NSTEMI

11

12

Likelihood of ACS by Hx/PE

• History/Examination – Pain in Chest or Left Arm

– CP Radiation

• Right Shoulder

• Left Arm

• Both Left & Right Arm

– Diaphoresis

– 3rd Heart Sound

– SBP < 80 mm Hg

– Pulmonary Crackles

Panju AA. JAMA. 1998;280:1256.

Suggesting AMILR 2.7

LR 2.9 (1.4‐6.0)

LR 2.3 (1.7‐3.1)

LR 7.1 (3.6‐14.2)

LR 2.0 (1.9‐2.2)

LR 3.2 (1.6‐6.5)

LR 3.1 (1.8‐5.2)

LR 2.1 (1.4‐3.1)

13

Likelihood of ACS by Hx/PE

• Clinical Examination –– Pleuritic Chest Pain– Sharp or Stabbing Pain– Positional Chest Pain– Reproducible Chest Pain

Against AMI

LR 0.2 (0.2-0.3)

LR 0.3 (0.2-0.5)

LR 0.3 (0.2-0.4)

LR 0.2-0.4

Panju AA. JAMA. 1998;280:1256.

Risk Stratification by ECG

• ECG Findings and Associated LR for AMI

– New ST‐E > 1mm LR 5.7‐53.9

– New Q waves LR 5.3‐24.8

– Any ST‐E LR 11.2 (7.1‐17.8)

– New Conduction Defect LR 6.3 ( 2.5‐15.7)

– New ST‐D LR 3.0‐5.2

– NORMAL ECG LR 0.1‐0.4Panju AA. JAMA. 1998;280:1256.

CAVEATS 1‐8% AMI have a normal ECGOnly Approx 50% of AMI patients have diagnostic changes on their initial ECG1 ECG cannot exclude AMIBrief sample of a dynamic processSmall regions of ischemia or infarction may be missed

Peter J. Zimetbaum, M.D., N Engl J Med 2003;348:933‐40.

Risk Stratification by Troponin

17

18

Incremental Sensitivity for Detecting ACS within 30 days

Ann Emerg Med 2002; 40: 584-594

Early Invasive

Conservative

19

Medical Therapy

20

Antiplatelet Therapy

Mechanism of Action of Antiplatelet Agents

21

Bhatt D. N Engl J Med 2007;10.1056

Role of Platelet Activation and Aggregation in Acute Coronary Syndromes

22

Role of Platelet Activation and Aggregation in Acute Coronary Syndromes

Adhesion, Activation

Amplification Aggregation

Bhatt D. N Engl J Med 2007;10.105623

Mechanism of Action of Antiplatelet Therapies

Schafer AI: Am J Med 1996:101;199

Clopidogrel, Prasugrel (irreversible)

Ticagrelor (reversible)

GPIIb/IIIa Antagonists:Abciximab (irreversible)Eptifibatide, Tirofiban

(reversible)

Collagen, Thrombin

TXA2

GPIIbIIIa Receptor

24

25

Level or Treatment Recommendations


Aspirin

26






(reversible)

Collagen, Thrombin

TXA2

GPIIbIIIa Receptor

27

UA/NSTEMI – Antiplatelet Therapy

ASA as soon as possible after presentation and continued indefinitely in patients who tolerate it

If ASA intolerant, clopidogrel, prasugrel (PCI) or ticagrelor(loading and maintenance dose)

28Jneid H et al. J Am Coll Cardiol 2012;60:645-81.

2012 ACCF/AHA UA/NSTEMI Focused Update

For both early invasive and conservative strategy

II IIaIIa

IIbIIb

IIIIII

A

B

ESC NSTEMI 2011:Recommendations for antiplatelet agents

Recommandations Class Level

Aspirin should be given to all patients without contraindications at an initial loading dose of 150-300 mg, and at a maintenance dose of 75-100 mg dailylong-term regardless of treatment strategy.

