ST Elevation MI How far can we go? · ST-segment elevation MI . Non-ST Elevation ACS* Non-ST...

ST Elevation MI

How far can we go?

Garrett B. Wong, M.D. UC Davis Medical Center

Disclosures

Speakers Bureau – Astra Zeneca – Bristol Myers/Sanofi – Daiichi Sankyo/Lilly

Decline in Deaths from Cardiovascular Disease in Relation to Scientific Advances

Nabel EG and Braunwald E. 2012;366:54-63

Emergency Department Visits Annually in the U.S.

95 MM visits1

8 MM for chest pain1

6.1 MM Non-cardiac1

0.6 MM for ST-

segment Myocardial Infarction2

1.0 MM for Unstable

Angina2

0.4 MM for Non-ST-

segment Myocardial Infarction2

1. Personal communication, W. Brian Gibler, MD, University of Cincinnati. 2. 2002 SMG Medicare Database.

Presenter

Presentation Notes

In the United States, each year, an estimated 2 million patients are admitted for hospitalization with an acute coronary syndrome. An estimated six hundred thousand show ECG changes consistent with ST-segment elevation MI. Nearly one and a half million patients present to U.S. Emergency Departments with unstable angina (UA) or non-ST-segment elevation myocardial infarction (NSTEMI), collectively known as non-ST-segment elevation acute coronary syndromes (NSTE ACS). Despite current management strategies, one in seven of these NSTE ACS patients dies or experiences an MI within the ensuing 30 days of presentation.

Diagnostic Algorithm for Acute Coronary Syndrome Management

Therapeutic goal: rapidly break apart fibrin mesh to quickly restore blood flow

ST-segment elevation MI Non-ST Elevation ACS* Non-ST Elevation MI

+ Tn &/or + CK-MB

Consider fibrinolytic therapy, if indicated, or primary percutaneous coronary

intervention (PCI)

Therapeutic goal: prevent progression to complete occlusion of coronary artery and

resultant MI or death

Consider GP IIb-IIIa inhibitor + aspirin + heparin before early diagnostic catheterization

&/or

Presenter

Presentation Notes

During the past 20 years, management of acute coronary syndromes (ACS) has focused on rapid identification and treatment of patients with STEMI. However, it is now recognized that the same urgency should also be used for management of patients with NSTEMI or unstable angina, because their morbidity and mortality rates are similar to those of patients with STEMI. Thus, in modern practice, the goal is to rapidly identify and appropriately treat not only patients with STEMI (who benefit from fibrinolytic therapy), but also high-risk NSTE ACS patients who may benefit from ACC/AHA Guidelines-recommended management, including early GP IIb-IIIa inhibitor therapy and early diagnostic catheterization.

Pathophysiology of Acute Coronary Syndromes

Plaque rupture

Platelet adhesion

Platelet activation and aggregation

Partially occlusive arterial thrombosis & unstable angina

Microembolization & non-ST-segment elevation MI

Totally occlusive arterial thrombosis & ST-segment elevation MI

Pathogenesis of Acute Coronary Syndromes

White HD. Am J Cardiol 1997;80 (4A):2B-10B.

Presenter

Presentation Notes

Acute coronary syndromes occur as a result of thrombus formation in response to rupture of an atherosclerotic plaque in the vessel wall. Spontaneous or intervention-induced plaque rupture promotes adhesion of platelets from the circulation, followed by platelet activation and platelet aggregation. Platelet aggregation leads to the formation of partially occlusive coronary thrombi, which clinically manifest as unstable angina (with occlusions > 70%), or, if prolonged occlusion results in myocardial damage, as NSTEMI. NSTEMI is caused by dislodgement and embolization of platelet-rich microthrombi into the coronary microvasculature, blocking blood flow, and causing heart muscle death. Complete occlusion of coronary arteries (>90%) manifests clinically as STEMI.

Acute Myocardial Infarction

Role of the Platelet in Non-ST-Elevation Acute Coronary Syndromes

Generally caused by partially-occlusive, platelet-rich thrombus in a coronary artery

Unobstructed lumen

Thrombus

Results from cross-linking of platelets by fibrinogen at

platelet receptors GP IIb-IIIa at site of plaque rupture

Platelet

Fibrinogen

Ruptured plaque

GP IIb-IIIa

Artery wall

Van de Werf F. Throm Haemost 1997;78(1):210-213.