I A

European Heart Journal (2011) 32:2999–3054; doi:10.1093/eurheartj/ehr23630

NEJM and Lancet 2010 31

ASA 75‐100 mg

ASA300‐325 mg HR 95% CI P

CV Death/MI/Stroke

Overall (2N=25,087) 4.4 4.2 0.97 0.86‐1.09 .61

PCI (2N=17,232) 4.2 4.1 0.98 0.84‐1.13 .76

No PCI (2N=7855) 4.7 4.4 0.92 0.75‐1.14 .44

Stent thrombosis 2.1 1.9 0.91 0.73‐1.12 .37

TIMI major bleed 1.4 1.6 1.09 0.89‐1.34 .39

CURRENT major bleed 2.3 2.3 0.99 0.84‐1.17 .90

CURRENT severe bleed 1.7 1.7 1.01 0.84‐1.22 1.00

GI Bleeds: 19 (0.2%) vs. 47 (0.4%), P=.04

CURRENT–OASIS 7 Investigators. N Engl J Med. 2010;363(10):930‐942.

Results: ASA Dose ComparisonPrimary Outcome and Bleeding

32


Clopidogrel

33






(reversible)

Collagen, Thrombin

TXA2

GPIIbIIIa Receptor

Thienopyridines and ticagrelor block the P2Y12 receptor and inhibit ADP-induced

platelet activation

34

Months of Follow‐up

Yusuf S et al. N Engl J Med. 2001;345:494‐502.

CURE Study Primary end point: MI/stroke/CV death

Clopidogrel + Aspirin(n=6259)

Placebo + Aspirin(n=6303)

P<0.001n=12,562

3 6 90 12

20%Relative RiskReduction

0.12

0.14

0.10

0.06

0.08

0.00

0.04

0.02Cumulative Hazard Rate

35

36


Before PCI, clopidogrel (300‐600 mg)

At the time of PCI, clopidogrel (if not begun earlier)

Duration of maintenance doseClopidogrel for at least 1yr

If risk of morbidity (bleeding) outweighs anticipated benefits, earlier discontinuation should be considered

Wright RS, et al. J Am Coll Cardiol 2011;57:1920–59.

2011 ACC/AHA UA/NSTEMI Focused Update Class I Recommendations (should be given, benefit >>> risk)

Early invasive strategy and conservative Rx with PCI

B

A

B

C

II IIaIIa IIIIIIII

IIbIIb

NEJM and Lancet 2010 37

Total population

PCI population

HR 0.86; P=0.039

CURRENT‐OASIS 7

38

High dose:600 mg load, 150 mg/day x 6d, then 75/dvs. Standard dose: 300 mg load, 75mg/d

NEJM and Lancet 2010

39


Clopidogrel 600 mg followed by a higher maintenance dose of 150 mg daily for 6 days, then 75 mg daily may be reasonable in patients not considered at high risk for bleeding


2011 ACC/AHA UA/NSTEMI Focused Update Class IIb Recommendations (may be considered, benefit > risk)EARLY INVASIVE STRATEGY

40

FDA Boxed Warning on ClopidogrelWARNING: DIMINISHED EFFECTIVENESS IN POOR

METABOLIZERS Effectiveness of clopidogrel depends on activation to an

active metabolite by the cytochrome P450 (CYP) system, principally CYP2C19

Poor metabolizers treated with clopidogrel at recommended doses exhibit higher cardiovascular event rates following acute coronary syndrome (ACS) or percutaneous coronary intervention (PCI) than patients with normal CYP2C19 function

Tests are available to identify a patient’s CYP2C19 genotype, and can be used as an aid in determining therapeutic strategy

Consider alternative treatment or treatment strategies in patients identified as CYP2C19 poor metabolizers

FDA Drug Safety Communication. March 12, 2010. http://www.fda.gov/drugs/drugsafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm203888.htm

Roles in Clopidogrel Activity of Proteins with Known Genetic Polymorphisms

Cytochrome P450 enzymes, especially CYP2C19, play an important role in the conversion of clopidogrel to its active metabolite1

Patients carrying reduced function CYP2C19 alleles2

Reduced level active metabolite

Less platelet inhibition Observed increased risk of

ischemic events

1. Reprinted from Simon T, et al. N Engl J Med. 2009;360(4): 363‐375.

2. Storey RF. Lancet. 2009;373(9660):276‐278.41

Mega J, et al. N Engl J Med. 2009;360(4):354‐362.