Presenter

Presentation Notes

In patients with NSTE ACS, chest pain is usually caused by prolonged partial occlusion of coronary arteries by platelet-rich thrombi, as shown in the photograph on the left side. Platelet-rich thrombi that precipitate NSTE ACS are formed by platelet aggregation, which involves binding of a single molecule of fibrinogen to two GP IIb-IIIa receptors on adjacent platelets. For this reason, disaggregation of existing thrombi1, as well as prevention of platelet aggregation and formation of platelet-rich thrombi with inhibitors of the platelet receptor GP IIb-IIIa is a rational strategy for treatment of patients with NSTE ACS. ____________________________________________________________________ 1Moser M, et al. J Cardiovasc Pharmacol 2003;41:586-592.

Role of the Thrombus in ST-segment Elevation MI (STEMI)

Results from stabilization by fibrin mesh of a platelet aggregate at

site of plaque rupture

platelet RBC

fibrin mesh

Generally caused by a completely occlusive

thrombus in a coronary artery

Van de Werf F. Throm Haemost 1997;78(1):210-213.

Presenter

Presentation Notes

The photograph on the left side shows complete thrombotic occlusion of a coronary artery, which manifests clinically as a STEMI. The completely occlusive thrombus consists of a platelet-rich core (formed by platelet aggregation) and superimposed network/mesh of cross-linked fibrin molecules (formed by activity of the coagulation cascade) and entrapped red blood cells, as shown in the graphic on the right side. This picture of a clot shows a fibrin mesh, formed by bonds between activated platelets and fibrinogen. Trapped inside are red blood cells. In STEMI patients, approximately >90% of the culprit vessel is occluded by thrombus.

Pathways to Platelet Activation

White HD. Am J Cardiol 1997; 80:2B-10B. Schafer A. J Clin Invest 1986; 78:73-79. DeJong MJ, et al. Critical Care Nursing Clin of N Am 1999; 11:355-371. Moser M, et al. J Cardiovasc Pharmacol 2003;41:586-592. Phillips DR, Scarborough RM. Am J Cardiol 1997;80(4A):11B-20B.

• GP IIb-IIIa inhibitors displace fibrinogen in existing thrombi to disaggregate thrombus and prevent further platelet cross-linking and thrombosis

• GP IIb-IIIa inhibitors prevent platelet activation by blocking GP IIb-IIa (outside-in signaling)

High-dose heparin stimulates PAF which activates platelets

Presenter

Presentation Notes

Platelets can be activated by many platelet agonists, such as thrombin, adenosine diphosphate, collagen, serotonin, epinephrine, CD40 ligand, and as many as 70 other mediators. Each of these agonists activates a separate signal transduction pathway within platelets. All of these pathways ultimately converge on the platelet receptor GP IIb-IIIa, converting it from an inactive into an active form. The platelet receptor GP IIb-IIIa is the final common pathway to platelet aggregation, which involves binding of a single molecule of fibrinogen to two GP IIb-IIIa molecules on the surface of adjacent platelets. _________________________________________________ 1. Phillips DR, Scarborough RM. Am J Cardiol 1997;80(4A):11B-20B.

Pathways to Clot Formation

White HD. AM J Cardiol 1997; 80:2B-10B Schafer A. J Clin Invest 1986; 78:73-79 DeJong MJ, et al. Critical Care Nursing Clin of N Am 1999; 11:355-371

Presenter

Presentation Notes

Partially occlusive platelet-rich thrombi responsible for clinical manifestations of NSTEMI/unstable angina are formed by binding of a single molecule of fibrinogen to two GP IIb-IIIa molecules on adjacent platelets. GP IIb-IIIa inhibitors prevent this interaction and the formation of platelet-rich thrombi, reducing acute and procedural-related ischemic events. Additionally, studies1-2 have shown GP IIb-IIIa inhibitors to disaggregate existing thrombus through competitive binding of fibrinogen. Anti-thrombin agents, such as direct thrombin inhibitors (bivalirudin, argatroban) and agents acting via anti-thrombin III (unfractionated heparin, low-molecular-weight heparins), reduce the formation of fibrin-rich mesh necessary for the generation of completely occlusive thrombi. However, as Dr. Jorge Saucedo presented at the American Heart Association 2002, these agents do not effectively inhibit platelet aggregation,3 because this process can be stimulated by many agonists other than thrombin.4 The ACC/AHA guidelines5 recommend that high-risk NSTE ACS patients should receive a combination of these complementary agents to target the platelets (e.g., aspirin, a GP IIb-IIIa inhibitor, and a thienopyridine) and to prevent the stabilization of the clot by fibrin (e.g., an anti-thrombin agent). ____________________________________________________________________ 1. Moser M, et al. J Cardiovasc Pharmacol 2003;41:586-592. 2. Collet JPh, et al. Circ Res 2003;90:428-434. 3. Wittkowsky AK. Pharmacotherapy 2002;22(6 Pt 2):97S-104S. 4. Saucedo J. Presented at the American Heart Association 2002. 5. Braunwald E, et al. 2002. http://www.acc.org/clinical/guidelines/unstable/unstable.pdf.

Inf MI, Wenckebach

Treatment of STEMI - Thrombosis

TPA PCI

Fibrinolytic therapy Did save lives compared to placebo, BUT

2 hours after t-PA

6 hours after t-PA

+ ICH 0.5-1.0%

of pts

- At best, restored TIMI 3 flow in 55% (rt-PA), + - ↑ Incidence of recurrent ischemia and reinfarction

Coronary Angiography – Occluded RCA

Aspiration Thrombectomy

Coronary Angiography - RCA

Severe residual lesion Angiosculpt Scoring


Stent deployment and post dilations


Final Angiograms

Adjunctive Medical Management of AMI Patient

Morphine

ACE inhibitors

Nitrates

Beta blockers

Calcium blockers

Dilate blood vessels; relax and expand arteries, increasing blood flow

Provides pain relief; dilates blood vessels; relaxes and expands artery, increasing blood flow

Slow pumping action of heart; reduce oxygen requirements

Dilate blood vessels; prevent fluid retention; ease the workload of the heart

Dilate blood vessels; reduce vascular smooth-muscle contraction

Anti-Ischemic Treatment Options to Help Stabilize ACS Patients

Presenter

Presentation Notes

Traditional therapies administered to patients presenting with unstable angina or non-ST-segment elevation MI include both anti-ischemic therapies and anti-thrombotic therapies. The initial anti-ischemic therapies administered include nitrates, beta blockers, ACE inhibitors, calcium channel blockers, and morphine. Importantly, these therapies only treat the pain of unstable angina, not the thrombosis causing the ischemic attack. For example, nitrates and morphine help to dilate blood vessels and help relieve chest pain, and beta blockers help slow the heart to reduce oxygen requirements. None of these therapies affect the thrombus, a primary cause of non-ST-segment elevation acute coronary syndromes.

Target Directed Therapy Antiplatelet Agents

Collagen Thrombin

TXA2

Aspirin

ADP

(Fibrinogen Receptor)

clopidogrel

TXA2

ADP

Dipyridamole

Phosphodiesterase

ADP

Gp IIb/IIIa Activation

COX

ticlopidine

ADP = adenosine diphosphate, TXA2 = thromboxane A2, COX = cyclooxygenase. Schafer AI. Am J Med 1996;101:199–209.

prasugrel

ticagrelor

Currently Available Antiplatelet Therapies

Oral Aspirin Dipyridamole Cilostazol Thienopyridines: P2Y12 inhibitor of platelet function

– Clopidogrel (Plavix) – Ticlopidine (Ticlid) – Prasugrel (Effient)

Ticagrelor (Brilinta)

Intravenous Glycoprotein (GP) IIb/IIIa inhibitor of platelet function

– ReoPro (abciximab) – Integrilin (eptifibatide) – Aggrastat (tirofiban)

IIb/IIIa Inhibitors with UFH in PCI and ACS

Odds Ratio & 95% CI

Placebo Better IIb/IIIa Better

Trial Placebo IIb/IIIa N

Overall 30,336 11.1% 9.0% 0.79 (0.73, 0.85) p < 10-9

0 1 2

IMPACT-II EPIC

4,010 2,099

8.4% 10.1%

7.1% 7.0%

RESTORE CAPTURE

2,139 1,265

6.3% 9.0%

5.1% 4.8%

EPILOG 2,792 9.1% 4.0%

PURSUIT 10,948 15.7% 14.2%

PRISM 3,231 7.0% 5.7% PRISM PLUS 1,570 11.9% 8.7% PARAGON 2,282 11.7% 11.3%

Topol EJ Lancet 1999;353:227-231

Death/MI at 30 Days

EPISTENT 2,399 10.2% 5.2%

Aspirin

The simplest drug available in cardiology – Old and oral, once a day

One of the most efficacious The cheapest available Therefore:

– The most cost-effective

100

200

300

400

500

600

0 7 14 21 28 35

Placebo alone: 568/4300 (13.2%)

Aspirin alone: 461/4295 (10.7%)

Streptokinase alone: 448/4300 (10.4%)

Streptokinase plus aspirin: 343/4292 (8.0%)

Cum

ulat

ive

Num

ber o

f Vas

cula

r Dea

ths

Days From Randomization

Aspirin in Acute MI: ISIS-2

Dose-Dependence and Aspirin Efficacy

Antithrombotic Trialists’ Collaboration

0 0.5 1.0 1.5 2.0

500–1500 mg 34 19 160–325 mg 19 26 75–150 mg 12 32

<75 mg 3 13 Any aspirin 65 23

ASA Better ASA Worse

Aspirin Dose # Trials OR* (%) Odds Ratio

BMJ. 2002;324:71-86.

Presenter

Presentation Notes

The Antithrombotic Trialists’ Collaboration compared data from 65 aspirin trials to examine the effects of aspirin dose on vascular events in high-risk patients (in some trials, the doses of aspirin used were in more than one of the comparisons).[1] Serious vascular events (the primary measure of outcome) included nonfatal MI, nonfatal stroke, death from vascular causes, and death from unknown causes. They found that all doses of aspirin studied reduced the risk for vascular events. The greatest number of trials (34) examined high aspirin doses (500 mg to 1500 mg) and revealed a proportional reduction in vascular events of 19%. Aspirin doses of 160 mg to 325 mg were associated with a 26% proportional reduction in vascular events, whereas 75 mg to 150 mg and <75 mg were associated with reductions of 32% and 13%, respectively.

Rationale for Newer Antiplatelet and Antithrombotic Therapies

Despite treatment with aspirin and heparin, the incidence of MI and CV death during hospitalization remains high at 6-8%

Long term, the incidence of these events remains high at 6-8% per year

Majority of patients who enter the hospital for acute coronary syndrome (ACS) are already on aspirin therapy

Oasis Registry Investigators. Lancet. 1998; 352:507-14.

Clopidogrel Across Spectrum of CAD

Price, MJ. 2009.

Is aspirin and clopidogrel enough for everyone? Do we have a need for newer agents?

Prasugrel (Effient)

Hydrolysis by intestinal carboxylesterases

Oxidation by intestinal and hepatic CYP-450

Increased potency > 75% inhibition

Ticagrelor (Brilinta): an oral reversible P2Y12 antagonist

Ticagrelor is a cyclo-pentyl-triazolo-pyrimidine (CPTP)

O H

O H

O

O H

N

F

S

N H

N N

N N

F

• Direct acting – Not a prodrug; does not require metabolic activation – Rapid onset of inhibitory effect on the P2Y12 receptor – Greater inhibition of platelet aggregation than clopidogrel

• Reversibly bound – Degree of inhibition reflects plasma concentration – Faster offset of effect than clopidogrel – Functional recovery of all circulating platelets

The therapeutic target for thienopyridines and CPTPs is the platelet P2Y12 receptor

Ticagrelor Prasugrel Esterification and 2-step oxidation to active metabolite

1-step oxidation to active metabolite Active metabolite

Presenter

Presentation Notes

With Plavix, we are in the unique position of knowing the site and mechanism of action of the drug, the platelet p2y12 receptor.

Inhibition of Platelet Aggregation (IPA): Prasugrel and Clopidogrel Loading Dose

80

60

40

20

0

100

0 4 8 12 16 Time After Administration (h)

Inhi

bitio

n of

Pla

tele

t Agg

rega

tion

(%)

20 μM Adenosine Diphosphate*

The relationship between IPA and clinical activity has not been established.