CV Risk with Clopidogrel CYP2C19 Reduced‐function Allele: TRITON‐TIMI 38

Days since randomization

HR, 1.53; 95% CI, 1.07‐2.19Incidence of CV death,

MI, or stroke (%)

Carriers

Noncarriers

12.112

10

0

2

4

6

8

0 30 90 180 270 360 450

8.0

42


Prasugrel

43

Active Metabolite Formation:Prasugrel and Clopidogrel

5. Kurihara et al. Drug Metab Rev. 2005;37(S2):99.6. Lagorce et al. J Chromatogr B Biomed Sci Appl. 1998;720:107‐117.7. Tang et al. J Pharmacol Exp Ther. 2006;319:1467‐1476.8. Plavix Full Prescribing Information.

1. Rehmel et al. Drug Metab Dispos. 2006;34:600‐607.2. Williams et al. Drug Metab Dispos. 2008;36:1227‐1232.3. Farid et al. J Clin Pharmacol. 2009 Nov 30. [Epub ahead of print].4. Savi et al. Thromb Haemost. 2000;84:891‐896.

Clopidogrel4–8Prasugrel1–3

Genetic variation in CYP2C19 can impair metabolism

No relevant effect of genetic variation in CYP2C19

GutHydrolysis

hCE2

Intermediate

Active metabolite

Gut & Liver Oxidation

CYP3A, 2B6,2C9, 2C19

1st Oxidation

CYP1A2, 2B6, 2C19

Intermediate

2nd Oxidation

CYP3A, 2B6,2C9, 2C19

Liver

LiverHydrolysishCE1

85% Inactive Metabolite8

Active Metabolite

44

Prasugrel Compared with Higher-dose Clopidogrel

Wiviott SD, et al; PRINCIPLE-TIMI 44 Investigators. Circulation. 2007;116(15):2923-2932.

P<.0001 for each

IPA (%; 20 μM ADP)

Hours

N=201

Prasugrel 60 mg

Clopidogrel 600 mg30.8

64.5

74.8

69.3

4.9

20.3

31.8

32.6

0

20

40

60

80

100

0 4 8 12 16 20 24 28

14 Days

IPA (%; 20 μM ADP)

P<.0001

Prasugrel 10 mg

Clopidogrel 150 mg

46.1

61.3

0

20

40

60

80

100

45

TRITON‐TIMI 38 Study Design

Wiviott SD et al. Am Heart J. 2006;152:627‐635.

UTVR = urgent target vessel revascularization

NSTEMI = non‐ST segment elevation MI

ACS (STEMI or UA/NSTEMI) & Planned PCI

ASA

PRASUGREL60 mg LD/ 10 mg MD

CLOPIDOGREL300 mg LD/ 75 mg MD

1o endpoint: CV death, MI, stroke2o endpoints: CV death, MI, stroke, rehosp‐rec isch CV death, MI, UTVR

n=13,600

Median duration of therapy ‐ 12 months

Double‐blind

46

47

TRITON TIMI‐38

Days

35events

HR 0.81(0.73‐0.90)P=0.0004

HR 1.32(1.03‐1.68)P=0.03

138events

NNT=46

NNH=167

Wiviott SD et al. N Engl J Med. 2007;357:2001‐2015.