20 24

†P<0.01 Mean ± SD

Prasugrel 60 mg Clopidogrel 300 mg

† † † †

†

† † †

1. Brandt et al. Am Heart J. 2007;153:66.e9-16. 2. Effient Full Prescribing Information.

1 2 6

*Represents healthy subjects in a crossover study who were not on concurrent ASA therapy (n=64).

Presenter

Presentation Notes

PRESENTATION TIPS There is faster onset of inhibition of platelet aggregation (IPA) with the prasugrel 60-mg loading dose (LD) compared with a clopidogrel 300-mg LD. Within 30 minutes of the LD administration and at all subsequent time points, prasugrel 60-mg LD achieved greater IPA to a 20-μM adenosine diphosphate (ADP) stimulus than the clopidogrel 300-mg LD. Similar results were obtained with 5 µmol/L ADP.1 Please highlight before moving to the next slide that the relationship between IPA and clinical activity has not been established. KEY POINTS A 60-mg LD of prasugrel was associated with a rapid onset, achieving faster onset and greater levels of IPA than a 300-mg LD of clopidogrel.1 Approximately 90% of patients receiving the 60-mg LD of prasugrel had at least 50% IPA by 1 hour and maximum platelet inhibition of about 80%.2 The IPA peak after dosing with prasugrel achieved a mean of 84.1% ± 9.5% for 5 µmol/L ADP (data not shown) and 78.8% ± 9.2% for 20 µmol/L ADP.1 Platelet aggregation gradually returned to baseline values over 5–9 days after discontinuation of prasugrel, this time course being a reflection of new platelet production rather than the pharmacokinetics of prasugrel.2 The relationship between IPA and clinical activity has not been established.2 BACKGROUND The studies from which the data for these graphs were obtained used light transmittance aggregometry. Similar results have been obtained using the VerifyNow® P2Y12 assay.3 REFERENCES Brandt JT, Payne CD, Wiviott SD, et al. A comparison of prasugrel and clopidogrel loading doses on platelet function: magnitude of platelet inhibition is related to active metabolite formation. Am Heart J. 2007;153:66.e9-66.e16. Effient® (prasugrel) prescribing information. Daiichi Sankyo, Inc. and Eli Lilly and Company. Jakubowski JA, Payne CD, Li YG, et al. The use of the VerifyNow P2Y12 point-of-care device to monitor platelet function across a range of P2Y12 inhibition levels following prasugrel and clopidogrel administration. Thromb Haemost. 2008;99:409-415.

P2Y12 Receptor Antagonists

Agent Class IPA

(20 uM ADP) mean

Time to peak onset

Reversibility (d/c before

CABG)

Ticlopidine 250 mg bid thienopyridine (pro-drug) 25% 48 hrs non reversible

5 days

Clopidogrel 300 mg LD Clopidogrel 600 mg LD Clopidogrel 75 mg qd Clopidogrel 150 mg qd

thienopyridine(pro-drug)

30% - 40% 35% - 50% 30% - 35% 45% - 50%

12 hrs 6 hrs

- -

non reversible 5 days

Prasugrel 60 mg LD* Prasugrel 10 mg qd* Prasugrel 5 mg qd*

thienopyridine(pro-drug)

80% 60% 40%

1-2 hrs - -

non reversible 7 days

Ticagrelor 180 mg LD* Ticagrelor 90 mg bid*

cyclo-pentyl-triazolo-

pyrimidine*

80% 70%

1-2 hrs -

reversible 2-5 days

*Less affected by genetic polymorphisms and drug interactions (e.g. PPIs)

**not a pro-drug

Prasugrel and Ticagrelor in STEMI Stent Thrombosis (definite or probable)

Montalescot G et al. Lancet 2009;373:723-31 Steg PG et al. Circulation 2010;122:2131-41

HR[95%CI] = 0.55 [0.30-1.00] P=0.048

HR[95%CI] = 0.74 [0.55-1.00] P=0.05

PLATO Primary PCI (<24°) 12 months

TRITON-TIMI-38 Primary PCI (<12°) 15 months

N=1235 N=1203 N=3792 N=3752

Prasugrel and Ticagrelor in STEMI Cardiovascular Death

Personal communicatoin, Eli Lilly Steg PG et al. Circulation 2010;122:2131-41

HR[95%CI] = 0.69 [0.43-1.11] P=N/A

HR[95%CI] = 0.83 [0.67–1.02] P=0.07

PLATO Primary PCI (<24°) 12 months

TRITON-TIMI-38 Primary PCI (<12°) 15 months

N=1235 N=1203 N=3792 N=3752

NEJM 357: 2001-2015, 2007 www.NEJM.org

NEJM 357: 2001-2015, 2007

Presenter

Presentation Notes

A detailed presentation of our primary results can be found in a paper that is now posted on the New England Journal of Medicine website . Also, the slides shown today and a full list of the trial participants are now posted on the TIMI website. Thank you very much for your attention.