End Point (%

)

12.1

9.9

1.8

2.4

0

5

10

15

0 30 60 90 180 270 360 450

CV Death/MI/stroke

TIMI Major Non‐CABG bleeds

Clopidogrel

Prasugrel

Prasugrel

Clopidogrel

HR = hazard ratioNNT = number needed to treatNNH = number needed to harm

Balance of efficacy and safety

48

TRITON TIMI‐38: Stent Thrombosis

Days

0

1

2

3

0 30 60 90 180 270 360 450

HR 0.48P<0.0001

Prasugrel

Clopidogrel 2.4(142)

74 events

NNT=77

1.1 (68)En

d Point (%

)

Any Stent at Index PCIn=12,844

Wiviott SD et al. N Engl J Med. 2007;357:2001‐2015.

ARC definite + probable

ARC = Academic Research Consortium PCI = Percutaneous Coronary Intervention

49

TRITON TIMI‐38 Net Clinical Benefit

Post‐hoc analysisWiviott SD et al. N Engl J Med. 2007;357:2001‐2015.

Overall

≥60 kg

<60 kg

<75

No

Yes

0.5 1 2

PriorStroke / TIA

Age

Weight

Risk (%)

+ 37

‐16

‐1

‐16

+3

‐14

‐13

Prasugrel better Clopidogrel betterHazard ratio

Pint = 0.006

Pint = 0.18

Pint = 0.36

≥75

Bleeding risk subgroups

50

CYP2C19 Reduced‐function Allele Carrier Status and Clinical Outcomes in Prasugrel Patients

Number at risk

Carriers*Non-carriers

407 383 376 320 276 1883641048 982991 951 849 750 541

Days after randomization

Mega et al. Circulation. 2009;119:2553‐2560.

0

2

4

6

8

10

12

14

CV

dea

th, n

onfa

tal M

I,

or n

onfa

tal s

trok

e (%

)

A Subanalysis from the TRITON-TIMI 38 trial

HR 0.89P=0.27

9.88.5

0 30 90 180 270 360 450

Non-carriers

Carriers

*Represents a mixture of intermediate and poor metabolizers

Days after randomization

CV

dea

th, n

onfa

tal M

I,or

non

fata

l str

oke

(%)

51

CYP2C19 Reduced‐function Allele Carrier Status and Clinical Outcomes in Clopidogrel Patients

Number at riskCarriers* 395 364 360 306 270 181348Non-carriers 1064 9991009 980 870 755 542

A Subanalysis from the TRITON-TIMI 38 trial

0

2

4

6

8

10

12

14

30 90 180 270 360 450

12.1

8.0

HR 1.53P=0.01

Non-carriers

Carriers

0

Mega et al. N Engl J Med. 2009;360:354‐362.*Represents a mixture of intermediate and poor metabolizers

52


At the time of PCIClopidogrel (if not begun earlier), or

Prasugrel, or

GP IIb/IIIa inhibitor

For patients with a prior history of stroke and/or TIA for whom PCI is planned, prasugrel is potentially harmful as part of a dual‐antiplatelet therapy regimen


2011 ACC/AHA UA/NSTEMI Focused Update Class I Recommendations (should be given, benefit >>> risk)

Early invasive strategy

II IIaIIa IIIIIIII

IIbIIb

BA

A

A

ESC NSTEMI 2011:Recommendations for antiplatelet agents

Recommendations Class Level

A P2Y12 inhibitor should be added to aspirin as soon as possible and maintained over 12 months, unless there are contraindications such as excessive risk of bleeding.

I A

Prasugrel (60 mg loading dose, 10 mg daily dose) is recommended forP2Y12-inhibitor-naïve patients (especially diabetics) in whom coronary anatomyis known and who are proceeding to PCI unless there is a high risk of life-threatening bleeding or other contraindications.

I B

European Heart Journal (2011) 32:2999–3054; doi:10.1093/eurheartj/ehr236 53

TRILOGY ACS Study Design

Medically Managed UA/NSTEMI Patients

Clopidogrel1

75 mg MD

Prasugrel1

5 or 10 mg MD

Minimum Rx Duration: 6 months; Maximum Rx Duration: 30 months

Primary Efficacy Endpoint: CV Death, MI, Stroke

Randomization Stratified by:Age, Country, Prior Clopidogrel Treatment(Primary analysis cohort — Age < 75 years)

Clopidogrel1300 mg LD

+75 mg MD

Prasugrel130 mg LD

+5 or 10 mg MD

Medical Management Decision ≤72 hrs(No prior clopidogrel given) — 4% of total

Medical Management Decision ≤ 10 days(Clopidogrel started ≤ 72 hrs in-hospital OR

on chronic clopidogrel) — 96% of total

1. All patients were on aspirin and low-dose aspirin (< 100 mg) was strongly recommended. For patients <60 kg or ≥75 years, 5 mg MD of prasugrel was given. Adapted from Chin CT et al. Am Heart J 2010;160:16-22.e1.

Median Time to Enrollment = 4.5 Days

Roe MT, et al. NEJM 2012;367:1297. 54

HR (95% CI) ≤ 1 Year:0.99 (0.84, 1.16)

HR (95% CI) > 1 Year:0.72 (0.54, 0.97)

Primary Efficacy Endpoint to 30 Months(Age < 75 years)

HR (95% CI):0.91 (0.79, 1.05)

P = 0.21

Interaction P = 0.07

Roe MT, et al. NEJM 2012;367:1297.

TIMI Major Bleeding to 30 Months(Age < 75 years)

HR (95% CI):1.31 (0.81, 2.11)

P = 0.27

Roe MT, et al. NEJM 2012;367:1297.


Ticagrelor

57

58

Ticagrelor – Pharmacology

Non‐thienopyridine platelet P2Y12 antagonistDirect acting (not a pro‐drug), does not require cytochrome P450 metabolic activation to exert its antiplatelet effect

Faster, greater and more consistent inhibition of platelet function than clopidogrel

Reversibly binds to the P2Y12 receptorPotential advantage if needing to discontinue therapy due to surgery

Adapted from: Owen RT et al. AZD6140. Drugs of the Future. 2007;32 :845‐853.

TIME (hours)Gurbel PA, et al. Circulation. 2009;120(25):2577‐2585.

59

Wallentin L, et al. N Engl J Med. 2009;361(11):1045‐1057. 60

Wallentin L, et al. N Engl J Med. 2009;361(11):1045‐1057.

UA/NSTEMI (moderate‐high risk)STEMI (if primary PCI)

All receiving ASAClopidogrel‐treated or naïve

Clopidogrel (n=6676)If pretreated, no additional load;if naïve, standard 300 mg load,then 75 mg daily maintenance

(additional 300 mg allowed pre‐PCI)

1 end point: CV death/MI/stroke2 end point: CV death/MI/stroke/revascularization with PCI;

CV death/MI/stroke; severe recurrent ischemia1 safety end point: total major bleeding

12‐month maximum exposure(min, 6 mo; max, 12 mo; mean, 11 mo)

N=18,624 patients

Ticagrelor (n=6732)180 mg load, then

90 mg bid maintenance(additional 90 mg pre‐PCI)

PLATO PLATelet Inhibition and Patient Outcomes

61

Early Randomization: ACS Patient

Admission Initial Management Angiography PCI

Hospital Course

PLATO TRITON

PLATO Key Feature #1

In ER, irrespective of Clopi Pre-Rx

In Cath Lab, with no Clopi Pre-Rx

James S, et al. Am Heart J. 2009;157:599-605; Wiviott SD, et al. N Engl J Med. 2007;357:2001-2015; Wiviott SD, et al. Am Heart J 2006;152:627235 62

Irrespective of Management Strategy

Start Antiplatelet therapy

(PLATO randomization)

StopAntiplatelet

Therapy

Emergency Room – Initial ECG

Invasive/CatheterizationLaboratory

Determine CV anatomy and clinical strategy

Manage Medically PCI

Continue antiplatelet therapy When medically

appropriate

CABG

STE (40%), NSTEMI (40%), UA (20%)


Irrespective of Management Sx

James S, et al. Am Heart J. 2009;157:599-605.