5

CV Death, MI or Stroke at 15 Months

10

15

0 0 50 100 150 200 250 300 350 400 450

9.5

6.5

12.4

10.0

HR=0.79 (0.65–0.97) NNT=42

p=0.02 RRR=21%

p=0.002 RRR=32%

Clopidogrel Prasugrel

Time (Days)

Montalescot G et al. Lancet 2009;373:723–31

TRITON-TIMI 38 STEMI C

V de

ath,

MI,

stro

ke

(%)

Stent Thrombosis: All ACS

Days After Randomization

Sten

t Thr

ombo

sis*

(%)

Any Stent Post-Randomization

0

1

2

3

0 50 100 200 300 400 450

HR=0.48 (95% CI, 0.4–0.6) P<0.0001

350 250 150

% (n/N)†

Prasugrel 1.1 (68/6422) Clopidogrel 2.2 (142/6422)

1. Wiviott et al. Lancet. 2008;371:1353-1363. 2. Data on file: #EFF20091204b: DSI/Lilly.

*Stent thrombosis defined as Academic Research Consortium definite or probable. †Observed data.

TRITON- TIMI 38

Presenter

Presentation Notes

PRESENTATION TIP1 The incidence of stent thrombosis was reduced by more than half in all patients receiving stents. KEY POINTS Percentages shown on the slide are based on the observed rates of stent thrombosis through the follow-up period. The FDA prefers the use of observed rates over Kaplan-Meier (KM) estimates. Stent thrombosis was a prespecified secondary endpoint using the Academic Research Consortium (ARC) definition of definite or probable. This analysis represents stent thrombosis in any stent post-randomization.1,2 All stent thrombosis events were reviewed. 12,844 patients received at least 1 coronary stent; 5743 received only drug-eluting stents (DES), and 6461 received only bare-metal stents (BMS). Of the patients who received at least 1 stent, 6422 were treated with prasugrel, and 6422 were treated with clopidogrel.1 KM data show that prasugrel reduced stent thrombosis compared with clopidogrel (1.1 vs 2.4%; HR 0.48 [95% CI, 0.4–0.6]; P<0.0001) in the stented cohort.1 BACKGROUND1 Definitions of stent thrombosis1,2: Definite stent thrombosis was defined as total occlusion originating in or within 5 mm of the stent, or visible thrombus within the stent, or within 5 mm of the stent in the presence of an acute ischemic clinical syndrome within 48 hours. Probable stent thrombosis was defined as any unexplained death within the first 30 days or any myocardial infarction that was related to documented acute ischemia in the territory of the implanted stent without angiographic confirmation of stent thrombosis and in the absence of any other obvious cause. Possible stent thrombosis was defined as any unexplained death from 30 days after intracoronary stenting until end of study follow-up. Events were assessed using available event reports, discharge summaries, death certificates, autopsy reports, and cardiac catheterization reports. Cardiac catheterization films were not reviewed by a core laboratory for the purpose of identifying stent thrombosis. REFERENCES Wiviott SD, Braunwald E, McCabe C, et al; the TRITON-TIMI 38 Investigators. Intensive oral antiplatelet therapy for reduction of ischaemic events including stent thrombosis in patients with acute coronary syndromes treated with percutaneous coronary intervention and stenting in the TRITON-TIMI 38 trial: a subanalysis of a randomized trial. Lancet. 2008;371:1353-1363. Wiviott SD, Braunwald E, McCabe C, et al; the TRITON-TIMI 38 Investigators. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2007;357:2001-2015.

NEJM. Sep 10, 2009.