63

ACS Patient

STEMI

NSTEMI

Primary PCI

Fibrinolytic Rx

No Reperf

Early Invasive Rx

Early Conservative Rx

PCI

Medical Rx

CABG

PCI

Medical Rx

CABG

Fibrinolytic excluded within24 hours


James S, et al. Am Heart J. 2009;157:599-605.

Broad ACS Population

64

Wallentin L, et al. N Engl J Med. 2009;361:1045–1057.

Both groups included aspirin.*NNT at one year.

PLATO: Primary Efficacy Endpoint(Composite of CV Death, MI, or Stroke)

65

No. at risk

Clopidogrel

Ticagrelor

9,291

9,333

Months After Randomization

8,521

8,628

8,362

8,460

8,124 6,650

6,743

5,096

5,161

4,047

4,1478,219

0 2 4 6 8 10 12

12111098765432

10

13

Cu

mu

lati

ve

In

cid

en

ce

(%

) 11.7 Clopidogrel

9.8 Ticagrelor

ARR=0.6%

RRR=12%

P=0.045

HR: 0.88 (95% CI, 0.77−1.00)

0–30 Days

4.8

5.4Clopidogrel

Ticagrelor

ARR=1.9%

RRR=16%

NNT=54*

P<0.001

HR: 0.84 (95% CI, 0.77–0.92)

0–12 Months

Secondary Efficacy EndpointsMI and CVD follows PEP

Wallentin L, et al. N Engl J Med. 2009;361:1045–1057.

ARR=1.1%

RRR=16%

NNT=91

P=0.005

HR: 0.84 (95% CI, 0.75–0.95)

ARR=1.1%

RRR=21%

NNT=91

P=0.001

HR: 0.79 (95% CI, 0.69–0.91)

66

67

68

PLATO: Time to major bleeding: primary safety endpoint

K-M

est

ima

ted

ra

te (

% a

t 1

ye

ar)

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

Days from first IP dose

10

5

0

15

0 60 120 180 240 300 360

Clopidogrel

Ticagrelor

11.2%11.6%

(HR 1.04; 95% CI, 0.95-1.13; P=0.43)

P=NS

#Both groups included aspirin

No. at risk

Ticagrelor 9235 7246 6826 6545 5129 3783 3433

Clopidogrel 9186 7305 6930 6670 5209 3841 3479

NS=non-significant

PLATO: bradycardia-related events and Holter monitoring programAll Patients

Ticagrelor (n=9235)

Clopidogrel (n=9186)

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*

Holter monitor first week, n (%) Ticagrelor (n=1451)


P value

Ventricular pauses ≥3 seconds 84 (5.8) 51 (3.6) 0.01

Ventricular pauses ≥5 seconds 29 (2.0) 17 (1.2) 0.10*

Holter monitor at 30 days, n (%) Ticagrelor (n=985)


P value



Wallentin L, et al. New Engl J Med. 2009;361:1045–1057.

* * Not significant*69

Dyspnoea in PLATO• Dyspnoea was reported more frequently by patients on

ticagrelor than clopidogrel (13.8% vs 7.8%; P<0.001)– More patients on ticagrelor discontinued study drug because of

dyspnoea, but numbers were small (0.9% vs 0.1%, P<0.001)

• The higher frequency of dyspnoea with ticagrelor was not associated with any detectable detrimental effect on pulmonary function compared with clopidogrel– Most episodes lasted less than a week

– Ticagrelor-associated dyspnoea was mostly mild to moderate and did not affect efficacy

Wallentin L, et al. N Engl J Med. 2009;361:1045-1057; Storey R, et al. JACC. 2010;55(Suppl 1):A108.E1007. 70

71

Mahaffey, Circ 2011;124:544 72

73

Patient disposition

18,624 patients randomized

CABG in 1899 patients during the course of the

study

CABG in 1261 patients with last intake of study drug ≤7 days

prior to surgery

632 patients treated with ticagrelor

629 patients treated with clopidogrel

CABG

Held C, et al. J Am Coll Cardiol 2011;57:000–00

74

75

Risk of the primary endpoint -CV death, MI, or stroke - after CABG

Months from CABG procedureNo. at risk

Clopidogrel

Ticagrelor

629

629

541

543

516

519

448 386

386

255

268

125

108458

0 1 2 3 4 5 6 7 8 9 10 11 12

14

13

12

11

10

9

8

7

6

5

4

3

2

1

Hazard ratio (HR): 0.84 (95% CI=0.60-1.16), P=0.29

13.1

10.6

Clopidogrel

Ticagrelor

Kap

lan

-Mei

er e

stim

ated

rat

e (%

)

ARR = 2.5%RRR = 16%

CABG


76

Risk of CV death after CABG

No. at risk

Clopidogrel

Ticagrelor629

629

565

583

539

557

472 404

415

269

291130

119491

0 1 2 3 4 5 6 7 8 9 10 11 12

8

7

6

5

4

3

2

1

0

Months from CABG procedure

HR: 0.52 (95% CI = 0.32-0.85), P<0.01

7.9

4.1

Clopidogrel

Ticagrelor

Kap

lan

-Mei

er e

stim

ated

rat

e (%

)

P=0.009

ARR = 3.8%RRR = 48%

CABG


ESC 2012 STEMI: Antiplatelet Recommendations

European Heart Journal (2011) 32:2999–3054; doi:10.1093/eurheartj/ehr23677

Comparison of Antiplatelet Agents

Loadingmaintenance

Clopidogrel300‐600 mg75 mg qday

Prasugrel60 mg

10 mg qday

Ticagrelor180 mg90 mg bid

UAP, NSTEMI, STEMI indication

Yes Yes Yes

Potency ++ +++ +++

Rapidity of onset + +++ ++++

Variable response Very variable No No

CYP2C19 carrier –clinical impact?

Yes No No

Reversibility Not reversible Not reversible Reversible

Hold before CABG 5 days 7 days 3‐5 days

Clinical experience ++++ +++ ++

Bleeding risk + ++ +

Side effects Rare Rare More common79


GP IIBIIIA Inhibitors

80






(reversible)

Collagen, Thrombin

TXA2

GPIIbIIIa Receptor

81

82

The FRISC II and TACTICS TIMI-18 trials demonstrated an additional benefit when a GP IIb/IIIa inhibitor was combined with an early invasive strategy. The largest benefit from early use of GP IIb/IIIa inhibitors is seen in patients at high risk, particularly those with significant elevations in troponin levels.

83

Recommendations for GP IIB-IIIA Inhibitor

Antiplatelet and Anticoagulation Treatments

84

85

86

Early Hospital CareAnti‐Ischemic Therapy• Class I

– Bed/Chair rest and Telemetry– Oxygen (maintain saturation >90%)– Nitrates (SLx3 Oral/topical. IV for ongoing ischemia, heart failure, hypertension)

– Oral B‐blockers in First 24‐hours if no contraindications. (IV B‐blockers class IIa indication)

– Non‐dihydropyridine Ca‐channel blockers for those with contraindication for B‐blockers

– ACE inhibitors in first 24‐hours for heart failure or EF<40% (Class IIa for all other pts) (ARBs for those intolerant)

– Statins

Early Hospital CareAnti‐Platelet Therapy

• Class I

– Aspirin (162‐325 mg), non enteric coated

– Clopidogrel for those with Aspirin allergy/intolerance (300‐600 mg load and 75 mg/d) (or Prasugrel or Ticagrelor)

– GI prophylaxis if a Hx of GI bleed

– GP IIb/IIIa inhibitors should be evaluated based on whether an invasive or conservative strategy is used

– GP IIb/IIIa inhibitors recommended for all diabetics and all patient in early invasive arm