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

12 11 10

9 8 7 6 5 4 3 2 1 0

13 C

umul

ativ

e in

cide

nce

(%)

9.8

11.7

8,219

HR 0.84 (95% CI 0.77–0.92)

p=0.0003

NNT=54

Clopidogrel

Ticagrelor

K-M = Kaplan-Meier; HR = hazard ratio; CI = confidence interval

Time to first primary efficacy event (composite of CV death, MI or stroke)

Antiplatelet Guideline Recommendations for STEMI Patients Aspirin

– Load with 325 mg

– Maintenance 75-325 mg daily

Clopidogrel – Load with 300-600 mg

– Maintenance 75 mg daily

Prasugrel – Load with 60 mg

– Maintenance 10 mg daily, 5 mg if < 60kg

Ticagrelor – Load with 180 mg

– Maintenance with 90 mg BID (aspirin <100 mg)

Emerging Therapies Factor Xa Inhibitors and Direct Thrombin Inhibitors

Harenberg J. Semin Thromb Hemost. 2009;35:574-586.

Tissue Factor/VIIa

IX

IXa

X

Xa

VIIIa

Va

II IIa

Fibrinogen Fibrin

Idrabiotaparinux

Rivaroxaban Betrixaban Apixaban YM150 DU-176b

Bivalirudin Dabigatran AZD-0837

Bivalirudin Bivalent Synthetic Direct Thrombin Inhibitor

Specifically inhibits – Fluid phase thrombin

– Clot-bound thrombin

– Thrombin-mediated

platelet aggregation

Reversible

T0.5 25 minutes

No HIT or HITTS

Bivalirudin

Topol EJ: Textbook of Interventional Cardiology

Harmonizing Outcomes with Revascularization and Stents in AMI

3602 pts with STEMI with symptom onset ≤12 hours

Emergent angiography, followed by triage to…

Primary PCI CABG – Medical Rx –

UFH + GP IIb/IIIa inhibitor (abciximab or eptifibatide)

Bivalirudin monotherapy (± provisional GP IIb/IIIa)

Aspirin, thienopyridine R 1:1

3006 pts eligible for stent randomization R 3:1

Bare metal EXPRESS stent Paclitaxel-eluting TAXUS stent

Clinical FU at 30d, 6 mo, 1 yr, and then yearly through 3 yrs; angio FU at 13 mo

Stone GW et al NEJM 2008;358:2218-30 & NEJM 2009;360:1946-1459

HORIZONS Three-Year All-Cause Mortality

P=0.03

3-yr HR [95%CI]= 0.75 [0.58, 0.97]

5.9%

7.7% A

ll-C

ause

Mor

talit

y (%

)

0

1

2

3

4

5

6

9

10

1611 1568

1660 1689 1670

1800 Bivalirudin alone

0 12 15 18 21 24 27 30 33 36

1098 1802 1643

Months 3 6 9

Number at risk

Heparin+GPIIb/IIIa 1633 1593

1574 1525 1043

0.66 [0.44, 1.00] P=0.048

30-day HR [95%CI]=

Bivalirudin alone (n=1800) Heparin + GPIIb/IIIa (n=1802)

7

8

3.1%

2.1%

Stone GW et al. Lancet 2011;377:2193-204.

Is there any way to further reduce mortality in STEMI?

The Future

Reduce infarct size!

Partial list of Pharmacologic Studies to Reduce Reperfusion Injury Which Have Failed!

Trial Agent Proposed mechanism TAMI 9 Fluosol Inhibit neutrophils, enhance O2 ISIS-4, MAGIC Magnesium Membrane stabilization CORE RheothRx Enhance O2 delivery EMIP-FR Trimetazidine Less H+, free radicals, neutrophils Flaherty hSOD Free radical scavenger CALYPSO Cylexin Inhibit p-selectin, neutrophils AMISTAD I, II Adenosine Inhibits neut., vasodilates, metab. HALT, LIMIT Anti-CD18 Inhibit neutrophils ESCAMI Eniporide Na+/H+ exchange inhibitor APEX-AMI Pexelizumab C5b-9b complement inhibition TRIUMPH Tilarginine Nitric oxide donor REVIVAL-3, HEBE-3, REVEAL EPO Enhances O2 delivery PROTECTION AMI Delcasertib Inhibits mitochondrial δ-protein kinase C

0

20

40

60

80

100

1 3 6 12 24

Extent of salvage (% of area at risk)

Treatment objectives Time to treatment is critical

Opening the IRA (PCI > lysis)

Hours

Relationship Between Myocardial Salvage and Survival: 2005

Gersh, Stone, Holmes. JAMA 2005

Median U.S. Sx-ER: 2°

Mor

talit

y re

duct

ion

(%)

90’ DBT

U.S. Goal: Symptoms to balloon: 3.5°

Modifying factors • Collaterals • Ischemic preconditioning • MVO2

2010+: Do whatever it takes to reduce time from symptom onset to ER arrival and to PCI!