Early Hospital CareAnticoagulant Therapy

• Class I

– Unfractionated Heparin

– Enoxaparin

– Bivalarudin

– Fondaparinux

– Relative choice depends on invasive vs conservative strategy and bleeding risk

Early Hospital CareStatin Therapy

• MIRACL TrialInclusion Criteria

– 3086 patients with Non ST ACS

– Total cholesterol <270 mg/dl

– No planned PCI

– Randomized to Atorvastatin vs Placebo

– Drug started at 24‐96 hours

Statin Evidence: MIRACL Study

Relative risk = 0.84P = .04895% CI 0.701-0.999

Atorvastatin

Placebo

0

5

10

15

0 4 8 12 16

Time Since Randomization (weeks)

Cu

mu

lativ

e I

nci

de

nce

(%

)

Time to first occurrence of:• Death (any cause)• Nonfatal MI• Resuscitated cardiac arrest• Worsening angina with new

objective evidence and urgent rehospitalization

17.4%

14.8%

Primary Efficacy Measure

Schwartz GG, et al. JAMA. 2001;285:1711-1718.

All-Cause Death or Major CV Events in All Randomized Subjects

0 3 18 21 24 27 306 9 12 15

% with Event

Months of Follow-up

Pravastatin 40mg(26.3%)

Atorvastatin 80mg(22.4%)

16% RR

(P = 0.005)

30

25

20

15

10

5

0

PROVE‐IT Trial

Invasive vs Conservative Strategies

Invasive vs Conservative Strategy Clinical Trials

TIMI IIIB (94)

ConservativeStrategy Favored

N=920

InvasiveStrategy Favored

N=7,018

VANQWISH (98)

MATE

FRISC II (99)

TACTICS-TIMI 18 (01)

VINO

RITA-3 (02)

TRUCS

ISAR-COOL

ICTUS (05)

No differenceN=2,874

Weight ofthe evidence

95

TIMI Risk Score

T: Troponin elevation (or CK-MB elevation)

H: History or CAD (>50% Stenosis)

R: Risk Factors: > 3 (HTN, Hyperlipidemia, Family Hx, DM II, Active Smoker)

E: EKG changes: ST elevation or depression 0.5 mm concordant leads

A2:Aspirin use within the past 7 days; Age over 65

T: Two or more episodes of CP within 2 hours

TIMI Risk ScorePredicts risk of death, new/recurrent MI, need for urgent revascularization within 14 days

98

99

How Early is Early?

100

Early Invasive vs Conservative Strategies

Definitive/Possible ACSInitiate ASA, BB, Nitrates, Anticoagulants, Telemetry

Early Invasive Strategy

• TIMI Risk Score >3• New ST segment

deviation• Positive biomarkers

Conservative Strategy

•TIMI Risk Score <3 (Esp. Women)•No ST segment deviation•Negative Biomarkers

Coronary angiography(24-48 hours)

Recurrent Signs/SymptomsHeart failureArrhythmias

Remains Stable↓

Assess EF and/or Stress Testing↓

EF<40% OR Positive stressGo to Angiography

•Hemodynamic instability•Elecrical instability•Refractory angina•PCI in past 6 months•CABG•EF <40%

Secondary PreventionClass I Indications• Aspirin• Beta‐blockers: (all pts, slow titration with moderate to severe failure

• ACE‐Inhibitors: CHF, EF<40%, HTN, DM(All pts‐Class IIa) ARB when intolerant to ACE. (Class IIa as alternative to ACEI)

• Aldosterone blockade: An ACEI, CHF with either EF<40% or DM and if CrCl>30 ml/min and K<5.0 mEq/L

• Statins• Standard Risk Factor Management

102

2012 Key Updates to UA/NSTEMI Guidelines

103

2012 Key Updates to UA/NSTEMI Guidelines

104

NSTEMI/Unstable Angina

*Ticagrelor is also considered

*

Summary

• Management guideline focus– Risk stratification

– Conservative vs Invasive therapy for UA/NSTEMI

• Aggressive attention to secondary prevention initiatives for ACS patients

• Beta blocker, ASA, ACE‐I, Statin

• Gear appropriate therapy towards the stratified pathway

106

Thank You

Questions?

107

Surveying the Landscape of NSTE ACS - icep.org€¦ · Surveying the Landscape of ... UA/NSTEMI †...

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