↑ Public awareness of MI Sx

Chest pain centers of excellence with lower DBTs

and excellent outcomes

Regional coordination

Ambulance ECG telemetry

Ambulance/ER CCL activation

ICs sleep in hospital

Continual QI

“TIME IS MUSCLE”

0

20

40

60

80

100

1 3 6 12 24




Hours

Relationship Between Myocardial Salvage and Survival: 2010


Median U.S. Sx-ER: 1.75°


Mor

talit

y re

duct

ion

(%)

U.S. Symptoms to balloon: 2.75°

60’ DBT

Krumholz HM et al. Circulation 2011;124:1038-1045

44.2%

91.4% Median 96 mins

Median 64 mins

N pts 48,977 52,028 51,298 53,032 53,682 42,150

Door-to-balloon Time <90 Mins at US Hospitals

100 Pe

rcen

tage

of P

atie

nts

with

D2B

tim

e <9

0 M

inut

es

90

80

70

60

50

40

30

20

10

0 2005 2006 2007 2008 2009 2010

0

20

40

60

80

100

1 3 6 12 24




Hours

Relationship Between Myocardial Salvage and Survival: 2015?


Mor

talit

y re

duct

ion

(%)

Median U.S. Sx-ER: 1.5°

45’ DBT

U.S. Symptoms to balloon: 2.25°


Mechanical Approaches to Thrombus Thrombectomy (AngioJet, X-Sizer)

GuardWire, FilterWire, AngioGuard, EmboShield, etc.

Distal protection (GuardWire, FilterWire, AngioGuard, etc.)

Thrombus aspiration (Rinspirator, Pronto, Export,

Rescue, Diver CE, etc.)

Distal Protection and Thrombectomy in AMI

Macroscopic embolic debris can be retrieved from >75% of cases

TAPAS: 1,071 pts with STEMI undergoing primary PCI randomized in the ER to manual aspiration

Vlaar et al. Lancet 2008;371:1915-20

30 days 4.0% vs. 2.1% P=0.07

Time (days)

Mor

talit

y (%

)

Conventional PCI Thrombus-Aspiration

0

0 100 200 300 400

2

4

6

8

10

12

1 year 7.6% vs. 4.0% P=0.04

MGuard Concept

STENT +

EMBOLIC PROTECTION

Myocardial Preservation

Therox Supersaturated aqueous oxygen infusion (PO2 760-1000 mmHg

TherOX: Hyperoxemic Perfusion

Aqueous oxygen

Control 90’ IC infusion of hyperoxemic blood immediately following

successful primary PCI

4F infusion catheter

Spears RS.

High Complexity PCI – Ventricular Assist Devices

Cardiogenic shock

Severe LV dysfunction

Severe multivessel disease

Unprotected LM disease

Complex bifurcation disease

History of Cath Lab Ventricular Support

IABP TandemHeart Impella Hemopump ECMO CPS

90’s 80’s 70’s 00’s

http://www.emedicine.com/ped/images/Large/15021502ECMO_Picture_1b.jpg�

TandemHeart pVAD System

Removes oxygenated blood from left atrium via transeptal cannula inserted via the femoral vein

Centrifugal external pump”aspirates” the blood outside the body

Returns blood via femoral artery Provides continuous flow to

systemic circulation

Impella pVAD System

Directly unloads the left ventricle

Rotary pump provides axial blood flow to ascending aorta

Ease of placement in the cath lab

STEMI Summary How can we improve outcomes further?

ACS encompasses a broad spectrum of pts – STEMI, NSTEMI, UA

STEMI requires early aggressive medical management for ischemia – Time is muscle!

Target directed therapy for both platelet and thrombin formation

Aspiration thrombectomy should be routine

Hemodynamic support early in the course of CS

New therapies are on the horizon

Thank You

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